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Archive for the ‘Cardiac Stem Cells’ Category

Keio University gets OK for iPS-based heart cell transplant plan – The Japan Times

A health ministry panel on Thursday approved a Keio University clinical research project to transplant heart muscle cells made from induced pluripotent stem (iPS) cells into heart disease patients.

The research will be carried out by a team led by Prof. Keiichi Fukuda for three people between 20 and 74 suffering from dilated cardiomyopathy, which lowers the hearts power to pump blood. The first transplant will be conducted by the end of this year at the earliest.

The team will use iPS cells made by Kyoto University from the blood of a person who has a special immunological type with less risk of rejection.

The team will transform the iPS cells into heart muscle cells and inject about 50 million of them into the heart using a special syringe. Immunosuppressive drugs will be used for about half a year, and the team will spend a year checking to see whether the treatment leads to the development of tumors and irregular heartbeat or whether it restores heart function.

In January, Osaka University conducted the worlds first transplant of heart muscle cells made from iPS cells. The heart muscle cells were made into sheets and pasted on the surface of the patients heart so that a substance they emit can help regenerate the heart muscles. The cells themselves, however, disappear quickly.

Meanwhile, Keio University has confirmed in an experiment on monkeys that cells colonize after a transplant and heart function improves.

The university expects that transplanted cells will colonize over a long period also in the upcoming clinical research project.

According to the team, there are about 25,000 dilated cardiomyopathy patients in Japan.

A startup led by Fukuda is planning a clinical trial aimed at commercializing the iPS-derived cells, hoping they will also be used for the treatment of other cardiac diseases.

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Keio University gets OK for iPS-based heart cell transplant plan - The Japan Times

Scientists grow the first functioning mini human heart model – MSUToday

Michigan State University researchers have created for the first time a miniature human heart model in the laboratory, complete with all primary heart cell types and a functioning structure of chambers and vascular tissue.

Aitor Aguirre, assistant professor of biomedical engineering at MSUs Institute for Quantitative Health Science and Engineering.

These minihearts constitute incredibly powerful models in which to study all kinds of cardiac disorders with a degree of precision unseen before, said Aitor Aguirre, the studys senior author and assistant professor of biomedical engineering at MSUs Institute for Quantitative Health Science and Engineering.

This study, Generation of Heart Organoids Modeling Early Human Cardiac Development Under Defined Conditions, appears on the bioRxiv preprint server and was funded by grants from the American Heart Association and the National Institutes of Health. In the United States, heart disease is the No. 1 cause of death.

The human heart organoids, or hHOs for short, were created by way of a novel stem cell framework that mimics the embryonic and fetal developmental environments.

Organoids meaning resembling an organ are self-assembling 3D cell constructs that recapitulate organ properties and structure to a significant extent, said Yonatan Israeli, a graduate student in the Aguirre Lab and first author of the study.

The innovation deploys a bioengineering process that uses induced pluripotent stem cells adult cells from a patient to trigger embryonic-like heart development in a dish generating a functional mini heart after a few weeks. The stem cells are obtained from consenting adults and therefore free of ethical concerns.

This process allows the stem cells to develop, basically as they would in an embryo, into the various cell types and structures present in the heart, Aguirre said. We give the cells the instructions and they know what they have to do when all the appropriate conditions are met.

Because the organoids followed the natural cardiac embryonic development process, the researchers studied, in real time, the natural growth of an actual fetal human heart.

This technology allows for the creation of numerous hHOs simultaneously with relative ease, contrasting with existing tissue engineering approaches that are expensive, labor intensive and not readily scalable.

One of the primary issues facing the study of fetal heart development and congenital heart defects is access to a developing heart. Researchers have been confined to the use of mammalian models, donated fetal remains and in vitro cell research to approximate function and development.

Now we can have the best of both worlds, a precise human model to study these diseases a tiny human heart without using fetal material or violating ethical principles. This constitutes a great step forward, Aguirre said.

Whats next? For Aguirre, the process is twofold. First, the heart organoid represents an unprecedented look into the nuts and bolts of how a fetal heart develops.

In the lab, we are currently using heart organoids to model congenital heart disease the most common birth defect in humans affecting nearly 1% of the newborn population, Aguirre said. With our heart organoids, we can study the origin of congenital heart disease and find ways to stop it.

And second, while the hHO is complex, it is far from perfect. For the team, improving the final organoid is another key avenue of future research. The organoids are small models of the fetal heart with representative functional and structural features, Israeli said. They are, however, not as perfect as a human heart yet. That is something we are working toward.

Aguirre and team are excited about the wide-ranging applicability of these miniature hearts. They enable an unprecedented ability to study many other cardiovascular-related diseases from chemotherapy-induced cardiotoxicity to the effect of diabetes, during pregnancy, on the developing fetal heart.

Other researchers involved in this study were Aaron Wasserman, Mitchell Gabalski and Kristen Ball at MSU; and Chao Zhou, Jinyon Zhou and Guangming Ni at Washington University in St. Louis.

(Note for media: Please include a link to the original paper in online coverage: https://www.biorxiv.org/content/10.1101/2020.06.25.171611v2)

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Scientists grow the first functioning mini human heart model - MSUToday

First lab-made ‘mini-hearts’ mimic the real thing – Futurity: Research News

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Researchers have created, for the first time, a miniature human heart model in the laboratory.

The mini-hearts are complete with all primary heart cell types and a functioning structure of chambers and vascular tissue.

The organoids are small models of the fetal heart with representative functional and structural features. They are, however, not as perfect as a human heart yet. That is something we are working toward.

These mini-hearts constitute incredibly powerful models in which to study all kinds of cardiac disorders with a degree of precision unseen before, says Aitor Aguirre, assistant professor of biomedical engineering at Michigan State Universitys Institute for Quantitative Health Science and Engineering and senior author of the study on the work on the bioRxiv preprint server. In the United States, heart disease is the leading cause of death.

The researchers created the human heart organoids, or hHOs for short,by way of a novel stem cell framework that mimics the embryonic and fetal developmental environments.

Organoidsmeaning resembling an organare self-assembling 3D cell constructs that recapitulate organ properties and structure to a significant extent, says first author Yonatan Israeli, a graduate student in Aguirres lab.

The innovation deploys a bioengineering process that uses induced pluripotent stem cellsadult cells from a patient to trigger embryonic-like heart development in a dishgenerating a functional mini-heart after a few weeks. The stem cells are obtained from consenting adults and therefore free of ethical concerns.

This process allows the stem cells to develop, basically as they would in an embryo, into the various cell types and structures present in the heart, Aguirre says. We give the cells the instructions and they know what they have to do when all the appropriate conditions are met.

Because the organoids followed the natural cardiac embryonic development process, the researchers studied, in real time, the natural growth of an actual fetal human heart.

This technology allows for the creation of numerous hHOs simultaneously with relative ease, contrasting with existing tissue engineering approaches that are expensive, labor intensive and not readily scalable.

One of the primary issues facing the study of fetal heart development and congenital heart defects is access to a developing heart. Researchers have been confined to the use of mammalian models, donated fetal remains, and in vitro cell research to approximate function and development.

Now we can have the best of both worlds, a precise human model to study these diseasesa tiny human heartwithout using fetal material or violating ethical principles. This constitutes a great step forward, Aguirre says.

Whats next? For Aguirre, the process is twofold. First, the heart organoid represents an unprecedented look into the nuts and bolts of how a fetal heart develops.

In the lab, we are currently using heart organoids to model congenital heart diseasethe most common birth defect in humans affecting nearly 1% of the newborn population, Aguirre says. With our heart organoids, we can study the origin of congenital heart disease and find ways to stop it.

And second, while the hHO is complex, it is far from perfect. For the team, improving the final organoid is another key avenue of future research.

The organoids are small models of the fetal heart with representative functional and structural features, Israeli says. They are, however, not as perfect as a human heart yet. That is something we are working toward.

The researchers are excited about the wide-ranging applicability of these miniature hearts. They enable an unprecedented ability to study many other cardiovascular-related diseasesincluding chemotherapy-induced cardiotoxicity and the effect of diabetes, during pregnancy, on the developing fetal heart.

Additional researchers from Michigan State and Washington University in St. Louis contributed to the work.

The American Heart Association and the National Institutes of Health funded the study.

Source: Michigan State University

Original Study DOI: 10.1101/2020.06.25.171611

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First lab-made 'mini-hearts' mimic the real thing - Futurity: Research News

Merck’s KEYTRUDA (pembrolizumab) in Combination With Chemotherapy Significantly Improved Overall Survival and Progression-Free Survival Compared With…

KENILWORTH, N.J.--(BUSINESS WIRE)--Aug 19, 2020--

Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced that the pivotal Phase 3 KEYNOTE-590 trial evaluating KEYTRUDA, Mercks anti-PD-1 therapy, in combination with chemotherapy (cisplatin plus 5-fluorouracil [5-FU]), met its primary endpoints of overall survival (OS) and progression-free survival (PFS) for the first-line treatment of patients with locally advanced or metastatic esophageal cancer. Based on an interim analysis conducted by an independent Data Monitoring Committee, KEYTRUDA in combination with chemotherapy demonstrated a statistically significant and clinically meaningful improvement in OS and PFS compared with chemotherapy (cisplatin plus 5-FU), the current standard of care, in the intention-to-treat (ITT) population. The study also met the key secondary endpoint of objective response rate (ORR), with significant improvements for KEYTRUDA in combination with chemotherapy compared with chemotherapy alone. The safety profile of KEYTRUDA in this trial was consistent with that observed in previously reported studies. Results will be shared with global regulatory authorities and have been submitted for presentation at the European Society for Medical Oncology (ESMO) Virtual Congress 2020.

Esophageal cancer is a devastating malignancy with a high mortality rate and few treatment options in the first-line setting beyond chemotherapy, said Dr. Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories. In this pivotal study, KEYTRUDA plus chemotherapy resulted in superior overall survival compared with the current standard of care in the full study population and across all patient groups evaluated. These results build upon our research reinforcing the survival benefits of KEYTRUDA, and we look forward to engaging regulatory authorities as quickly as possible.

KEYTRUDA is currently approved in the U.S. and China as monotherapy for the second-line treatment of patients with recurrent locally advanced or metastatic squamous cell carcinoma of the esophagus whose tumors express PD-L1 (Combined Positive Score [CPS] 10). Merck is continuing to study KEYTRUDA across multiple settings and stages of gastrointestinal cancer including gastric, hepatobiliary, esophageal, pancreatic, colorectal and anal cancers through its broad clinical program.

About KEYNOTE-590

KEYNOTE-590 is a randomized, double-blind, Phase 3 trial (ClinicalTrials.gov, NCT03189719 ) evaluating KEYTRUDA in combination with chemotherapy compared with placebo plus chemotherapy for the first-line treatment of patients with locally advanced or metastatic esophageal carcinoma (adenocarcinoma or squamous cell carcinoma of the esophagus or Siewert type 1 adenocarcinoma of the esophagogastric junction). The primary endpoints are OS and PFS. The secondary endpoints include ORR, duration of response and safety. The study enrolled 749 patients who were randomized to receive:

About Esophageal Cancer

Esophageal cancer, a type of cancer that is particularly difficult to treat, begins in the inner layer (mucosa) of the esophagus and grows outward. The two main types of esophageal cancer are squamous cell carcinoma and adenocarcinoma. Esophageal cancer is the seventh most commonly diagnosed cancer and the sixth leading cause of death from cancer worldwide. Globally, it is estimated there were more than 572,000 new cases of esophageal cancer diagnosed and nearly 509,000 deaths resulting from the disease in 2018. In the U.S. alone, it is estimated there will be nearly 18,500 new cases of esophageal cancer diagnosed and more than 16,000 deaths resulting from the disease in 2020.

About KEYTRUDA (pembrolizumab) Injection, 100 mg

KEYTRUDA is an anti-PD-1 therapy that works by increasing the ability of the bodys immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck has the industrys largest immuno-oncology clinical research program. There are currently more than 1,200 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient's likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

Selected KEYTRUDA (pembrolizumab) Indications

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.

KEYTRUDA is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection.

Non-Small Cell Lung Cancer

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [tumor proportion score (TPS) 1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is stage III where patients are not candidates for surgical resection or definitive chemoradiation, or metastatic.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS 1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

Small Cell Lung Cancer

KEYTRUDA is indicated for the treatment of patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy and at least 1 other prior line of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Head and Neck Squamous Cell Cancer

KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [combined positive score (CPS) 1] as determined by an FDA-approved test.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma (cHL), or who have relapsed after 3 or more prior lines of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Primary Mediastinal Large B-Cell Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 [combined positive score (CPS) 10], as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

KEYTRUDA is indicated for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.

Microsatellite Instability-High or Mismatch Repair Deficient Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR)

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer

KEYTRUDA is indicated for the first-line treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC).

Gastric Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Esophageal Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic squamous cell carcinoma of the esophagus whose tumors express PD-L1 (CPS 10) as determined by an FDA-approved test, with disease progression after one or more prior lines of systemic therapy.

Cervical Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Hepatocellular Carcinoma

KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Merkel Cell Carcinoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Renal Cell Carcinoma

KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

Tumor Mutational Burden-High

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [10 mutations/megabase (mut/Mb)] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established.

Cutaneous Squamous Cell Carcinoma

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) that is not curable by surgery or radiation.

Selected Important Safety Information for KEYTRUDA

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases. Pneumonitis occurred in 3.4% (94/2799) of patients with various cancers receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%). Pneumonitis occurred in 8.2% (65/790) of NSCLC patients receiving KEYTRUDA as a single agent, including Grades 3-4 in 3.2% of patients, and occurred more frequently in patients with a history of prior thoracic radiation (17%) compared to those without (7.7%). Pneumonitis occurred in 6% (18/300) of HNSCC patients receiving KEYTRUDA as a single agent, including Grades 3-5 in 1.6% of patients, and occurred in 5.4% (15/276) of patients receiving KEYTRUDA in combination with platinum and FU as first-line therapy for advanced disease, including Grades 3-5 in 1.5% of patients.

Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 or recurrent Grade 2 pneumonitis.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 2 (0.4%), 3 (1.1%), and 4 (<0.1%). Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.

Immune-Mediated Hepatitis (KEYTRUDA) and Hepatotoxicity (KEYTRUDA in Combination With Axitinib)

Immune-Mediated Hepatitis

KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.4%), and 4 (<0.1%). Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

Hepatotoxicity in Combination With Axitinib

KEYTRUDA in combination with axitinib can cause hepatic toxicity with higher than expected frequencies of Grades 3 and 4 ALT and AST elevations compared to KEYTRUDA alone. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased ALT (20%) and increased AST (13%) were seen. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed.

Immune-Mediated Endocrinopathies

KEYTRUDA can cause adrenal insufficiency (primary and secondary), hypophysitis, thyroid disorders, and type 1 diabetes mellitus. Adrenal insufficiency occurred in 0.8% (22/2799) of patients, including Grade 2 (0.3%), 3 (0.3%), and 4 (<0.1%). Hypophysitis occurred in 0.6% (17/2799) of patients, including Grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%). Hypothyroidism occurred in 8.5% (237/2799) of patients, including Grade 2 (6.2%) and 3 (0.1%). The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC (16%) receiving KEYTRUDA, as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. Hyperthyroidism occurred in 3.4% (96/2799) of patients, including Grade 2 (0.8%) and 3 (0.1%), and thyroiditis occurred in 0.6% (16/2799) of patients, including Grade 2 (0.3%). Type 1 diabetes mellitus, including diabetic ketoacidosis, occurred in 0.2% (6/2799) of patients.

Monitor patients for signs and symptoms of adrenal insufficiency, hypophysitis (including hypopituitarism), thyroid function (prior to and periodically during treatment), and hyperglycemia. For adrenal insufficiency or hypophysitis, administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for Grade 2 adrenal insufficiency or hypophysitis and withhold or discontinue KEYTRUDA for Grade 3 or Grade 4 adrenal insufficiency or hypophysitis. Administer hormone replacement for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer antihyperglycemics in patients with severe hyperglycemia.

Immune-Mediated Nephritis and Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.1%), and 4 (<0.1%) nephritis. Nephritis occurred in 1.7% (7/405) of patients receiving KEYTRUDA in combination with pemetrexed and platinum chemotherapy. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue for Grade 3 or 4 nephritis.

Immune-Mediated Skin Reactions

Immune-mediated rashes, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) (some cases with fatal outcome), exfoliative dermatitis, and bullous pemphigoid, can occur. Monitor patients for suspected severe skin reactions and based on the severity of the adverse reaction, withhold or permanently discontinue KEYTRUDA and administer corticosteroids. For signs or symptoms of SJS or TEN, withhold KEYTRUDA and refer the patient for specialized care for assessment and treatment. If SJS or TEN is confirmed, permanently discontinue KEYTRUDA.

Other Immune-Mediated Adverse Reactions

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue in patients receiving KEYTRUDA and may also occur after discontinuation of treatment. For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Resume KEYTRUDA when the adverse reaction remains at Grade 1 or less following corticosteroid taper. Permanently discontinue KEYTRUDA for any Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

The following clinically significant immune-mediated adverse reactions occurred in less than 1% (unless otherwise indicated) of 2799 patients: arthritis (1.5%), uveitis, myositis, Guillain-Barr syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, sarcoidosis, and encephalitis. In addition, myelitis and myocarditis were reported in other clinical trials, including classical Hodgkin lymphoma, and postmarketing use.

Treatment with KEYTRUDA may increase the risk of rejection in solid organ transplant recipients. Consider the benefit of treatment vs the risk of possible organ rejection in these patients.

Infusion-Related Reactions

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% (6/2799) of patients. Monitor patients for signs and symptoms of infusion-related reactions. For Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Immune-mediated complications, including fatal events, occurred in patients who underwent allogeneic HSCT after treatment with KEYTRUDA. Of 23 patients with cHL who proceeded to allogeneic HSCT after KEYTRUDA, 6 (26%) developed graft-versus-host disease (GVHD) (1 fatal case) and 2 (9%) developed severe hepatic veno-occlusive disease (VOD) after reduced-intensity conditioning (1 fatal case). Cases of fatal hyperacute GVHD after allogeneic HSCT have also been reported in patients with lymphoma who received a PD-1 receptorblocking antibody before transplantation. Follow patients closely for early evidence of transplant-related complications such as hyperacute graft-versus-host disease (GVHD), Grade 3 to 4 acute GVHD, steroid-requiring febrile syndrome, hepatic veno-occlusive disease (VOD), and other immune-mediated adverse reactions.

In patients with a history of allogeneic HSCT, acute GVHD (including fatal GVHD) has been reported after treatment with KEYTRUDA. Patients who experienced GVHD after their transplant procedure may be at increased risk for GVHD after KEYTRUDA. Consider the benefit of KEYTRUDA vs the risk of GVHD in these patients.

Increased Mortality in Patients With Multiple Myeloma

In trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of these patients with a PD-1 or PD-L1 blocking antibody in this combination is not recommended outside of controlled trials.

Embryofetal Toxicity

Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. Advise women of this potential risk. In females of reproductive potential, verify pregnancy status prior to initiating KEYTRUDA and advise them to use effective contraception during treatment and for 4 months after the last dose.

Adverse Reactions

In KEYNOTE-006, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients with advanced melanoma; adverse reactions leading to permanent discontinuation in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). The most common adverse reactions (20%) with KEYTRUDA were fatigue (28%), diarrhea (26%), rash (24%), and nausea (21%).

In KEYNOTE-002, KEYTRUDA was permanently discontinued due to adverse reactions in 12% of 357 patients with advanced melanoma; the most common (1%) were general physical health deterioration (1%), asthenia (1%), dyspnea (1%), pneumonitis (1%), and generalized edema (1%). The most common adverse reactions were fatigue (43%), pruritus (28%), rash (24%), constipation (22%), nausea (22%), diarrhea (20%), and decreased appetite (20%).

In KEYNOTE-054, KEYTRUDA was permanently discontinued due to adverse reactions in 14% of 509 patients; the most common (1%) were pneumonitis (1.4%), colitis (1.2%), and diarrhea (1%). Serious adverse reactions occurred in 25% of patients receiving KEYTRUDA. The most common adverse reaction (20%) with KEYTRUDA was diarrhea (28%).

In KEYNOTE-189, when KEYTRUDA was administered with pemetrexed and platinum chemotherapy in metastatic nonsquamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 20% of 405 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney injury (2%). The most common adverse reactions (20%) with KEYTRUDA were nausea (56%), fatigue (56%), constipation (35%), diarrhea (31%), decreased appetite (28%), rash (25%), vomiting (24%), cough (21%), dyspnea (21%), and pyrexia (20%).

In KEYNOTE-407, when KEYTRUDA was administered with carboplatin and either paclitaxel or paclitaxel protein-bound in metastatic squamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 15% of 101 patients. The most frequent serious adverse reactions reported in at least 2% of patients were febrile neutropenia, pneumonia, and urinary tract infection. Adverse reactions observed in KEYNOTE-407 were similar to those observed in KEYNOTE-189 with the exception that increased incidences of alopecia (47% vs 36%) and peripheral neuropathy (31% vs 25%) were observed in the KEYTRUDA and chemotherapy arm compared to the placebo and chemotherapy arm in KEYNOTE-407.

In KEYNOTE-042, KEYTRUDA was discontinued due to adverse reactions in 19% of 636 patients with advanced NSCLC; the most common were pneumonitis (3%), death due to unknown cause (1.6%), and pneumonia (1.4%). The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia (7%), pneumonitis (3.9%), pulmonary embolism (2.4%), and pleural effusion (2.2%). The most common adverse reaction (20%) was fatigue (25%).

In KEYNOTE-010, KEYTRUDA monotherapy was discontinued due to adverse reactions in 8% of 682 patients with metastatic NSCLC; the most common was pneumonitis (1.8%). The most common adverse reactions (20%) were decreased appetite (25%), fatigue (25%), dyspnea (23%), and nausea (20%).

Adverse reactions occurring in patients with SCLC were similar to those occurring in patients with other solid tumors who received KEYTRUDA as a single agent.

In KEYNOTE-048, KEYTRUDA monotherapy was discontinued due to adverse events in 12% of 300 patients with HNSCC; the most common adverse reactions leading to permanent discontinuation were sepsis (1.7%) and pneumonia (1.3%). The most common adverse reactions (20%) were fatigue (33%), constipation (20%), and rash (20%).

In KEYNOTE-048, when KEYTRUDA was administered in combination with platinum (cisplatin or carboplatin) and FU chemotherapy, KEYTRUDA was discontinued due to adverse reactions in 16% of 276 patients with HNSCC. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonia (2.5%), pneumonitis (1.8%), and septic shock (1.4%). The most common adverse reactions (20%) were nausea (51%), fatigue (49%), constipation (37%), vomiting (32%), mucosal inflammation (31%), diarrhea (29%), decreased appetite (29%), stomatitis (26%), and cough (22%).

In KEYNOTE-012, KEYTRUDA was discontinued due to adverse reactions in 17% of 192 patients with HNSCC. Serious adverse reactions occurred in 45% of patients. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. The most common adverse reactions (20%) were fatigue, decreased appetite, and dyspnea. Adverse reactions occurring in patients with HNSCC were generally similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy, with the exception of increased incidences of facial edema and new or worsening hypothyroidism.

In KEYNOTE-087, KEYTRUDA was discontinued due to adverse reactions in 5% of 210 patients with cHL. Serious adverse reactions occurred in 16% of patients; those 1% included pneumonia, pneumonitis, pyrexia, dyspnea, GVHD, and herpes zoster. Two patients died from causes other than disease progression; 1 from GVHD after subsequent allogeneic HSCT and 1 from septic shock. The most common adverse reactions (20%) were fatigue (26%), pyrexia (24%), cough (24%), musculoskeletal pain (21%), diarrhea (20%), and rash (20%).

In KEYNOTE-170, KEYTRUDA was discontinued due to adverse reactions in 8% of 53 patients with PMBCL. Serious adverse reactions occurred in 26% of patients and included arrhythmia (4%), cardiac tamponade (2%), myocardial infarction (2%), pericardial effusion (2%), and pericarditis (2%). Six (11%) patients died within 30 days of start of treatment. The most common adverse reactions (20%) were musculoskeletal pain (30%), upper respiratory tract infection and pyrexia (28% each), cough (26%), fatigue (23%), and dyspnea (21%).

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Merck's KEYTRUDA (pembrolizumab) in Combination With Chemotherapy Significantly Improved Overall Survival and Progression-Free Survival Compared With...

Exosome Therapeutic Market (Covid 19 Impact Analysis) Data Highlighting Major Vendors, Promising Regions, Anticipated Growth Forecast To 2027 -…

Global Exosome Therapeutic Market By Type (Natural Exosomes, Hybrid Exosomes), Source (Dendritic Cells, Mesenchymal Stem Cells, Blood, Milk, Body Fluids, Saliva, Urine Others), Therapy (Immunotherapy, Gene Therapy, Chemotherapy), Transporting Capacity (Bio Macromolecules, Small Molecules), Application (Oncology, Neurology, Metabolic Disorders, Cardiac Disorders, Blood Disorders, Inflammatory Disorders, Gynecology Disorders, Organ Transplantation, Others), Route of administration (Oral, Parenteral), End User (Hospitals, Diagnostic Centers, Research & Academic Institutes), Geography (North America, Europe, Asia-Pacific and Latin America)

Exosome therapeutic market is expected to gain market growth in the forecast period of 2019 to 2026. Data Bridge Market Research analyses that the market is growing with a CAGR of 21.9% in the forecast period of 2019 to 2026 and expected to reach USD 31,691.52 million by 2026 from USD 6,500.00 million in 2018. Increasing prevalence of lyme disease, chronic inflammation, autoimmune disease and other chronic degenerative diseases are the factors for the market growth.

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Increased number of exosome therapeutics as compared to the past few years will accelerate the market growth. Companies are receiving funding for exosome therapeutic research and clinical trials. For instance, In September 2018, EXOCOBIO has raised USD 27 million in its series B funding. The company has raised USD 46 million as series a funding in April 2017. The series B funding will help the company to set up GMP-compliant exosome industrial facilities to enhance production of exosomes to commercialize in cosmetics and pharmaceutical industry.

This exosome therapeutic market report provides details of market share, new developments, and product pipeline analysis, impact of domestic and localised market players, analyses opportunities in terms of emerging revenue pockets, changes in market regulations, product approvals, strategic decisions, product launches, geographic expansions, and technological innovations in the market. To understand the analysis and the market scenario contact us for an Analyst Brief, our team will help you create a revenue impact solution to achieve your desired goal.

Increasing demand for anti-aging therapies will also drive the market. Unmet medical needs such as very few therapeutic are approved by the regulatory authority for the treatment in comparison to the demand in global exosome therapeutics market will hamper the market growth market. Availability of various exosome isolation and purification techniques is further creates new opportunities for exosome therapeutics as they will help company in isolation and purification of exosomes from dendritic cells, mesenchymal stem cells, blood, milk, body fluids, saliva, and urine and from others sources. Such policies support exosome therapeutic market growth in the forecast period to 2019-2026.

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Exosome is an extracellular vesicle which is released from cells, particularly from stem cells. Exosome functions as vehicle for particular proteins and genetic information and other cells. Exosome plays a vital role in the rejuvenation and communication of all the cells in our body while not themselves being cells at all. Research has projected that communication between cells is significant in maintenance of healthy cellular terrain. Chronic disease, age, genetic disorders and environmental factors can affect stem cells communication with other cells and can lead to distribution in the healing process.

The growth of the global exosome therapeutic market reflects global and country-wide increase in prevalence of autoimmune disease, chronic inflammation, Lyme disease and chronic degenerative diseases, along with increasing demand for anti-aging therapies. Additionally major factors expected to contribute in growth of the global exosome therapeutic market in future are emerging therapeutic value of exosome, availability of various exosome isolation and purification techniques, technological advancements in exosome and rising healthcare infrastructure.

The major players covered in the report are evox THERAPEUTICS, EXOCOBIO, Exopharm, AEGLE Therapeutics, United Therapeutics Corporation, Codiak BioSciences, Jazz Pharmaceuticals, Inc., Boehringer Ingelheim International GmbH, ReNeuron Group plc, Capricor Therapeutics, Avalon Globocare Corp., CREATIVE MEDICAL TECHNOLOGY HOLDINGS INC., Stem Cells Group among other players domestic and global. Exosome therapeutic market share data is available for Global, North America, Europe, Asia-Pacific, and Latin America separately. DBMR analysts understand competitive strengths and provide competitive analysis for each competitor separately.

The country section of the report also provides individual market impacting factors and changes in regulation in the market domestically that impacts the current and future trends of the market. Data points such as new sales, replacement sales, country demographics, regulatory acts and import-export tariffs are some of the major pointers used to forecast the market scenario for individual countries. Also, presence and availability of global brands and their challenges faced due to large or scarce competition from local and domestic brands, impact of sales channels are considered while providing forecast analysis of the country data.

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Exosome Therapeutic Market (Covid 19 Impact Analysis) Data Highlighting Major Vendors, Promising Regions, Anticipated Growth Forecast To 2027 -...

Stem Cell Therapy Market Landscape Assessment By Type and Analysis Current Trends by Forecast To 2025 – The Daily Chronicle

Global Stem Cell Therapy Market: Overview

Also called regenerative medicine, stem cell therapy encourages the reparative response of damaged, diseased, or dysfunctional tissue via the use of stem cells and their derivatives. Replacing the practice of organ transplantations, stem cell therapies have eliminated the dependence on availability of donors. Bone marrow transplant is perhaps the most commonly employed stem cell therapy.

Osteoarthritis, cerebral palsy, heart failure, multiple sclerosis and even hearing loss could be treated using stem cell therapies. Doctors have successfully performed stem cell transplants that significantly aid patients fight cancers such as leukemia and other blood-related diseases.

Know the Growth Opportunities in Emerging Markets

Global Stem Cell Therapy Market: Key Trends

The key factors influencing the growth of the global stem cell therapy market are increasing funds in the development of new stem lines, the advent of advanced genomic procedures used in stem cell analysis, and greater emphasis on human embryonic stem cells. As the traditional organ transplantations are associated with limitations such as infection, rejection, and immunosuppression along with high reliance on organ donors, the demand for stem cell therapy is likely to soar. The growing deployment of stem cells in the treatment of wounds and damaged skin, scarring, and grafts is another prominent catalyst of the market.

On the contrary, inadequate infrastructural facilities coupled with ethical issues related to embryonic stem cells might impede the growth of the market. However, the ongoing research for the manipulation of stem cells from cord blood cells, bone marrow, and skin for the treatment of ailments including cardiovascular and diabetes will open up new doors for the advancement of the market.

Global Stem Cell Therapy Market: Market Potential

A number of new studies, research projects, and development of novel therapies have come forth in the global market for stem cell therapy. Several of these treatments are in the pipeline, while many others have received approvals by regulatory bodies.

In March 2017, Belgian biotech company TiGenix announced that its cardiac stem cell therapy, AlloCSC-01 has successfully reached its phase I/II with positive results. Subsequently, it has been approved by the U.S. FDA. If this therapy is well- received by the market, nearly 1.9 million AMI patients could be treated through this stem cell therapy.

Another significant development is the granting of a patent to Israel-based Kadimastem Ltd. for its novel stem-cell based technology to be used in the treatment of multiple sclerosis (MS) and other similar conditions of the nervous system. The companys technology used for producing supporting cells in the central nervous system, taken from human stem cells such as myelin-producing cells is also covered in the patent.

The regional analysis covers:

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Global Stem Cell Therapy Market: Regional Outlook

The global market for stem cell therapy can be segmented into Asia Pacific, North America, Latin America, Europe, and the Middle East and Africa. North America emerged as the leading regional market, triggered by the rising incidence of chronic health conditions and government support. Europe also displays significant growth potential, as the benefits of this therapy are increasingly acknowledged.

Asia Pacific is slated for maximum growth, thanks to the massive patient pool, bulk of investments in stem cell therapy projects, and the increasing recognition of growth opportunities in countries such as China, Japan, and India by the leading market players.

Global Stem Cell Therapy Market: Competitive Analysis

Several firms are adopting strategies such as mergers and acquisitions, collaborations, and partnerships, apart from product development with a view to attain a strong foothold in the global market for stem cell therapy.

Some of the major companies operating in the global market for stem cell therapy are RTI Surgical, Inc., MEDIPOST Co., Ltd., Osiris Therapeutics, Inc., NuVasive, Inc., Pharmicell Co., Ltd., Anterogen Co., Ltd., JCR Pharmaceuticals Co., Ltd., and Holostem Terapie Avanzate S.r.l.

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TMR Research is a premier provider of customized market research and consulting services to business entities keen on succeeding in todays supercharged economic climate. Armed with an experienced, dedicated, and dynamic team of analysts, we are redefining the way our clients conduct business by providing them with authoritative and trusted research studies in tune with the latest methodologies and market trends.

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Stem Cell Therapy Market Landscape Assessment By Type and Analysis Current Trends by Forecast To 2025 - The Daily Chronicle

ASU engineers get to the heart of organs-on-a-chip – ASU Now

August 17, 2020

Denver is known for its relatively mild climate and its four distinct seasons. Its also known for its temperature fluctuations over the course of a day or even hours. But what does that mean for the citys residents and for that matter, the rest of the inhabitants of the continental United States when it comes to temperature extremes?

Thats what Ashley Broadbentwanted to know. Specifically, he wanted to know how populations throughout the United States will experience heat and cold during the 21st century.

So, Broadbent, an assistant research professor in Arizona State Universitys School of Geographical Sciences and Urban Planning, used state-of-the-art modeling tools to analyze how three key variables would affect human exposure to extreme temperatures from the beginning of this century to its end.

He and his collaborator Matei Georgescu, an associate professor in the School of Geographical Sciences and Urban Planning, concentrated on the following three key factors: climate change brought about by greenhouse gas emissions, urban development-induced impacts arising from the growth of cities, and population change in individual cities.

The paper, "The motley drivers of heat and cold exposure in 21st century U.S. cities," was published onlineAug. 17 in the Proceedings of the National Academy of Sciences. It is the first study of its kind to consider population-weighted heat and cold exposure that directly and simultaneously account for greenhouse gas and urban development-induced warming.

Graphic by Alex Davis/ASU Media Relations and Strategic Communications

To describe how these three variables would affect temperatures, and in turn populations, Broadbent, Georgescu and co-author Eric Scott Krayenhoff, assistant professor at the University of Guelph, Ontario, in Canada, used a metric they dubbed person-hours, to describe humans exposure to extreme heat and cold.

Its an intuitive metric, Broadbent said. For example, when one person is exposed to one hour of an extreme temperature, that exposure equals one person-hour of exposure. Likewise, if 10 people are exposed to 10 hours of an extreme temperature, that exposure equals 100 person-hours.

I think this definition is more representative of what people experience, which is what this study is about versus a study that simply communicates temperature changes without any human element attached to it, Broadbent said.

Overall, the researchers found that the average annual heat exposure at the start of this century in the United States was about 5.2 billion person-hours. Assuming a worst-case scenario of peak global warming, population growth and urban development, the annual heat exposure would rise to 150 billion person-hours by the end of the century, a nearly 30-fold increase.

The combined effect of these three drivers will substantially increase the average heat exposure across the United States, but heat exposure is not projected to increase uniformly in all cities across the U.S., Broadbent said. There will be hot spots where heat exposure grows sharply.

To that end, the researchers defined heat thresholds based on local city definitions, something previous studies have not done. Instead, prior studies have used fixed-temperature thresholds that may be inappropriate for some cities. Afterall, a 90-degree day in Phoenix feels much different than a 90-degree day in New York City, given relative humidity differences.

Its well-known that cities have locally defined thresholds where heat and cold cause mortality and morbidity, Broadbent explained. In other words, people die at different temperatures in different cities because what is extreme in one city may be normal in another.

Importantly, areas of the United States where human exposure would increase the most is where climate change and population increase in tandem. Meanwhile, urban development has a smaller, yet not negligible effect.

According to the results of the study, the largest absolute changes in population heat exposure are projected to occur in major U.S. metropolitan regions, such as New York, Los Angeles and Atlanta.

The study also finds the largest relativechanges in person-hours related to heat exposure are projected to occur in rapidly growing cities located in the Sun Belt, including Austin, Texas; Orlando, Florida; and Atlanta.

The increase in exposure is quite large if you look at it relative to the start of the century, Broadbent said. Some cities across the Sun Belt, according to our projections, will have 90 times the number of person-hours of heat exposure. For example, cities in Texas that see substantial population growth and strong greenhouse gas-induced climate warming could be markedly affected.

One way to prepare for increased heat exposure is to reduce greenhouse gas emissions on a global scale, which would reduce the number of hours people are exposed to extreme temperatures. Other options include localized infrastructure adaptation that provides buffering effects against rising temperatures such as planting trees, providing shade and cooling areas and constructing buildings using materials that absorb less heat.

Although the average temperature in the United States will be warmer in the future, the study finds that cold exposure will increase slightly compared with the start of the century, primarily because of population growth. While there is a generaldecreasein the number of projected extreme cold events by the end of this century, the number of individuals exposed to extreme cold is projected toincrease,as population growth means that the total number of person-hours of cold exposure will go up, Broadbent said.

Cold is currently more of a national health problem than heat, but our results suggest that by the end of the century heat exposure may become a larger health problem than cold exposure, Broadbent said. However, cold exposure will not disappear completely as the climate warms. In fact, according to one of the teams simulations, Denver is projected to have more extreme cold at the end of the century compared with the beginning, according to the study.

Thats the interesting thing about climate change. We know the average temperature is going to increase, said Broadbent. But we know less about how the extremes are going to change, and often the extremes are the most important part of our daily lives.

There are several takeaway messages from this work, but one of the central ones concerns the future resiliency of our cities, Georgescu said.

The successful steps taken will require holistic thinking that embraces contributions from urban planners, engineers, social scientists and climate scientists with a long-range vision of how we want our cities to be.

"We therefore call on cities to start asking some very foundational questions regarding the projected exposure of their constituents to future environmental change," Georgescu said. "Is the work of the urban climate modeling community being integrated into their environmental adaptation plans? If so, how, and if not, why not?

This work was funded by the National Science Foundation.

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ASU engineers get to the heart of organs-on-a-chip - ASU Now

bluebird bio to Present New Data from Clinical Studies of elivaldogene autotemcel (eli-cel, Lenti-D) Gene Therapy for Cerebral Adrenoleukodystrophy…

CAMBRIDGE, Mass.--(BUSINESS WIRE)--bluebird bio, Inc. (Nasdaq: BLUE) today announced that new data from the clinical development program for its investigational elivaldogene autotemcel (eli-cel, Lenti-D) gene therapy in patients with cerebral adrenoleukodystrophy (CALD), including data from the Phase 2/3 Starbeam study (ALD-102) and available data from the Phase 3 ALD-104 study, will be presented at the 46th Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT 2020), taking place virtually from August 29 - September 1, 2020.

New Cerebral Adrenoleukodystrophy (CALD) Data at EBMT 2020

Lenti-D hematopoietic stem cell gene therapy stabilizes neurologic function in boys with cerebral adrenoleukodystrophy (ALD-102 and ALD-104)Presenting Author: Dr. Jrn-Sven Khl, Department of Pediatric Oncology, Hematology and Hemostaseology, Center for Womens and Childrens Medicine, University Hospital LeipzigPoster Session & Number: Gene Therapy; ePoster O077

Additional bluebird bio data at EBMT 2020 includes encore presentations from the companys CALD, sickle cell disease (SCD), transfusion-dependent -thalassemia (TDT) and multiple myeloma programs.

Cerebral Adrenoleukodystrophy (CALD) Encore Data at EBMT 2020

Outcomes of allogeneic hematopoietic stem cell transplant in patients with cerebral adrenoleukodystrophy vary by donor cell source, conditioning regimen, and stage of cerebral disease status (ALD-103)Presenting Author: Dr. Jaap Jan Boelens, Chief, Pediatric Stem Cell Transplantation and Cellular Therapies Service, Memorial Sloan Kettering Cancer CenterPoster Session & Number: Haemoglobinopathy and inborn errors; ePoster O106

Multiple Myeloma Correlative Encore Data at EBMT 2020

Markers of initial and long-term responses to idecabtagene vicleucel (ide-cel; bb2121) in the CRB-401 study in relapsed/refractory multiple myelomaPresenting Author: Dr. Ethan G. Thompson, Bristol Myers SquibbPoster Session & Number: CAR-based Cellular Therapy clinical; ePoster A089

Sickle Cell Disease (SCD) Encore Data at EBMT 2020

LentiGlobin for sickle cell disease (SCD) gene therapy (GT): updated results in Group C patients from the Phase 1/2 HGB-206 studyPresenting Author: Dr. Markus Y. Mapara, Director, Adult Blood and Marrow Transplantation Program, Columbia University Medical CenterOral Session & Number: Inborn Errors; O080Date & Time: September 1, 2020; 4:35 4:42 PM CET/10:35 10:42 AM ET

Transfusion-Dependent -Thalassemia (TDT) Encore Data at EBMT 2020

Clinical outcomes following autologous hematopoietic stem cell transplantation with LentiGlobin gene therapy in the Phase 3 Northstar-2 and Northstar-3 studies for transfusion-dependent -thalassemiaPresenting Author: Professor Franco Locatelli, Director, Department of Pediatric Hematology and Oncology, Ospedale Pediatrico Bambino GesPoster Session & Number: Gene Therapy; ePoster O074

LentiGlobin gene therapy treatment of two patients with transfusion-dependent -thalassemia (case report)Presenting Author: Dr. Mattia Algeri, Department of Pediatric Oncohematology - Transplantation Unit and Cell Therapies, Ospedale Pediatrico Bambino GesPoster Session & Number: Haemoglobinopathy and inborn errors; ePoster A328

Cross Indication Encore Data at EBMT 2020

Safety of autologous hematopoietic stem cell transplantation with gene addition therapy for transfusion-dependent -thalassemia, sickle cell disease, and cerebral adrenoleukodystrophyPresenting Author: Dr. Evangelia Yannaki, Director, Gene and Cell Therapy Center, Hematology Department, George Papanicolaou HospitalPoster Session & Number: Gene Therapy; ePoster O078

Abstracts outlining bluebird bios accepted data at EBMT 2020 are available on the Annual Meeting website. On August 29, 2020, at 12:30 PM CET/6:30 AM ET, the embargo will lift for ePosters and oral presentations accepted for EBMT 2020. Presentations will be available for virtual viewing throughout the duration of the live meeting and content will be accessible online following the close of the meeting until November 1, 2020.

About elivaldogene autotemcel (eli-cel, Lenti-D gene therapy)In July 2020, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) granted an accelerated assessment to eli-cel gene therapy for cerebral adrenoleukodystrophy (CALD). bluebird bio is currently on track to submit the Marketing Authorization Application (MAA) in the EU for eli-cel for CALD by year-end 2020, and the Biologics License Application (BLA) in the U.S. in mid-2021.

bluebird bio is currently enrolling patients for a Phase 3 study (ALD-104) designed to assess the efficacy and safety of eli-cel after myeloablative conditioning using busulfan and fludarabine in patients with CALD. Contact clinicaltrials@bluebirdbio.com for more information and a list of study sites.

Additionally, bluebird bio is conducting a long-term safety and efficacy follow-up study (LTF-304) for patients who have been treated with eli-cel for CALD and completed two years of follow-up in bluebird bio-sponsored studies.

The Phase 2/3 Starbeam study (ALD-102) has completed enrollment. For more information about the ALD-102 study visit: http://www.bluebirdbio.com/our-science/clinical-trials or clinicaltrials.gov and use identifier NCT01896102.

Adrenoleukodystrophy (ALD) is a rare, X-linked metabolic disorder that is estimated to affect one in 21,000 male newborns worldwide. Approximately 40 percent of boys with ALD will develop CALD, the most severe form of ALD. CALD is a progressive neurogenerative disease that involves breakdown of myelin, the protective sheath of the nerve cells in the brain that are responsible for thinking and muscle control. Symptoms of CALD usually occur in early childhood and progress rapidly, if untreated, leading to severe loss of neurologic function, and eventual death, in most patients.

The European Medicines Agency (EMA) accepted eli-cel gene therapy for the treatment of CALD into its Priorities Medicines scheme (PRIME) in July 2018, and previously granted Orphan Medicinal Product designation to eli-cel.

The U.S. Food and Drug Administration (FDA) granted eli-cel Orphan Drug status, Rare Pediatric Disease designation, and Breakthrough Therapy designation for the treatment of CALD.

Eli-cel is not approved for any indication in any geography.

About idecabtagene vicleucel (ide-cel; bb2121)Ide-cel is a B-cell maturation antigen (BCMA)-directed genetically modified autologous chimeric antigen receptor (CAR) T cell immunotherapy. The ide-cel CAR is comprised of a murine extracellular single-chain variable fragment (scFv) specific for recognizing BCMA, attached to a human CD8 hinge and transmembrane domain fused to the T cell cytoplasmic signaling domains of CD137 4-1BB and CD3- chain, in tandem. Ide-cel recognizes and binds to BCMA on the surface of multiple myeloma cells leading to CAR T cell proliferation, cytokine secretion, and subsequent cytolytic killing of BCMA-expressing cells.

In addition to the pivotal KarMMa trial evaluating ide-cel in patients with relapsed and refractory multiple myeloma, bluebird bio and Bristol Myers Squibbs broad clinical development program for ide-cel includes clinical studies (KarMMa-2, KarMMa-3, KarMMa-4) in earlier lines of treatment for patients with multiple myeloma, including newly diagnosed multiple myeloma. For more information visit clinicaltrials.gov.

In July 2020, Bristol Myers Squibb (BMS) and bluebird bio submitted the Biologics License Application for ide-cel to the U.S. Food and Drug Administration for the treatment of adult patients with multiple myeloma who have received at least three prior therapies, including an immunomodulatory agent, a proteasome inhibitor and an anti-CD38 antibody. Ide-cel is the first CAR T cell therapy submitted for regulatory review to target BCMA and for multiple myeloma.

Ide-cel was granted Breakthrough Therapy Designation (BTD) by the U.S. Food and Drug Administration (FDA) and PRIority Medicines (PRIME) designation, as well as Accelerated Assessment status, by the European Medicines Agency for relapsed and refractory multiple myeloma.

Ide-cel is being developed as part of a Co-Development, Co-Promotion and Profit Share Agreement between BMS and bluebird bio.

Ide-cel is not approved for any indication in any geography.

About LentiGlobin for Sickle Cell DiseaseLentiGlobin for sickle cell disease (SCD) is an investigational gene therapy being studied as a potential treatment for SCD. bluebird bios clinical development program for LentiGlobin for SCD includes the ongoing Phase 1/2 HGB-206 study and the ongoing Phase 3 HGB-210 study.

bluebird bio is conducting a long-term safety and efficacy follow-up study (LTF-303) for people who have participated in bluebird bio-sponsored clinical studies of betibeglogene autotemcel and LentiGlobin for SCD. For more information visit: https://www.bluebirdbio.com/our-science/clinical-trials or clinicaltrials.gov and use identifier NCT02633943 for LTF-303.

SCD is a serious, progressive and debilitating genetic disease caused by a mutation in the -globin gene that leads to the production of abnormal sickle hemoglobin (HbS). HbS causes red blood cells (RBCs) to become sickled and fragile, resulting in chronic hemolytic anemia, vasculopathy and painful vaso-occlusive crises (VOCs). For adults and children living with SCD, this means painful crises and other life-altering or life-threatening acute complicationssuch as acute chest syndrome (ACS), stroke and infections. If patients survive the acute complications, vasculopathy and end-organ damage, resulting complications can lead to pulmonary hypertension, renal failure and early death; in the U.S. the median age of death for someone with sickle cell disease is 43 - 46 years.

LentiGlobin for SCD received Orphan Medicinal Product designation from the European Commission for the treatment of SCD.

The U.S. Food and Drug Administration (FDA) granted Orphan Drug status and Regenerative Medicine Advanced Therapy (RMAT) designation and rare pediatric disease designation for LentiGlobin for the treatment of SCD.

bluebird bio reached general agreement with the U.S. Food and Drug Administration (FDA) that the clinical data package required to support a Biologics Licensing Application (BLA) submission for LentiGlobin for SCD will be based on data from a portion of patients in the HGB-206 study Group C that have already been treated. The planned submission will be based on an analysis using complete resolution of severe vaso-occlusive events (VOEs) as the primary endpoint with at least 18 months of follow-up post-treatment with LentiGlobin for SCD. Globin response will be used as a key secondary endpoint.

bluebird bio anticipates additional guidance from the FDA regarding the commercial manufacturing process, including suspension lentiviral vector. bluebird bio announced in a May 11, 2020 press release it plans to seek an accelerated approval and expects to submit the U.S. BLA for SCD in the second half of 2021.

LentiGlobin for SCD is investigational and has not been approved in any geography.

About betibeglogene autotemcel (beti-cel; formerly LentiGlobin gene therapy for -thalassemia)The European Commission granted conditional marketing authorization (CMA) for betibeglogene autotemcel, marketed as ZYNTEGLO gene therapy, for patients 12 years and older with transfusion-dependent -thalassemia (TDT) who do not have a 0/0 genotype, for whom hematopoietic stem cell (HSC) transplantation is appropriate, but a human leukocyte antigen (HLA)-matched related HSC donor is not available. On April 28, 2020, the European Medicines Agency (EMA) renewed the CMA for ZYNTEGLO, supported by data from 32 patients treated with ZYNTEGLO, including three patients with up to five years of follow-up.

In the HGB-207 clinical study supporting the conditional marketing approval of ZYNTEGLO, the primary endpoint was transfusion independence (TI) by Month 24, defined as a weighted average Hb 9 g/Dl without any RBC transfusions for a continuous period of 12 months at any time during the study after infusion of ZYNTEGLO. Ten patients were evaluable for assessment of TI. Of these, 9/10 (90.0%, 95% CI 55.5-99.7%) achieved TI at last follow-up. Among these nine patients, the median (min, max) weighted average Hb during TI was 12.22 (11.4, 12.8) g/dLl.

TDT is a severe genetic disease caused by mutations in the -globin gene that result in reduced or significantly reduced hemoglobin (Hb). In order to survive, people with TDT maintain Hb levels through lifelong chronic blood transfusions. These transfusions carry the risk of progressive multi-organ damage due to unavoidable iron overload.

Beti-cel adds functional copies of a modified form of the -globin gene (A-T87Q-globin gene) into a patients own hematopoietic (blood) stem cells (HSCs). Once a patient has the A-T87Q-globin gene, they have the potential to produce HbAT87Q, which is gene therapy-derived hemoglobin, at levels that may eliminate or significantly reduce the need for transfusions.

Non-serious adverse events (AEs) observed during the clinical studies that were attributed to betibeglogene autotemcel included abdominal pain, thrombocytopenia, leukopenia, neutropenia, hot flush, dyspnoea, pain in extremity, and non-cardiac chest pain. Two serious adverse events (SAE) of thrombocytopenia were considered possibly related to beti-cel.

Additional AEs observed in clinical studies were consistent with the known side effects of HSC collection and bone marrow ablation with busulfan, including SAEs of veno-occlusive disease.

The CMA for beti-cel is valid in the 27 member states of the EU as well as UK, Iceland, Liechtenstein and Norway. For details, please see the Summary of Product Characteristics (SmPC).

The U.S. Food and Drug Administration granted beti-cel Orphan Drug status and Breakthrough Therapy designation for the treatment of TDT. Beti-cel is not approved in the United States.

Beti-cel continues to be evaluated in the ongoing Phase 3 Northstar-2 and Northstar-3 studies. For more information about the ongoing clinical studies, visit http://www.northstarclinicalstudies.com or clinicaltrials.gov and use identifier NCT02906202 for Northstar-2 (HGB-207), NCT03207009 for Northstar-3 (HGB-212).

About bluebird bio, Inc.bluebird bio is pioneering gene therapy with purpose. From our Cambridge, Mass., headquarters, were developing gene therapies for severe genetic diseases and cancer, with the goal that people facing potentially fatal conditions with limited treatment options can live their lives fully. Beyond our labs, were working to positively disrupt the healthcare system to create access, transparency and education so that gene therapy can become available to all those who can benefit.

bluebird bio is a human company powered by human stories. Were putting our care and expertise to work across a spectrum of disorders including cerebral adrenoleukodystrophy, sickle cell disease, -thalassemia and multiple myeloma, using three gene therapy technologies: gene addition, cell therapy and (megaTAL-enabled) gene editing.

bluebird bio has additional nests in Seattle, Wash.; Durham, N.C.; and Zug, Switzerland. For more information, visit bluebirdbio.com.

Follow bluebird bio on social media: @bluebirdbio, LinkedIn, Instagram and YouTube.

Lenti-D and bluebird bio are trademarks of bluebird bio, Inc.

Forward-Looking StatementsThis release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, including statements regarding the companys financial condition, results of operations, as well as statements regarding the plans for regulatory submissions for beti-cel (marketed as ZYTENGLO in the European Union), eli-cel, ide-cel, and LentiGlobin for SCD, including anticipated endpoints to support regulatory submissions and timing expectations; the companys expectations regarding the potential for the suspension manufacturing process for lentiviral vector; its expectations for commercialization efforts for ZYNTEGLO in Europe; as well as the companys intentions regarding the timing for providing further updates on the development and commercialization of ZYNTEGLO and the companys product candidates. Any forward-looking statements are based on managements current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. These risks and uncertainties include, but are not limited to, the risks that the COVID-19 pandemic and resulting economic conditions will have a greater impact on the companys operations and plans than anticipated; that our amended collaboration with BMS will not continue or be successful; that preliminary positive efficacy and safety results from our prior and ongoing clinical trials will not continue or be repeated in our ongoing or future clinical trials; the risk that our plans for submitting a BLA for LentiGlobin for SCD may be delayed if the FDA does not accept our comparability plans for the use of the suspension manufacturing process for lentiviral vector; the risk that the submission of BLA for ide-cel is not accepted for filing by the FDA or approved in the timeline we expect, or at all; the risk of cessation or delay of any of the ongoing or planned clinical studies and/or our development of our product candidates, including due to delays from the COVID-19 pandemics impact on healthcare systems; the risk that the current or planned clinical trials of our product candidates will be insufficient to support regulatory submissions or marketing approval in the United States and European Union; the risk that regulatory authorities will require additional information regarding our product candidates, resulting in delay to our anticipated timelines for regulatory submissions, including our applications for marketing approval; the risk that we will encounter challenges in the commercial launch of ZYNTEGLO in the European Union, including in managing our complex supply chain for the delivery of drug product, in the adoption of value-based payment models, or in obtaining sufficient coverage or reimbursement for our products; and the risk that any one or more of our product candidates, will not be successfully developed, approved or commercialized. For a discussion of other risks and uncertainties, and other important factors, any of which could cause our actual results to differ from those contained in the forward-looking statements, see the section entitled Risk Factors in our most recent Form 10-K, as well as discussions of potential risks, uncertainties, and other important factors in our subsequent filings with the Securities and Exchange Commission. All information in this press release is as of the date of the release, and bluebird bio undertakes no duty to update this information unless required by law.

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bluebird bio to Present New Data from Clinical Studies of elivaldogene autotemcel (eli-cel, Lenti-D) Gene Therapy for Cerebral Adrenoleukodystrophy...

Re: Management of post-acute covid-19 in primary care – The BMJ

Dear EditorExcellent review and so needed and well-timedThe only issue that did not get the attention it needs are the neuropsychiatric symptoms of mild COVID-19. This is important for medical professionals to know, to avoid labeling the patients' problems as psychiatric and even hysterical as some recently did in a major newspaper here in Belgium.There are two sides to the mental sequelae of mild COVID.a) the consequences of the impact of going through a global pandemic, of lockdown, of COVID patients in their immediate environment, of the fear of infection or infecting others, of losing their job, and finally of their own infection.b) the mental symptoms of an organic disorder.In the subject literature about COIVD-19 (and MERS, SARS and other infections) several mechanisms are mentioned.-A direct neurotropic impact of the virus, especially, but not only via ACE2, both in neurons and glial cells, especially targeting the brain stem which plays a role in emotions. and brought there, among other things, via the direct connection of the olfactory bulb.-Inflammatory and immune reactions that result in cognitive and psychiatric symptoms:(the "misty brain" cited by many patients)-Reactions of the autonomic nervous system, eg cardiac arrhythmias can also be very scary.-Alteration of the gas exchange -oxygen nd carbon dioxide- due to damage to the alveoli resulting in a suboptimal pH.These results in mental symptoms of an organic disorder: memory problems, word finding disorders, confusion, major sleeping problems, insecure motor skills, anorexia, etc. and of course very often chronic fatigue, muscle weakness and anxiety.Of course, fear or anger of the patient are amplified when the doctor labels this as purely psychological, while the patient who has never been ill before, clearly experiences its not.

Because we have only known the disease for six months and we still know so little about it, it is therefore better to take the experiences of the patients seriously, instead of brushing them off as purely psychological or psychiatric.

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Re: Management of post-acute covid-19 in primary care - The BMJ

RT-PCR is the most reliable test in the covid diagnosis: Dr A. Velumani, CEO, Thyrocare Technologies Ltd. – ETHealthworld.com

Shahid Akhter, editor, ETHealthworld, spoke to. Dr A. Velumani, Promoter, Chairman, Managing Director and Chief Executive Officer, Thyrocare Technologies, to know more about the challenges and opportunities associated with Covid diagnostics business.

Covid-19 : ChallengesBecause of the lockdown, the existing non-covid healthcare and diagnostics business collapsed. It collapsed to 2% suddenly within a week and it didn't allow it to resume for three months.Multiple advisory's multiple tests, whom to test and whom not to, along with plenty of show cause notice because a lot of administrators wanted to under-report positivity and some probably wanted the professional gains, so a lot of time they took in the review. These were the challenges but there were a lot of opportunities as well.

Covid-19: LearningsIn my opinion, Lockdown is not the solution, repeating lockdowns, having every different strict guideline for every different state is not the solution. It won't help to reduce. Secondly, Rapid antigen kits are useless, it doesn't solve anything so we've learned the RT-PCR is the most reliable one in the covid diagnosis.Covid-19: Government's InitiativeAlso, the government labs have contributed significantly which wasn't expected, we were all thinking it is just the private labs who are truly scaling up but government labs too scaled up and contributed more in more than 50% of the testing.

Covid-19: Immunity and antibodyImmunity matters, I don't think lockdown can stop Covid. It is the antibodies that can stop the Covid and India is blessed as only 30% tests are there per million whereas in the US there are 600 tests per million. The antibody power is important to be seen as well if not then there is a problem.

Covid-19: Towards a new normalWork from home will continue, even in healthcare, it is just 17% which is working from home. Also, there will be two different religions in healthcare that will be Covid and Non-Covid so that infection will not pass on to one covid patient to another and non-covid will not move to covid hospitals. The spending on hygiene needs to be high because the general population is scared, medical doctors are scared and the patients are scared.

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RT-PCR is the most reliable test in the covid diagnosis: Dr A. Velumani, CEO, Thyrocare Technologies Ltd. - ETHealthworld.com

Covid-19 patients with heart problems more likely to die: Study – ETHealthworld.com

London: In a major study, researchers have found that Covid-19 patients with cardiovascular comorbidities or risk factors are more likely to develop heart complications while hospitalised, and more likely to die from the virus.

According to the study, published in the journal PLOS ONE, it is crucial for clinicians working with cardiovascular patients to understand the clinical presentation and risk factors for Covid-19 infection in this group.

"For most people, the Novel Coronavirus Disease 2019 (Covid-19) causes mild illness, however, it can generate severe pneumonia and lead to death in others," said study authors from the Magna Graecia University in Italy.

At the time they were admitted to the hospital, 12.89 per cent of the patients had cardiovascular comorbidities, 36.08 per cent had hypertension and 19.45 per cent had diabetes.

The findings showed that cardiovascular complications were documented during the hospital stay of 14.09 per cent of Covid-19 patients.

According to the researchers, the most common of these complications were arrhythmias or palpitations; significant numbers of patients also had myocardial injury.

Myocardial injury is considered acute if there is a rise and fall of cardiac troponin concentrations exceeding biological and analytical variation.

When the researchers analysed the data, they found that pre-existing cardiovascular comorbidities or risk factors were significant predictors of cardiovascular complications, but age and gender were not.

The study showed that both age and pre-existing cardiovascular comorbidities or risk factors were significant predictors of death.

"Cardiovascular complications are frequent among Covid-19 patients and might contribute to adverse clinical events and mortality," the study author concluded.

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Covid-19 patients with heart problems more likely to die: Study - ETHealthworld.com

Stem Cell Therapy Market Application Growth, Technology, Trends and Key Players Developments on Regional Industry Size Till 2023 – eRealty Express

Global Stem Cell Therapy Market is expected to reach an approximate CAGR of 10.3% during the forecast period. The use of stem cell for treating medical conditions is referred to as stem cell therapy. Stem cells are undifferentiated cells and differentiate into specialized cell types.

This ability of stem cells to differentiate into cells of interest is used to treat diseases like diabetes, heart disease, hematopoietic disorders (for example leukemia, thalassemia, and others), degenerative disorders (osteoarthritis, Alzheimers disease, Parkinsons disease, chronic renal failure, congestive cardiac failure,) and others.

Some of the key players are Osiris Therapeutics, Inc. (US), MEDIPOST Co., Ltd. (South Korea), Anterogen Co., Ltd. (South Korea), Pharmicell Co., Ltd. (South Korea), Holostem Terapie Avanzate S.r.l. (Italy), JCR Pharmaceuticals Co., Ltd. (Japan), NuVasive, Inc. (US), RTI Surgical, Inc. (US), and AlloSource (US), Thermo Fisher Scientific are some of the key players operating in the global stem cell therapy market.

Avail Sample copy For this Report at: https://www.marketresearchfuture.com/sample_request/6422

Global Stem Cell Therapy Market, by Technique,

Global Stem Cell Therapy Market, by Product Type

Global Stem Cell Therapy Market, by Application

Global Stem Cell Therapy Market, by End-User

Geographically, Americas is the largest in the market owing to the increasing prevalence of heart diseases and growing healthcare expenditure. According to the Centers for Disease Control and Prevention in November 2017, report every year 735,000 Americans have a heart problem. Such a high number of heart patients in the Americas drives the market growth in this region.

Brows Full Report at: https://www.marketresearchfuture.com/reports/stem-cell-therapy-market-6422

Europe (UK, Belgium, France, and Netherlands) is the second largest global stem cell therapy market during the forecast period. The increasing occurrence of stroke, cancer, and osteoarthritis drives the market in this region. According to Anthony Nolan organization 2017, annual review 1.4million people register for donating stem cell in 2017. Also, more than 2,200 searches for a lifesaving stem cell transplant were made in 2017 by UK people. Such a high demand for Stem cell transplantation in this region promotes the market.

Asia-Pacific was projected to be the fastest growing region for the global stem cell therapy market in 2017. The market is expected to witness growth owing to the rising prevalence of smoking in this region.

According to the American Cancer Society, Inc 2018, report China 48.9%, India 16.2%, Japan 11.2% accounts of cancer cases in this region. Such a high cancer rate in this region favors the stem cell therapy market in this region.

The Middle East and Africa accounts for the least share due to low per capita income and lack of availability of well-trained healthcare professionals. However, the rising oncology and technology both at the hospital level and in the community are expected to influence the market in a positive way.

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Key factors responsible for the market growth are the rising awareness for therapeutic application of stem cells in disease management, rising research for stem cell therapy applications, development of advanced genetic analysis techniques, increasing public-private investments for stem cell research, growing research in identification of new stem cell lines, and new developments in stem cell banking infrastructure are driving the growth of the global stem cell therapy market. Stem cells are used in the treatment of Alzheimers by replacing the diseased cells with stem cells

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Stem Cell Therapy Market Application Growth, Technology, Trends and Key Players Developments on Regional Industry Size Till 2023 - eRealty Express

At Least 97,000 Children in the U.S. Tested Positive in Last 2 Weeks of July – The New York Times

This briefing has ended. Read live coronavirus updates here.

At least 97,000 children in the United States tested positive for the coronavirus the last two weeks of July alone, according to a new report from the American Academy of Pediatrics and the Childrens Hospital Association. The report says that at least 338,000 children have tested positive since the pandemic began, meaning more than a quarter have tested positive in just those two weeks.

The report comes as parents and education leaders grapple with the challenges of resuming schooling as the virus continues to surge in parts of the country.

More than seven out of 10 infections were from states in the South and West, according to the report, which relied on data from 49 states along with Washington, D.C., Puerto Rico and Guam. The count could be higher because the report did not include complete data from Texas and information from parts of New York State outside of New York City.

Missouri, Oklahoma, Alaska, Nevada, Idaho and Montana were among the states with the highest percent increase of child infections during that period, according to the report.

New York City, New Jersey and other states in the Northeast, where the virus peaked in March and April, had the lowest percent increase of child infections, according to the report.

In total, 338,982 children have been infected, according to the report.

Not every locality where data was collected categorized children in the same age range. Most places cited in the report considered children to be people no older than 17 or 19. In Alabama, though, the age limit was 24; in Florida and Utah the age limit was 14.

The report noted that children rarely get severely sick from Covid-19, but another report, from the Centers for Disease Control and Prevention, highlighted how the threat from a new Covid-19-related condition, called Multisystem Inflammatory Syndrome in Children or MIS-C, has disproportionately affected people of color.

The C.D.C. said that from early March through late July, it received reports of 570 young people ranging from infants to age 20 who met the definition of MIS-C. Most of those patients were previously healthy, the report said.

About 40 percent were Hispanic or Latino; 33 percent were Black and 13 percent were white, the report said. Ten died and nearly two-thirds were admitted to intensive care units, it said. Symptoms include a fever, rash, pinkeye, stomach distress, confusion, bluish lips, muscle weakness, racing heart rate and cardiac shock.

A reopened high school in Georgia that drew national attention over images of its crowded hallways has had at least nine coronavirus cases reported in the last week, and is switching to online-only instruction for at least the next two days while the school is disinfected and officials assess the situation.

At this time, we know there were six students and three staff members who were in school for at least some time last week who have since reported to us that they have tested positive, Gabe Carmona, the principal of North Paulding High School in Dallas, Ga., said in a letter to parents and guardians of the schools students on Saturday.

The superintendent of the Paulding County School District, Brian Otott, sent them another letter Sunday advising them about the switch to online instruction for Monday and Tuesday, at the least.

Both letters encouraged parents to check their childrens temperature twice daily and to monitor them for symptoms. Neither letter made any mention of social distancing or wearing masks, which the school has said are encouraged but not mandatory.

Photos circulated widely online last week showed North Paulding students crowded in a school hallway with few in masks. Hannah Watters, a 15-year-old student who posted one of the images, was initially suspended for doing so but the suspension was rescinded.

After the photo spread over social media, Mr. Otott said masks were not required at the school, which has about 2,000 students, because there is no practical way to enforce a mandate to wear them.

But Dr. Gary Voccio, the health director for Paulding County and nine other counties in Northwest Georgia, said that masks were crucial to containing the spread of the virus.

Of course you have to change classrooms, and its going to be very difficult to physically distance when that occurs, Dr. Voccio said in a video posted on Facebook. But the masks, again, are the important part of this problem. And we will have significant cases within the schools, Im sure.

At least 66 new coronavirus deaths and 4,032 new cases were reported in Georgia on Saturday, according to a New York Times database.

Governor DeWine got the positive result when he was screened before President Trump arrived in Ohio for campaign appearances.

That test was an antigen test manufactured by the diagnostic health care company Quidel, one of two such tests given emergency use authorization by the Food and Drug Administration. These tests, while fast and convenient, are known to be less accurate than PCR tests, which were used to retest Governor DeWine twice on Thursday and once more on Saturday. All three PCR tests came back negative, confirming that the governor is not infected.

His experience could raise concerns about how much states will rely on antigen tests to augment other forms of testing that are in short supply. Ohio is one of seven states that said this week that they were banding together to purchase a total of 3.5 million rapid coronavirus tests, including antigen tests, along with other vital supplies. Governor DeWine said on CNN Sunday that he had already been in touch with Gov. Larry Hogan of Maryland to talk about the tests and the seven-state agreement.

If anyone needed a wake-up call with antigens, how careful you have to be, we certainly saw that with my test, Governor DeWine said. And were going to be very careful in how we use it.

He added that he would direct any funding from a new federal relief package to expanded testing and helping schools adapt.

We have doubled our testing in the last four weeks, he said. We need to double it again and then double it again. And so that is not going to be cheap to do.

PCR tests are in short supply nationwide, and turnaround times for results have stretched past two weeks in some parts of the country, rendering the information useless.

Compared with PCR tests, Quidels antigen test is more likely to return a false negative result, missing up to 20 percent of cases that PCR detects, though the figure may drop below 5 percent for patients with high virus levels. But Governor DeWines antigen test produced the opposite error: a false positive.

He noted on Sunday that antigen tests function especially well as screening tests, delivering a quick preliminary indication that can be confirmed by the more accurate but slower PCR tests.

Virus cases have surged in the United States in recent weeks, particularly in the Sun Belt states and in communities where officials moved quickly to reopen. According to a New York Times database, the United States leads the world in confirmed cases with more than five million a milestone reached on Saturday followed by Brazil and India. Experts have warned that the actual number of people infected is far greater than the confirmed case count. Brazil also reached a milestone of 100,000 deaths on Saturday.

Trumps moves on economic aid draw fire on the Sunday news shows.

Administration officials struggled in television appearances on Sunday to explain President Trumps attempts to circumvent Congress in the absence of an agreement on a coronavirus aid package, sowing further confusion over whether tens of millions of Americans will receive the promised relief.

The president announced executive steps on Saturday that he said were intended to address lapsed unemployment benefits, reinstate an eviction ban, provide relief for student borrowers and suspend collection of payroll taxes. They came after crucial benefits provided under earlier aid bills had lapsed, and after two weeks of talks between congressional Democrats and administration officials failed to yield an agreement on a broader relief package.

But Mr. Trumps steps appeared unlikely to have a meaningful impact on the sputtering economy, raising questions about whether Mr. Trump had taken them mainly to gain more leverage in his face-off with Congress.

Democrats criticized the actions on Sunday as executive overreach, and warned that the nations social safety net could be jeopardized.

The presidents meager, weak and unconstitutional actions further demand that we have an agreement, Speaker Nancy Pelosi of California said on Fox News Sunday.

She, along with Senator Chuck Schumer of New York, the minority leader, urged administration officials to resume talks and seek a compromise on a broad relief package.

The presidents executive orders, described in one word, could be paltry; in three words, unworkable, weak and far too narrow, Mr. Schumer said on the ABC program This Week.

Mr. Trumps top economic advisers were on the defensive Sunday about whether the president had the authority to bypass Congress, which retains the constitutional power of the purse, and redirect billions of dollars in spending. But there was some acknowledgment that the measures were not as potent as congressional action would be.

The downside of executive orders is, you cant address some of the small business incidents that are there, said Mark Meadows, the White House chief of staff, in a prerecorded interview that was broadcast Sunday on Gray Television. You cant necessarily get direct payments, because it has to do with appropriations. Thats something that the president doesnt have the ability to do. So, you miss on those two key areas. You miss on money for schools. You miss on any funding for state and local revenue needs that may be out there.

Kansas City, a potential hot spot, needs federal aid to cope, the mayor says.

Like many communities, Kansas City, Mo., has been having a tough time lately, and it will get tougher if Congress and the White House cant reach a deal on more aid, the citys mayor, Quinton Lucas, said on Sunday.

Dr. Deborah Birx, the White House coronavirus coordinator, recently named Kansas City as one of 10 potential coronavirus hot spots around the country because of troubling signs in its testing data. Daily case counts have been declining, but the city is experiencing huge backlogs in testing that are delaying results by as much as two weeks, making them nearly useless in heading off the spread of the disease.

What will it take to address the problem? Money, Mr. Lucas said Sunday on the CBS program Face the Nation. We need more resources to get more testing, to get faster testing through.

Kansas Citys Covid-19 response has already cost the city millions, and without federal aid, a growing budget deficit may soon force officials to start furloughing workers and eliminating jobs.

This isnt just theoretical for us, he said. These are issues that are significant and in the now, and so we are looking for a deal.

Kansas City has delayed the start of its school year until after Labor Day to buy more time to make its schools safe to reopen. But the schools need more money to buy protective equipment and implement social distancing measures, Mr. Lucas said.

He said it was difficult to make the right decisions locally without clear guidance from the federal government: Im a lawyer by training. I talk to doctors and health care professionals here, but these are calls necessarily that sometimes mayors may not be equipped to make, or some governors.

With the number of severely ill patients rising and with remdesivir, the only drug shown to speed recovery, in short supply, an urgent need to quickly increase remdesivir production has arisen. Some U.S. hospitals have been forced to ration the drug, using various systems to decide who should get it.

Now, in a rare agreement between drug companies, Pfizer has entered into an agreement with Gilead Sciences, the maker of remdesivir, to manufacture the drug at a facility in Kansas. It is meant to be part of an effort to quickly increase the drugs supply.

Pfizer will be one of 40 companies in North America, Europe and Asia that will be making the drug. Gilead says it plans to produce more than two million courses of treatment by the end of 2020. It says it also will produce another several million doses of remdesivir in 2021 if they are needed.

Remdesivir is an anti-viral drug that failed as a treatment for hepatitis C but was tested in Covid-19 patients because it seemed effective against the virus in laboratory studies and because its safety had already been determined. It is supplied intravenously.

The evidence of its effectiveness against the new coronavirus comes from a federal study of 1,000 hospitalized patients who received remdesivir or a placebo. Preliminary results were announced on April 27, and on May 1, the Food and Drug Administration gave the drug emergency use authorization, allowing Gilead to sell remdesivir even though it has not yet been approved. The price for a five-day course is $3,120.

Gilead explains the supply problems by saying it is difficult and time consuming to make remdesivir. The company says manufacturing is a long, linear chemical synthesis process that must be completed sequentially and includes several specialized chemistry steps and novel substances with limited global availability.

Your immune system may already recognize the coronavirus.

Eight months ago, the new coronavirus was unknown. But to some human immune cells, it was already something of a familiar foe.

A flurry of recent studies has revealed that a large proportion of the population in some places, 20 to 50 percent of people may harbor immunity assassins called T cells that recognize the new coronavirus despite having never encountered it before.

These T cells, which lurked in the bloodstreams of people long before the pandemic began, are most likely stragglers from past scuffles with other related coronaviruses, including four that frequently cause common colds. Its a case of family resemblance: In the eyes of the immune system, germs with common roots can look alike, such that when a cousin comes to call, the body may already have an inkling of its intentions.

The presence of these T cells has intrigued experts, who say it is too soon to tell whether the cells will play a helpful, harmful or entirely negligible role against the current coronavirus.

Updated August 12, 2020

But should these cross-reactive T cells exert even a modest influence on the bodys immune response, they might make the disease milder and perhaps partly explain why some people who catch the germ become very sick while others are dealt only a glancing blow.

This contact tracer is fighting two contagions: the virus and fear.

Radhika Kumar goes to work every morning hoping to save lives. As a contact tracer for Los Angeles County, her job, at least on paper, entails phoning people who have tested positive for the coronavirus, along with others they may have exposed, and providing them with guidance on how to isolate so as not to infect others.

If that sounds easy, it is not.

To persuade people to cooperate, she has to get them to trust her. She has to convince them that they might be infected, even if they have no symptoms. She has to let people curse at her and hang up, then she has to call them back the next day.

And if she wants them to heed her advice, she has to listen, really listen, to how scared they are that if they stay home from their jobs, they might not be able to feed their families.

Sometimes it can really get to you, she said. The other day I had one young lady, and she was screaming on the phone, You dont understand I have three kids. I have to go to work.

I kept calling back and calling back, Ms. Kumar said. Im very relentless like that. I thought about it all night what am I going to do? I called her again first thing in the morning, and I was so relieved when she picked up.

Even as officials at the Centers for Disease Control and Prevention continue to tout the effectiveness of contact tracing, and state and local health agencies across the United States deploy new armies of tracers, tracking down everyone with the coronavirus is proving to be a Sisyphean task.

France is imposing a new requirement that people wear face masks outdoors in crowded areas of Paris and other major cities beginning on Monday as the number of coronavirus infections rises at the fastest rate since a national quarantine ended in mid-May.

The country had gotten the number of infections under control, but the pandemic is creeping back, with 2,288 new Covid-19 cases reported on Friday the third consecutive day of sharp increase. In the Paris Ile-de-France region, the rate of infections reached 2.4 percent on Friday, compared with a 1.6 percent national average.

The rise of new clusters has led the government to warn of the possibility of a second wave of infections in the autumn. In an effort to stem the spread of the virus, masks will now be mandatory for people age 11 and above in high-traffic areas, from the tourist havens of Saint Tropez and Biarritz to the Seine river in Paris, Montmartre and other popular sites, as well as at outdoor food markets and in Pariss crowded suburbs.

The police will be enforcing the measures which will be in place for at least a month in Paris and are subject to review in other areas with a fine of 135 euros ($159).

The authorities are especially concerned about the popularity of free parties, in which hundreds of young people gather in the Parisien woods and other areas, often without wearing masks.

Wearing a mask in crowded enclosed spaces, including museums, shopping malls and on public transportation, has been compulsory in France since mid-July.

Here is what else is happening around the world:

At least nine people were killed after a fire broke out on Sunday at a hotel in southern India that was being used as a makeshift facility for Covid-19 patients, officials said. The police attributed the accident to a short circuit in an air-conditioner on the ground floor of the Swarna Palace.

New Zealand on Sunday marked 100 days without any new reported cases of local transmission of the coronavirus, a milestone as the pandemic continues to devastate countries across the world. New Zealand, a nation of five million people, reported in March that it had stamped out the virus after strict lockdown measures were implemented. Dr. Ashley Bloomfield, the countrys top health official, said it was a significant milestone but added we cant afford to be complacent.

BUSINESS ROUNDUP

In 2009, when H1N1, better known as swine flu, was stoking fears of a devastating pandemic, a small biotech company named Inovio Pharmaceuticals rushed to create a vaccine. After announcing promising early results, the companys stock soared more than 1,000 percent.

In the years since, Inovio has announced encouraging news about its work on vaccines for malaria, the Zika virus and even a cancer vaccine. The declarations have caused the companys stock price to leap, enriching investors and senior executives.

There is a catch, though: Inovio has never brought a vaccine to market.

Now, Inovio is working on a vaccine for the coronavirus, and a flurry of positive news releases about its funding and preliminary results have helped the company attract money from the U.S. government and investors.

But some scientists and financial analysts question the viability of Inovios technology. While there are some early signs of promise with its vaccine, Inovio has released only bare-bones data from the first phase of clinical trials. It is locked in a legal battle with a key manufacturing partner that claims Inovio stole its technology.

And while the company has said that it is part of Operation Warp Speed the flagship federal effort to quickly produce treatments and vaccines for the coronavirus Inovio is not on the list of companies selected to receive financial support to mass-produce vaccines.

The absence of that funding, coupled with their ongoing litigation, coupled with the need to scale a device, coupled with the absence of complete Phase 1 data, makes people skeptical, said Stephen Willey, an analyst at Stifel, an investment firm.

Inovio could provide an update on its progress with the vaccine when it releases its second-quarter financial results on Monday.

In other business news:

Saudi Aramco, the worlds largest oil company, said on Sunday that its quarterly earnings had plunged more than 73 percent compared with a year ago, as lockdowns imposed to curb the pandemic drastically cut the demand for oil. Despite the steep fall in earnings, to $6.6 billion from $24.7 billion, the company said it would continue paying a quarterly dividend of $18.75 billion nearly all of which will go to the Saudi government.

Meet the people at the big biker rally, undaunted by the virus.

Despite the coronavirus pandemic, tens of thousands of motorcycle enthusiasts converged over the weekend outside the small South Dakota community of Sturgis for the 80th annual Sturgis Motorcycle Rally. Officials said about 250,000 enthusiasts were expected this year about half the number who attended last year, but a figure that would still make the rally one of the countrys largest public gatherings since the first coronavirus cases emerged in the spring.

Many in attendance said they were not concerned about the virus as they walked around without masks.

A New Hampshire poet laureate brightens up her citys Covid-19 advisories.

On Sundays, thousands of residents of Portsmouth, N.H., find a poem nestled inside the citys Covid-19 newsletter.

The poems, written by Tammi J. Truax, the citys poet laureate, help offset the gloom of the pandemic while giving residents a chance to pause briefly and reflect on something other than the coronavirus.

Since the beginning of the pandemic, there have been more than 6,800 cases and at least 419 deaths in New Hampshire, according to a New York Times database, with a recent average of 28 cases per day.

The idea for featuring the poems came from Stephanie Seacord, the public information officer in Portsmouth, a city of about 21,000 residents about 60 miles north of Boston. Ms. Seacord was compiling information about the virus and health updates in a weekly city newsletter sent to about 5,000 email subscribers and circulated on social media.

When the pandemic hit, it became quickly clear that people needed information more than once a week, Ms. Seacord recalled in an interview last week, adding that things were changing almost on a daily basis.

In mid-March, the newsletter turned into a daily advisory of coronavirus cases and tips, like where to find personal protective equipment. Around that time, Ms. Seacord had the idea that including a poem in the Sunday newsletter would be a good calm moment in the middle of the intensity, she said.

If you are feeling ready to go somewhere slightly out of the way, you may be worried about the buses, trains or planes you need to get there. Heres some information to help ease your anxiety and remain safe on mass transit.

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At Least 97,000 Children in the U.S. Tested Positive in Last 2 Weeks of July - The New York Times

A Jazz Drummers Fight to Keep His Own Heart Beating – The New York Times

In the 1960s, Milford Graves became a groundbreaking drummer in avant-garde jazz, but intertwined with his career had been his constant study of musics impact on the human heart.

Now Mr. Graves, a 78-year-old who lives in Jamaica, Queens, has become his own subject: He has amyloid cardiomyopathy, sometimes called stiff heart syndrome.

Doctors have informed him that the condition, also called cardiac amyloidosis, has no cure. When he received the diagnosis in 2018, he was told he had six months to live.

Since then, Mr. Graves said, he has come close to death several times because of fluid filling his lungs. His legs too weakened to walk, he remains in a recliner in his living room with a tube feeding medicine to his heart and another draining fluid from his midsection.

But he has hardly surrendered to the illness. Although he is under the care of a cardiologist, he is also treating himself with the alternative techniques he has spent decades researching.

Since the 1970s, Mr. Graves has studied the heartbeat as a source of rhythm and has maintained that recording musicians most prevalent heart rhythms and pitches, and then incorporating those sounds into their playing, would help them produce more personal music.

He also believes that heart problems can be helped by recording a patients unhealthy heart and musically tweaking it into a healthier rhythm to use as biofeedback.

In recent months, Mr. Graves has been listening constantly to his own heart with a stethoscope and monitoring it with an ultrasound device he bought on eBay.

It turns out, I was studying the heart to prepare for treating myself, he said.

His diagnosis has only invigorated his research, musical explorations and creative output as a visual artist, said Mr. Graves, whose daily fight against the disease has become something of a performance art project.

He said he is rushing to further his research and organize it, so that it can be continued after his death by his students, who are fastidiously documenting and videotaping his daily activity, both for his archives and for an exhibition in September at the Institute of Contemporary Art in Philadelphia.

The shows curator, Mark Christman, visits Mr. Graves and gathers his latest work, from sculptures to customized drums to new videos of Mr. Graves playing.

Mr. Graves has no idea how long he will live It could be three days, it could be a month, or longer but he is adamant that he will be strong enough to play live for the show, perhaps streamed from his recliner.

Where some might see cruel irony in being afflicted by heart disease, which he has studied for 45 years, he sees a challenge.

Its like some higher power saying, OK, buddy, you wanted to study this, here you go, he said. Now the challenge is inside of me.

He wonders if he has somehow internalized the subject of his study.

I ask myself, Why did I get something that, in my research, Ive been trying to rectify? he said. Its a rare disease with very little research on it. The experts say theres nothing to be done, so I have to look inward for answers.

Mr. Graves has long said that a healthy heart beats with flexible, varying rhythms that respond to stimuli from the body. The rhythms, he said, bear similarities to some traditional Nigerian drumming styles, and he has fashioned some of his drumming approaches along these lines.

Because of the abnormal heartbeats caused by his disease, which stiffens the heart muscle and can lead to heart failure, what he hears now in his own heart is the sound of survival, he said.

It sounds less elastic and more plodding than before the diagnosis, he said, with a more metronomic regularity that he has called a rigid, unhealthy quality in a heartbeat.

He is practicing his biofeedback techniques by listening to his heart with a stethoscope and mimicking the rhythm and melody by singing and playing on a drum near his recliner. He also plays recordings of his own hearts sounds on the drumhead with the help of electronic transducers, effectively turning the drumhead into a speaker.

That has helped him come up with drumming techniques, including adjustments in drumhead tensions and new stick styles. Its still drum practice, but with higher stakes.

Mr. Graves has seen a resurgence in popularity in recent years, with exhibitions of his art and research, festival performances and an acclaimed full-length documentary, Milford Graves Full Mantis.

Instead of going into despair, his response was, Ive been asked to look deeper at this, said Jake Meginsky, the films co-director and a longtime assistant of Mr. Graves. Hes surviving this prognosis, and through his creative process hes offering us a record on what that survival is like.

Mr. Graves approach is no surprise to those familiar with his unconventional life path.

He grew up in the South Jamaica housing projects and in the 1960s played with such avant-garde musicians as Cecil Taylor and Albert Ayler, with whom he performed at John Coltranes funeral in 1967. He turned down offers from Miles Davis to join Daviss band.

In more recent years, he has also collaborated with the rocker Lou Reed, the pianist Jason Moran and the avant-garde saxophonist John Zorn.

Mr. Graves became a largely self-taught musician and scientific researcher, delving into herbal medicine, holistic healing, acupuncture, martial arts and other disciplines.

With only a high school diploma and minimal formal medical training, he taught music healing and drumming classes at Bennington College in Vermont for nearly 40 years before retiring in 2012.

He developed a martial-arts style modeled after the movements of the praying mantis and dance traditions from West African styles and the Lindy Hop.

He did pretty much everything on his own, and its very important that his work continue, so he wants to leave everything in the right places with the right people, his wife, Lois, said. He knows he has more work to do and hes going to get it done.

Since 1970, Mr. and Ms. Graves have lived in a home in Queens that he has decorated with a Gaudesque mosaic of stones and colored glass. The Graveses have turned the yard into a lush garden, dense with citrus trees, herbs and exotic plants. He converted a free-standing garage into an ornate temple that was often used as a dojo for martial arts.

But it is the basement where his heart research was mainly conducted. The space is packed with African idols, anatomical models, herbal extracts, African drums and a hodgepodge of heart-monitoring equipment displaying intricate electrocardiogram readouts.

Here, he said, he has treated students, neighbors and colleagues, and since 1990 has recorded perhaps 5,000 heartbeats. Mr. Graves created programs to analyze the hearts rhythms and pitches caused by muscle and valve movement. He found ways to amplify the more obscure patterns and complex melody lines in the vibration frequencies underneath the basic thump-THUMP heartbeat, and use them for both musical and medical analysis.

In 2000, he received a Guggenheim grant to purchase heart-monitoring equipment. And in 2017, he co-patented technology for using heart melodies to regenerate stem cells.

Dr. Baruch Krauss, who teaches pediatrics at Harvard Medical School and is an emergency physician at Boston Childrens Hospital, said Mr. Gravess work has a lot of potential and possibility if it were to be furthered in a clinical setting.

Theres a lot there to be studied and used as a basis for further research, said Dr. Krauss, who follows Mr. Gravess work.

Hes continuously inquisitive and creative and interested, he added, and this condition really hasnt slowed him down.

In his living room on a recent Sunday, one of Mr. Gravess students, Peyton Pleninger, 24, helped him set up a device to play heart sounds and assisted him with making an assemblage for the art show.

I dont want to leave the planet with things undone, Mr. Graves said.

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A Jazz Drummers Fight to Keep His Own Heart Beating - The New York Times

Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia – Science…

Abstract:

Altered olfactory function is a common symptom of COVID-19, but its etiology is unknown. A key question is whether SARS-CoV-2 (CoV-2) the causal agent in COVID-19 affects olfaction directly, by infecting olfactory sensory neurons or their targets in the olfactory bulb, or indirectly, through perturbation of supporting cells. Here we identify cell types in the olfactory epithelium and olfactory bulb that express SARS-CoV-2 cell entry molecules. Bulk sequencing demonstrated that mouse, non-human primate and human olfactory mucosa expresses two key genes involved in CoV-2 entry, ACE2 and TMPRSS2. However, single cell sequencing revealed that ACE2 is expressed in support cells, stem cells, and perivascular cells, rather than in neurons. Immunostaining confirmed these results and revealed pervasive expression of ACE2 protein in dorsally-located olfactory epithelial sustentacular cells and olfactory bulb pericytes in the mouse. These findings suggest that CoV-2 infection of non-neuronal cell types leads to anosmia and related disturbances in odor perception in COVID-19 patients.

SARS-CoV-2 (CoV-2) is a pandemic coronavirus that causes the COVID-19 syndrome, which can include upper respiratory infection (URI) symptoms, severe respiratory distress, acute cardiac injury and death (1-4). CoV-2 is closely related to other coronaviruses, including the causal agents in pandemic SARS and MERS (SARS-CoV and MERS-CoV, respectively) and endemic viruses typically associated with mild URI syndromes (hCoV-OC43, hCoV-HKU1, hCoV-229E and hCoV-NL63) (5-7). Clinical reports suggest that infection with CoV-2 is associated with high rates of disturbances in smell and taste perception, including anosmia (8-13). While many viruses (including coronaviruses) induce transient changes in odor perception due to inflammatory responses, in at least some cases COVID-related anosmia has been reported to occur in the absence of significant nasal inflammation or coryzal symptoms (11, 14-16). Furthermore, recovery from COVID-related anosmia often occurs over weeks (11, 17, 18), while recovery from typical post-viral anosmia which is often caused by direct damage to olfactory sensory neurons (OSNs) frequently takes months (19-21). These observations suggest that CoV-2 might target odor processing through mechanisms distinct from those used by other viruses, although the specific means through which CoV-2 alters odor perception remains unknown.

CoV-2 like SARS-CoV infects cells through interactions between its spike (S) protein and the ACE2 protein on target cells. This interaction requires cleavage of the S protein, likely by the cell surface protease TMPRSS2, although other proteases (such as Cathepsin B and L, CTSB/CTSL) may also be involved (4-6, 22-25). Other coronaviruses use different cell surface receptors and proteases to facilitate cellular entry, including DPP4, FURIN and HSPA5 for MERS-CoV, ANPEP for HCoV-229E, TMPRSS11D for SARS-CoV (in addition to ACE2 and TMPRSS2), and ST6GAL1 and ST3GAL4 for HCoV-OC43 and HCoV-HKU1 (6, 26-28).

We hypothesized that identifying the specific cell types susceptible to direct CoV-2 infection (due to e.g., ACE2 and TMPRSS2 expression) would provide insight into possible mechanisms through which COVID-19 alters smell perception. The nasal epithelium is divided into a respiratory epithelium (RE) and olfactory epithelium (OE), whose functions and cell types differ. The nasal RE is continuous with the epithelium that lines much of the respiratory tract and is thought to humidify air as it enters the nose; main cell types include basal cells, ciliated cells, secretory cells (including goblet cells), and brush/microvillar cells (29, 30) (Fig. 1). The OE, in contrast, is responsible for odor detection, as it houses mature OSNs that interact with odors via receptors localized on their dendritic cilia. OSNs are supported by sustentacular cells, which act to structurally support sensory neurons, phagocytose and/or detoxify potentially damaging agents, and maintain local salt and water balance (31-33); microvillar cells and mucus-secreting Bowmans gland cells also play important roles in maintaining OE homeostasis and function (29, 34) (Fig. 1). In addition, the OE contains globose basal cells (GBCs), which are primarily responsible for regenerating OSNs during normal epithelial turnover, and horizontal basal cells (HBCs), which act as reserve stem cells activated upon tissue damage (35-37). Although studies defining the lineage relationships between GBCs, HBCs and their progeny have necessarily been performed in rodents, basal progenitor populations with similar transcriptional profiles are present in adult human olfactory epithelium, suggesting closely related homeostatic and injury-response mechanisms (37, 38). Odor information is conveyed from the OE to the brain by OSN axons, which puncture the cribriform plate at the base of the skull and terminate in the olfactory bulb (OB). Within the OB local circuits process olfactory information before sending it to higher brain centers (Fig. 1).

Sagittal view of the human nasal cavity, in which respiratory and olfactory epithelia are colored (left). For each type of epithelium, a schematic of the anatomy and known major cell types are shown (right). In the olfactory bulb in the brain (tan) the axons from olfactory sensory neurons coalesce into glomeruli, and mitral/tufted cells innervate these glomeruli and send olfactory projections to downstream olfactory areas. Glomeruli are also innervated by juxtaglomerular cells, a subset of which are dopaminergic.

It has recently been demonstrated through single cell RNA sequencing analysis (referred to herein as scSeq) that cells from the human upper airway including nasal RE goblet and ciliated cells express high levels of ACE2 and TMPRSS2, suggesting that these RE cell types may serve as a viral reservoir during CoV-2 infection (39, 40). However, analyzed samples in these datasets did not include any OSNs or sustentacular cells, indicating that tissue sampling in these experiments did not include the OE (41, 42). Here we query both new and previously published bulk RNA-Seq and scSeq datasets from the olfactory system for expression of ACE2, TMRPSS2 and other genes implicated in coronavirus entry. We find that non-neuronal cells in the OE and olfactory bulb, including support, stem and perivascular cells, express CoV-2 entry-associated transcripts and their associated proteins, suggesting that infection of these non-neuronal cell types contributes to anosmia in COVID-19 patients.

To determine whether genes relevant to CoV-2 entry are expressed in OSNs or other cell types in the human OE, we queried previously published bulk RNA-Seq data derived from the whole olfactory mucosa (WOM) of macaque, marmoset and human (43), and found expression of almost all CoV-entry-related genes in all WOM samples (Figure S1A). To identify the specific cell types in human OE that express ACE2, we quantified gene expression in scSeq derived from four human nasal biopsy samples recently reported by Durante et al. (38). Neither ACE2 nor TMPRSS2 were detected in mature OSNs, whereas these genes were detected in both sustentacular cells and HBCs (Fig. 2A-D and S1B-E). In contrast, genes relevant to cell entry of other CoVs were expressed in OSNs, as well as in other OE cell types. We confirmed the expression of ACE2 proteins via immunostaining of human olfactory epithelium biopsy tissue, which revealed expression in sustentacular and basal cells, and an absence of ACE2 protein in OSNs (Figs. 2E and S2). Together, these results demonstrate that sustentacular and olfactory stem cells, but not mature OSNs, are potentially direct targets of CoV-2 in the human OE.

Coronavirus cell entry-related genes are expressed in human respiratory and olfactory epithelium but are not detected in human OSNs. (A) UMAP representation of cell types in human nasal biopsy scSeq data from Durante et al. 2020 (38). Each dot represents an individual cell, colored by cell type (HBC = horizontal basal cell, OSN = olfactory sensory neuron, SUS = sustentacular cell, MV: microvillar cell, Resp.: respiratory, OEC = olfactory ensheathing cell, SMC=smooth muscle cell). (B) UMAP representations of 865 detected immature (GNG8) and mature (GNG13) OSNs. Neither ACE2 nor TMPRSS2 are detected in either population of OSNs. The color represents the normalized expression level for each gene (number of UMIs for a given gene divided by the total number of UMIs for each cell). (C) UMAP representations of all cells, depicting the normalized expression of CoV-2 related genes ACE2 and TMPRSS2, as well as several cell type markers. ACE2 and TMPRSS2 are expressed in respiratory and olfactory cell types, but not in OSNs. ACE2 and TMPRSS2 are detected in HBC (KRT5) and sustentacular (CYP2A13) cells, as well as other respiratory epithelial cell types, including respiratory ciliated (FOXJ1) cells. (D) Percent of cells expressing ACE2 and TMPRSS2. ACE2 was not detected in any OSNs, but was observed in sustentacular cells and HBCs, among other olfactory and respiratory epithelial cell types. Olfactory and respiratory cell types are shown separately. ACE2 and TMPRSS2 were also significantly co-expressed (Odds ratio 7.088, p-value 3.74E-57, Fishers exact test). (E) ACE2 immunostaining of human olfactory mucosal biopsy samples (taken from a 28-year old female). ACE2 protein (green) is detected in sustentacular cells and KRT5-positive HBCs (red; white arrowhead). Nuclei were stained with DAPI (blue). Bar = 25 m. The ACE2 and KRT5 channels from the box on the left are shown individually on the right.

Given that the nasopharynx is a major site of infection for CoV-2 (10), we compared the frequency of ACE2 and TMPRSS2 expression among the cell types in the human RE and OE (38). Sustentacular cells exhibited the highest frequency of ACE2 expression in the OE (2.9% of cells) although this frequency was slightly lower than that observed in respiratory ciliated and secretory cells (3.6% and 3.9%, respectively). While all HBC subtypes expressed ACE2, the frequency of expression of ACE2 was lower in olfactory HBCs (0.8% of cells) compared to respiratory HBCs (1.7% of cells) (Fig. 2D). In addition, all other RE cell subtypes showed higher frequencies of ACE2 and TMPRSS2 expression than was apparent in OE cells.

These results demonstrate the presence of key CoV-2 entry-related genes in specific cell types in the OE, but at lower levels of expression than in RE isolated from the human nasal mucosa. We wondered whether these lower levels of expression might nonetheless be sufficient for infection by CoV-2. It was recently reported that the nasal RE has higher expression of CoV-2 entry genes than the RE that lines the trachea or lungs (44), and we therefore asked where the OE fell within this previously established spectrum of expression. To address this question, we developed a two step alignment procedure in which we first sought to identify cell types that were common across the OE and RE, and then leveraged gene expression patterns in these common cell types to normalize gene expression levels across all cell types in the OE and RE (Figs. 3 and S3). This approach revealed a correspondences between submucosal gland goblet cells in the RE and Bowmans gland cells in the OE (96% mapping probability, see Methods), and between pulmonary ionocytes in the RE and a subset of microvillar cells in the OE (99% mapping probability, see Methods and Figure S3); after alignment, human OE sustentacular cells were found to express ACE2 and TMPRSS2 at levels similar to those observed in the remainder of the non-nasal respiratory tract (44) (Fig. 3C). As CoV-2 can infect cells in the lower respiratory tract (40, 45), these results are consistent with the possibility that specific cell types in the human olfactory epithelium express ACE2 at a level that is permissive for direct infection.

Coronavirus cell entry-related genes are expressed at comparable levels across respiratory and olfactory epithelial datasets. (A) Schematic of the mapping strategy used to identify similar cell types across datasets, applied to a toy example. Each cell type from Dataset 1 dataset is mapped to cell types from the Dataset 2. From left to right: Each Dataset 1 cell voted on its 5 most similar cells in Dataset 2; the total number of votes cast for each Dataset 2 cell type was quantified; and vote totals were Z-scored against 1000 shuffles where cell type labels were permutated. (B) Mapping was performed bi-directionally between the Deprez et al. (41) and Durante et al. (38) datasets, and the mapping Z-scores in each direction are compared. The set of cell type correspondences with high Z-scores (>25) in both directions are colored red (top). The set of cell type correspondences with high bi-directional mappings shown in red in top panel are highlighted in yellow (bottom). (C) Gene expression across cell types and tissues in Durante et al. (top) and Deprez et al. (bottom). Each gene is normalized to its maximum value across all tissues. Gene expression from Durante et al. was normalized to that in Deprez et al. to enable comparisons (see Methods and Figure S3). The tissues correspond to the indicated positions along the airway from nasal to distal lung. ACE2 expression in olfactory HBC and sustentacular cells is comparable to that observed in other cell types in the lower respiratory tract.

To further explore the distribution of CoV-2 cell entry genes in the olfactory system we turned to the mouse, which enables interrogative experiments not possible in humans. To evaluate whether mouse expression patterns correspond to those observed in the human OE, we examined published datasets in which RNA-Seq was independently performed on mouse WOM and on purified populations of mature OSNs (46-48). The CoV-2 receptor Ace2 and the protease Tmprss2 were expressed in WOM, as were the cathepsins Ctsb and Ctsl (Figs. 4A and S4A) (46). However, expression of these genes (with the exception of Ctsb) was much lower and Ace2 expression was nearly absent in purified OSN samples (Figs. 4A and S4A, see Legend for counts). Genes used for cell entry by other CoVs (except St3gal4) were also expressed in WOM, and de-enriched in purified OSNs. The de-enrichment of Ace2 and Tmprss2 in OSNs relative to WOM was also observed in two other mouse RNA-Seq datasets (47, 48) (Figure S4B). These data demonstrate that, as in humans, Ace2 and other CoV-2 entry-related genes are expressed in the mouse olfactory epithelium.

ACE2 is expressed in the mouse nasal epithelium but not in mature OSNs. (A) Log2-fold change (FC) in mean across-replicate gene expression between olfactory sensory neurons (OSNs) and whole olfactory mucosa (WOM) for coronavirus (CoV)-related genes and cell type markers (HBC = horizontal basal cells, SUS = sustentacular cells), data from Saraiva et al. (46). (B) UMAP representation of scSeq data from the WOM, colored by cell types (mOSN: mature OSN, iOSN: immature OSN, INP: immediate neural precursor, GBC: globose basal cell, MV: microvillar cell, Resp.: respiratory). (C) Percent of cells expressing Ace2 and Tmprss2 in olfactory and respiratory cell types in the WOM (Drop-seq) dataset. Detection was considered positive if any transcripts (UMIs) were expressed for a given gene. Sustentacular cells (SUS) from dorsal and ventral zones are quantified separately. Ace2 is detected in dorsal sustentacular, Bowmans gland, HBCs, as well as respiratory cell types. (D) UMAP representation of sustentacular cells, with expression of CoV-2 related genes Ace2 and Tmprss2, as well as marker genes for SUS (both pan-SUS marker Cbr2 and dorsal specific marker Sult1c1) indicated. The color represents the normalized expression level for each gene (number of UMIs for a given gene divided by the total number of UMIs for each cell; in this plot Ace2 expression is binarized for visualization purposes). Ace2-positive sustentacular cells are found within the dorsal Sult1c1-positive subset. UMAP plots for other cell types are shown in Figure S4.

The presence of Ace2 and Tmprss2 transcripts in mouse WOM and their (near total) absence in purified OSNs suggest that the molecular components that enable CoV-2 entry into cells are expressed in non-neuronal cell types in the mouse nasal epithelium. To identify the specific cell types that express Ace2 and Tmprss2, we performed scSeq (via Drop-seq, see Methods) on mouse WOM (Fig. 4B). These results were consistent with observations made in the human epithelium: Ace2 and Tmprss2 were expressed in a fraction of sustentacular and Bowmans gland cells, and a very small fraction of stem cells, but not in OSNs (zero of 17,666 identified mature OSNs, Figs. 4C and S4C-D). Of note, only dorsally-located sustentacular cells, which express the markers Sult1c1 and Acsm4, were positive for Ace2 (Figs. 4D and S4D-E). Indeed, reanalysis of the ACE2-positive subset of human sustentacular cells revealed that all positive cells expressed genetic markers associated with the dorsal epithelium (Figure S1D). An independent mouse scSeq data set (obtained using the 10x Chromium platform, see Methods) confirmed that olfactory sensory neurons did not express Ace2 (2 of 28,769 mature OSNs were positive for Ace2), while expression was observed in a fraction of Bowmans gland cells and HBCs (Figure S5, see Methods). Expression in sustentacular cells was not observed in this dataset, which included relatively few dorsal sustentacular cells (a possible consequence of the specific cell isolation procedure associated with the 10x platform; compare Figures S5C and 4D).

Staining of the mouse WOM with anti-ACE2 antibodies confirmed that ACE2 protein is expressed in sustentacular cells and is specifically localized to the sustentacular cell microvilli (Fig. 5). ACE2-positive sustentacular cells were identified exclusively within the dorsal subregion of the OE; critically, within that region many (and possibly all) sustentacular cells expressed ACE2 (Fig. 5B-E). Staining was also observed in Bowmans gland cells but not in OSNs, and in subsets of RE cells (Fig. 5F-G). Taken together, these data demonstrate that ACE2 is expressed by sustentacular cells that specifically reside in the dorsal epithelium in both mouse and human.

ACE2 protein is detected in the mouse olfactory and respiratory epithelium. (A) ACE2 immunostaining of mouse main olfactory epithelium. As shown in this coronal section, ACE2 protein is detected in the dorsal zone and respiratory epithelium. The punctate Ace2 staining beneath the epithelial layer is likely associated with vasculature. Bar = 500 m. Arrowheads depict the edges of ACE2 expression, corresponding to the presumptive dorsal zone (confirmed in G). Dashed boxes indicate the areas shown in B and G (left). (B) ACE2 protein is detected in the dorsal zone of the olfactory epithelium. Bar = 50 m. (C) Dorsal zone-specific expression of ACE2 in the olfactory epithelium was confirmed by co-staining with NQO1, a protein expressed in dorsal-zone OSNs. Bar = 50 m. (D) ACE2 signal in dorsal olfactory epithelium does not overlap with the cilia of olfactory sensory neurons, as visualized by CNGA2. Bar = 50 m. (E) High magnification image of the apical end of the olfactory epithelium reveals that ACE2 signal is localized at the tip of villi of sustentacular cells, visualized by Phalloidin (F-Actin), but does not overlap with cilia of olfactory sensory neurons, as visualized by Acetylated Tubulin (Ac. Tubulin). Bar = 10 m. (F) Bowmans glands, which span from the lamina propria to the apical surface (arrowheads), were positive for ACE2 staining. Bar = 50 m. (G) ACE2 expression in the respiratory epithelium was confirmed by co-staining with TUBB4. Bar = 50 m.

Viral injury can lead to broad changes in OE physiology that are accompanied by recruitment of stem cell populations tasked with regenerating the epithelium (35, 37, 49). To characterize the distribution of Ace2 expression under similar circumstances, we injured the OE by treating mice with methimazole (which ablates both support cells and OSNs), and then employed a previously established lineage tracing protocol to perform scSeq on HBCs and their descendants during subsequent regeneration (see Methods) (36). This analysis revealed that after injury Ace2 and Tmprss2 are expressed in subsets of sustentacular cells and HBCs, as well as in the activated HBCs that serve to regenerate the epithelium (Figs. 6A-C and S6A; note that activated HBCs express Ace2 at higher levels than resting HBCs). Analysis of the Ace2-positive sustentacular cell population revealed expression of dorsal epithelial markers (Fig. 6D). To validate these results, we re-analyzed a similar lineage tracing dataset in which identified HBCs and their progeny were subject to Smart-seq2-based deep sequencing, which is more sensitive than droplet-based scSeq methods (36). In this dataset, Ace2 was detected in more than 0.7% of GBCs, nearly 2% of activated HBCs and nearly 3% of sustentacular cells but was not detected in OSNs (Figures S6B). Immunostaining with anti-ACE2 antibodies confirmed that ACE2 protein was present in activated stem cells under these regeneration conditions (Fig. 6E). These results demonstrate that activated stem cells recruited during injury express ACE2 and do so at higher levels than those in resting stem cells.

ACE2 is expressed in the mouse nasal epithelium in an injury model. (A) UMAP representation of data from an scSeq HBC lineage dataset, which includes several timepoints after epithelial injury induced by methimazole (mOSN: mature OSN, iOSN: immature OSN, INP: immediate neural precursor, SUS: sustentacular cell, GBC: globose basal cell, HBC: horizontal basal cell, HBC*: activated or cycling HBCs. MV: microvillar cell, Resp.: respiratory). (B) UMAP representation of CoV-2 related genes Ace2 and Tmprss2, as well as marker genes for the HBC-derived cell types. The color represents normalized expression (number of UMIs for a given gene divided by the total number of UMIs for each cell). (C) Percent of cells expressing Ace2 and Tmprss2. Ace2 is detected in sustentacular cells, HBC, activated/cycling HBC and respiratory cells. (D) UMAP representation of all sustentacular cells, indicating the normalized expression of CoV-2 related genes Ace2 and Tmprss2, as well as sustentacular (Ermn) cell markers. Ace2-positive sustentacular cells are largely a subset of dorsal SUS cells, as identified via the expression of Sult1c1. Sult1c1-positive sustentacular cells have higher levels of Ace2 (p=1.87E-03, Mann-Whitney test) and Ace2-positive sustentacular cells have higher levels of Sult1c1 (p=8.06E-07, Mann-Whitney test). (E) ACE2 immunostaining of mouse nasal epithelium after methimazole treatment, together with cycling cell marker Ki67 and HBC marker KRT5. At 48 hours after treatment, ACE2 signal is detected in Ki67+/KRT5+ activated HBCs (top). At 96 hours after treatment, ACE2 signal is observed at the apical surface of Ki67+ cells (bottom). Some ACE2-positive cells express low levels of the HBC marker KRT5 and have immunostaining patterns similar to that of dorsal sustentacular cells, suggesting that they are sustentacular cells in the process of differentiating from their HBC precursors. Bar = 25 m.

Given the potential for the RE and OE in the nasal cavity to be directly infected with CoV-2, we assessed the expression of Ace2 and other CoV entry genes in the mouse olfactory bulb (OB), which is directly connected to OSNs via cranial nerve I (CN I); in principle, alterations in OB function could cause anosmia independently of functional changes in the OE. To do so, we performed scSeq (using Drop-seq, see Methods) on the mouse OB, and merged these data with a previously published OB scSeq analysis, yielding a dataset with nearly 50,000 single cells (50) (see Methods). This analysis revealed that Ace2 expression was absent from OB neurons and instead was observed only in vascular cells, predominantly in pericytes, which are involved in blood pressure regulation, maintenance of the blood-brain barrier, and inflammatory responses (51) (Figs. 7A-D and S7-8). Although other potential CoV proteases were expressed in the OB, Tmprss2 was not expressed.

Expression of coronavirus entry genes in mouse olfactory bulb. (A) UMAP visualization of OB scSeq highlighting the main cell classes and subtypes from two integrated scSeq datasets (see Methods). VIP, vasoactive intestinal peptide-expressing neurons; ETCs, external tufted cells; OPCs, oligodendrocyte precursor cells; IPCs, intermediate precursor cells; OECs, olfactory ensheathing cells. Cluster information is summarized in Figures S7-8. (B) UMAP representation of the vascular cell cluster showing expression of CoV-2 entry genes (Ace2 and Tmprss2) and Kcnj8, a pericyte marker. Color scale depicts log-normalized UMI counts. (C) Normalized gene expression of coronavirus entry genes and cell class markers in mouse olfactory bulb. Color scale shows scaled mean expression level per cell type, normalized by their maximum expression across cell types. Ace2 is specifically expressed in vascular cells. (D) Percent of cells expressing Ace2. Other vascular denotes all vascular cells excluding pericytes. Ace2 expression was only detected in vascular cell types. (E) Log2-normalized expression (Log2(TPM+1)) of coronavirus entry genes and dopaminergic neuron markers in manually sorted and deeply-sequenced single olfactory bulb dopaminergic neurons. (F) ACE2 immunostaining of the mouse main olfactory bulb. Left, section of olfactory bulb containing the glomerular layer (with example glomeruli circled), mitral cell layer (MCL) and granule cell layer (GCL). ACE2 protein is present in vascular mural cells but not in OB neurons or OSN axons. Boxes i and ii indicate the locations of enlarged images. Bar = 100 m. (i) enlarged image of glomerular layer (middle). ACE2 protein staining was restricted to vascular cells. Bar = 50 m. (ii) enlarged image of MCL (dashed line) and GCL showing the lack of ACE2 (right). Bar = 50 m. (G) An olfactory bulb section showing ACE2 protein is detected in PDGFRB-positive mural cells, including smooth muscle cells (SMC) and pericytes. Bar = 25 m.

We also performed Smart-seq2-based deep sequencing of single OB dopaminergic juxtaglomerular neurons, a population of local interneurons in the OB glomerular layer that (like tufted cells) can receive direct monosynaptic input from nasal OSNs (Figs. 7E and S9, see Methods); these experiments confirmed the virtual absence of Ace2 and Tmprss2 expression in this cell type. Immunostaining in the OB revealed that blood vessels expressed high levels of ACE2 protein, particularly in pericytes; indeed nearly all pericytes exhibited some degree of staining with ACE2 antibodies. Consistent with the scSeq results, staining was not observed in any neuronal cell type (Fig. 7F-G). These observations may also hold true for at least some other brain regions, as re-analysis of 10 deeply sequenced SMART-Seq2-based scSeq datasets from different regions of the nervous system demonstrated that Ace2 and Tmprss2 expression is almost completely absent from neurons, consistent with prior immunostaining results (52, 53) (Figure S10). Given the extensive similarities detailed above in expression patterns for ACE2 and TMPRSS2 in the mouse and human, these findings (from mouse experiments) suggest that OB neurons are likely not a primary site of infection, but that vascular pericytes may be sensitive to CoV-2

Here we show that subsets of OE sustentacular cells, HBCs, and Bowmans gland cells in both mouse and human samples express the CoV-2 receptor ACE2 and the spike protein protease TMPRSS2. Human OE sustentacular cells express these genes at levels comparable to those observed in lung cells. In contrast, we failed to detect ACE2 expression in mature OSNs at either the transcript or protein levels. Similarly, mouse vascular pericytes in the OB express ACE2, while we did not detect ACE2 in OB neurons. Thus primary infection of non-neuronal cell types rather than sensory or bulb neurons may be responsible for anosmia and related disturbances in odor perception in COVID-19 patients.

The identification of non-neuronal cell types in the OE and OB susceptible to CoV-2 infection suggests four possible, non-mutually-exclusive mechanisms for the acute loss of smell reported in COVID-19 patients. First, local infection of support and vascular cells in the nose and bulb could cause significant inflammatory responses (including cytokine release) whose downstream effects could block effective odor conduction, or alter the function of OSNs or OB neurons (14, 54). Second, damage to support cells (which are responsible for local water and ion balance) could indirectly influence signaling from OSNs to the brain (55). Third, damage to sustentacular cells and Bowmans gland cells in mouse models can lead to OSN death, which in turn could abrogate smell perception (56). Finally, vascular damage could lead to hypoperfusion and inflammation leading to changes in OB function.

Although scSeq revealed ACE2 transcripts in only a subset of OE cells, this low level of observed expression matches or exceeds that observed in respiratory cells types that are infected by CoV-2 in COVID-19 patients (39) (Fig. 3). Critically, immunostaining in the mouse suggests that ACE2 protein is (nearly) ubiquitously expressed in sustentacular cells in the dorsal OE, despite sparse detection of Ace2 transcripts using scSeq. Similarly, nearly all vascular pericytes also expressed ACE2 protein, although only a fraction of OB pericytes were positive for Ace2 transcripts when assessed using scSeq. Although Ace2 transcripts were more rarely detected than protein, there was a clear concordance at the cell type level: expression of Ace2 mRNA in a particular cell type accurately predicted the presence of ACE2 protein, while Ace2 transcript-negative cell types (including OSNs) did not express ACE2 protein. These observations are consistent with recent findings in the respiratory epithelium suggesting that scSeq substantially underestimates the fraction of a given cell type that expresses the Ace2 transcript, but that new Ace2-expressing cell types are not discovered with more sensitive forms of analysis (40). If our findings in the mouse OE translate to the human (a reasonable possibility given the precise match in olfactory cell types that express CoV-2 cell entry genes between the two species), then ACE2 protein is likely to be expressed in a significant subset of human sustentacular cells. Thus, there may be many olfactory support cells available for CoV-2 infection in the human epithelium, which in turn could recruit a diffuse inflammatory process. However, it remains possible that damage to the OE could be caused by more limited cell infection. For example, infection of subsets of sustentacular cells by the SDAV coronavirus in rats ultimately leads to disruption of the global architecture of the OE, suggesting that focal coronavirus infection may be sufficient to cause diffuse epithelial damage (56).

We observe that activated HBCs, which are recruited after injury, express Ace2 at higher levels than those apparent in resting stem cells. The natural history of CoV2-induced anosmia is only now being defined; while recovery of smell on timescales of weeks in many patients has been reported, it remains unclear whether in a subset of patients smell disturbances will be long-lasting or permanent (8-12, 57). While on its own it is unlikely that infection of stem cells would cause acute smell deficits, the capacity of CoV-2 to infect stem cells may play an important role in those cases in which COVID-19-associated anosmia is persistent, a context in which infection of stem cells could inhibit OE regeneration and repair over time.

Two anosmic COVID-19 patients have presented with fMRI-identified hyperintensity in both OBs that reverted to normal after resolution of the anosmia (58, 59), consistent with central involvement in at least some cases. Many viruses, including coronaviruses, have been shown to propagate from the nasal epithelium past the cribriform plate to infect the OB; this form of central infection has been suggested to mediate olfactory deficits, even in the absence of lasting OE damage (60-65). The rodent coronavirus MHV passes from the nose to the bulb, even though rodent OSNs do not express Ceacam1, the main MHV receptor (61, 66) (Figures S4C, S5E, S6A), suggesting that CoVs in the nasal mucosa can reach the brain through mechanisms independent of axonal transport by sensory nerves; interestingly, OB dopaminergic juxtaglomerular cells express Ceacam1 (Fig. 7E), which likely supports the ability of MHV to target the bulb and change odor perception. Although SARS-CoV has been shown to infect the OB in a transgenic mouse model that ectopically expresses human ACE2 (65), it is unclear to what extent similar results will be observed for CoV-2 in these and in recently-developed mouse models expressing human ACE2 that better recapitulate native expression patterns (67-69). One speculative possibility is that local seeding of the OE with CoV-2-infected cells can result in OSN-independent transfer of virions from the nose to the bulb, perhaps via the vascular supply shared between the OB and the OSN axons that comprise CN I. Although CN I was not directly queried in our datasets, it is reasonable to infer that vascular pericytes in CN I also express ACE2, which suggests a possible route of entry for CoV-2 from the nose into the brain. Given the absence of ACE2 in mouse OB neurons and the near-ubiquity of ACE2 expression in OB pericytes we speculate that any central olfactory dysfunction in COVID-19 is the secondary consequence of inflammation arising locally from pericytes, or in response to diffusable factors arising from more distant sources (51).

Multiple immunostaining studies reveal that ACE2 protein in the human brain is predominantly or exclusively expressed in vasculature (and specifically expressed within pericytes) (52, 53, 70), and many neurological symptoms associated with CoV-2 infection like stroke or altered consciousness are consistent with an underlying vasculopathy (71-76). In addition, human CSF samples have failed thus far to reveal CoV-2 RNA (73, 77), and autopsies from human patients have found that the brain contains the lowest levels of CoV-2 across organs sampled (78). On the other hand, multiple other studies have suggested that ACE2 may be expressed in human neurons and glia (79-82). Additionally, two recent studies in mouse models expressing human ACE2 have found CoV-2 in the brain after intranasal inoculation (67, 68), although neither specifically queried the OB; this work stands in contrast to results in a non-human primate model of COVID-19, in which nasal infection did not lead to the presence of identifiable CoV-2 antigens in the brain (83). Further work will be required to resolve these inconsistencies, and to definitively characterize the distribution of ACE2 protein and ultimately CoV2-infected cells in the human OB and brain.

We note several caveats that temper our conclusions. Although current data suggest that ACE2 is the most likely receptor for CoV-2 in vivo, it is possible (although it has not yet been demonstrated) that other molecules such as BSG may enable CoV-2 entry independently of ACE2 (84, 85) (Figures S1E, S4C, S5E, S6A). In addition, it has recently been reported that low level expression of ACE2 can support CoV-2 cell entry (86); it is possible, therefore, that ACE2 expression beneath the level of detection in our assays may yet enable CoV-2 infection of apparently ACE2 negative cell types. We also propose that damage to the olfactory system is either due to primary infection or secondary inflammation; it is possible (although has not yet been demonstrated) that cells infected with CoV-2 can form syncytia with cells that do not express ACE2. Such a mechanism could damage neurons adjacent to infected cells. Finally, it has recently been reported that inflammation can induce expression of ACE2 in human cells (87, 88). It is therefore possible that our survey of ACE2 expression, and other recent reports demonstrating expression of ACE2 in OE support and stem cells but not neurons (81, 89, 90), might under-represent the cell types that express ACE2 under conditions of CoV-2 infection.

Any reasonable pathophysiological mechanism for COVID-19-associated anosmia must account for the high penetrance of smell disorders relative to endemic viruses (12, 91, 92), the apparent suddenness of smell loss that can precede the development of other symptoms (11, 13), and the transient nature of dysfunction in many patients (11, 17, 18); definitive identification of the disease mechanisms underlying COVID-19-mediated anosmia will require additional research. Nonetheless, our identification of cells in the OE and OB expressing molecules known to be involved in CoV-2 entry illuminates a path forward for future studies.

Human scSeq data from Durante et al. (38) was downloaded from the GEO at accession GSE139522. 10x Genomics mtx files were filtered to remove any cells with fewer than 500 total counts. Additional preprocessing was performed as described above, including total counts normalization and filtering for highly variable genes using the SPRING gene filtering function filter_genes with parameters (90, 3, 10). The resulting data were visualized in SPRING and partitioned using Louvain clustering on the SPRING k-nearest-neighbor graph. Four clusters were removed for quality control, including two with low total counts (likely background) and two with high mitochondrial counts (likely stressed or dying cells). Putative doublets were also identified using Scrublet and removed (7% of cells). The remaining cells were projected to 40 dimensions using PCA. PCA-batch-correction was performed using Patient 4 as a reference, as previously described (93). The filtered data were then re-partitioned using Louvain clustering on the SPRING graph and each cluster was annotated using known marker genes, as described in (38). For example, immature and mature OSNs were identified via their expression of GNG8 and GNG13, respectively. HBCs were identified via the expression of KRT5 and TP63 and olfactory HBCs were distinguished from respiratory HBCs via the expression of CXCL14 and MEG3. Identification of SUS cells (CYP2A13, CYP2J2), Bowmans gland (SOX9, GPX3), and MV ionocytes-like cells (ASCL3, CFTR, FOXI1) was also performed using known marker genes. For visualization, the top 40 principal components were reduced to two dimensions using UMAP with parameters (n_neighbors=15, min_dist=0.4).

The filtered human scSeq dataset contained 33358 cells. Each of the samples contained cells from both the olfactory and respiratory epithelium, although the frequency of OSNs and respiratory cells varied across patients, as previously described (38). 295 cells expressed ACE2 and 4953 cells expressed TMPRSS2. Of the 865 identified OSNs, including both immature and mature cells, none of the cells express ACE2 and only 2 (0.23%) expressed TMPRSS2. In contrast, ACE2 was reliably detected in at least 2% and TMPRSS2 was expressed in close to 50% of multiple respiratory epithelial subtypes. The expression of both known cell type markers and known CoV-related genes was also examined across respiratory and olfactory epithelial cell types. For these gene sets, the mean expression in each cell type was calculated and normalized by the maximum across cell types.

Data from Deprez et al. (41) were downloaded from the Human Cell Atlas website (https://www.genomique.eu/cellbrowser/HCA/; Single-cell atlas of the airway epithelium (Grch38 human genome)). A subset of these data was combined with a subset of the Durante data for mapping between cell types. For the Deprez data, the subset consisted of samples from the nasal RE that belonged to a cell type with >20 cells, including Basal, Cycling Basal, Suprabasal, Secretory, Mucous Multiciliated cells, Multiciliated, SMS Goblet and Ionocyte. We observed two distinct subpopulations of Basal cells, with one of the two populations distinguished by expression of Cxcl14. The cells in this population were manually identified using SPRING and defined for downstream analysis as a separate cell type annotation called Basal (Cxcl14+). For the Durante data, the subset consisted of cells from cell types that had some putative similarity to cells in the Deprez dataset, including Olfactory HBC, Cycling respiratory HBC, Respiratory HBC, Early respiratory secretory cells, Respiratory secretory cells, Sustentacular cells, Bowmans gland, Olfactory microvillar cells.

To establish a cell type mapping:

1) Durante et al. (38) and Deprez et al. (41) data were combined and gene expression values were linearly scaled so that all cells across datasets had the same total counts. PCA was then performed using highly variable genes (n=1477 genes) and PCA-batch-correction (93) with the Durante et al. data as a reference set.

2) Mapping was then performed bidirectionally between the two datasets. Each cell from Dataset 1 voted for the 5 most similar cells in the Dataset 2, using distance in PCA space as the measure of similarity. A table T counting votes across cell types was then computed, where for cell type i in the Dataset 1 and cell type j in the Dataset 2,

Tij = {number of votes cast from cells of type i to cells of type j}Thus, if Dataset 1 has N cells, then T would count 5*N votes (Tij=5N)

3) The table of votes T was Z-scored against a null distribution, generated by repeating the procedure above 1000 times with shuffled cell type labels.

The resulting Z-scores were similar between the two possible mapping directions (Durante -> Deprez vs. Deprez -> Durante; R=0.87 Pearson correlation of mapping Z-scores). The mapping Z-scores were also highly robust upon varying the number of votes-cast per cell (R>0.98 correlation of mapping Z-scores upon changing the vote numbers to 1 or 50 as opposed to 5). Only cell-type correspondences with a high Z-score in both mapping directions (Z-score > 25) were used for downstream analysis.

To establish a common scale of gene expression between datasets, we restricted to cell type correspondences that were supported both by bioinformatic mapping and shared a nominal cell type designation based on marker genes. These included: Basal/suprabasal cells = respiratory HBCs from Durante et al., and basal and suprabasal cells from Deprez et al. Secretory cells = rly respiratory secretory cells and respiratory secretory cells from Durante et al., and secretory cells from Deprez et al. Multiciliated cells = respiratory ciliated cells from Durante et al., and multiciliated cells from Deprez et al.

We next sought a transformation of the Durante et al. data so that it would agree with the Deprez et al. data within the corresponding cell types identified above To account for differing normalization strategies applied to each dataset prior to download (log normalization and rescaling with cell-specific factors for Deprez et al. but not for Durante et al.), we used the following ansatz for the transformation, where the pseudocount p is a global latent parameter and the rescaling factors fi are fit to each gene separately. In the equation below, T denotes the transformation and eij represents a gene expression value for cell i and gene j in the Durante data:

The parameter p was fit by maximizing the correlation of average gene expression across all genes between each of the cell type correspondences listed above. The rescaling factors fi. were then fitted separately for each gene by taking the quotient of average gene expression between the Deprez et al. data and the log-transformed Durante et al. data, again across the cell type correspondences above.

Normalized gene expression tables were obtained from previous published datasets (43, 46-48) (Table 1). For the mouse data sets, the means of the replicates from WOM or OSN were used to calculate Log2 fold changes. For the mouse data from Saraiva et al. and the primate data sets (43, 46), the normalized counts of the genes of interest from individual replicates were plotted.

Three different mouse bulk RNA-seq datasets were used, each with replicates from WOM or purified OSNs. An additional dataset contained bulk RNA-seq data from humans and non-human primates.

Tissue dissection and single-cell dissociation for nasal epithelium. A new dataset of whole olfactory mucosa scSeq was generated from adult male mice (812 weeks-old). All mouse husbandry and experiments were performed following institutional and federal guidelines and approved by Harvard Medical Schools Institutional Animal Care and Use Committee (IACUC). Briefly, dissected main olfactory epithelium were cleaned up in 750 l of EBSS (Worthington) and epithelium tissues were isolated in 750 L of Papain (20 U/mL in EBSS) and 50 L of DNase I (2000 U/mL). Tissue pieces were transferred to a 5 mL round-bottom tube (BD) and 1.75 mL of Papain and 450 L of DNase I were added. After 11.5 hour incubation with rocking at 37C, the suspension was triturated with a 5 mL pipette 15 times and passed through 40 m cell strainer (BD) and strainer was washed with 1 mL of DMEM + 10% FBS (Invitrogen). The cell suspension was centrifuged at 300 g for 5 min. Cells were resuspended with 4 mL of DMEM + 10% FBS and centrifuged at 300 g for 5 min. Cells were suspended with PBS + 0.01% BSA and concentration was measured by hemocytometer.

Drop-seq experiments. Drop-seq experiments were performed as previously described (94). Microfluidics devices were obtained from FlowJEM and barcode beads were obtained from chemgenes. 8 of 15 min Drop-seq runs were collected in total, which were obtained from 5 mice.

Sequencing of Drop-seq samples. 8 replicates of Drop-seq samples were sequenced across 5 runs on an Illumina NextSeq 500 platform. Paired end reads from the fastq files were trimmed, aligned, and tagged via the Drop-seq tools (v1.13) pipeline, using STAR (v2.5.4a) with genomic indices from Ensembl Release 93. The digital gene expression matrix was generated for 4,000 cells for 0126_2, 5,000 cells for 0105, 0126_1, 051916_DS11, 051916_DS12, 051916_DS22, 5,500 cells for 051916_DS21, and 9,500 cells for 0106.

Preprocessing of Drop-seq samples. Processing of the WOM Drop-seq samples was performed in Seurat (v2.3.1). Cells with less than 500 UMIs or more than 15,000 UMIs, or higher than 5% mitochondrial genes were removed. Potential doublets were removed using Scrublet. Cells were initially preprocessed using the Seurat pipeline. Variable genes FindVariableGenes (y.cutoff = 0.6) were scaled (regressing out effects due to nUMI, the percent of mitochondrial genes, and replicate ids) and the data was clustered using 50 PCs with the Louvain algorithm (resolution=0.8). In a fraction of sustentacular cells, we observed co-expression of markers for sustentacular cells and other cell types (e.g., OSNs). Re-clustering of sustentacular cells alone separately out these presumed doublets from the rest of the sustentacular cells, and the presumed doublets were removed for the analyses described below.

Processing of Drop-seq samples. The filtered cells from the preprocessing steps were reanalyzed in python using Scanpy and SPRING. In brief, the raw gene counts in each cell were total counts normalized and variable genes were identified using the SPRING gene filtering function filter_genes with parameters (85, 3, 3); mitochondrial and olfactory receptor genes were excluded from the variable gene lists. The resulting 2083 variable genes were z-scored and the dimensionality of the data was reduced to 35 via principal component analysis. The k-nearest neighbor graph (n_neighbors=15) of these 35 PCs was clustered using the leiden algorithm (resolution=1.2) and was reduced to two dimensions for visualization via the UMAP method (min_dist=0.42). Clusters were manually annotated on the basis of known marker genes and those sharing markers (e.g., olfactory sensory neurons) were merged.

The mouse WOM Drop-seq dataset contained 29585 cells that passed the above filtering. Each of the 16 clusters identified contained cells from all 8 replicates in roughly equal proportions. Of the 17666 mature OSNs and the 4674 immature OSNs, none of the cells express Ace2. In contrast, in the olfactory epithelial cells, Ace2 expression was observed in the Bowmans gland, olfactory HBCs, dorsal sustentacular cells.

Mouse olfactory epithelium tissue processing. Mice were sacrificed with a lethal dose of xylazine and nasal epithelium with attached olfactory bulbs were dissected and fixed in 4% paraformaldehyde (Electron Microscope Sciences, 19202) in phosphate-buffered saline (PBS) for overnight at 4C or for 2 hours at room temperature. Tissues were washed in PBS for 3 times (5 min each) and incubated in 0.45M EDTA in PBS overnight at 4C. The following day, tissues were rinsed by PBS and incubated in 30% Sucrose in PBS for at least 30 min, transferred to Tissue Freezing Medium (VWR, 15146-025) for at least 45 min and frozen on crushed dry ice and stored at -80C until sectioning. Tissue sections (20 m thick for the olfactory bulb and 12 m thick for nasal epithelium) were collected on Superfrost Plus glass slides (VWR, 48311703) and stored at -80C until immunostaining.

For methimazole treated samples, Adult C57BL/6J mice (6-12 weeks old, JAX stock No. 000664) were given intraperitoneal injections with Methimazole (Sigma M8506) at 50 g/g body weight and sacrificed at 24, 48, and 96-hour timepoints.

Immunostaining for mouse tissue. Sections were permeabilized with 0.1% Triton X-100 in PBS for 20 min then rinsed 3 times in PBS. Sections were then incubated for 45-60 min in blocking solution that consisted of PBS containing 3% Bovine Serum Albumin (Jackson Immunoresearch, 001-000-162) and 3% Donkey Serum (Jackson ImmunoResearch, 017-000-121) at room temperature, followed by overnight incubation at 4C with primary antibodies diluted in the same blocking solution. Primary antibodies used are as follows. Goat anti-ACE2 (Thermo Fisher, PA5-47488, 1:40), mouse anti-TUBB4 (Sigma, T7941, 1:4000), rabbit anti-KRT5 (abcam, ab52635, 1:200), goat anti-NQO1 (abcam, ab2346, 1:200), mouse anti-acetylated Tubulin (abcam, ab24610, 1:500), rabbit anti-CNGA2 (abcam, ab79261, 1:100), rat anti-CD140b/PDGFRB (Thermo Fisher, 14-1402-82, 1:100).

On the following day, sections were rinsed once and washed three times for 5-10 min in PBS, then incubated for 45 min with secondary antibodies diluted in blocking solution at 1:300 ratios and/or Alexa 555-conjugated Phalloidin (1:400). Secondary antibodies used were as follows: Donkey anti-Goat IgG Alexa 488 (Jackson ImmunoResearch, 705-546-147), donkey anti-Goat IgG Alexa 555, (Invitrogen, A21432), donkey anti-Rabbit IgG Alexa 555 (Invitrogen, A31572), donkey anti-Rabbit IgG Alexa 647 (Jackson ImmunoResearch, 711-605-152), donkey anti-Mouse IgG Alexa 555 (Invitrogen, A31570), donkey anti-Mouse IgG Alexa 647 (Invitrogen, A31571), and donkey anti-Rat IgG Alexa 488 (Invitrogen, A21208).

After secondary antibody incubation, sections were washed twice for 5-10 min in PBS, incubated with 300 nM DAPI in PBS for 10 min and then rinsed with PBS. Slides were mounted with glass coverslips using Vectashield Mounting Medium (Vector Laboratories, H-1000) or ProLong Diamond Antifade Mountant (Invitrogen, P36961).

For co-staining of ACE2 and NQO1, slides were first stained with ACE2 primary antibody and donkey anti-Goat IgG Alexa 488 secondary. After 3 washes of secondary antibody, tissues were incubated with unconjugated donkey anti-Goat IgG Fab fragments (Jackson ImmunoResearch, 705-007-003) at 30 g/mL diluted in blocking solution for 1 hour at room temperature. Tissues were washed twice with PBS, once in blocking solution, and incubated in blocking solution for 30-40 min at room temperature, followed by a second round of staining with the NQO1 primary antibody and donkey anti-Goat IgG Alexa 555 secondary antibody.

Confocal images were acquired using a Leica SPE microscope (Harvard Medical School Neurobiology Imaging Facility) with 405 nm, 488 nm, 561 nm, and 635 nm laser lines. Multi-slice z-stack images were acquired, and their maximal intensity projections are shown. For Fig. 5A, tiled images were acquired and stitched by the Leica LAS X software. Images were processed using Fiji ImageJ software (95), and noisy images were median-smoothed using the Remove Outliers function built into Fiji.

Fluorescent in situ hybridization for mouse tissue. Sult1c1 RNA was detected by fluorescent RNAscope assay (Advanced Cell Diagnostics, kit 320851) using probe 539921-C2, following the manufacturers protocol (RNAscope Fluorescent Multiplex Kit User Manual, 320293-UM Date 03142017) for paraformaldehyde-fixed tissue. Prior to initiating the hybridization protocol, the tissue was pre-treated with two successive incubations (first 30 min, then 15 min long) in RNAscope Protease III (Advanced Cell Diagnostics, 322337) at 40C, then washed in distilled water. At the end of protocol, the tissue was washed in PBS and subjected to the 2-day immunostaining protocol described above.

Immunostaining of human nasal tissue. Human olfactory mucosa biopsies were obtained via IRB-approved protocol at Duke University School of Medicine, from nasal septum or superior turbinate during endoscopic sinus surgery. Tissue was fixed with 4% paraformaldehyde and cryosectioned at 10 m and sections were processed for immunostaining, as previously described (38).

Sections from a 28-year old female nasal septum biopsy were stained for ACE2 (Fig. 2E) using the same Goat anti-ACE2 (Thermo Fisher, PA5-47488, 1:40) and the protocol described above for mouse tissue. The human sections were co-stained with Rabbit anti-keratin 5 (Abcam, ab24647; AB_448212, 1:1000) and were detected with AlexaFluor 488 Donkey anti-goat (Jackson ImmunoResearch, 705-545-147) and AlexaFluor 594 Donkey anti-rabbit (Jackson ImmunoResearch, 711-585-152) secondary antibodies (1:300).

As further validation of ACE2 expression and to confirm the lack of ACE2 expression in human olfactory sensory neurons (Figure S2), sections were stained with a rabbit anti-ACE2 (Abcam, ab15348; RRID:AB_301861, used at 1:100) antibody immunogenized against human ACE2 and a mouse Tuj1 antibody against neuron-specific tubulin (BioLegend, 801201; RRID:AB_2313773). Anti-ACE2 was raised against a C-terminal synthetic peptide for human ACE2 and was validated by the manufacturer to not cross-react with ACE1 for immunohistochemical labeling of ACE2 in fruit bat nasal tissue as well as in human lower airway. Recombinant human ACE2 abolished labeling with this antibody in a previous study in human tissue, further demonstrating its specificity (53). The Tuj1 antibody was validated, as previously described (38). Biotinylated secondary antibodies (Vector Labs), avidin-biotinylated horseradish peroxidase kit (Vector) followed by fluorescein tyramide signal amplification (Perkin Elmer) were applied per manufacturers instructions. For dual staining, Tuj1 was visualized using AlexaFluor 594 Goat anti-Mouse (Jackson ImmunoResearch, 115-585-146; RRID: AB_2338881).

Human sections were counterstained with 4,6-diamidino-2-phenylindole (DAPI) and coverslips were mounted using Prolong Gold (Invitrogen) for imaging, using a Leica DMi8 microscope system. Images were processed using Fiji ImageJ software (NIH). Scale bars were applied directly from the Leica acquisition software metadata in ImageJ Tools. Unsharp Mask was applied in ImageJ, and brightness/contrast was adjusted globally.

Mice. 2 month-old and 18 month-old wild type C57BL/6J mice were obtained from the National Institute on Aging Aged Rodent Colony and used for the WOM experiments; each experimental condition consisted of one male and one female mouse to aid doublet detection. Mice containing the transgenic Krt5-CreER(T2) driver (96) and Rosa26-YFP reporter allele (97) were used for the HBC lineage tracing dataset. All mice were assumed to be of normal immune status. Animals were maintained and treated according to federal guidelines under IACUC oversight at the University of California, Berkeley.

Single-Cell RNA Sequencing. The olfactory epithelium was surgically removed, and the dorsal, sensory portion was dissected and dissociated, as previously described (36). For WOM experiments, dissociated cells were subjected to fluorescence-activated cell sorting (FACS) using propidium iodide to identify and select against dead or dying cells; 100,000 cells/sample were collected in 10% FBS. For the HBC lineage tracing experiments Krt5-CreER; Rosa26YFP/YFP mice were injected once with tamoxifen (0.25 mg tamoxifen/g body weight) at P21-23 days of age and sacrificed at 24 hours, 48 hours, 96 hours, 7 days and 14 days post-injury, as previously described (36, 98). For each experimental time point, YFP+ cells were isolated by FACS based on YFP expression and negative for propidium iodide, a vital dye.

Cells isolated by FACS were subjected to single-cell RNA-seq. Three replicates (defined here as a FACS collection run) per age were analyzed for the WOM experiment; at least two biological replicates were collected for each experimental condition for the HBC lineage tracing experiment. Single cell cDNA libraries from the isolated cells were prepared using the Chromium Single Cell 3 System according to the manufacturers instructions. The WOM preparation employed v3 chemistry with the following modification: the cell suspension was directly added to the reverse transcription master mix, along with the appropriate volume of water to achieve the approximate cell capture target. The HBC lineage tracing experiments were performed using v2 chemistry. The 0.04% weight/volume BSA washing step was omitted to minimize cell loss. Completed libraries were sequenced on Illumina HiSeq4000 to produce paired-end 100nt reads.

Sequence data were processed with the 10x Genomics Cell Ranger pipeline (2.0.0 for v2 chemistry), resulting in the initial starting number before filtering of 60,408 WOM cells and 25,469 HBC lineage traced cells. The scone R/Bioconductor package (99) was used to filter out lowly-expressed genes (fewer than 2 UMIs in fewer than 5 cells) and low-quality libraries (using the metric_sample_filter function with arguments hard_nreads = 2000, zcut = 4).

Preliminary Filtering. Cells with co-expression of male (Ddx3y, Eif2s3y, Kdm5d, and Uty) and female marker genes (Xist) were removed as potential doublets from the WOM dataset. For both datasets, doublet cell detection was performed per sample using DoubletFinder (100) and Scrublet (101). Genes with at least 3 UMIs in at least 5 cells were used for downstream clustering and cell type identification. For the HBC lineage tracing dataset, the Bioconductor package scone was used to pick the top normalization (none,fq,ruv_k=1,no_bio,batch), corresponding to full quantile normalization, batch correction and removing one factor of unwanted variation using RUV (102). A range of cluster labels were created by clustering using the partitioning around medoids (PAM) algorithm and hierarchical clustering in the clusterExperiment Bioconductor package (103), with parameters k0s= (10, 13, 16, 19, 22, 25) and alpha=(NA,0.1,0.2,0.3). Clusters that did not show differential expression were merged (using the function mergeClusters with arguments mergeMethod = adjP, cutoff = 0.01, and DEMethod = limma for the lineage-traced dataset). Initial clustering identified one Macrophage (Msr1+) cluster consisting of 252 cells; upon its removal and restarting from the normalization step a subsequent set of 15 clusters was obtained. These clusters were used to filter out 1515 cells for which no stable clustering could be found (i.e., unassigned cells), and four clusters respectively consisting of 31, 29 and 23 and 305 cells. Doublets were identified using DoubletFinder and 271 putative doublets were removed. Inspection of the data in a three-dimensional UMAP embedding identified two groups of cells whose experimentally sampled timepoint did not match their position along the HBC differentiation trajectory, and these additional 219 cells were also removed from subsequent analyses.

Analysis of CoV-related genes in WOM and HBC lineage 10x datasets. Analysis of WOM scSeq data were performed in python using the open-source Scanpy software starting from the raw UMI count matrix of the 40179 cells passing the initial filtering and QC criteria described above. UMIs were total-count normalized and scaled by 10,000 (TPT, tag per ten-thousands) and then log-normalized. For each gene, the residuals from linear regression models using the total number of UMIs per cell as predictors were then scaled via z-scoring. PCA was then performed on a set of highly-variable genes (excluding OR genes) calculated using the highly_variable_genes function with parameters: min_mean=0.01, max_mean=10, min_disp=0.5. A batch corrected neighborhood graph was constructed by the bbknn function with 42 PCs with the parameters: local_connectivity=1.5, and embedding two-dimensions using the UMAP function with default parameters (min_dist = 0.5). Cells were clustered using the neighborhood graph via the Leiden algorithm (resolution = 1.2). Identified clusters were manually merged and annotated based on known marker gene expression. We removed 281 cells containing mixtures of marker genes with no clear gene expression signature. The identified cell types and the number of each of the remaining 39898 cells detected were as follows. 28,769 mOSN: mature OSN; 2,607 iOSN: immature OSN; 859 INP: Immediate Neural Precursor; 623 GBC: Globose Basal Cell; HBC: Horizontal Basal Cell (1,083 Olfactory and 626 Respiratory); 480 SUS: sustentacular cell; 331 BG: Bowmans gland; MV: Microvillar cell (563 Brush-like and 1,530 Ionocyte-like); 92 OEC: Olfactory Ensheathing Cell; 76 Resp. Secretory cells; 227 Resp. unspecified cells; 172 atypical OSN; 1,757 various immune cells, 103 RBC: Red Blood Cell. TPT gene expression levels were visualized in two-dimensional UMAP plots.

The filtered HBC lineage dataset containing 21722 cells was analyzing in python and processed for visualization using pipelines in SPRING and Scanpy (104, 105). In brief, total counts were normalized to the median total counts for each cell and highly variable genes were selected using the SPRING gene filtering function (filter_genes) using parameters (90, 3, 3). The dimensionality of the data was reduced to 20 using principal components analysis (PCA) and visualized in two-dimensions using the UMAP method with parameters (n_neighbors=20, min_dist=0.5). Clustering was performed using the Leiden algorithm (resolution=1.45) and clusters were merged manually using known marker genes. The identified cell types and number of each type were: 929 mOSN: mature OSN; 2073 iOSN: immature OSN; 786 INP: Immediate Neural Precursor; 755 GBC: Globose Basal Cell; HBC: Horizontal Basal Cell (7782 Olfactory, 5418 Regenerating, and 964 Respiratory); 2666 SUS: sustentacular cell; and 176 Ionocyte-like Microvillar (MV) cell.

Expression of candidate CoV-2-related genes was defined if at least one transcript (UMI) was detected in that cell, and the percent of cells expressing candidate genes was calculated for each cell type. In the WOM dataset Ace2 was only detected in 2 out of 28,769 mature OSNs (0.007%), and in the HBC lineage dataset, Ace2 was not detected in any OSNs. Furthermore, Ace2 was not detected in immature sensory neurons (GBCs, INPs, or iOSNs) in either dataset.

Single-cell RNA-seq data from HBC-derived cells from Fletcher et al. and Gadye et al. (36, 98), labeled via Krt5-CreER driver mice, were downloaded from GEO at accession GSE99251 using the file GSE95601_oeHBCdiff_Cufflinks_eSet_counts_table.txt.gz. Processing was performed as described above, including total counts normalization and filtering for highly variable genes using the SPRING gene filtering function filter_genes with parameters (75, 20, 10). The resulting data were visualized in SPRING and a subset of cells were removed for quality control, including a cluster of cells with low total counts and another with predominantly reads from ERCC spike-in controls. Putative doublets were also identified using Scrublet and removed (6% of cells) (101). The resulting data were visualized in SPRING and partitioned using Louvain clustering on the SPRING k-nearest-neighbor graph using the top 40 principal components. Cell type annotation was performed manually using the same set of markers genes listed above. Three clusters were removed for quality control, including one with low total counts and one with predominantly reads from ERCC spike-in controls (likely background), and one with high mitochondrial counts (likely stressed cells). For visualization, and clustering the remaining cells were projected to 15 dimensions using PCA and visualized with UMAP with parameters (n_neighbors=15, min_dist=0.4, alpha=0.5, maxiter=500). Clustering was performed using the Leiden algorithm (resolution=0.4) and cell types were manually annotated using known marker genes.

The filtered dataset of mouse HBC-derived cells contained 1450 cells. The percent of cells expressing each marker gene was calculated as described above. Of the 51 OSNs identified, none of them expressed Ace2, and only 1 out of 194 INPs and iOSNs expressed Ace2. In contrast, Ace2 and Tmprss2 were both detected in HBCs and SUS cells.

Juvenile mouse data. Single-cell RNAseq data from whole mouse olfactory bulb (50) were downloaded from mousebrain.org/loomfiles_level_L1.html in loom format (l1 olfactory.loom) and converted to a Seurat object. Samples were obtained from juvenile mice (age postnatal day 26-29). This dataset comprises 20514 cells passing cell quality filters, excluding 122 cells identified as potential doublets.

Tissue dissection and single-cell dissociation. A new dataset of whole olfactory bulb scSeq was generated from adult male mice (812 weeks-old). All mouse husbandry and experiments were performed following institutional and federal guidelines and approved by Harvard Medical Schools Institutional Animal Care and Use Committee (IACUC). Briefly, dissected olfactory bulbs (including the accessory olfactory bulb and fractions of the anterior olfactory nucleus) were dissociated in 750 l of dissociation media (DM: HBSS containing 10mM HEPES, 1 mM MgCl2, 33 mM D-glucose) with 28 U/mL Papain and 386 U/mL DNase I (Worthington). Minced tissue pieces were transferred to a 5 mL round-bottom tube (BD). DM was added to a final volume of 3.3 mL and the tissue was mechanically triturated 5 times with a P1000 pipette tip. After 1-hour incubation with rocking at 37C, the suspension was triturated with a 10 mL pipette 10 times and 2.3 mL was passed through 40 m cell strainer (BD). The suspension was then mechanically triturated with a P1000 pipette tip 10 times and 800 L were filtered on the same strainer. The cell suspension was further triturated with a P200 pipette tip 10 times and filtered. 1 mL of Quench buffer (22 mL of DM, 2.5 mL of protease inhibitor prepared by resuspending 1 vial of protease inhibitor with 32 mL of DM, and 2000U of DNase I) was added to the suspension and centrifuged at 300 g for 5 min. Cells were resuspended with 3 mL of Quench buffer and overlaid gently on top of 5 mL of protease inhibitor, then spun down at 70 g for 10min. The pellet was resuspended using DM supplemented with 0.04% BSA and spun down at 300 g for 5 min. Cells were suspended in 400 L of DM with 0.04% BSA.

Olfactory bulb Drop-seq experiments. Drop-seq experiments were performed as previously described (94). Microfluidics devices were obtained from FlowJEM and barcode beads were obtained from chemgenes. Two 15 min Drop-seq runs were collected from a single dissociation preparation obtained from 2 mice. Two such dissociations were performed, giving 4 total replicates.

Sequencing of Drop-seq samples. 4 replicates of Drop-seq samples were pooled and sequenced across 3 runs on an Illumina NextSeq 500 platform. Paired end reads from the fastq files were trimmed, aligned, and tagged via the Drop-seq tools (1-2.0) pipeline, using STAR (2.4.2a) with genomic indices from Ensembl Release 82. The digital gene expression matrix was generated for 8,000 cells per replicate.

Preprocessing of Drop-seq samples. Cells with low numbers of genes (500), low numbers of UMIs (700) or high numbers of UMIs (>10000) were removed (6% of cells). Potential doublets were identified via Scrublet and removed (3.5% of cells). Overall, this new dataset comprised 27004 cells.

Integration of whole olfactory bulb scRNAseq datasets. Raw UMI counts from juvenile and adult whole olfactory bulb samples were integrated in Seurat (106). Integrating the datasets ensured that clusters with rare cell types could be identified and that corresponding cell types could be accurately matched. As described below (see Figure S7), although some cell types were observed with different frequencies, the integration procedure yielded stable clusters with cells from both datasets. Briefly, raw counts were log-normalised separately and the 10000 most variable genes identified by variance stabilizing transformation for each dataset. The 4529 variable genes present in both datasets and the first 30 principal components (PCs) were used as features for identifying the integration anchors. The integrated expression matrix was scaled and dimensionality reduced using PCA. Based on their percentage of explained variance, the first 28 PCs were chosen for UMAP visualization and clustering.

Graph-based clustering was performed using the Louvain algorithm following the standard Seurat workflow. Cluster stability was analyzed with Clustree on a range of resolution values (0.4 to 1.4), with 0.6 yielding the most stable set of clusters (107). Overall, 26 clusters were identified, the smallest of which contained only 43 cells with gene expression patterns consistent with blood cells, which were excluded from further visualization plots. Clustering the two datasets separately yielded similar results. Moreover, the distribution of cells from each dataset across clusters was homogenous (Figure S7) and the clusters corresponded previous cell class and subtype annotations (50). As previously reported, a small cluster of excitatory neurons (cluster 13) contained neurons from the anterior olfactory nucleus. UMAP visualizations of expression level for cell class and cell type markers, and for genes coding for coronavirus entry proteins, depict log-normalized UMI counts. The heatmap in Fig. 7C shows the mean expression level for each cell class, normalised to the maximum mean value. The percentage of cells per cell class expressing Ace2 was defined as the percentage of cells with at least one UMI. In cells from both datasets, Ace2 was enriched in pericytes but was not detected in neurons.

Tissue dissociation and manual cell sorting. Acute olfactory bulb 300 m slices were obtained from Dat-Cre/Flox-tdTomato (B6.SJL-Slc6a3tm1.1(cre) Bkmn/J, Jax stock 006660 / B6.Cg Gt(ROSA)26Sortm9(CAG-tdTomato)Hze, Jax stock 007909) P28 mice as previously described (108). As part of a wider study, at P27 these mice had undergone brief 24 hours unilateral naris occlusion via a plastic plug insert (N = 5 mice) or were subjected to a sham control manipulation (N = 5 mice); all observed effects here were independent of these treatment groups. Single cell suspensions were generated using the Neural Tissue Dissociation Kit Postnatal Neurons (Miltenyi Biotec. Cat no. 130-094-802), following manufacturers instructions for manual dissociation, using 3 fired-polished Pasteur pipettes of progressively smaller diameter. After enzymatic and mechanical dissociations, cells were filtered through a 30 m cell strainer, centrifuged for 10 min at 4C, resuspended in 500 l of ACSF (in mM: 140 NaCl, 1.25 KCl, 1.25 NaH2PO4, 10 HEPES, 25 Glucose, 3 MgCl2, 1 CaCl2) with channel blockers (0.1 M TTX, 20 M CNQX, 50 M D-APV) and kept on ice to minimise excitotoxicity and cell death.

For manual sorting of fluorescently labeled dopaminergic neurons we adapted a previously described protocol (109). 50 l of single cell suspension was dispersed on 3.5mm petri dishes (with a Sylgard-covered base) containing 2 ml of ACSF + channel blockers. Dishes were left undisturbed for 15 min to allow the cells to sink and settle. Throughout, dishes were kept on a metal plate on top of ice. tdTomato-positive cells were identified by their red fluorescence under a stereoscope. Using a pulled glass capillary pipette attached to a mouthpiece, individual cells were aspirated and transferred to a clean, empty dish containing 2 ml ACSF + channel blockers. The same cell was then transferred to a third clean plate, changing pipettes for every plate change. Finally, each individual cell was transferred to a 0.2 ml PCR tube containing 2 l of lysis buffer (RLT Plus - Qiagen). The tube was immediately placed on a metal plate sitting on top of dry ice for flash-freezing. Collected cells were stored at -80C until further processing. Positive (more than 10 cells) and negative (sample collection procedure without picking a cell) controls were collected for each sorting session. In total, we collected samples from 10 mice, averaging 50 tdTomato-positive cells collected per session. Overall, less than 2.5 hours elapsed between mouse sacrifice and collection of the last cell in any session.

Preparation and amplification of full-length cDNA and sequencing libraries. Samples were processing using a modified version of the Smart-Seq2 protocol(110). Briefly, 1 l of a 1:2,000,000 dilution of ERCC spike-ins (Invitrogen. Cat. no. 4456740) was added to each sample and mRNA was captured using modified oligo-dT biotinylated beads (Dynabeads, Invitrogen). PCR amplification was performed for 22 cycles. Amplified cDNA was cleaned with a 0.8:1 ratio of Ampure-XP beads (Beckman Coulter). cDNAs were quantified on Qubit using HS DNA reagents (Invitrogen) and selected samples were run on a Bioanalyzer HS DNA chip (Agilent) to evaluate size distribution.

For generating the sequencing libraries, individual cDNA samples were normalised to 0.2ng/l and 1l was used for one-quarter standard-sized Nextera XT (Illumina) tagmentation reactions, with 12 amplification cycles. Sample indexing was performed using index sets A and D (Illumina). At this point, individual samples were pooled according to their index set. Pooled libraries were cleaned using a 0.6:1 ratio of Ampure beads and quantified on Qubit using HS DNA reagents and with the KAPA Library Quantification Kits for Illumina (Roche). Samples were sequenced on two separate rapid-runs on HiSeq2500 (Illumina), generating 100bp paired-end reads. An additional 5 samples were sequenced on MiSeq (Illumina).

Full-length cDNA sequencing data processing and analysis. Paired-end read fastq files were demultiplexed, quality controlled using FastQC (https://www.bioinformatics.babraham.ac.uk/projects/fastqc/) and trimmed using Trim Galore (https://www.bioinformatics.babraham.ac.uk/projects/trim_galore/). Reads were pseudoaligned and quantified using kallisto (111) against a reference transcriptome from Ensembl Release 89 (Gencode Release M17 GRCm38.p6) with sequences corresponding to the ERCC spike-ins and the Cre recombinase and tdT genes added to the index. Transcripts were collapsed into genes using the sumAcrossFeatures function in scater.

Cell level quality control and cell filtering was performed in scater (112). Cells with <1000 genes, <100,000 reads, >75% reads mapping to ERCC spike-ins, >10% reads mapping to mitochondrial genes or low library complexity were discarded (14% samples). The population of olfactory bulb cells labeled in DAT-tdTomato mice is known to include a minor non-dopaminergic calretinin-positive subgroup (113), so calretinin-expressing cells were excluded from all analyses. The scTransform function in Seurat was used to remove technical batch effects.

An analysis of single-cell gene expression data from 10 studies was performed to investigate the expression of genes coding for coronavirus entry proteins in neurons from a range of brain regions and sensory systems. Processed gene expression data tables were obtained from scSeq studies that evaluated gene expression in retina (GSE81905) (114) inner ear sensory epithelium (GSE115934) (115, 116) and spiral ganglion (GSE114997) (117), ventral midbrain (GSE76381) (118), hippocampus (GSE100449) (119), cortex (GSE107632) (120), hypothalamus (GSE74672) (121), visceral motor neurons (GSE78845) (122), dorsal root ganglia (GSE59739) (123) and spinal cord dorsal horn (GSE103840) (124). Smart-Seq2 sequencing data from Vsx2-GFP positive cells was used from the retina dataset. A subset of the expression matrix that corresponds to day 0 (i.e., control, undisturbed neurons) was used from the layer VI somatosensory cortex dataset. A subset of the data containing neurons from untreated (control) mice was used from the hypothalamic neuron dataset. From the ventral midbrain dopaminergic neuron dataset, a subset comprising DAT-Cre/tdTomato positive neurons from P28 mice was used. A subset comprising Type I neurons from wild type mice was used from the spiral ganglion dataset. The unclassified neurons were excluded from the visceral motor neuron dataset. A subset containing neurons that were collected at room temperature was used from the dorsal root ganglia dataset. Expression data from dorsal horn neurons obtained from C57/BL6 wild type mice, vGat-cre-tdTomato and vGlut2-eGFP mouse lines was used from the spinal cord dataset. Inspection of all datasets for batch effects was performed using the scater package (version 1.10.1) (112). Publicly available raw count expression matrices were used for the retina, hippocampus, hypothalamus, midbrain, visceral motor neurons and spinal cord datasets, whereas the normalized expression data was used from the inner ear hair cell datasets. For datasets containing raw counts, normalization was performed for each dataset separately by computing pool-based size factors that are subsequently deconvolved to obtain cell-based size factors using the scran package (version 1.10.2) (125). Violin plots were generated in scater.

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Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia - Science...

Physiological Relevance of Angiotensin Converting Enzyme 2 As a Metabolic Linker and Therapeutic Implication of Mesenchymal Stem Cells in COVID-19 and…

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Stem Cell Rev Rep. 2020 Aug 3. doi: 10.1007/s12015-020-10012-x. Online ahead of print.

ABSTRACT

Severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) is a single stranded RNA virus and responsible for infecting human being. In many cases the individual may remain asymptomatic. Some recently reported studies revealed that individuals of elderly age group and with pre-existing medical conditions such as hypertension, diabetes mellitus had severe consequences, even may lead to death. However, it is not clearly delineated whether hypertension itself or associated comorbidities or antihypertensive therapy contributes to the grave prognosis of COVID-19 infections. This review is aimed to decipher the exact mechanisms involved at molecular level from existing evidence and as reported. It has been reported that SARS-CoV-2 enters into the host cell through interaction between conserved residues of viral spike protein and angiotensin converting enzyme 2 (ACE2) receptor which is highly expressed in hosts cardiac and pulmonary cells and finally transmembrane protease, serine-2 (TMPRSS2), helps in priming of the surface protein. Subsequently, symptom related to multi organ involvement is primarily contributed by cytokine storm. Although various clinical trials are being conducted on renin- angiotensin- system inhibitor, till to date there is no standard treatment protocol approved for critically ill COVID-19 positive cases with pre-existing hypertension. Recently, several studies are carried out to document the safety and efficacy outcome of mesenchymal stem cell transplantation based on its immunomodulatory and regenerative properties. Therefore, identification of future novel therapeutics in the form of mesenchymal stem cell either alone or in combination with pharmacological approach could be recommended for combating SARS-CoV-2 which might be dreadful to debilitating elderly people. Graphical Abstract.

PMID:32748331 | DOI:10.1007/s12015-020-10012-x

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Physiological Relevance of Angiotensin Converting Enzyme 2 As a Metabolic Linker and Therapeutic Implication of Mesenchymal Stem Cells in COVID-19 and...

CAREDX : MANAGEMENT’S DISCUSSION AND ANALYSIS OF FINANCIAL CONDITION AND RESULTS OF OPERATIONS (form 10-Q) – marketscreener.com

The following discussion and analysis of our financial condition and results ofoperations should be read together with the unaudited condensed consolidatedfinancial statements and related notes included elsewhere in Item 1 of Part I ofthis Quarterly Report on Form 10-Q and with the audited consolidated financialstatements and the related notes included in our Annual Report on Form 10-K forthe fiscal year ended December 31, 2019, filed with the Securities and ExchangeCommission, or the SEC, on February 28, 2020.SPECIAL NOTE REGARDING FORWARD-LOOKING STATEMENTSThis Quarterly Report on Form 10-Q contains forward-looking statements withinthe meaning of Section 27A of the Securities Act of 1933, as amended, andSection 21E of the Securities Exchange Act of 1934, as amended. All statementscontained in this Quarterly Report on Form 10-Q other than statements ofhistorical fact, including statements regarding our future results of operationsand financial position, our business strategy and plans, and our objectives forfuture operations, are forward-looking statements. The words "believe," "may,""will," "potentially," "estimate," "continue," "anticipate," "intend," "could,""should," "would," "project," "plan," "target," "contemplate," "predict,""expect" and the negative and plural forms of these words and similarexpressions are intended to identify forward-looking statements.These forward-looking statements may include, but are not limited to, statementsconcerning the following:the potential impact to our business, revenue, financial condition andemployees, including disruptions to our testing services, laboratories, clinicaltrials, supply chain and operations, due to the COVID-19 global pandemic;our ability to take advantage of opportunities under the Coronavirus Aid,Relief, and Economic Security Act, or the CARES Act, and the potential impact ofthe CARES Act on our business, results of operations, financial condition orliquidity;our ability to generate revenue and increase the commercial success of ourcurrent and future testing services, products and digital solutions;our ability to obtain, maintain and expand reimbursement coverage from payersfor our current and other future testing services, if any;our plans and ability to continue updating our testing services, products anddigital solutions to maintain our leading position in transplantations;the outcome or success of our clinical trial collaborations and registrystudies; including Kidney Allograft Outcomes AlloSure Registry, or K-OAR, theOutcomes of KidneyCare on Renal Allografts registry study, or OKRA, and theSurveillance HeartCare Outcomes Registry, or SHORE;the favorable review of our testing services and product offerings, and ourfuture solutions, if any, in peer-reviewed publications;our ability to obtain additional financing on terms favorable to us, or at all;our anticipated cash needs and our anticipated uses of our funds, including ourestimates regarding operating expenses and capital requirements;anticipated trends and challenges in our business and the markets in which weoperate;our dependence on certain of our suppliers, service providers and otherdistribution partners; 25-------------------------------------------------------------------------------- Table of Contentsdisruptions to our business, including disruptions at our laboratories andmanufacturing facilities;our ability to retain key members of our management team;our ability to make successful acquisitions or investments and to manage theintegration of such acquisitions or investments;our ability to expand internationally;our compliance with federal, state and foreign regulatory requirements;our ability to protect and enforce our intellectual property rights, ourstrategies regarding filing additional patent applications to strengthen ourintellectual property rights, and our ability to defend against intellectualproperty claims that may be brought against us;our ability to successfully assert, defend against or settle any litigationbrought by or against us or other legal matters or disputes; andour ability to comply with the requirements of being a public company.These forward-looking statements are subject to a number of risks, uncertaintiesand assumptions, including those described in the section entitled "RiskFactors" in this Quarterly Report on Form 10-Q and in our Annual Report on Form10-K for the fiscal year ended December 31, 2019, filed with the SEC onFebruary 28, 2020. Moreover, we operate in a very competitive and rapidlychanging environment, and new risks emerge from time to time. It is not possiblefor our management to predict all risks, nor can we assess the impact of allfactors on our business or the extent to which any factor, or combination offactors, may cause actual results to differ materially and adversely from thosecontained in any forward-looking statements we may make. In light of theserisks, uncertainties and assumptions, the forward-looking events andcircumstances discussed in this report may not occur and actual results coulddiffer materially and adversely from those anticipated or implied in theforward-looking statements.You should not rely upon forward-looking statements as predictions of futureevents. Although we believe that the expectations reflected in theforward-looking statements are reasonable, we cannot guarantee that the futureresults, levels of activity, performance or events and circumstances reflectedin the forward-looking statements will be achieved or occur. Moreover, neitherwe nor any other person assumes responsibility for the accuracy and completenessof the forward-looking statements. Except as required by law, we undertake noobligation to update publicly any forward-looking statements for any reasonafter the date of this report to conform these statements to actual results orto changes in our expectations.You should read this Quarterly Report on Form 10-Q and the documents that wereference in this Quarterly Report on Form 10-Q and have filed with the SEC asexhibits to this Quarterly Report on Form 10-Q with the understanding that ouractual future results, levels of activity, performance and events andcircumstances may be materially different from what we expect. We qualify allforward-looking statements by these cautionary statements.Overview and Recent HighlightsCareDx, Inc. (collectively, the "Company", "we", "us" and "our") is a leadingprecision medicine company focused on the discovery, development andcommercialization of clinically differentiated, high-value diagnostic solutionsfor transplant patients and caregivers. We offer testing services, products, anddigital healthcare solutions along the pre- and post-transplant patient journey,and we are a leading provider of genomics-based information for transplantpatients.Highlights for the Three Months Ended June 30, 2020 and Recent HighlightsAchieved total revenue of $41.8 million for the three months ended June 30,2020, increasing 33% year-over-yearProvided over 17,100 AlloSure Kidney and AlloMap Heart patient results, withover 40% originating from RemoTraC and mobile phlebotomyRecorded first-ever AlloCell revenue from a cell therapy partnershipCompleted successful public offering raising $134.6 million in net proceeds,increasing cash and cash equivalents to approximately $211.4 millionTesting ServicesHeart 26-------------------------------------------------------------------------------- Table of ContentsAlloMap Heart is a gene expression test that helps clinicians monitor andidentify heart transplant recipients with stable graft function who have a lowprobability of moderate-to-severe acute cellular rejection. Since 2008, we havesought to expand the adoption and utilization of our AlloMap Heart solutionthrough ongoing studies to substantiate the clinical utility and actionability,secure positive reimbursement decisions from large private and public payers,develop and enhance our relationships with key members of the transplantcommunity, including opinion leaders at major transplant centers, and exploreopportunities and technologies for the development of additional solutions forpost-transplant surveillance.We believe the use of AlloMap Heart, in conjunction with other clinicalindicators, can help healthcare providers and their patients better managelong-term care following a heart transplant, can improve patient care by helpinghealthcare providers avoid the use of unnecessary, invasive surveillancebiopsies and may help to determine the appropriate dosage levels ofimmunosuppressants. In 2008, AlloMap Heart received 510(k) clearance from theU.S. Food and Drug Administration for marketing and sale as a test to aid in theidentification of heart transplant recipients, who have a low probability ofmoderate/severe acute cellular rejection at the time of testing, in conjunctionwith standard clinical assessment.AlloMap Heart has been a covered service for Medicare beneficiaries sinceJanuary 1, 2006. The Medicare reimbursement rate for AlloMap Heart is currently$3,240. AlloMap Heart has also received positive coverage decisions forreimbursement from many of the largest U.S. private payers, including Aetna,Anthem, Cigna, Health Care Services Corporation, or HCSC, Humana, KaiserFoundation Health Plan, Inc. and UnitedHealthcare.We have also successfully completed a number of landmark clinical trials in thetransplant field demonstrating the clinical utility of AlloMap Heart forsurveillance of heart transplant recipients. We initially established theanalytical and clinical validity of AlloMap Heart on the basis of our CardiacAllograft Rejection Gene Expression Observational (Deng, M. et al., Am JTransplantation 2006), or CARGO, study, which was published in the AmericanJournal of Transplantation. A subsequent clinical utility trial, InvasiveMonitoring Attenuation through Gene Expression (Pham MX et al., N. Eng. J. Med.,2010), or IMAGE, published in The New England Journal of Medicine, demonstratedthat clinical outcomes in recipients managed with AlloMap Heart surveillancewere equivalent (non-inferior) to outcomes in recipients managed withbiopsies. The results of our clinical trials have also been presented at majormedical society congresses. AlloMap Heart is now recommended as part of theInternational Society for Heart and Lung Transplantation, or ISHLT, guidelines.HeartCareHeartCare includes the gene expression profiling technology of AlloMap Heartwith the dd-cfDNA analysis of AlloSure Heart in one surveillance solution. Anapproach to surveillance using HeartCare provides information from twocomplementary measures: (i) AlloMap Heart - a measure of immune activation, and(ii) AlloSure Heart - a measure of graft injury.Clinical validation data from the Donor-Derived Cell-Free DNA-Outcomes AlloMapRegistry (NCT02178943), or D-OAR, was published in American Journal ofTransplant, or AJT, in 2019. D-OAR was an observational, prospective,multicenter study to characterize the AlloSure-Heart dd-cfDNA in a routine,clinical surveillance setting with heart transplant recipients. The D-OAR studywas designed to validate that plasma levels of AlloSure-Heart dd-cfDNA candiscriminate acute rejection from no rejection, as determined by endomyocardialbiopsy criteria.HeartCare provides robust information about distinct biological processes, suchas immune quiescence, active injury, Acute Cellular Rejection, or ACR, andAntibody Mediated Rejection. In September 2018, we initiated the SHORE study.SHORE is a prospective, multi-center, observational, registry of patientsreceiving HeartCare for surveillance. Patients enrolled in SHORE will befollowed for 5 years with collection of clinical data and assessment of 5-yearoutcomes.In August 2019, AlloSure Heart received a positive draft Local CoverageDetermination for Medicare coverage. We have not yet made any applications toprivate payers for reimbursement coverage of AlloSure Heart.KidneyAlloSure Kidney, our transplant surveillance solution, which was commerciallylaunched in October 2017, is our donor-derived cell-free DNA, or dd-cfDNA,offering built on a Next Generation Sequencing, or NGS, platform. Intransplantation, 109 papers from 55 studies globally have shown the value ofdd-cfDNA in the management of solid organ transplantation. AlloSure allowssequencing of DNA and RNA much more quickly than the previously used Sangersequencing. AlloSure is able to discriminate dd-cfDNA from recipient-cell-freeDNA, targeting polymorphisms between donor and recipient. This single-nucleotidepolymorphism, or SNPs, approach across all the somatic chromosomes isspecifically designed for transplantation, allowing a scalable, high-qualitytest to differentiate dd-cfDNA.AlloSure Kidney has received positive coverage decisions for reimbursement fromMedicare. The Medicare reimbursement rate for AlloSure Kidney is $2,841.AlloSure Kidney has also received positive coverage decisions from BCBS SouthCarolina and BCBS Kansas City, and is reimbursed by other private payers on acase-by-case basis. 27-------------------------------------------------------------------------------- Table of ContentsMultiple studies have demonstrated that significant allograft injury can occurin the absence of changes in serum creatinine. Thus, clinicians have limitedability to detect injury early and intervene to prevent long term damage usingthis marker. While histologic analysis of the allograft biopsy specimen remainsthe standard method used to assess injury and differentiate rejection from otherinjury in kidney transplants, as an invasive test with complications, repetitivebiopsies are not well tolerated. AlloSure provides a non-invasive test,assessing allograft injury that enables more frequent, quantitative and saferassessment of allograft rejection and injury status. Beyond allograft rejection,the assessment of molecular inflammation has shown further utility in theassessment of proteinuria, formation of De Novo donor specific antibodies, orDSAs, and also as a surrogate predictive measure of estimated glomerularfiltration rate, or eGFR, decline. Monitoring of graft injury through AlloSureallows clinicians to optimize allograft biopsies, identify allograft injury andguide immunosuppression management more accurately.Since the analytical validation paper in the Journal of Molecular Diagnostics in2016 before the commercial launch of AlloSure Kidney, an increasing body ofevidence supports the use of AlloSure dd-cfDNA in the assessment andsurveillance of kidney transplants. Bloom et al evaluated 102 kidney recipientsand demonstrated that dd-cfDNA levels could discriminate accurately andnon-invasively distinguish rejection from other types of graft injury. Incontrast, serum creatinine has area under the curve, or AUC, of 50%, showing nosignificant difference between patients with and without rejection. Multiplepublications and abstracts have shown AlloSure's value in the management of BKviremia, as well as numerous pathologies that cause molecular inflammation andinjury such as DSAs and eGFR decline. Most recently its utility in theassessment of T-cell mediated rejection (TCMR) 1A and borderline rejection hasalso been published in the AJT.The prospective multicenter trial: Kidney Allograft Outcomes AlloSure KidneyRegistry, or the K-OAR study, is currently ongoing and has enrolled over 1,600patients, with plans to survey patients with AlloSure for 3 years and providefurther clinical utility of AlloSure Kidney in the surveillance of kidneytransplant recipients.KidneyCareKidneyCare combines the dd-cfDNA analysis of AlloSure Kidney with the geneexpression profiling technology of AlloMap Kidney and the predictive artificialintelligence technology of KidneyCare iBox in one surveillance solution. We havenot yet made any applications to payers for reimbursement coverage of AlloMapKidney or KidneyCare iBox.In September 2019, we announced the enrollment of the first patient in the OKRAstudy, which is an extension of the K-OAR study. OKRA is a prospective,multi-center, observational registry of patients receiving KidneyCare forsurveillance. Combined with K-OAR, 4,000 patients will be enrolled into thestudy.LungIn February 2019, AlloSure Lung became available for lung transplant patientsthrough a compassionate use program while the test is undergoing furtherstudies. AlloSure Lung applies proprietary NGS technology to measure dd-cfDNAfrom the donor lung in the recipient bloodstream to monitor graft injury. Wehave not yet made any applications to payers for reimbursement coverage ofAlloSure Lung.Cellular TherapyIn April 2020, we initiated a research partnership for AlloCell, a surveillancesolution that monitors the level of engraftment and persistence of allogeneiccells for patients who have received cell therapy transplants. AlloCell willinitially be commercialized through collaborative research agreements withbiopharma companies developing cell therapies.ProductsWe develop, manufacture, market and sell products that increase the chance ofsuccessful transplants by facilitating a better match between a solid organ orstem cell donor and a recipient, and help to provide post-transplantsurveillance of these recipients.QTYPE enables Human Leukocyte Antigen or HLA typing at a low to intermediateresolution for samples that require a fast turn-around-time and uses real-timepolymerase chain reaction, or PCR, methodology. Olerup SSP is used to type HLAalleles based on the sequence specific primer, or SSP, technology. Olerup SBT isa complete product range for sequence-based typing of HLA alleles.On May 4, 2018, we entered into a license agreement with Illumina, Inc., or theIllumina Agreement, which provides us with worldwide distribution, developmentand commercialization rights to Illumina's NGS products and technologies for usein transplantation diagnostic testing.On June 1, 2018, we became the exclusive worldwide distributor of Illumina'sTruSight HLA product line. TruSight HLA is a high-resolution solution that usesNGS methodology. In addition, we were granted the exclusive right to develop andcommercialize other NGS product lines in the field of bone marrow and solidorgan transplantation on diagnostic testing. These 28-------------------------------------------------------------------------------- Table of ContentsNGS products include: AlloSeq Tx, a high-resolution HLA typing solution, AlloSeqcfDNA, our surveillance solution designed to measure dd-cfDNA in blood to detectactive rejection in transplant recipients, and AlloSeq HCT, a NGS solution forchimerism testing for stem cell transplant recipients.In September 2019, we commercially launched AlloSeq cfDNA, our surveillancesolution designed to measure dd-cfDNA in blood to detect active rejection intransplant recipients, and we received CE mark approval on January 10, 2020. Ourability to increase the clinical uptake for AlloSeq cfDNA will be a result ofmultiple factors including local clinical education, customer lab technicalproficiency and levels of country-specific reimbursement.Also in September 2019, we commercially launched AlloSeq Tx, the first of itskind NGS high-resolution HLA typing solution utilizing hybrid capturetechnology. This technology enables the most comprehensive sequencing, coveringmore of the HLA genes than current solutions and adding coverage of non-HLAgenes that may impact transplant patient matching and management. AlloSeq Tx hassimple NGS workflow, with a single tube for processing and steps to reduceerrors. AlloSeq Tx 17 received CE mark approval on May 15, 2020.In June 2020, we commercially launched AlloSeq HCT, a NGS solution for chimerismtesting for stem cell transplant recipients. This technology can provide bettersensitivity and data analysis compared to current solutions on the market.DigitalIn 2019, we began providing digital solutions to transplant centers followingthe acquisition of Ottr Complete Transplant Management, or OttrCare, andXynManagement, Inc., or XynManagement.On May 7, 2019, we acquired 100% of the outstanding common stock of OttrCare.OttrCare was formed in 1993 and is a leading provider of transplant patienttracking software, or the Ottr software, which provides comprehensive solutionsfor transplant patient management. The Ottr software enables integration withelectronic medical records, systems, including Cerner and Epic, providingpatient surveillance management tools and outcomes data to transplant centers.On August 26, 2019, we acquired 100% of the outstanding common stock ofXynManagement. XynManagement provides two unique solutions, XynQAPI software, orXynQAPI, and Waitlist Management. XynQAPI simplifies transplant quality trackingand Scientific Registry of Transplant Recipients, or SRTR, reporting. WaitlistManagement includes a team of transplant assistants who maintain regular contactwith patients on the waitlist to help prepare for their transplant and maintaineligibility.COVID-19 ImpactIn the final weeks of March and during April 2020, with hospitals increasinglycaring for COVID-19 patients, hospital administrators chose to limit or evendefer, non-emergency procedures. Immunosuppressed transplant patients eitherself-prescribed or were asked to avoid transplant centers and caregiver visitsto reduce the risk of contracting COVID-19. As a result, with transplantsurveillance visits down, we experienced a slowdown in testing services volumesin the final weeks of March and during April 2020. As a response to the COVID-19pandemic, and to enable immune-compromised transplant patients to continue tohave their blood drawn, in late March 2020 we launched RemoTraC, a remotehome-based blood draw solution using mobile phlebotomy for AlloSure and AlloMapsurveillance tests, as well as for other standard monitoring tests. To date,more than 150 transplant centers can offer RemoTraC to their patients and over4,000 kidney, heart, and lung transplant patients have enrolled. Based onexisting and new relationships with partners, we have established a nationwidenetwork of more than 10,000 mobile phlebotomists. Following the introduction ofRemoTraC and with the easing of stay-at-home restrictions and the opening up ofmany hospitals to non-COVID-19 patients, our testing services volumes returnedto levels consistent with those experienced immediately prior to the impact ofCOVID-19, and volumes continued to be at or above those levels throughout May2020 and June 2020. However, our product business experienced a reduction inforecasted sales volume throughout the second quarter 2020, as we were unable toundertake onsite discussions and demonstrations of our recently launched NGSproducts, including AlloSeq Tx 17, which was awarded CE mark approval in May2020.We are maintaining our testing, manufacturing, and distribution facilities whileimplementing specific protocols to reduce contact among our employees. In areaswhere COVID-19 impacts healthcare operations, our field-based sales and clinicalsupport teams are supporting providers through telephone and online platforms.To reduce the risk to employees and their families from potential exposure toCOVID-19, most of our corporate employees have been asked to work from home. Wehave also restricted non-essential business travel to protect the health andsafety of its employees, patients, and customers. In addition, we have created aCOVID-19 task force that is responsible for crisis decision making, employeecommunications, enforcing pre-arrival temperature checking, daily healthcheck-ins and enhanced safety training/protocols in our offices for employeesthat cannot work from home.Due to COVID-19, quarantines, shelter-in-place and similar government orders, orthe perception that such orders, shutdowns or other restrictions on the conductof business operations could occur or could impact personnel at third-partysuppliers in the United States and other countries, or the availability or costof materials, there may be disruptions in our supply chain. Any 29-------------------------------------------------------------------------------- Table of Contentsmanufacturing supply interruption of materials could adversely affect ourability to conduct ongoing and future research and testing activities.In addition, our clinical studies may be affected by the COVID-19 pandemic.Clinical site initiation and patient enrollment may be delayed due toprioritization of hospital resources toward the COVID-19 pandemic. Some patientsmay not be able to comply with clinical study protocols if quarantines impedepatient movement or interrupt healthcare services. Similarly, the ability torecruit and retain patients and principal investigators and site staff who, ashealthcare providers, may have heightened exposure to COVID-19, may adverselyimpact our clinical trial operations.Financial Operations OverviewRevenueWe derive our revenue from testing services, products sales and digital andother revenues. Revenue is recorded considering a five-step revenue recognitionmodel that includes identifying the contract with a customer, identifying theperformance obligations in the contract, determining the transaction price,allocating the transaction price to the performance obligations and recognizingrevenue when, or as, an entity satisfies a performance obligation.Testing Services RevenueOur testing services revenue is derived from AlloSure Kidney and AlloMap Hearttests, which represented 87% and 84% of our total revenues for the three and sixmonths ended June 30, 2020, respectively, and 82% of our total revenues for eachof the three and six months ended June 30, 2019. Our testing services revenuedepends on a number of factors, including (i) the number of tests performed;(ii) establishment of coverage policies by third-party insurers and governmentpayers; (iii) our ability to collect from payers with whom we do not havepositive coverage determination, which often requires that we pursue acase-by-case appeals process; (iv) our ability to recognize revenues on testsbilled prior to the establishment of reimbursement policies, contracts orpayment histories; (v) our ability to expand into markets outside of the UnitedStates; and (vi) how quickly we can successfully commercialize new productofferings.We currently market testing services to healthcare providers through our directsales force that targets transplant centers and their physicians, coordinatorsand nurse practitioners. The healthcare providers that order the tests and onwhose behalf we provide our testing services are generally not responsible forthe payment of these services. Amounts received by us vary from payer to payerbased on each payer's internal coverage practices and policies. We generallybill third-party payers upon delivery of a test result report to the orderingphysician. As such, we take the assignment of benefits and the risk ofcollection from the third-party payer and individual patients.In April 2020, we announced our first biopharma research partnership forAlloCell, a surveillance solution that monitors the level of engraftment andpersistence of allogeneic cells for patients who have received cell therapytransplants. AlloCell will initially be commercialized through collaborativeresearch agreements with biopharma companies developing cell therapies.Product RevenueOur product revenue is derived primarily from sales of Olerup SSP, QTYPE,TruSight and AlloSeq Tx products. Product revenue represented 8% and 10% oftotal revenue for the three and six months ended June 30, 2020, respectively,and 15% and 16% of total revenue for the three and six months ended June 30,2019, respectively. We recognize product revenue from the sale of products toend-users, distributors and strategic partners when all revenue recognitioncriteria are satisfied. We generally have a contract or a purchase order from acustomer with the specified required terms of order, including the number ofproducts ordered. Transaction prices are determinable and products are deliveredand risk of loss passed to the customer upon either shipping or delivery, as perthe terms of the agreement. There are no further performance obligations relatedto a contract and revenue is recognized at the point of delivery consistent withthe terms of the contract or purchase order.Digital and Other RevenueOur digital and other revenue is mainly derived from sales of our Ottr softwareand XynQAPI licenses and services and other licensing agreements. Digital andother revenue represented 5% and 6% of total revenue for the three and sixmonths ended June 30, 2020, respectively, and 4% and 2% of total revenue for thethree and six months ended June 30, 2019, respectively.Critical Accounting Policies and Significant Judgments and EstimatesOur management's discussion and analysis of our financial condition and resultsof operations is based on our unaudited condensed consolidated financialstatements, which have been prepared in accordance with United States generallyaccepted accounting principles. The preparation of these unaudited condensedconsolidated financial statements requires us to make estimates and assumptionsthat affect the reported amounts of assets and liabilities and the disclosure ofcontingent assets and liabilities at the date of the unaudited condensedconsolidated financial statements, as well as the reported revenue generated 30-------------------------------------------------------------------------------- Table of Contentsand expenses incurred during the reporting periods. Our estimates are based onour historical experience and on various other factors that we believe arereasonable under the circumstances, the results of which form the basis formaking judgments about the carrying value of assets and liabilities that are notreadily apparent from other sources. Actual results may differ from theseestimates under different assumptions or conditions.We believe that the following critical accounting policies reflect the moresignificant estimates and assumptions used in the preparation of our financialstatements. We believe the following critical accounting policies are affectedby significant judgments and estimates used in the preparation of our unauditedcondensed consolidated financial statements:Revenue recognition;Business combination;Acquired intangible assets;Impairment of goodwill, intangible assets and other long-lived assets; andCommon stock warrant liability.There were no material changes in the matters for which we make criticalaccounting estimates in the preparation of our unaudited condensed consolidatedfinancial statements during the three and six months ended June 30, 2020 ascompared to those disclosed in Management's Discussion and Analysis of FinancialCondition and Results of Operations included in our annual report on Form 10-Kfor the year ended December 31, 2019, except that there is no derivativeliability outstanding as of December 31, 2019 and June 30, 2020 and thedetermination of the estimated present value of lease payments using ourincremental borrowing rate as discussed in Note 2, Summary of SignificantAccounting Policies, in the unaudited condensed consolidated financialstatements included elsewhere in this Quarterly Report on Form 10-Q.Recently Issued Accounting StandardsRefer to Note 2, Summary of Significant Accounting Policies - Recent AccountingPronouncements, to the unaudited condensed consolidated financial statementsincluded elsewhere in this Quarterly Report on Form 10-Q for a description ofrecently issued accounting pronouncements, including the expected dates ofadoption and estimated effects on our results of operations, financial positionand cash flows. 31-------------------------------------------------------------------------------- Table of ContentsResults of OperationsComparison of the Three Months Ended June 30, 2020 and 2019(In thousands) Three Months Ended June 30, 2020 2019 ChangeRevenue:Testing services revenue $ 36,293$ 25,677$ 10,616Product revenue 3,291 4,593 (1,302)Digital and other revenue 2,217 1,184 1,033Total revenue 41,801 31,454 10,347Cost of revenue 15,025 11,512 3,513Gross profit 26,776 19,942 6,834Operating expenses:Research and development 13,129 7,630 5,499Sales and marketing 12,134 10,644 1,490General and administrative 12,316 8,512 3,804Total operating expenses 37,579 26,786 10,793Loss from operations (10,803) (6,844) (3,959)Other income (expense):Interest income, net 21 300 (279)

Change in estimated fair value of common stock warrantliability

Change in estimated fair value of common stock warrantliability

Effect of exchange rate changes on cash, cash equivalents andrestricted cash

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Progenitor Cell Product Market Provides In-Depth Analysis of the Industry, With Current Trends and Future Estimations to Elucidate The Investment…

Up Market Research (UMR), a prominent market research firm in its own industry, has published a detailed report on Global Progenitor Cell Product Market. This market research report provides comprehensive and in-depth analysis on the market which can possibly help an enterprise to identify lucrative opportunities and assist them with fabricating creative business strategies. The market report provides information about the current market scenario regarding the global supply and demand, key market trends and opportunities in the market, and challenges and threats faced by the industry players.

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Impacts of Advancements and COVID-19 on the market.

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Market Segmentation

Some of the major companies that are covered in the report.

NeuroNova ABStemCellsReNeuron LimitedAsterias BiotherapeuticsThermo Fisher ScientificSTEMCELL TechnologiesAxol BioR&D SystemsLonzaATCCIrvine ScientificCDI

Note: Additional companies

Based on the type, the market is segmented into

Pancreatic progenitor cellsCardiac Progenitor CellsIntermediate progenitor cellsNeural progenitor cells (NPCs)Endothelial progenitor cells (EPC)Others

Based on the application, the market is segregated into

Medical careHospitalLaboratory

Based on the geographical location, the market is segregated into

Asia Pacific: China, Japan, India, and Rest of Asia PacificEurope: Germany, the UK, France, and Rest of EuropeNorth America: The US, Mexico, and CanadaLatin America: Brazil and Rest of Latin AmericaMiddle East & Africa: GCC Countries and Rest of Middle East & Africa

Up Market Research (UMR) provides yearly updates on the Progenitor Cell Product market that assist the clients to stay ahead in the competitive space.

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The market research report provides all valuable constituents of the market such as revenue growth, product pricing & analysis, growth potential, and guidelines to tackle the challenges in the market. The report covers all the crucial mergers & acquisitions, partnerships, and collaborations that created further created opportunities or in some cases, challenges for the industry players.

This report includes latest product news, advancements, and updates from the prominent player of the industry that has leveraged their position in the market. It also provides business strategies implemented by the key players and yardstick to arrive on informed business decisions. Moreover, it gives insights on the consumer behavior patterns that can help the enterprise to curate the business strategies accordingly.

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Complete Table Content of the Market

Executive Summary

Assumptions and Acronyms Used

Research Methodology

Progenitor Cell Product Market Overview

Progenitor Cell Product Supply Chain Analysis

Progenitor Cell Product Pricing Analysis

Global Progenitor Cell Product Market Analysis and Forecast by Type

Global Progenitor Cell Product Market Analysis and Forecast by Application

Global Progenitor Cell Product Market Analysis and Forecast by Sales Channel

Global Progenitor Cell Product Market Analysis and Forecast by Region

North America Progenitor Cell Product Market Analysis and Forecast

Latin America Progenitor Cell Product Market Analysis and Forecast

Europe Progenitor Cell Product Market Analysis and Forecast

Asia Pacific Progenitor Cell Product Market Analysis and Forecast

Middle East & Africa Progenitor Cell Product Market Analysis and Forecast

Competition Landscape

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About the Company

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Global Amniotic Fluid Stem Cell Therapy Market to Witness Rapid Development During the Period 2018 2026 – Market Research Vista

Stem cells are biological cells which have the ability to distinguish into specialized cells, which are capable of cell division through mitosis. Amniotic fluid stem cells are a collective mixture of stem cells obtained from amniotic tissues and fluid. Amniotic fluid is clear, slightly yellowish liquid which surrounds the fetus during pregnancy and is discarded as medical waste during caesarean section deliveries. Amniotic fluid is a source of valuable biological material which includes stem cells which can be potentially used in cell therapy and regenerative therapies. Amniotic fluid stem cells can be developed into a different type of tissues such as cartilage, skin, cardiac nerves, bone, and muscles. Amniotic fluid stem cells are able to find the damaged joint caused by rheumatoid arthritis and differentiate tissues which are damaged. Medical conditions where no drug is able to lessen the symptoms and begin the healing process are the major target for amniotic fluid stem cell therapy. Amniotic fluid stem cells therapy is a solution to those patients who do not want to undergo surgery. Amniotic fluid has a high concentration of stem cells, cytokines, proteins and other important components. Amniotic fluid stem cell therapy is safe and effective treatment which contain growth factor helps to stimulate tissue growth, naturally reduce inflammation. Amniotic fluid also contains hyaluronic acid which acts as a lubricant and promotes cartilage growth.

With increasing technological advancement in the healthcare, amniotic fluid stem cell therapy has more advantage over the other therapy. Amniotic fluid stem cell therapy eliminates the chances of surgery and organs are regenerated, without causing any damage. These are some of the factors driving the growth of amniotic fluid stem cell therapy market over the forecast period. Increasing prevalence of chronic diseases which can be treated with the amniotic fluid stem cell therapy propel the market growth for amniotic fluid stem cell therapy, globally. Increasing funding by the government in research and development of stem cell therapy may drive the amniotic fluid stem cell therapy market growth. But, high procedure cost, difficulties in collecting the amniotic fluid and lack of reimbursement policies hinder the growth of amniotic fluid stem cell therapy market.

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The global amniotic fluid stem cell therapy market is segmented on basis of treatment, application, end user and geography:

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Rapid technological advancement in healthcare, and favorable results of the amniotic fluid stem cells therapy will increase the market for amniotic fluid stem cell therapy over the forecast period. Increasing public-private investment for stem cells in managing disease and improving healthcare infrastructure are expected to propel the growth of the amniotic fluid stem cell therapy market.

However, on the basis of geography, global Amniotic Fluid Stem Cell Therapy Market is segmented into six key regionsviz. North America, Latin America, Europe, Asia Pacific Excluding China, China and Middle East & Africa. North America captured the largest shares in global Amniotic Fluid Stem Cell Therapy Market and is projected to continue over the forecast period owing to technological advancement in the healthcare and growing awareness among the population towards the new research and development in the stem cell therapy. Europe is expected to account for the second largest revenue share in the amniotic fluid stem cell therapy market. The Asia Pacific is anticipated to have rapid growth in near future owing to increasing healthcare set up and improving healthcare expenditure. Latin America and the Middle East and Africa account for slow growth in the market of amniotic fluid stem cell therapy due to lack of medical facilities and technical knowledge.

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Some of the key players operating in global amniotic fluid stem cell therapy market are Stem Shot, Provia Laboratories LLC, Thermo Fisher Scientific Inc. Mesoblast Ltd., Roslin Cells, Regeneus Ltd. etc. among others.

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Exosome Therapeutic Market Size, 2020-New Technological Change Helping Market, Application, Driver, Trends, Share and Forecasts by 2027 – Bulletin…

A New Business Intelligence Report released by Data Bridge Market Research with title GlobalExosome Therapeutic Marketsize, share, growth, Industry Trends and Forecast 2027 has abilities to raise as the most significant market worldwide as it has remained playing a remarkable role in establishing progressive impacts on the universal economy. The Global Exosome Therapeutic Market Report offers energetic visions to conclude and study the market size, market hopes, and competitive surroundings. The research is derived through primary and secondary statistics sources and it comprises both qualitative and quantitative detailing. This report has been crafted as the result of persistent efforts lead by knowledgeable forecasters, innovative analysts and brilliant researchers who indulge in detailed and diligent research on different markets, trends and emerging opportunities in the successive direction for the business needs.

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DBMR Analyses that the Exosome Therapeutic Market is growing with a CAGR of 21.9% in the forecast period of 2019 to 2026 and expected to reach USD 31,691.52 million by 2026 from USD 6,500.00 million in 2018. Increasing prevalence of lyme disease, chronic inflammation, autoimmune disease and other chronic degenerative diseases are the factors for the market growth.

Increased number of exosome therapeutics as compared to the past few years will accelerate market growth. Companies are receiving funding for exosome therapeutic research and clinical trials. For instance, In September 2018, EXOCOBIO has raised USD 27 million in its series B funding. The company has raised USD 46 million as series a funding in April 2017. The series B funding will help the company to set up GMP-compliant exosome industrial facilities to enhance production of exosomes to commercialize in cosmetics and pharmaceutical industry.

KNOW YOUR OPTIONS IN THE FIGHT AGAINST COVID-19

The COVID-19 Pandemic has created bottlenecks across industry pipelines, sales funnels, and supply chain activities. This has created unprecedented budget pressure on company spending for industry leaders. This has increased requirement for opportunity analysis, price trend knowledge and competitive outcomes. Use the DBMR team to create new sales channels and capture new markets previously unknown. DBMR helps its clients to grow in these uncertain markets.

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The Global Exosome Therapeutic market 2020 research provides a basic overview of the industry including definitions, classifications, applications and industry chain structure. The Global Exosome Therapeutic Market Share analysis is provided for the international markets including development trends, competitive landscape analysis, and key regions development status. Development policies and plans are discussed as well as manufacturing processes and cost structures are also analyzed. This report also states import/export consumption, supply and demand Figures, cost, price, revenue and gross margins. For each manufacturer covered, this report analyzes their Exosome Therapeutic manufacturing sites, capacity, production, ex-factory price, revenue and market share in global market.

Major Players in Global Exosome Therapeutic Market Include

evox THERAPEUTICSEXOCOBIOExopharmAEGLE TherapeuticsUnited Therapeutics CorporationCodiak BioSciencesJazz Pharmaceuticals, Inc.Boehringer Ingelheim International GmbHReNeuron Group plcCapricor TherapeuticsAvalon Globocare Corp.CREATIVE MEDICAL TECHNOLOGY HOLDINGS INC.Stem Cells Group..

Complete Report is Available (Including Full TOC, List of Tables & Figures, Graphs, and Chart)@https://www.databridgemarketresearch.com/toc/?dbmr=global-exosome-therapeutic-market

New Exosome Therapeutic Market Developments in 2019

In January 2019, Codiak BioSciences has collaborated with Jazz Pharmaceuticals, Inc. to develop and commercialize exosome therapeutics to treat cancer. The collaboration will help the company to address issues which have been often implicated in solid tumors and hematological malignancies.

In October 2018, Avalon GloboCare Corp. has collaborated with Weill Cornell Medicine to form standards in cGMP-grade for human endothelial cells sourced exosome which is significant for organ regeneration and vascular health and isolation and identification of exosomes sourced from tissue for liquid biopsy and clinical use. The collaboration will help the company to lead market as exosome isolation system as will be first in the world for standardization processing of cGMP-grade exosomes for clinical studies.

In July 2018, Capricor Therapeutics has formed collaboration with the U.S. Army Institute of Surgical Research (USAISR) to discover potential for CAP-2003 (exosomes) in order to address trauma-related conditions and injuries. The collaboration will help to test CAP-2003 as a tool for preservation of life.

This research is categorized differently considering the various aspects of this market. It also evaluates the current situation and the future of the market by using the forecast horizon. The forecast is analyzed based on the volume and revenue of this market. The tools used for analyzing the Global Exosome Therapeutic Market research report include SWOT analysis.

The Global Exosome Therapeutic segments and Market Data Break Down are illuminated below:

By Type (Natural Exosomes, Hybrid Exosomes

By Source (Dendritic Cells, Mesenchymal Stem Cells, Blood, Milk, Body Fluids, Saliva, Urine Others)

By Therapy (Immunotherapy, Gene Therapy, Chemotherapy)

By Transporting Capacity (Bio Macromolecules, Small Molecules

By Application (Oncology, Neurology, Metabolic Disorders, Cardiac Disorders, Blood Disorders, Inflammatory Disorders, Gynecology Disorders, Organ Transplantation, Others)

By Route of administration (Oral, Parenteral)

By End User (Hospitals, Diagnostic Centers, Research & Academic Institutes)

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The Global Exosome Therapeutic Market in terms of investment potential in various segments of the market and illustrate the feasibility of explaining the feasibility of a new project to be successful in the near future. The core segmentation of the global market is based on product types, SMEs and large corporations. The report also collects data for each major player in the market based on current company profiles, gross margins, sales prices, sales revenue, sales volume, photos, product specifications and up-to-date contact information.

What are the strengths and weaknesses of the key vendors?

Definitively, this report will give you an unmistakable perspective on every single reality of the market without a need to allude to some other research report or an information source. Our report will give all of you the realities about the past, present, and eventual fate of the concerned Market.

Scope of the Exosome Therapeutic Market

The global exosome therapeutic market is segmented on the basis of countries into U.S., Mexico, Turkey, Hong Kong, Australia, South Korea, Argentina, Colombia, Peru, Chile, Ecuador, Venezuela, Panama, Dominican Republic, El Salvador, Paraguay, Costa Rica, Puerto Rico, Nicaragua and Uruguay.

All country based analysis of the exosome therapeutic market is further analyzed based on maximum granularity into further segmentation. On the basis of type, the market is segmented into natural exosomes and hybrid exosomes. Based on source, the market is segmented into dendritic cells, mesenchymal stem cells, blood, milk, body fluids, saliva, urine and others. On the basis of therapy, the market is segmented into immunotherapy, gene therapy and chemotherapy. On the basis of transporting capacity, the market is segmented into bio macromolecules and small molecules. On the basis of application, the market is segmented into oncology, neurology, metabolic disorders, cardiac disorders, blood disorders, inflammatory disorders, gynecology disorders, organ transplantation and others. On the basis of route of administration, the market is segmented into pa oral and parenteral. On the basis of end user, the market is segmented into hospitals, diagnostic centers and research & academic institutes and others.

Some Points from Table of Content:

1 Report Overview1.1 Study Scope1.2 Key Market Segments1.3 Regulatory Scenario by Region/Country1.4 Market Investment Scenario Strategic1.5 Market Analysis by Type1.5.1 Global Exosome Therapeutic Market Share by Type (2020-2027)1.5.2 Type 11.5.3 Type 21.5.4 Other1.6 Market by Application1.6.1 Global Exosome Therapeutic Market Share by Application (2020-2027)1.6.2 Application 11.6.3 Application 21.6.4 Other1.7 Exosome Therapeutic Industry Development Trends under COVID-19 Outbreak1.7.1 Region COVID-19 Status Overview1.7.2 Influence of COVID-19 Outbreak on Exosome Therapeutic Industry Development

Global Market Growth Trends2.1 Industry Trends2.1.1 SWOT Analysis2.1.2 Porters Five Forces Analysis2.2 Potential Market and Growth Potential Analysis2.3 Industry News and Policies by Regions2.3.1 Industry News2.3.2 Industry Policies3 Value Chain of Exosome Therapeutic Market3.1 Value Chain Status3.2 Exosome Therapeutic Manufacturing Cost Structure Analysis3.2.1 Production Process Analysis3.2.2 Manufacturing Cost Structure of Exosome Therapeutic3.2.3 Labor Cost of Exosome Therapeutic3.3 Sales and Marketing Model Analysis3.4 Downstream Major Customer Analysis (by Region)

4 Players Profiles4.1 Player 14.1.1 Player 1 Basic Information4.1.2 Exosome Therapeutic Product Profiles, Application and Specification4.1.3 Player 1 Exosome Therapeutic Market Performance (2015-2020)4.1.4 Player 1 Business Overview4.2 Player 24.2.1 Player 2 Basic Information4.2.2 Exosome Therapeutic Product Profiles, Application and Specification4.2.3 Player 2 Exosome Therapeutic Market Performance (2015-2020)4.2.4 Player 2 Business Overview4.3 Player 34.3.1 Player 3 Basic Information4.3.2 Exosome Therapeutic Product Profiles, Application and Specification4.3.3 Player 3 Exosome Therapeutic Market Performance (2015-2020)4.3.4 Player 3 Business Overview4.4 Player 44.4.1 Player 4 Basic Information4.4.2 Exosome Therapeutic Product Profiles, Application and Specification4.4.3 Player 4 Exosome Therapeutic Market Performance (2015-2020)4.4.4 Player 4 Business Overview4.5 Player 54.5.1 Player 5 Basic Information4.5.2 Exosome Therapeutic Product Profiles, Application and Specification4.5.3 Player 5 Exosome Therapeutic Market Performance (2015-2020)

4.5.4 Player 5 Business Overview5 Global Exosome Therapeutic Market Analysis by Regions5.1 Global Exosome Therapeutic Sales, Revenue and Market Share by Regions5.1.1 Global Exosome Therapeutic Sales by Regions (2015-2020)5.1.2 Global Exosome Therapeutic Revenue by Regions (2015-2020)5.2 North America Exosome Therapeutic Sales and Growth Rate (2015-2020)5.3 Europe Exosome Therapeutic Sales and Growth Rate (2015-2020)5.4 Asia-Pacific Exosome Therapeutic Sales and Growth Rate (2015-2020)5.5 Middle East and Africa Exosome Therapeutic Sales and Growth Rate (2015-2020)5.6 South America Exosome Therapeutic Sales and Growth Rate (2015-2020)

11 Global Exosome Therapeutic Market Segment byTypes12 Global Exosome Therapeutic Market Segment by Applications13 Exosome Therapeutic Market Forecast by Regions (2020-2027)ContinuedComplete Report Is Available| Get Free TOC @https://www.databridgemarketresearch.com/toc/?dbmr=global-exosome-therapeutic-market

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Exosome Therapeutic Market Size, 2020-New Technological Change Helping Market, Application, Driver, Trends, Share and Forecasts by 2027 - Bulletin...

Global Stem Cell Reconstructive Market- Industry Analysis and Forecast (2020-2027)-by Sources, Cell Type, Application, End User and Region. – WOLE TV

Global Stem Cell Reconstructive Marketwas valued US$ XX Mn in 2019 and is expected to reach US$ XX Mn by 2027, at a CAGR of 24.5% during a forecast period.

Market Dynamics

The Research Report gives an in-depth account of the drivers and restraints in the stem cell reconstructive market. Stem cell reconstructive surgery includes the treatment of injured or dented part of body. Stem cells are undifferentiated biological cells, which divide to produce more stem cells. Growing reconstructive surgeries led by the rising number of limbs elimination and implants and accidents are boosting the growth in the stem cell reconstructive market. Additionally, rising number of aged population, number of patients suffering from chronic diseases, and unceasing development in the technology, these are factors which promoting the growth of the stem cell reconstructive market. Stem cell reconstructive is a procedure containing the use of a patients own adipose tissue to rise the fat volume in the area of reconstruction and therefore helping 3Dimentional reconstruction in patients who have experienced a trauma or in a post-surgical event such as a mastectomy or lumpectomy, brain surgery, or reconstructive surgery as a result of an accident or injury. Stem cell reconstructive surgeries are also used in plastic or cosmetic surgeries as well. Stem cell and regenerative therapies gives many opportunities for development in the practice of medicine and the possibility of an array of novel treatment options for patients experiencing a variety of symptoms and conditions. Stem cell therapy, also recognised as regenerative medicine, promotes the repair response of diseased, dysfunctional or injured tissue using stem cells or their derivatives.

The common guarantee of all the undifferentiated embryonic stem cells (ESCs), foetal, amniotic, UCB, and adult stem cell types is their indefinite self-renewal capacity and high multilineage differentiation potential that confer them a primitive and dynamic role throughout the developmental process and the lifespan in adult mammal.However, the high expenditure of stem cell reconstructive surgeries and strict regulatory approvals are restraining the market growth.

The report study has analyzed revenue impact of covid-19 pandemic on the sales revenue of market leaders, market followers and disrupters in the report and same is reflected in our analysis.

Global Stem Cell Reconstructive Market Segment analysis

Based on Cell Type, the embryonic stem cells segment is expected to grow at a CAGR of XX% during the forecast period. Embryonic stem cells (ESCs), derived from the blastocyst stage of early mammalian embryos, are distinguished by their capability to distinguish into any embryonic cell type and by their ability to self-renew. Owing to their plasticity and potentially limitless capacity for self-renewal, embryonic stem cell therapies have been suggested for regenerative medicine and tissue replacement after injury or disease. Additionally, their potential in regenerative medicine, embryonic stem cells provide a possible another source of tissue/organs which serves as a possible solution to the donor shortage dilemma. Researchers have differentiated ESCs into dopamine-producing cells with the hope that these neurons could be used in the treatment of Parkinsons disease. Upsurge occurrence of cardiac and malignant diseases is promoting the segment growth. Rapid developments in this vertical contain protocols for directed differentiation, defined culture systems, demonstration of applications in drug screening, establishment of several disease models, and evaluation of therapeutic potential in treating incurable diseases.

Global Stem Cell Reconstructive Market Regional analysis

The North American region has dominated the market with US$ XX Mn. America accounts for the largest and fastest-growing market of stem cell reconstructive because of the huge patient population and well-built healthcare sector. Americas stem cell reconstructive market is segmented into two major regions such as North America and South America. More than 80% of the market is shared by North America due to the presence of the US and Canada.

Europe accounts for the second-largest market which is followed by the Asia Pacific. Germany and UK account for the major share in the European market due to government support for research and development, well-developed technology and high healthcare expenditure have fuelled the growth of the market. This growing occurrence of cancer and diabetes in America is the main boosting factor for the growth of this market.

The objective of the report is to present a comprehensive analysis of the Global Stem Cell Reconstructive Market including all the stakeholders of the industry. The past and current status of the industry with forecasted market size and trends are presented in the report with the analysis of complicated data in simple language. The report covers all the aspects of the industry with a dedicated study of key players that includes market leaders, followers and new entrants. PORTER, SVOR, PESTEL analysis with the potential impact of micro-economic factors of the market has been presented in the report. External as well as internal factors that are supposed to affect the business positively or negatively have been analysed, which will give a clear futuristic view of the industry to the decision-makers.

The report also helps in understanding Global Stem Cell Reconstructive Market dynamics, structure by analysing the market segments and projects the Global Stem Cell Reconstructive Market size. Clear representation of competitive analysis of key players by Application, price, financial position, Product portfolio, growth strategies, and regional presence in the Global Stem Cell Reconstructive Market make the report investors guide.Scope of the Global Stem Cell Reconstructive Market

Global Stem Cell Reconstructive Market, By Sources

Allogeneic Autologouso Bone Marrowo Adipose Tissueo Blood Syngeneic OtherGlobal Stem Cell Reconstructive Market, By Cell Type

Embryonic Stem Cell Adult Stem CellGlobal Stem Cell Reconstructive Market, By Application

Cancer Diabetes Traumatic Skin Defect Severe Burn OtherGlobal Stem Cell Reconstructive Market, By End-User

Hospitals Research Institute OthersGlobal Stem Cell Reconstructive Market, By Regions

North America Europe Asia-Pacific South America Middle East and Africa (MEA)Key Players operating the Global Stem Cell Reconstructive Market

Osiris Therapeutics NuVasives Cytori Therapeutics Takeda (TiGenix) Cynata Celyad Medi-post Anterogen Molmed Baxter Eleveflow Mesoblast Ltd. Micronit Microfluidics TAKARA BIO INC. Tigenix Capricor Therapeutics Astellas Pharma US, Inc. Pfizer Inc. STEMCELL Technologies Inc.

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Best hair transplant clinics in the world – The Upcoming

Best hair transplant clinics in the world

Hair restoration is a surgical performance which entails the removal of hair from an area known as the donor site to an area facing balding which is called the receiving site. This method is primarily used to counter alopecia in males as it is a less invasive technique which uses grafts containing grafts which have hair follicles that are genetically resistant to balding. These grafts are most often harvested from the back of the head. The harvested hair is then transplanted to the patchy region. Hair restoration can also be used to restore eyebrows, eyelashes, beard hair, pubic hair, and chest hair. Hair restoration is also possible in areas that have experienced hair loss as a result of scars from accidents or surgery, such as previous hair transplant surgery. There are two conventional methods for hair restoration hair transplanting and skin grafting. In a skin grafting procedure, the grafts harbour nearly all the dermis and epidermis neighbouring the hair follicles. A hair transplant involves numerous little grafts which are replaced instead of a distinct strip of skin.

Hair restoration is not a new pursuit. For instance, dating back to the 19th century is the use of scalp blinkers, such that a band of tissue containing the unique blood resource is allocated to another bald area. Back in 1897, Menahem Hodara successfully transplanted hair that was sourced from the unaffected regions of the scalp to the scars that were left bare by favus. The use of modern transplant methods started back in the 1930s, when the surgical team made use of small grafts and follicular unit grafts to substitute the impaired regions of the eyelashes and the eyebrows. Still, the method was not used to treat baldness. The surgeons continuous efforts did not receive any attention, and the traumas caused by World War II kept their discoveries unknown for the subsequent two decades.

The current age of hair restoration in the western world began in the late 1950s when the then New York-based Norman Orentreich started experimentation using free donor grafts to zones that had been faced by alopecia in patients experiencing male-related baldness. Earlier on, it was supposed that the restored hair would not flourish just like the unique hair in the receiving region.

Follicular Unit Extraction (FUE) is the favoured method for hair restoration. Dr. Asim Shahmalak, MD, hair transplant surgeon, broadcaster and founder of the Crown Clinic in Manchester, says 70% of his clients opt for the FUE method. The procedure takes about six to seven hours, with many clients going home the same day. Dr. Shahmalak explains: With FUE, specific follicles are detached from the back and side of the scalp and then transferred by a surgeon to the balding regions, which are mainly the top of the scalp. The benefit of this technique is that there is minimal scarring. The patients who opt for this method usually tend to heal after two weeks. FUE is predominantly appropriate for clients who like their hair short or shaved, as the scars are hardly noticeable. During the process, the giver part, which is usually the back of the scalp, is numbed with an anaesthetic. Then the donor follicles are detached separately, leaving behind minor scars where the hair is attached.

In the last few years, FUE has increased in popularity relative to Follicular Unit Transplantation (FUT). This can, in part, be attributed to the growing number of celebrities who have chosen FUE. FUE is also recommended for men who want to shave their heads or wear their hair short. The FUE technique is also faster, with an average of five hours to complete a procedure. This is because the extraction of hair from the hair follicles is quicker. FUE will also deliver a faster healing process than FUT, as in FUT a strip of skin is detached from a patient so as to get the donor hair rather than the separate follicles.

Best hair transplant clinics

CapilClinic, the largest private hospital group in Istanbul, specialises in hair transplantation. They are the leader in the field of hair transplants and the primary referral hospital recognised as the international model for the best service and results. CapilClinic began operations in 2015. The facility is known for its world-renowned medical staff, many of them with more than ten years of experience in hair transplantation procedures and patients from all over the world. The facility outshines the others as a result of its renowned specialists, top-notch facilities, state-of-the-art equipment, machinery and tools.

Dr Ouz Kayiran is a plastic surgeon, aesthetic surgeon and medical director at CapilClinic. As a plastic surgeon, he has over nine years experience in the industry, regularly takes part in cutting edge scientific research, and is featured in international publications.

The clinic has a luxury hotel used to accommodate its clients from abroad before they jet back to their home country. The hotel is located in the Kadky area of Istanbul, a large, populous and cosmopolitan district that boasts colourful murals, indie boutiques, hip cafes and Anatolian eateries. The hotel provides wireless internet in the rooms, business centre, meeting areas, and public areas.

As an added benefit to your luxury experience at CapilClinic, the hospital provides concierge airport transfers for its patients. CapilClinic will have a staff member at the airport waiting to receive you on arrival and then transfer you to the hotel. It is not uncommon on arrival in Istanbul for travellers to complain about long waits or delays at the airport. CapilClinic has removed that obstacle for its patients. Simply identify yourself to the waiting driver and enjoy a quick transfer to the hotel.

https://www.capilclinic.uk

Dr. Thomas Frist started the Hospital Corporation of America (HCA) in 1968. He had a dream to generate a healthcare institution with scope, expertise, and resources to provide the highest global standards of client care. HCA now has over 300 branches in the US and the UK and boasts 37,000 doctors, 240,000 nurses and a total of 27 million patient visits each year. Experienced staff strive to provide a quality of service and excellence that they desire for themselves, family members and loved ones.

HCA opened in the UK in 1995. Since that time, the institution has put up a world-class chain of more than thirty clinics in London and Manchester, equipped with modern diagnostic and handling equipment. In 2017, they expanded their operations to include diagnostic and outpatient services in Elstree, Chelsea, Marylebone, and Chiswick, thereby conveying high-quality services to those communities.

Patient care is the priority at the Harley Street Clinic. The clinic provides a variety of compound care for patients, through its specialisation in areas such as neurosciences for adults, children and babies, cardiology, and oncology. From heart surgery of newborn infants to the leading procedures for combating cancer, the technicians work in harmony to render exceptional service and treatments for their clients. The hospital also has one of the biggest private paediatric ICU units in Europe, with 12 beds. The paediatric ICU facilitates a variety of complicated treatments for babies and children, including thoracic and cardiac surgery, spinal surgery, and cancer care. The hospital is proud to be working with world-class experts who also have jobs in the UKs leading NHS teaching hospitals. Consultants, expert in their respective fields, have offices at the hospital; they look after their patients themselves throughout the entire treatment process.

Bernstein Medical is a renowned hair transplant clinic and also a referral centre devoted to the treatment of alopecia in both genders with the use of state-of-the-art technologies. It was founded by the worlds leading hair transplant developer, Dr. Robert M. Bernstein, back in the year 2005. The clinic is situated in midtown Manhattan, New York City. Hair restoration surgery at this clinic is conducted using the FUT and FUE methods, which were introduced by Dr. Bernstein. FUE technique is performed with the use of the mechanical hair transplant system. The clinic provides the best and highest level of care and treatment to the patients who visit them.

Dr. Bernstein is a pioneer of the current hair transplant surgery and founder of Bernstein Medical, which caters to all hair transplantation needs in New York City. Dr. Bernstein is globally recognised for having introduced the FUE and FUT to the medical community. These are the techniques that revolutionizsd the surgical hair restoration industry.

Bernstein Clinic offers the following services to its clients:

Located in Vancouver, Canada, the Hasson & Wong Clinic is proud of its results from hair transplant procedures. They feature their work on the company webpage with clear photos of real patients that have undergone hair restoration procedures at their clinic.

Hasson & Wong Clinic takes pride in the number of patients who, at their own initiative, have gone to the internet to document their positive experience and applaud the quality of their medical staff and facilities. The vast majority of their clients are pleased with the achieved results.

This clinic has acquired a global reputation for its consistency in offering excellent results. They welcome patients from all over the world, with approximately 50 per cent of the patients originating from Europe, Canada, the United States and Asia.

For hair restoration surgery, Hasson & Wong is one of the best hair restoration clinics to help patients achieve their desired goals.

Their team of professionals offer world-class service to the patients who visit the facility.

Dr. Jerry Wong graduated with a medical doctor degree from the University of Alberta. He then worked for many years as a GP at a hospital in Maple Ridge, Canada. In 1991, Dr. Dorman, a hair renewal surgeon based in Vancouver, ushered Dr. Wong into the field of hair restoration. Dr. Wong was excited about the microsurgical method of the technique. In 1992, he attended a hair transplant surgery school in Australia. On top of micro-mini grafting, he also obtained the necessary skills to perform lift and lap techniques and scalp reductions. Trained know-how in major scalp surgery is important for repair cases. Since then, the two doctors have remained to be great friends, taking part in conferences and occasionally sharing vacations.

Hasson & Wong Clinic is consistently able to work for long hours as a result of the experienced and dedicated team of surgeons. They have also been able to conduct massive mega sessions of hair restoration at their clinic with efficiency and safety, acquiring more than 5000 grafts over a single session. Their dedication to the development of hair restoration procedures is evidenced by the contribution they have made to the medical community.

Founded by Beverly Hills hair professionals Dr. George Abrahamian and Jacques Abrahamian, LA FUE Hair Clinic provide FUE hair renewal and FUE hair transplant services to patients who want a natural-looking final result. The clinic offers excellent services to its clients and prides itself on being the top choice for hair restoration needs. The doctors opened LA FUE Clinic after both having performed hair transplants for prominent people, including global celebrities, politicians, producers, musicians and successful businesspeople.

The LA FUE Hair Clinic offers a team of surgeons with over ten years of combined experience in the FUE hair transplant and FUE hair restoration field. As one of the few hair transplant clinics in Pasadena and the Los Angeles surrounding areas, the facility is proud to offer the best FUE Hair Transplant technique to help their clients get the look they desire.

The LA clinic offers the following services to its customers:

LA FUE Hair Clinic was founded with the mission of providing natural-looking hair renewal and restoration services to those suffering from alopecia. The clinic strives to be the first option for hair restoration services.

The editorial unit

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A Year After Gene Therapy, Boys With Muscular Dystrophy Are Healthier and Stronger – Singularity Hub

Two and a half years ago, a study published in Science Advances detailed how the gene editing tool CRISPR/Cas-9 repaired genetic mutations related to Duchenne Muscular Dystrophy (DMD). The study was a proof of concept, and used induced pluripotent stem cells (iPSCs).

But now a similar treatment has not only been administered to real people, it has worked and made a difference in their quality of life and the progression of their disorder. Nine boys aged 6 to 12 who have been living with DMD since birth received a gene therapy treatment from pharmaceutical giant Pfizer, and a year later, 7 of the boys show significant improvement in muscle strength and function.

Though the treatments positive results are limited to a small group, theyre an important breakthrough for gene therapy, and encouraging not just for muscular dystrophy but for many other genetic diseases that could soon see similar treatments developed.

DMD is a genetic disorder that causes muscles to progressively degenerate and weaken. Its caused by mutations in the gene that makes dystrophin, a protein that serves to rebuild and strengthen muscle fibers in skeletal and cardiac muscles. As the gene is carried on the X chromosome, the disorder primarily affects boys. Many people with DMD end up in wheelchairs, on respirators, or both, and while advances in cardiac and respiratory care have increased life expectancy into the early 30s, theres no cure for the condition.

The gene therapy given to the nine boys by Pfizer was actually developed by a research team at the UNC Chapel Hill School of Medicineand it took over 30 years.

The team was led by Jude Samulski, a longtime gene therapy researcher and professor of pharmacology at UNC. As a grad student in 1984, Samulski was part of the first team to clone an adeno-associated virus, which ended up becoming a leading method of gene delivery and thus crucial to gene therapy.

Adeno-associated viruses (AAVs) are small viruses whose genome is made up of single-stranded DNA. Like other viruses, AAVs can break through cells outer membranesespecially eye and muscle cellsget inside, and infect them (and their human hosts). But AAVs are non-pathogenic, meaning they dont cause disease or harm; the bodies of most people treated with AAVs dont launch an immune response, because their systems detect that the virus is harmless.

Samulskis gene therapy treatment for DMD used an adeno-associated virus to carry a healthy copy of the dystrophin gene; the virus was injected into boys with DMD, broke into their muscle cells, and replaced their non-working gene.

Samulski said of the adeno-associated virus, Its a molecular FedEx truck. It carries a genetic payload and its delivering it to its target. The company Samulski founded sold the DMD treatment to Pfizer in 2016 so as to scale it and make it accessible to more boys suffering from the condition.

A year after receiving the gene therapy, seven of nine boys are showing positive results. As reported by NPR, the first boy to be treated, a nine-year old from Connecticut, saw results that were not only dramatic, but fast. Before treatment he couldnt walk up more than four stairs without needing to stop, but within three weeks of treatment he was able to run up the full flight of stairs. I can run faster. I stand better. And I can walk [] more than two miles and I couldnt do that before, he said.

The muscle cells already lost to DMD wont grow back, but the treatment appears to have restored normal function of the protein that fixes muscle fibers and helps them grow, meaning no further degeneration should take place.

Gene therapy trials are underway for several different genetic diseases, including sickle cell anemia, at least two different forms of inherited blindness, and Alzheimers, among others. Its even been used as part of cancer treatment.

Its only been a year, we dont yet know whether these treatments may have some sort of detrimental effect in the longer term, and the treatment itself can still be improved. But all of that considered, signs point to the DMD treatment being a big win for gene therapy.

Before it can be hailed as a resounding success, though, scientists feel that a more extensive trial of the therapy is needed, and are working to launch such a trial later this year.

Image Credit: pixelRaw from Pixabay

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A Year After Gene Therapy, Boys With Muscular Dystrophy Are Healthier and Stronger - Singularity Hub

Autologous Stem Cell Based Therapies Market Consumption Sales By Type, Product Specifications, Market Research Methodology, Market Forecast To 2023 -…

A new intelligence report Autologous Stem Cell Based Therapies Market has been Lately Added into Adroit Market Research collection of top-line market research reports. Global Autologous Stem Cell Based Therapies Market report is a meticulous comprehensive analysis of this market that provides access to direct first-hand insights on the growth trail of market in near term and long term. On the basis of factual advice sourced from authentic industry pros and extensive main industry research, the report provides insights about the historical growth pattern of Autologous Stem Cell Based Therapies Market and current market situation. It then provides short- and long-term market development projections.

Projections are purely based on the detailed analysis of key Market dynamics that are expected to influence Autologous Stem Cell Based Therapies Market performance and their intensity of impacting market growth within the span of assessment period.

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Competitive companies And manufacturers in global market

segment by Type, the product can be split intoEmbryonic Stem CellResident Cardiac Stem CellsUmbilical Cord Blood Stem CellsMarket segment by Application, split intoNeurodegenerative DisordersAutoimmune DiseasesCardiovascular Diseases

Market segment by Regions/Countries, this report coversNorth AmericaEuropeChinaJapanSoutheast AsiaIndiaCentral & South America

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Key Regions and Countries Covered in Global Autologous Stem Cell Based Therapies Market Report-

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COVID-19 Autopsies Hint at Direct Viral Infection of the Heart – TCTMD

The myocardial injury that has been documented in patients with COVID-19 may stem from active virus replicating in heart tissue, a German autopsy study suggests.

In the paper, published online July 27, 2020, in JAMA Cardiology, the researchers say it appears that the presence of SARS-CoV-2 in cardiac tissue does not necessarily cause an inflammatory reaction consistent with clinical myocarditis, and that the long-term consequences of this cardiac infection requires further investigation.

Speaking with TCTMD, Gregg C. Fonarow, MD (University of California, Los Angeles), said it is important to bear in mind that the autopsy reports from COVID-19 patients published to date, including this one, have all been relatively small and either single-center or pooled data in select, most elderly patients.

But on the other hand, they do give important insights for which there are clinical correlates, he added. Specifically, with this autopsy series, it's enlightening because from the very earliest reports coming out of China regarding COVID-19, there were elevations in cardiac troponins, and there was a lot of puzzlement as to what that actually meant.

Fonarow, who along with Clyde W. Yancy, MD (Northwestern University, Chicago, IL), wrote an editorial accompanying the study, said if anything, its reassuring that we're, at least in these cases, not seeing acute myocarditis with the frequency that some people speculated very early on when reports started to come in. But it also shows that there is more cardiac involvement than initially suspected, some of it clearly subclinical, he added.

Interstitial Cell Involvement

Hamburg, Germany, where the autopsies were performed, has mandated full-body postmortems for all COVID-19 deaths in the city, senior study author Dirk Westermann, MD (University Heart and Vascular Centre Hamburg), noted in an email. TCTMD has previously reported on a smaller series of autopsies from the Hamburg region that described lung weights that ranged from two- to fourfold higher than average.

In the new report, Westermann and colleagues led by Diana Lindner, PhD (University Heart and Vascular Centre, Hamburg, Germany), used reverse transcriptase-polymerase chain reaction testing to identify SARS-CoV-2 RNA in the myocardium of 24 of 39 patients (61.5%) who died in April 2020. All had tested positive for the virus prior to death, and none had clinically fulminant myocarditis. The median age was 85 years and the cause of death in 89% was pneumonia. The cardiac tissue included two specimens from the left ventricle.

In 16 cases, a viral load above 1,000 copies per g RNA was noted. Those patients also had increased proinflammatory genes. Virus replication in the myocardium was documented in five patients with the highest virus load.

Lindner and colleagues also conducted in situ hybridization of SARS-CoV-2 RNA and found virus present in interstitial cells or macrophages within the cardiac tissue rather than in myocardiocytes.

Importantly, fulminant myocarditis was not associated with SARS-CoV-2 infection in this study with no significant change in transendothelial migration of inflammatory cells in the myocardium in patients with high virus load vs no virus, they write. In the published cases in which myocardial inflammation was present, there was also evidence of clinical myocarditis, and therefore the current cases underlie a different pathophysiology.

While the findings provide important new clues as to the possible mechanism of myocardial injury in COVID-19 infected patients, Lindner and colleagues say the clues provided by the autopsies are limited and that future studies are needed to reveal whether cytokine expression correlates with cardiac dysfunction during the disease and its aftermath. They also question whether myocardial biomarkers might be upregulated due to the SARS-CoV-2 infection.

Indeed, the literature to date has been mixed on the extent to which this virus is infiltrating the heart, with another recent autopsy analysis reported by TCTMD making the case that not all patients with cardiac manifestations of COVID-19 show signs of direct viral infiltration. Indeed, 15 of the patients in the current autopsy analysis showed no SARS-CoV-2 RNA in the myocardium.

According to Fonarow, many avenues for additional research can grow out of these sorts of clues, especially in the current environment where there is still so much left to learn about COVID-19, its management, and any lasting impact on the heart.

It would be really interesting with therapies like dexamethasone, for example, to look at . . . whether we see a corresponding decline in troponin levels in those who respond that parallel that time course, he said. Further insight from autopsy studies showing how COVID-19 impacts the heart also may help lead to the creation of strategies involving cardioprotective medications. Thats an idea also put forward by the authors of another article out this week in JAMA Cardiology that found evidence of myocardial inflammation on MRI in recovered COVID-19 patients more than 2 months after their initial positive COVID-19 test, even those who never experienced severe illness.

Even in that period where clinically patients are recovering, theres still evidence of myocardial inflammation, reflecting this injury, he noted. Those findings also need to be replicated to see how generalizable they are and [if] we see that same frequency of involvement of the heart through cardiac MRI.

Read more from the original source:
COVID-19 Autopsies Hint at Direct Viral Infection of the Heart - TCTMD

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