To the Editor:

Re Why Is the Right Forcing Women Who Miscarry to Suffer?, by Michelle Goldberg (column, July 19):

They dont tell you this in medical school, but to be an OB-GYN physician is to know heartache up close and personal, over and over again. I have been a practicing physician in Portland, Ore., for the last 37 years. My colleagues span the political spectrum, but almost everyone I have known has put the interest of the mothers life before that of the embryo or fetus. And if for reasons of conscience they could not, they would find another provider who could.

With the Dobbs decision, my specialty has been thrown into disarray. Miscarriage is one of the most common conditions we treat, as it occurs in about 10 to 20 percent of known pregnancies.

These new laws in anti-choice states just ban termination of pregnancy, some immediately after fertilization. They have no subtlety, they have no algorithms to guide practice.

Now providers are in an extremely precarious situation, risking prosecution. When the only exception for pregnancy termination is the mothers risk of death, how close must she be for them to act? Most pregnant people are young and healthy, and they cope well with blood loss and infection, until suddenly they do not, and by then it may be too late to save them.

America will now see what happens when politicians exploit the care of women for their political gain. It is brutal. Anyone who thought it would take a long time to see the consequence of banning a common medical procedure will soon see the tears, blood and death that we told them was coming. It is inevitable, and it will continue.

Marguerite P. CohenPortland, Ore.The writer is a fellow of the American College of Obstetricians and Gynecologists.

To the Editor:

Re Risks to Patients as Doctors Deal With Abortion Exceptions (news article, July 21):

As a Missouri resident living under a new abortion ban, I am enraged and disgusted. Advocates warned of the dangers of bans for years, unheeded. Even now, as doctors describe how pregnant women will die from substandard care as a result of this ban, our leaders shrug.

Days after Missouri enacted an abortion ban except in medical emergencies, I called the attorney generals office for clarification. I shared that I had experienced two life-threatening conditions in my last pregnancy, and I was concerned that my obstetrician might be constrained if a similar complication arose today.

The staff attorney told me that he was unable to offer guidance, as giving legal advice could jeopardize his law license. I replied that this ban could jeopardize my life. His response? That I could leave the state.

Unfortunately, I worry that many Missouri families like mine will take him up on his suggestion. I worry that our womens health providers will choose to practice elsewhere. I worry that Missouris elected officials will be shortsighted enough to celebrate these losses. The state deserves better.

Katy NimmonsSt. Louis

To the Editor:

Re Im Terrified for My Patients, by David N. Hackney (Opinion guest essay, July 10):

Dr. Hackney describes the pain experienced by a pregnant woman who learns that her child has a lethal condition yet has no option but to carry to term. While accurate, the potential pain of learning your fetus has a serious abnormality goes well beyond this.

A variety of severe, life-altering birth defects and genetic syndromes can be diagnosed prenatally, and many of these conditions are not lethal or not lethal immediately but serious enough that the affected child faces a lifetime of severe disability and, in many cases, pain.

Being told in the middle of a much wanted pregnancy that your child will have severe neurological or physical disabilities, that she will never walk, or talk or even be able to roll over by herself, and yet will survive, is as devastating as being told your child will die at birth, but with far different consequences.

Despite Justice Amy Coney Barretts assertion, these children are unlikely to be adopted. It is unethical to diagnose a medical condition and not provide the patient with reasonable and safe therapeutic options, but the laws of many states now make it impossible to do the ethical thing. More pain for everyone.

Katharine WenstromProvidence, R.I.The writer is a professor at the Alpert Medical School of Brown University and past president of the Society for Maternal Fetal Medicine.

To the Editor:

Dr. David Hackney joins so many doctors highlighting the serious life and health risks pregnant women now face. President Biden and Congress cannot restore comprehensive abortion rights in any manner that will survive future elections.

So congressional Democrats should immediately legislate a strong national right to abortion if continued pregnancy would risk the life, physical health or mental health of the mother, or if the fetus will not survive.

Further, there should be reasonable protection for medical providers who perform these medically necessary procedures. Otherwise, physician hesitation may cost womens lives.

I would hope there might be bipartisan support for this.

Without these protections, hikes to doctors liability insurance could render obstetrics care grossly overpriced and take already scarce funding away from all medical care.

Mary Jo NapoliColumbus, Ohio

To the Editor:

Re Abortion Bans Will Affect Both Rich and Poor Americans (Opinion guest essay, July 7):

Elizabeth Spiers describes the impact of abortion restrictions as a crisis for all American women, with delays in therapeutic abortions resulting in fatal consequences. As an emergency physician who routinely cares for women with pregnancy-related complications, I echo Ms. Spierss concerns.

I frequently treat obstetric emergencies. In recent weeks I cared for pregnant women with the following complications: ectopic pregnancy, undetectable fetal heartbeat with decreasing pregnancy hormone levels, and copious vaginal bleeding with an open cervix.

My patients were not asked their political affiliation or religious persuasion. I didnt need to know whether their pregnancies were planned or desired. My focus was on the timely care of three vulnerable patients, with pain and bleeding, who looked to our medical team for compassionate treatment and emotional support. All three patients had therapeutic abortions.

As abortion bans proliferate throughout our country, I feel fortunate to practice in New York Citys public hospital system, where the law supports sound medical decision making combined with a womans choice. No time for complacency, however. The lives and well-being of millions of women will depend on it.

Bonny J. BaronBrooklyn

Read this article:
Opinion | New Risks Facing Doctors and Their Pregnant Patients - The New York Times

Recommendation and review posted by Bethany Smith

Study participants

We evaluated data from 70 consecutive patients with PAI on conventional steroid treatment in a real-life study. Patients were consecutively referred to the Division of Endocrinology of Palermo University from January 2012 to December 2020. Patients were on conventional steroid treatment (cortisone acetate and HC), administered twice or three times a day. Thirty-five patients, 15 males and 20 females, maintained conventional steroid therapy (17 cortisone acetate and 18 HC) (group A) while the other 35, (16 who were on cortisone acetate and 19 who were on HC), 11 males and 24 females, were switched from conventional steroid treatment to DR-HC (group B) administered orally in the morning in a fasting state. Patients had a 60-month follow-up. In group A there were 5 women in menopause, while in group B there were 6 women in menopause. Exclusion criteria were the following: age18years, secondary AI (SAI), treatment with other steroids (prednisone), pregnancy, breastfeeding, premature ovarian failure, hypoparathyroidism, hyperparathyroidism, treatment with estrogens and underweight (BMI<18.5kg/m2). The switch to DR-HC was judged to be appropriate on clinical grounds in those patients who complained of fatigue and weakness, presented hyponatraemia (<134mmol/L) or hypoglycaemia (2.78mmol/L) or showed more than two comorbidities such as diabetes, osteoporosis/osteopenia, arterial hypertension and central obesity. The switch from HC to DR-HC was made with an equivalent dose, while the dose was reduced from cortisone acetate to DR-HC taking into consideration the minor steroid activity of cortisone acetate compared to HC and patients clinical characteristics.

PAI was diagnosed as recommended by international guidelines9.

In detail, among the total of 70 patients, 42 had autoimmune polyglandular syndrome (APS), while 28 had isolated autoimmune AI. Among patients with APS, 26 had combined Addisons disease and autoimmune thyroid disease, 6 had combined Addisons disease, type 1 diabetes mellitus and autoimmune hypothyroidism and 10 had combined Addisons disease, autoimmune hypothyroidism and celiac disease. Patients with celiac disease were on a stable gluten-free diet. All patients with PAI were also on stable treatment with fludrocortisone (0.050.1mg/day, once). Patients with hypothyroidism were treated with levo-thyroxine at the average dose of 1.21.5 mcg/kg. Patients with type 1 diabetes were on basal-bolus treatment on flash blood glucose monitoring. Five postmenopausal women had been treated with DHEA for a ranging period of 618months, before being included in the study.

During the 60-month treatment period, the conventional steroid and the DR-HC doses were changed based on the physicians judgement of a patients need in both groups of patients (Table 1). Each patient received instructions for treatment in special or emergency situations. Patients treated with DR-HC were instructed to add a rescue dose of HC during an intercurrent illness or stress (5 or 10mg according to severity of stress and symptoms). Overall, 8 patients had to take a rescue dose of HC, 5 of them less than 10 times and 3 of them from 20 to 30 times during the 60-month period.

The current study was carried out in accordance with the recommendations of the Paolo Giaccone Policlinico ethics committee, with written informed consent from all subjects. All subjects gave written informed consent in accordance with the Declaration of Helsinki. The protocol was approved by the Paolo Giaccone Policlinico ethics committee (protocol 06/2021).

At baseline and after 18, 36 and 60months of conventional steroid and DR-HC treatment, clinical and bone metabolic parameters were evaluated.

Anthropometric parameters such as BMI and waist circumference (WC), measured at the midpoint between the lower rib and the iliac crest, were evaluated. In addition, sodium, potassium, serum 25hydroxyvitamin-D (vitaminD), parathyroid hormone, calcium, phosphorus, creatinine, osteocalcin and bone alkaline phosphatase were assayed.

The blood sample was taken about 2h after steroid administration (patients took the dose in the morning on waking) to avoid patients experiencing fatigue or other symptoms due to delayed intake of the drug.

In both groups, hypovitaminosis D was observed at baseline and a pharmacological supplementation was started in 26 patients of group A and 25 of group B, at the mean dose of 800 UI/day and maintained during the follow-up. Hypovitaminosis D was defined as a serum 25-hydroxy vitamin D level below the normal range (<30ng/ml). All patients supplemented with vitamin D reached the threshold of 30ng/ml.

BMD was measured by DXA at lumbar spine and femoral neck (Hologic Horizon Inc., QDR-4500W Waltham, MA) at baseline and after 18, 36 and 60months of follow-up.

In patients aged 50 or more, BMD was expressed as the T-score, comparing the results with those obtained in a sex-matched Caucasian population at the peak of bone mass. A T-score less than or equal to 2.5 SD at the neck or spine was defined as osteoporosis, whereas osteopenia was defined as a T-score between 1 and 2.5 SD. In patients younger than 50years, the results were expressed as a/the Z-score, comparing the results with those obtained in an age and sex-matched Caucasian population. A Z-score of 2.0 SD or lower was used to define a BMD below the expected range for age10. The coefficients of variation in the DXA measurements for BMD, bone mineral content (BMC) and area were 0.61%, 2.98% and 2.89%, respectively.

We also evaluated rib, femoral neck and hip fractures rate during the follow-up in both groups.

Sodium, potassium, serum 25hydroxyvitamin-D (vitamin-D), parathyroid hormone, calcium, phosphorus, creatinine, osteocalcin and bone alkaline phosphatase were measured with standard methods (Modular P800, Roche, Milan) at our hospital centralized laboratory. The intra- and interassay coefficients of variation were the following: Sodium 0.5% to 1.2% and 1.28% to 1.44%, respectively; potassium 1% to 2.1% and 2.2% to 3.08%, respectively; vitaminD 0.9% to 1.6% and 1.7% to 2.56%, respectively, parathyroid hormone 1.2% to 2.6% and 2.8% to 3.9%, respectively; calcium 1.8% to 3.5% and 3.75% to 4.23%, respectively; phosphorus 1.6% to 3.3% and 3.5% to 4.2%, respectively; creatinine 1.7% to 2.9% and 3.3% to 4.6%, respectively; osteocalcin 1.9% to 3.3% and 3.6% to 4.9%, respectively; bone alkaline phosphatase 2.7% to 3.6% and 3.8% to 5.2%, respectively.

The Statistical Packages for Social Science SPSS version 19 (SPSS, Inc., IBM, New York, USA) were used for data analysis. The normality of quantitative variables was tested with the Shapiro-Wilk test. The baseline characteristics of the groups were presented as meanSD for continuous variables, while the rates and proportions were calculated for categorical data. The differences between groups were performed using ANOVA for quantitative variables and the 2-test for categorical variables. A comparison between numerical variables at baseline, 18-, 36- and 60-month follow-up was performed with the Friedman analysis. In addition, multiple linear regression analysis was performed to identify independent predictors of the dependent variables lumbar spine and femoral neck T and Z scores and of dependent variable fracture. A p value<0.05 was considered statistically significant.

Read more:
Long-term outcomes of conventional and novel steroid replacement therapy on bone health in primary adrenal insufficiency | Scientific Reports -...

Recommendation and review posted by Bethany Smith

For anyone who doesnt have a thyroid condition, it might be easy to forget about the gland in the front of their neck that controls hormone production. But behind the scenes, the thyroid does a lot of work to help metabolize and maintain blood pressure, body temperature and heart rate.

Thyroid disease affects approximately 20 million people in the US and about one in eight women. The two most common types of thyroid disorders are hyperthyroidism and hypothyroidism.

Hyperthyroidism produces too much thyroxine hormone (an overactive thyroid) and hypothyroidism does not produce enough (an underactive thyroid). Although the two conditions have different signs and symptoms, there can be some overlap.

There is no replacement for getting the proper diagnosis and starting medication when necessary, said Vatche Zohrabian, DO, primary care physician with the Hartford HealthCare Medical Group, but there are some lifestyle modifications that can help augment conventional treatment and help keep your thyroid on track.

Here are the five things Dr. Zohrabian recommends you do to upkeep a healthy thyroid:

Dr. Zohrabian encourages anyone who experiences the following symptoms to have their thyroid function checked by their primary care provider:

Continue reading here:
Five Easy Steps to Keep Your Thyroid Healthy - Health News Hub

Recommendation and review posted by Bethany Smith

Emily Daniels, who lives with her husband and their young son in Golden, CO, was 32 years old, and in the 33rd week of her pregnancy, she began feeling tightness in her chest.

She wisely had it checked out, and a CT scan found two blood clots in her lungs. The scan also discovered a mass, which a biopsy confirmed was stage IV lung cancer.

Daniels, who has never smoked, was shocked to hear the diagnosis.

Her doctors arent sure how she got cancer. But they told her it was best to induce labor for the sake of the babys health and the mothers.

I had undergone a year and a half of fertility treatment, and if I had to guess, my body wasnt strong enough in that stress mode because of fertility and the hormones. It made things go crazy in my body, she told Healthline.

My doctor thinks this is valid. But we dont know.

Daniels is still living with lung cancer. Shes been through chemotherapy and several other treatments and procedures. Its been difficult, and her life has changed dramatically.

But shes taking it all in stride because shes still alive. And her baby boy, Brady, is now four and a half. Daniels will soon celebrate her 37th birthday.

Lung cancer has given me a perspective on what is important and how you want to live your life, she told Healthline. I want to live every day with no regrets.

Today is World Lung Cancer Day, and the American Lung Association released the Lung Health Barometer, a new survey revealing critical lung cancer awareness statistics.

The good news is that lung cancer overall is down.

The bad news is that it remains the leading cause of cancer death in the U.S.

Smoking is still the most common cause of lung cancer, but an increasing percentage of lung cancer patients like Daniels who have never smoked and are under age 40 are being diagnosed with the disease.

While rates of lung cancer have fallen in the last 15 years because tobacco control is better and there are more preventive measures, theres a higher percentage now of never smokers who are getting lung cancer, David Tom Cooke, MD, F.A.C.S. chief division of general thoracic surgery at UC Davis, told Healthline.

Cooke said there are multiple reasons why people who have never smoked get lung cancer.

They include exposure to second-hand smoke, radon, asbestos fibers, air pollution, toxins from increasing wildfires worldwide, and genetic factors.

Its important to look at the big picture. The death rate from lung cancer has been falling in our country for 10 years, Cooke said.

Thats because of tobacco recovery and prevention, advances in surgery for early stage, immunotherapy, and precision medicine.

The adoption of precision medicine includes the deployment of liquid biopsies, which are simple blood tests that look at circulating tumor DNA in the blood, Cooke said.

These assays can detect cancer and find driver mutations. Its a promising technology, and its most effective in patients with advanced lung cancer, Cooke said.

It makes sense that the more cancer you have in [your] body, the more you will have circulating tumor DNA in [the] blood.

He said that its not as effective with early-stage lung cancer when the tumor is very small and may not be shedding DNA into the bloodstream.

According to the American Lung Association survey, lung cancer is the leading cause of cancer deaths in the U.S., but the disease often remains in the shadows.

Its estimated that more than 235,000 Americans will be diagnosed this year with lung cancer.

But only 29% of Americans know that lung cancer is the leading cause of cancer deaths in the U.S.

Only about one in four respondents (26%) knew that the lung cancer survival rate increased by over 30% in the past ten years.

Seventy-three percent of adults have not spoken with their doctor about their risk for lung cancer, and only 40% are concerned they might get the disease.

And nearly 70% of respondents were unfamiliar with the availability of lung cancer screening for early detection of the disease.

The American Lung Association is working to defeat lung cancer.

To do so, the organization is engaging a variety of tactics and stakeholders to address the disease.

This low awareness is due in part to an undeserved stigma that has followed lung cancer for decades. The fact is that anyone can get lung cancer, and no one deserves it, Harold Wimmer, national president and CEO of the American Lung Association, said in a press statement.

The good news is that the lung cancer survival rate has risen substantially, and awareness of this deadly disease has steadily increased, he stated.

Greater awareness of lung cancer is key to securing research funding, encouraging lung cancer screening, reducing stigma around this disease, and ultimately, saving lives, Wimmer said.

Read the rest here:
Lung Cancer Remains the Leading Cause of Cancer Deaths in the U.S. - Healthline

Recommendation and review posted by Bethany Smith

Mark Purcell: Welcome to Thoughts on the Market. I'm Mark Purcell, Head of Morgan Stanley's European Pharmaceuticals Team.

Terence Flynn: And I'm Terence Flynn, Head of the U.S. Pharmaceuticals Team.

Mark Purcell: And on this special episode of Thoughts on the Market, we'll be talking about the global obesity challenge and our outlook for the next decade. It's Tuesday, August the 2nd, and it's 1 p.m. in London.

Terence Flynn: And 8 a.m. in New York.

Terence Flynn: So Mark, more than 650 million people worldwide are living with obesity as we speak. The personal, social and economic costs from obesity are huge. The World Health Organization estimates that obesity is responsible for 5% of all global deaths, which impacts global GDP by around 3%. Obesity is linked to over 200 health complications from osteoarthritis, to kidney disease, to early loss of vision. So tackling the obesity epidemic would impact directly or indirectly multiple sectors of the economy. Lots to talk about today, but let's start with one of the key questions here: why are we talking about all this now? Are we at an inflection point? And is the obesity narrative changing?

Mark Purcell: Yeah Terence look, there's a category of medicine called GLP-1's which have been used to treat diabetes for over a decade. GLP-1 is an appetite suppressing hormone. It works on GLP-1 receptors, you could think of these as hunger receptors, and it helps to regulate how much food our bodies feel they need to consume. Therefore, these GLP-1 medicines could become an important weapon in the fight against obesity. The latest GLP-1 medicines can help individuals who are obese lose 15 to 20% of their body weight. That is equivalent to 45 to 60% of the excess weight these individuals carry in the form of fat which accumulates around the waist and important organs in our bodies such as the liver. There is a landmark obesity study called SELECT, which has been designed to answer the following key question: does weight management save lives? An interim analysis of this SELECT study is anticipated in the next two months, and our work suggests that GLP-1 medicines could deliver a 27% reduction in the risk of heart attacks, strokes and cardiovascular deaths. We believe that governments and insurance companies will broaden the reimbursement of GLP-1 medicines in obesity if they are proven to save lives. This comes at a time when new GLP-1 medicines are becoming available with increasing levels of effectiveness. It's an exciting time in the war against obesity, and we wanted to understand the implications of the SELECT study before it reads out.

Terence Flynn: So, our collaborative work suggests that obesity may be the new hypertension. What exactly do we mean by that, Mark? How do we size the global opportunity and what's the timeline here?

Mark Purcell: Back in the 1960s and 1970s, hypertension was seen as a lifestyle disease caused by stress and old age. Over time, it was shown that high blood pressure could be treated, and in doing so, doctors could prevent heart attacks and save lives. A new wave of medicines were introduced to the market in the mid 1980s to treat individuals with high blood pressure and doctors found the most effective way to treat high blood pressure was to use combinations of these medicines. By the end of the 1990's, the hypertension market reached $30 billion in sales, that's equivalent to over $15 billion today adjusting for inflation. Obesity is seen by many as a lifestyle disease caused by a lack of self-control when it comes to eating too much. However, obesity is now classified as a preventable chronic disease by medical associations, just like hypertension. Specialists in the obesity field now recognize that our bodies have evolved over hundreds of thousands of years to put on weight, to survive times where there is a lack of food available and a key way to fight obesity is to reset the balance of how much food our bodies think they need. With the availability of new, effective obesity medicines, we believe that obesity is on the cusp of moving into mainstream primary care management. And the obesity market is where the treatment of high blood pressure was in the mid to late 1980s. We built a detailed obesity model focusing on the key bottlenecks, patient activation, physicians engagement and payer recognition. And we believe that the obesity global sales could exceed $50 billion by the end of this decade.

Terence Flynn: So Mark, what are the catalysts aligning to unlock the potential of this $50 billion obesity opportunity?

Mark Purcell: We believe there are full catalysts which should begin to unlock this opportunity over the next six months. Firstly, the SELECT study, which we talked about. It could be stopped early in the next two months if GOP P1 medicines are shown overwhelmingly to save lives by reducing excess weight. Secondly, the demand for GLP-1 medicines to treat obesity was underappreciated by the pharmaceutical industry. But through the second half of this year, GLP-1 medicines, supply constraints will be addressed and we'll be able to appreciate the underlying patient demand for these important medicines. Thirdly, analysis shows that social media is already creating a recursive cycle of education, word of mouth and heightened demand for these weight loss medicines. Lastly, diabetes treatment guidelines are actively evolving to recognize important comorbidities, and we expect a greater emphasis on weight treatment goals by the end of this year.

Terence Flynn: Mark, you mentioned some bottlenecks with respect to the obesity challenge. One of those was patient activation. What's the story there and how does social media play into it?

Mark Purcell: Yes, great question Terence, look it's estimated that less than 10% of individuals suffering from obesity are diagnosed and actively managed by doctors. And that compares to 80 to 90% of individuals who suffer from high blood pressure, or diabetes, or high levels of cholesterol. Once patients come forward to see their doctors, 40% of them are treated with an anti-obesity medicine. And as more effective medicines become available, we just think this percentage is going to rise. Lastly, studies designed to answer the question, what benefit does 15 to 20% weight loss deliver in terms of reducing the risk of high blood pressure, diabetes, kidney disease and cardiovascular disease? Will help activate governments and insurance companies to reimburse obesity medicines. But it all starts with individuals suffering from obesity coming forward and seeking help, and this is where we expect social media to play a really important key role.

Terence Flynn: To a layperson, there's significant overlap between diabetes and obesity. How do we conceptualize the obesity challenge vis a vis diabetes, Mark?

Mark Purcell: Terence, you're absolutely right. There is significant overlap between diabetes and obesity and it makes it difficult and complicated to model. It's estimated that between 80 to 85% of diabetics are overweight. It's estimated that 35% of diabetics are obese and around 10% of diabetics are severely obese. GLP-1 medicines have been used to treat diabetes for over a decade, not only being extremely effective in lowering blood sugar, but also in reducing the risk of cardiovascular events like heart attacks and removing excess body weight, which is being recognized as increasingly important. This triple whammy of benefit means that the use of GLP-1 medicines is increasing rapidly, and sales in diabetes are expected to reach over $20 billion this year, compared to just over $2 billion in obesity. By the end of the decade our work suggests that the use of GLP-1 based medicines in obesity could exceed the use in diabetes by up to 50%.

Terence Flynn: Mark, thanks for taking the time to talk.

Mark Purcell: Great speaking with you again, Terrence.

Terence Flynn: And thanks for listening. If you enjoy Thoughts on the Market, please leave us a review on Apple Podcasts and share the podcast with a friend or colleague today.

Go here to read the rest:
Pharmaceuticals: Thoughts on the Market - Morgan Stanley

Recommendation and review posted by Bethany Smith

ADAPT Triad minimal residual disease analysis study intended to evaluate the association between circulating tumor DNA (ctDNA) positivity and recurrence intervals

MADISON, Wis., Aug. 2, 2022 /PRNewswire/ -- Exact Sciences Corp. (NASDAQ: EXAS), a global leader in cancer diagnostics, announced today that it has entered a collaboration agreement with the West German Study Group (WSG), an international research institution that focuses on practice-changing clinical studies in breast cancer. Together, Exact Sciences and WSG plan to conduct a prospective, multicenter validation study in hormone receptor (HR)-positive, HER2-negative early breast cancer patients. The study is intended to demonstrate the ability of Exact Sciences' tumor-informed ctDNA liquid biopsy test to detect minimal residual disease (MRD) and to collect important long-term follow-up and outcome data.

Exact Sciences Corporation Logo (PRNewsfoto/EXACT SCIENCES CORP)

The combined analysis, called ADAPT Triad, is expected to include data from approximately 3,000 German patients enrolled in two ongoing WSG ADAPT trials and one WSG registry study. All patients included in the analysis are stratified using the Oncotype DX Breast Recurrence Score test. The study is part of Exact Sciences' global initiative to generate clinical validation data for its tumor-informed ctDNA MRD liquid biopsy test, currently in development.

"This ADAPT Triad project with WSG offers a tremendous opportunity to help inform treatment decisions and recurrence monitoring, and ultimately improve future outcomes for breast cancer patients," said Rick Baehner, MD, chief medical officer of Precision Oncology for Exact Sciences."In addition to helping validate our MRD assay, we're also eager to better understand the potential synergies involving the predictive and prognostic information provided by our Oncotype DX Breast Recurrence Score test. WSG's expertise in breast cancer research makes them ideal collaborators to conduct these important MRD studies in HR positive, HER2-negative early breast cancer."

Story continues

The ADAPT Triad MRD analysis study in breast cancer builds on Exact Sciences and the National Surgical Adjuvant Breast and Bowel Project's (NSABP) CORRECT-MRD II clinical validation studyto detect MRD in colorectal cancer patients. These studies will help create a solid evidence foundation for Exact Sciences' MRD program in two core cancer types where the company has established leadership.

"The WSG's ADAPT study program examines ways to achieve patient-specific decision-making for the treatment of early breast cancer based on biological markers," said Professor Nadia Harbeck, Scientific Director of the WSG and Head of the Breast Centre at LMU Klinikum Munich, Germany. "Partnering with our long-time collaborators at Exact Sciences to evaluate the association of post-initial therapy, pre-recurrence ctDNA with distant recurrence-free interval is a worthy addition to our program and will help change the treatment and monitoring program for solid tumors."

About Minimal Residual DiseaseMinimal residual disease (MRD) refers to the presence of tumor-specific DNA in the body after cancer treatment. These fragments of genetic information, known as circulating tumor DNA (ctDNA), are shed into the blood by solid tumors as part of the tumor growth cycle. Their presence may indicate that a tumor is likely to return. Solid tumors are typically undetected until they are advanced enough to be picked up by a radiologic image or physician examination. The detection of ctDNA at extremely low levels has the potential to provide crucial insights that may help discover cancer recurrence earlier and inform treatment decisions.

About Exact Sciences' MRD ProgramThe Exact Sciences' MRD program is powered by our in-house capabilities to advance a tumor-informed or a tumor-nave solution, with an initial focus on tumor-informed (bespoke) with whole exome or whole genome sequencing.This approach identifies somatic genomic alterations in DNA extracted from the patient's tumor tissue and detects a subset of these mutations in ctDNA present in the patient's blood. The MRD test that Exact Sciences is developing is intended for patients diagnosed with solid tumor malignancies to detect ctDNA before, during, and after cancer treatment. Such information may be used for guidance of adjuvant therapy decisions and/or for monitoring of cancer recurrence, in conjunction with other clinicopathological findings, providing more than 12 million testing opportunities in the United States alone.1

About Exact Sciences Corp.A leading provider of cancer screening and diagnostic tests, Exact Sciences relentlessly pursues smarter solutions providing the clarity to take life-changing action, earlier. Building on the success of Cologuard and Oncotype tests, Exact Sciences is investing in its product pipeline to support patients before and throughout their cancer diagnosis and treatment. Exact Sciences unites visionary collaborators to help advance the fight against cancer. For more information, please visit the company's website at http://www.exactsciences.com, follow Exact Sciences on Twitter @ExactSciences, or find Exact Sciences on Facebook.

About the West German Study Group and ADAPTThe West German Study Group (WSG) is a collaborative academic research group that focuses on the design, organization, and implementation of clinical studies in the field of breast cancer. Its ADAPT studies aim to develop new therapeutic strategies that significantly improve efficacy and tolerability in comparison with existing standard therapies. Its scientific work focusses on the individualization of breast cancer treatment and the development of de-escalated therapeutic strategies with the aim of finding the best possible treatment for each patient. More than 12,000 patients have already participated in WSG studies.

NOTE: Oncotype, Oncotype DX, and Oncotype DX Breast Recurrence Score are trademarks or registered trademarks of Genomic Health, Inc. Exact Sciences and Cologuard are trademarks or registered trademarks of Exact Sciences Corporation. All other trademarks and service marks are the property of their respective owners.

Forward-Looking StatementsThis news release contains forward-looking statements concerning our expectations, anticipations, intentions, beliefs or strategies regarding the future.These forward-looking statements are based on assumptions that we have made as of the date hereof and are subject to known and unknown risks and uncertainties that could cause actual results, conditions and events to differ materially from those anticipated. There can be no assurance as that the WSG ADAPT MRD analysis study will successfully validate Exact Sciences' MRD test or that Exact Sciences will be able to successfully develop or market any MRD or recurrence monitoring tests. Therefore, you should not place undue reliance on forward-looking statements. Risks and uncertainties that may affect our forward-looking statements are described in the Risk Factors sections of Exact Sciences' most recent Annual Report on Form 10-K and any subsequent Quarterly Reports on Form 10-Q, and in Exact Sciences' other reports filed with the Securities and Exchange Commission. Exact Sciences undertakes no obligation to publicly update any forward-looking statement, whether written or oral, that may be made from time to time, whether as a result of new information, future developments or otherwise.

Exact SciencesU.S. Media Contact:Steph Spanos, sspanos@exactsciences.com, 608-556-4380Int'l Media Contact:Federico Maiardi, fmaiardi@exactsciences.com, +41 79-138-1326Investor Contact:Megan Jones, meganjones@exactsciences.com, 608-535-8815

WSG Media Contact: Michael Stdele, Michael.Staedele@wsg-online.com, +49 216156623 10

1 Source: U.S. Census data, Exact Sciences estimates; includes U.S. markets only

Cision

View original content to download multimedia:https://www.prnewswire.com/news-releases/exact-sciences-and-west-german-study-group-announce-new-study-to-validate-detection-of-minimal-residual-disease-in-early-stage-breast-cancer-patients-301598380.html

SOURCE EXACT SCIENCES CORP

Here is the original post:
Exact Sciences and West German Study Group Announce New Study to Validate Detection of Minimal Residual Disease in Early-Stage Breast Cancer Patients...

Recommendation and review posted by Bethany Smith

Figure:

antidote, EM best practice, antidote derangement syndrome, toxicology

I love the Oxford English dictionary definition of antidotea medicine given to counteract the influence of poison or an attack of diseasebecause it is subtly correct. It suggests that an antidote is given with the belief that it will successfully treat a poisoning.

It does not imply that the antidote will treat the poison, reverse toxic effects, or be necessary to improve clinical outcome. Taken literally, it implies that the concept of antidote is, like Santa Claus or the Tooth Fairy, a matter of belief, not necessarily fact.

I'd propose a second definition of antidote from the Gussow Dictionary of Rational Toxicology: something that stops all critical thinking and provides clinicians with a false sense of security in medical toxicology cases.

Not infrequently, we at the poison center find that a physician, having learned that drug B is the antidote to poisoning from substance A, becomes stubbornly fixated on administering antidote B, even before asking some critical questions:

Too often, it's easy for the physician to feel that his job is done and the patient is out of danger once an antidote is given. This misconception can lead the medical team to lessen its attention to basic supportive care and careful monitoring. An antidote is not magic; it is just one more thing in the medical toxicologist's toolbox that may or may not be helpful in a specific situation.

Take glucagon, a counterregulatory hormone moderating the effects of insulin by increasing blood glucose. It is synthetized in pancreatic a-cells, and has long been considered an antidote to beta-blocker poisoning because it increases myocardial cAMP though the actions of specific glucagon receptors that are separate from the adrenergic b pathway.

But does the use of glucagon in beta-blocker poisoning actually improve clinical outcomes? This has not been well studied. Early animal research and case reports suggested that it might improve some hemodynamic parameters such as heart rate. But this has never been evaluated in controlled clinical trials. It is also important to realize that most of that research was done prior to 1998 and used glucagon derived from cow or pig pancreas. These preparations contained insulin. It is not clear to what extent that insulin affected the results and case outcomes.

Aside from the lack of convincing evidence of clinical efficacy, additional potential problems arise with administering glucagon. First, bolus doses frequently cause significant nausea and vomiting, not a good development in patients who may be bradycardic or have decreased mental status.

Second, glucagon has a very short duration of action10 to 20 minutesmeaning that a post-bolus infusion will be necessary to maintain its effect. Third, glucagon is surprisingly expensive. The acquisition cost of a 1 mg IV dose is $180 to $280, so administering a 10 mg bolus followed by an infusion of 10 mg per hour quickly adds up to real money. Many hospitals do not stock enough of the drug to treat even a single patient effectively because of the expense.

A recent systematic review on beta-blocker poisoning concluded that glucagon appears to have a minimal effect on improving hemodynamics, and proposed a management scheme that did not include glucagon at all, focusing instead on supportive care with fluids, atropine, and pressors. (Clin Toxicol [Phila]. 2020;58[10]:943.) An even more recent survey of cardiotoxic medication poisoning noted, Although glucagon has been touted as the traditional antidote to beta-blocker poisoning, evidence supporting its use is limited. The authors suggested, however, that it may be useful in treating small accidental overdoses of beta-blockers, or as a transient therapy to bridge patients to more definitive therapies. (Emerg Med Clin North Am. 2022;40[2]:395.)

The bottom line: Glucagon has several significant adverse effects but has not been proven to improve clinical outcomes in beta-blocker poisoning. It seems to be more effective at increasing heart rate than optimizing hemodynamics. It is not mandatory in all cases of beta-blocker overdose and is never definitive treatment. Considering it an antidote can lead to faulty clinical decision-making.

I have discussed other examples of antidote derangement syndrome in previous columns, noting that some online medical databases list cyproheptadine (Periactin) as an antidote for serotonin syndrome, and some clinicians fixate on using it in all such cases. Its clinical efficacy has not been demonstrated, however, and it has no established dose regimen. (No Evidence Supports Using Cyproheptadine for Treating Serotonin Syndrome. EMN. 2020;42[10]:18; https://bityl.co/Cmuk.)

High-dose insulin was introduced as an antidote to calcium channel blocker toxicity, and most cases of significant overdose back then involved verapamil and diltiazem, both of which are predominantly myocardial depressants. Today, the majority of overdoses at our poison center involve amlodipine, which is primarily a vasodilator. High-dose insulin is an inotrope but not a vasopressor, and it dilates blood vessels. (The Truth about High-Dose Insulin. EMN. 2021;43[12]:5; https://bityl.co/Cmul.) The use of the term antidote covers over this nuance.

We should abandon the term antidote. It often leads to muddy thinking. These drugs may or may not be indicated in specific circumstances. It's our job to think this through and determine optimal treatment for the patient in front of us.

One more definition: Antidote derangement syndrome refers to clinical decision-making induced by the delusion that the term antidote is synonymous with panacea.

Share this article on Twitter and Facebook.

Access the links in EMN by reading this on our website: http://www.EM-News.com.

Comments? Write to us at [emailprotected].

Dr. Gussowis a voluntary attending physician at the John H. Stroger Hospital of Cook County in Chicago, an assistant professor of emergency medicine at Rush Medical College, a consultant to the Illinois Poison Center, and a lecturer in emergency medicine at the University of Illinois Medical Center in Chicago. Read his blog atwww.thepoisonreview.com, follow him on Twitter@poisonreview, and read his past columns athttp://bit.ly/EMN-ToxRounds.

See the article here:
Toxicology Rounds: Abandon the Term 'Antidote' and Its... : Emergency Medicine News - LWW Journals

Recommendation and review posted by Bethany Smith

-- Top-line readout of data expected in October 2022 --

-- U.S. regulatory submission planned for the first half of 2023 --

-- Phexxi may become the first-ever woman-controlled prophylactic for the prevention of chlamydia and gonorrhea --

SAN DIEGO, Aug. 1, 2022 /PRNewswire/ --Evofem Biosciences, Inc., (Nasdaq: EVFM) today announced that the last subject has completed her last visit in EVOGUARD, the Company'sregistrational Phase 3 trial evaluating the efficacy and safety of Phexxi (lactic acid, citric acid, potassium bitartrate) for the prevention of chlamydia and gonorrhea infection in women. There are no prescription pharmaceuticals approved to prevent these sexually transmitted infections (STIs).

Evofem Biosciences (Nasdaq: EVFM) (PRNewsfoto/Evofem Biosciences, Inc.)

Top-line data fromEVOGUARDis expected in October 2022. Evofem expects positive outcomes would enable the Company to submit regulatory applications in the first half of 2023 to the U.S. Food and Drug Administration (FDA) to expand Phexxi's approved indications to include prevention of urogenital chlamydia and gonorrhea in women. Phexxi is currently approved in the U.S. for the prevention of pregnancy.

"This is a major milestone for Evofem and brings us closer to our goal of providing women a safe and effective, woman-controlled prophylactic measure against chlamydia and gonorrhea, the two most commonly reported sexually transmitted infections in the U.S.," said Saundra Pelletier, Chief Executive Officer of Evofem. "We believe these potential new indications represent significant upside for shareholders, above and beyond the multi-billion-dollar birth control market which we continue to increasingly penetrate with Phexxi for hormone-free contraception."

20% of people in the U.S. had an STI on any given day in 2018,according to a 2021 study in the journal Sexually Transmitted Diseases. The CDC estimates that 4.0 million and 1.6 million new cases of chlamydia and gonorrhea, respectively, occurred that year.1Infected people are often unaware of, and do not seek treatment for their infections. Almost 60% of women infected with chlamydia have no symptoms.2

Story continues

Chlamydiais the most frequently reported bacterial infection in the U.S. and can infect both men and women. It can cause serious, permanent damage to a woman's reproductive system and make it difficult or impossible for a woman to become pregnant later in life.

Chlamydia and gonorrhea have been reported to be responsible for one-third to half of pelvic inflammatory disease (PID) cases. PID can cause serious, long-term problems including infertility, ectopic pregnancy, and chronic pelvic pain.

EVOGUARDbuilds on the positive, statistically significant outcomes of AMPREVENCE, the randomized, double-blind placebo-controlled Phase 2b/3 study evaluating Phexxi for the prevention of chlamydia and gonorrhea. AMPREVENCE met its primary and secondary endpoints and showed that the product was generally safe and well-tolerated.

The FDA has granted Fast Track designation and "Qualified Infectious Disease Product" (QIDP) designation to Evofem's product candidatefor the prevention of both chlamydia and gonorrhea in women.

TheFast Track program facilitates the expedited development and review of new drugs or biologics that are intended to treat serious or life-threatening conditions and demonstrate the potential to address unmet medical needs. The purpose is to get important new drugs to the patient earlier.

QIDP designation is intended to encourage development of new products for the treatment of serious or life-threatening infections. A drug or product in development that receives this designationqualifies for an additional five years of marketing exclusivity following FDA approval for that indication.

Evofem is grateful to the study investigators and coordinators at the more than 100 participating study centers across the U.S., as well as the 1,903 women who participated in this landmark study.

About Evofem BiosciencesEvofem Biosciences, Inc., (Nasdaq: EVFM) is developing and commercializing innovative products to address unmet needs in women's sexual and reproductive health, including hormone-free, woman-controlled contraception and protection from chlamydia and gonorrhea. The Company's first FDA-approved product,Phexxi(lactic acid, citric acid and potassium bitartrate), is ahormone-free, on-demand prescription contraceptive vaginal gel. It comes in a box of 12 pre-filled applicators and is applied 0-60 minutes before each act of sex. The Company expects to report top-line data this fall from its registrational Phase 3 EVOGUARDclinical trial evaluating Phexxi for two potential new indications prevention of chlamydia and prevention of gonorrhea in women. Learn more atphexxi.comandevofem.com.

Phexxiis a registered trademark of Evofem Biosciences, Inc.

About PhexxiPhexxi is an on-demand method of birth control used to prevent pregnancy. Phexxi is not effective when used after sex.

Important Safety Information

Rare cases (0.36%) of bladder and kidney infections have been reported. If you have a history of urinary tract problems that keep coming back, you should not use Phexxi.

Contact your healthcare provider if you are experiencing genitourinary side effects such as vaginal burning, itching, discharge, genital discomfort (including in male partners), yeast infection, urinary tract infection, or bacterial vaginosis.

Phexxi does not protect against sexually transmitted infections, including HIV.

For more information about Phexxi, talk to your healthcare provider and see full Product Information atwww.phexxi.com. Please report side effects by contacting Evofem Biosciences toll-free at 1-833-EVFMBIO or contact FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch.

Intended forUnited Statesresidents only.

Forward-Looking StatementsThis press release includes "forward-looking statements," within the meaning of the safe harbor for forward-looking statements provided by Section 21E of the Securities Exchange Act of 1934, as amended, and the Private Securities Litigation Reform Act of 1995, including, without limitation, the expansion of Phexxi's label, any FDA approvals of new indications and the resulting effect on stockholder value, evaluations and judgments regarding Evofem, its products, its product candidates and their development, and demand for Evofem's products and product candidates. Various factors could cause actual results to differ materially from those discussed or implied in the forward-looking statements, and you are cautioned not to place undue reliance on these forward-looking statements, which are current only as of the date of this press release. Each of these forward- looking statements involves risks and uncertainties.Important factors that could cause actual results to differ materially from those discussed or implied in the forward-looking statements, or that could impair the value of Evofem Biosciences' assets and business are disclosed in the Company's SEC filings, including its Annual Report on Form 10-K for the year endedDecember 31, 2021, filed with the SEC onMarch 10, 2022 and its Quarterly Report on Form 10-Q filed with the SEC on May 10, 2022. All forward-looking statements are expressly qualified in their entirety by such factors. The Company does not undertake any duty to update any forward-looking statement except as required by law.

Sources:

https://www.cdc.gov/std/infertility/default.htm#infnote1

Patel, Chirag G et al. "The Proportion of Young Women Tested for Chlamydia Who Had Urogenital Symptoms in Physician Offices." Sexually Transmitted Diseases vol. 45,9 (2018)

Cision

View original content to download multimedia:https://www.prnewswire.com/news-releases/evofem-announces-completion-of-last-subject-last-visit-lslv-in-registrational-phase-3-evoguard-trial-evaluating-phexxi-for-the-prevention-of-chlamydia-and-gonorrhea-in-women-301596733.html

SOURCE Evofem Biosciences, Inc.

Original post:
Evofem Announces Completion of Last Subject Last Visit (LSLV) in Registrational Phase 3 "EVOGUARD" Trial Evaluating Phexxi for the...

Recommendation and review posted by Bethany Smith

For some women, menopausal symptoms such as hot flashes and vaginal changes can be severe and debilitating, greatly affecting their quality of life. In search of relief, some consider hormone replacement therapy (HRT), which is proven to help these symptoms. But HRT also can mean risks that arent completely understood yet. Our understanding of HRT is still evolving as the medical community pieces together the findings of different studies and continues its research.

Knowledge about HRTs impact on breast cancer risk is also developing. But still, there is great concern about women with a history of breast cancer taking HRT, because we know that hormones can fuel breast cancer growth. There are similar concerns about HRT for women who are at high risk of breast cancer because of a strong family history or a positive genetic test result.

What we do know is that the issue of HRT is complex and controversial. In making decisions about HRT, each woman has to work closely with her doctor to weigh the risks and potential benefits in her particular situation. The information we present here can get you started:

Read this article:
Hormone replacement therapy - Breastcancer.org

Recommendation and review posted by Bethany Smith

This article was featured in One Story to Read Today, a newsletter in which our editors recommend a single must-read from The Atlantic, Monday through Friday. Sign up for it here.

I looked at the clock glowing on the nightstand in my bedroom and it read 1:23, one-two-three, a neat set of numbers. I tossed and turned and writhed and looked again, and it read 1:17. Had I misread the clock? Maybe I was dreaming about the time. Maybe I was just confused.

I slept, I woke up, I slept, I woke up. I hobbled into the bathroom, feeling shooting pain each time I moved my left side. The veins in the stone on the vanity writhed and breathed. Everything smelled metallic. I was hallucinating. I itched, and so I scratched, clawing at the damp back of my knees, my soft belly, my ribs. I broke open the scabs on my legs, watching my blood bead on my irritated skin. Back in the bedroom, a strange pair of eyes, slate-blue with yellow sclera, stared at me in the mirror. I had given birth to my second child a week before, and nothing made sense.

The hallucinations that arrived post-delivery were far from my worst symptoms. I experienced debilitating nerve pain during the second pregnancylike having a tattoo gun alight on my skin, over and over. I itched unceasingly and uncontrollably during both: For 136 days the first time and 167 days the second, I was itchy every single moment of every single day. The sensation ranged between the tight skin of a sunburn and the agony of poison ivy. The itching intensified after sundown, causing sleeplessness and exhaustion. I was itchy in my dreams. I sometimes wonder whether my son, sharing my body, might have been itchy too.

For me, pregnancy was obscene, in the phrasing of one of my doctors. And mysterious. Over the course of my two pregnancies, more than 40 physicians and midwives, by my count, failed to explain why my blood work kept coming back with so many anomalies, why so many debilitating complications kept piling up in an otherwise healthy woman.

Though my experience was unusual, I did have something in common with countless other pregnant people: Despite recent medical advances, bearing a child remains startlingly dangerous, a fact that Americas lawmakers on the bench have chosen to ignore. One in five pregnant people experiences a significant complication. And one in 4,000 dies during pregnancy, in childbirth, or shortly after delivering, including one in 1,800 Black mothers. Yet Justice Samuel Alitos opinion in Dobbs v. Jackson Womens Health Organization takes the interests of the unborn human being into account while dismissing those of the person forced to carry a pregnancy to term.

Gone are Roe v. Wade and Planned Parenthood v. Casey, which protected the constitutional right to termination. Eight states and counting have banned abortions, with no or minimal exemptions for medical reasons. But there is no standard for what preserving the health or the life of the mother means.

Read: The Roe baby

What actually counts as the life of the mother? asks the physician Jennifer Jury McIntosh, a spokesperson for the Society of Maternal-Fetal Medicine, an organization for obstetricians who handle high-risk pregnancies. Is that her life today? Is that her life during this pregnancy? How close to losing her life does she have to be for us to decide to terminate? That feels really weighty, because my interpretation of what I feel is lifesavingdoes that align with a particular prosecutors interpretation? She told me that she feared situations in which not ending a pregnancy might constitute medical malpractice, but doing so might open her up to criminal prosecution. (She practices in Wisconsin, where nearly all abortions are now banned under a law passed in 1849.)

Worst-of-the-worst stories are beginning to surface in the press, an appalling countdown clock tick-tocking until Americans learn of the first woman who dies after being denied a termination since Roe was overturned. Media attention focuses rightly on those worst-of-the-worst cases, in which abortion is obviously lifesaving. In countless other cases, the circumstances will be murkier and stranger, but the elimination of the option of abortion will nevertheless do grievous harm.

As it would for me. My two pregnancies left me disabled, a word I am still struggling to come to terms with. They put my life at significant risk. Some of my doctors have made clear that they do not think I should bear a child again. Still, if I got pregnant, I would likely be forced to carry to term in much of the country, despite how sick I was, despite all the damage and pain I endured.

The 2018 midterms were looming, and my husband and I were planning to relocate from Washington, D.C., to California, when I learned that I was pregnant the first time. At our first ultrasound, we sat besotted, looking at the gummy-bear contour on the screen as a wub-wub-wub sound filled the room. The first jump scare came minutes later. The technician went silent, moving the wand over my pelvis again and again. In time, a doctor came in to tell me there was a mass the size of a softballroughly the size my babys head would be at 40 weeks, she notedsitting on the left side of my pelvis. She was not worried about it affecting the pregnancy. But she was worried about it twisting and cutting off the blood supply to one of my ovaries. That would be a nine or 10 out of 10 on the pain scale, the doctor said, as flatly as if she were letting me know the time.

Duly noted, I guess. She expected the baby to arrive at the end of March or early April, and with that deadline set, my husband and I hastened our move across the country. Toward the end of my first trimester, as we were packing boxes and giving away books, the itching showed up, as I noted in my diary at the time. I first noticed it in the morning. Lots of people stretch and then scratch themselves when they wake up, right? Next, I noticed it in the evening, a reaction to our laundry detergent, perhaps? Soon there was no noticing necessary. I could not not notice it. Especially in warm weather and at night, I felt centipedes scuttling over my feet and hot needles poking my shoulder blades.

From the May 1997 issue: Abortion in American history

Things I tried to make it stop: hypoallergenic detergents and soaps; pine-tar soap; eczema wash; calamine lotion and capsaicin lotion; oatmeal baths; shea butter and dozens of other emollients; antihistamine cream; a variety of over-the-counter and prescription oral antihistamines; topical steroids; showering with cold water; holding bags of frozen corn against my body; wearing loose clothing; acupuncture (not fun when you are itchy); screaming. Only three things helped: ice, a cream called Sarna that made me smell like an unsmoked Newport, and scratching. So I iced, applied lotion, and scratched. I tore the webbing between my toes and the thin skin around my belly button. I clawed out clumps of hair. I fantasized about being able to scratch my wet bones or the jelly in my eyeballs.

My West Coast providers were sympathetic, if not overly concerned. Itching was not unusual during gestation, my new obstetrician noted. She suspected I had intrahepatic cholestasis of pregnancy, a dangerous condition that affects roughly one in 1,000 pregnancies. She ordered weekly blood tests to look for a telltale increase in bile acids. In the meantime, she told me to use cold compresses.

Aside from the pruritusthe medical term for itchingI felt joyous as my belly swelled and we got used to our new home, hiking on the beach with our dogs and trying out baby names. My husband and I took the cult low-intervention birthing class everybody we knew took, called, ahem, Yes to Birth! I read book after book about how I was built for this.

As the weeks dragged on, though, the itching kept getting worse, and the blood work showed nothing. By the middle of my second trimester, struggling to function, I called my providers, sobbing and begging for help. The nurse on call asked me if I had taken antihistamines. Of course I had. If you felt like you had poison ivy for months, I snapped, did you think you would have taken a fucking Benadryl? She had me leave an escalatory message on some voicemail. Nobody called me back. So we moved on to our third set of medical providers, a team of crunchy, evidence-based midwives in Oakland.

At our first meeting, my new lead midwife took one look at my skinwhich, from all my scratching, had undergone a process called lichenification, becoming thick and leathery and covered in weltsand referred me to a dermatologist, who guessed I had either scabies or cholestasis and prescribed a strong topical steroid. (Alas, I did not have scabies.) The new drug would work, I promised myself. I lurked at home, talking to my baby, who we had learned was a boy, telling him I could not wait to meet him.

That happened sooner than Id imagined. Early in my third trimester, my midwife kept muttering Fuck as she took my blood pressure. It had spiked to 170 over 90, a level suggesting that I had preeclampsia. She called in an obstetrician who deals with high-risk cases to take over my care, as I had risked out of her scope of practice.

That new doctor, No. 4, confirmed that I had preeclampsia, with anomalies in my liver and kidney labs. She admitted me to the hospital at 31 weeks so she could monitor my organ function and asked me to stay there until I gave birth, which was likely to be at least a month early. Well deliver you at 36 weeks, she told me. But youre not going to make it that long.

I raged. How dare she! I would delivernot uswhen my body and my baby were ready. I was healthy. I was built for this. (I was in denial.) Her face softened. She had a feeling about some pregnancies, she told me. Mine was one of them. Then she told me about two patients who had had severe pruritus during pregnancy. The first gave herself frostbite during a blizzard, ripping her clothes off and letting the snow numb her. The second threw herself out a window.

Doctor No. 4 agreed to discharge me if I would come back for monitoring in the hospital every third day, so we did that, and I would cry listening to my sons heartbeat in the dark of the sonogram room. Two long weeks later, I went in and got a 220 over 100 blood-pressure reading, then 180 over 110. Then time sped up: The chatty sonogram technician going silentthats not good. Itching. Machines beeping, cuffs squeezing, panicked phone calls. Itching. A meeting with a gray-faced neonatologist, the decision to induce. IV poles. Itching. It was Valentines Day, I realizedred hearts, blood-soaked linens. A dozen people rushing into the room. No time to induce, time to move to surgery. Sign this form. Stay still. Your husband has to wait outside. Cutting, tugging, pulling on my insides, as if I were a prey animal being eaten alive. The discovery that my placenta was shearing away from my uterus, a complication that could have killed me and the baby.

I am not sure exactly when I became a mother. He was quiet at birth, and the neonatal team whisked him away before I could see him. We met hours later, my tiny valentine in his glowing plastic box, covered in wires, fed by a tube.

I was eating soft pretzels with my siblings in a mall food court a year later when my younger sister tried to discourage me from having another child. Dont do it, she told me. You could have died. The baby could have died. Dont do it.

We did not die, though. My three-pound newborn had grown into a thriving toddler, all wacky smiles and fistfuls of spaghetti. As for me, at four days post-delivery, I was so itchy that I demanded a surgeon amputate my legs. (Well take that under advisement.) The next day, the itch disappeared, leaving my doctors and me never really knowing what it was. Months of intensive trauma therapy, started when my son was in the NICU, had restored my mental health in a way I did not think possible at first.

In the end, it was my kid, in all his chaotic wonder, who convinced me to try again. Wasnt it worth it? What wouldnt I sacrifice for him? I prayed that the complications would not come back and that the baby would be safe in my body until we reached full term. But if they did, I knew I had the right to a termination for medical reasons.

When I got pregnant the second time, my providers considered me high-risk from the start. A team of clinicians scrutinized my body and blood, anticipating problems rather than reacting to them. The irregularities started to show up in the first trimester, againproblems with my liver labs, then itching, then nerve pain and insomnia.

My providers could do little to manage my symptoms. As the pregnancy wore on, the aperture of my life drew smaller and smaller. I struggled to think. My hair fell out. I developed gestational diabetes, snatching away the routine of a sandwich, the delight of a good banana. Injecting insulin into the tight drum of my abdomen made me itch every time I did it; I took to stabbing my thighs with my finger-stick lancet after I was done, because pain inhibits itching. I became so foggy-headed that I drove the family car into a concrete pylon. From time to time, I felt so overwhelmed with love that I could not imagine not being pregnant. From time to time, I felt a yen not so much to die as to not exist at all.

Early on, my high-risk-pregnancy obstetrician had called in a hepatologist, a genial older guy with a cravat and an indeterminate European accent. He initially told me I did have intrahepatic cholestasis, both in my first pregnancy and in this one. But well into my second trimester, he left me a voicemail: I would like to discuss your disease. My disease? He had added some tests to my blood work, he explained. My body was teeming with an antibody indicating that my immune system was attacking my bile ducts. I had a disease called primary biliary cholangitisslow-moving, rare, degenerative, and incurable. The hormone load of pregnancy was exacerbating its symptoms.

Hot astonishment, cold relief. I was sick. I had been sick for years. I would be on medication for the rest of my life. I would likely be diagnosed with other autoimmune conditions in time, and was now more susceptible to developing a host of diseases, including liver cancer. My pregnancies had unmasked this reality, as my hepatologist put it. And in creating life for my children, I caught a glimpse of how my own might end: brain-fogged, fatigued, vitamin-deficient, dry-eyed, and, yes, itchy.

But such symptoms might not emerge for years, if at all. After I delivered my son, I hoped, I would again be delivered from the miseries of my own body. The day finally came, and I decided to opt for an induction instead of a C-section, given how much I had hated the latter experience the first time. I labored, feeling the itching subside with the pain of every contraction, breathing myself closer and closer to relief.

Of course, we were in for a few final scares. During one cervical check, my midwife said my son was emerging hand-first. She would have to push him back up to reposition him. (This, well, hurts.) And she worried about his heart rate, which kept dropping, indicating that my contractions might be compressing the umbilical cord and he might have to come out via C-section after all.

From the August 1965 issue: One womans abortion

A doctor placed an epidural. Beeping, people crowding the room. Pushing. I thought I was supposed to feel pressure but not pain. The need to get him out, now. The decision to try forceps. My husband blanching as he stared at the monitor. A request from the doctor for more anesthesia, a warning that it would take a few minutes to kick in. Searing pain, leading me to scream at the doctor to stop. The doctor with the forceps not stopping. Nurses pinning my legs down in the stirrups. The sense of being eviscerated, the room going Technicolor. I did not know I could feel so much pain.

At least it was over quickly. The baby emerged quiet, floppy, purplish. My first reaction was to laugh. I went through all of that to have a baby who was dead? But soon he started to breathe, letting out a raspy cry. The extra anesthesia kicked in, so I keeled over in the bed as the doctor explained that hed performed an episiotomy while wresting the baby out. I was insufficiently anesthetized at the time. Im sorry, he said softly.

My experience of pregnancy was over, and I slammed the door shut. I thanked my clinicians and meant it. I ate three adult portions of spaghetti, ignoring the admonishments of the nurse who had to come in to give me more insulin. I washed away the blood the nurses had missed between my toes and ministered to my stitches and scratch marks. I declined to go back to trauma therapy, though I knew I needed it. I had a beautiful newborn, a beautiful toddler, a beautiful husband. I took my torn-up body home.

Some heartbroken part of me wants to have another kid. I am a middle child, my parents are both middle children, and I am married to a middle child; I have a deep-seated intuition that families are most fun when they are big. Plus, I did heal postpartum. The hallucinations went away when the itching stopped and I started sleeping again. My doctors found a cocktail of medications that have ameliorated many of my symptoms. But I know I cannot give birth againnot least because I need to be a parent to the children I already have and love. And I cannot imagine being forced to.

A majority of Supreme Court justices and a number of state legislators not only can imagine that scenario, but would make it a reality. They would let states force childbirth on victims of rape, incest, and intimate-partner violence; on people without the means or desire to raise a child; even on literal children. The decision is about life, supposedlythe anticipated lives of the embryos and fetuses people will be required to gestate against their will, like brood mares. The lives of those pregnant people do not matter. My experience does not matter. What matter are the opinions of judges and politicians, most of them men with no medical expertise and no experience of being pregnant, no visceral understanding of how messy and hard it can be, even in the best of circumstances.

Even those best of circumstances can be obscenely dangerous, and Dobbs has made them more so. The ruling will absolutely lead to an increase in maternal morbidity and mortality, McIntosh told me. Physicians are now waiting for women with prematurely ruptured membranes to decompensate before providing an abortion. They are reconsidering how to care for pregnant people with cancer, among other ailments. There are reports of people being denied drugs that could be used as abortifacients, even if those drugs are being prescribed for a different purpose.

Read: How the end of Roe would change prenatal care

The judiciary is forcing pregnant people and their doctors to justify care that was once allowed by constitutional right. What if I had had to plead my own case? Would I have been denied a termination if I had never gotten my proper diagnosis, and had only a history of extreme symptoms and abnormal test results? Would I have qualified on the basis of my liver disease and diabetes, both now diagnosed as permanent? How about my chronic fatigue, or my history of pregnancy-related mental-health troubles? Would a physician have been able to end my pregnancy if Id had another placental abruption or another bout of dangerously high blood pressure? Would the state have required me to itch for months on end as my body and my mind deteriorated?

These queries are personal, but Dobbs has raised more metaphysical ones too. What does the life and health of mothers mean? How could it possibly mean so little? What are we supposed to do?

Continue reading here:
What Counts as the Life of the Mother? - The Atlantic

Recommendation and review posted by Bethany Smith

Nearly twenty-five years ago, the scientific breakthrough of mammalian cloning marked a monumental moment in medicine and science. Anticipating the collision it would have with ethical decision making in medicine, I, the only physician-scientist in the U.S. Senate at the time, journeyed to the University of Edinburgh in Scotland to personally visit Sir Ian Wilmut at his research lab at the Roslin Institute.

My house call to Dolly in 1997: I stand with Dolly, the first ever mammal to be cloned from an adult ... [+] somatic cell, during my journey to visit her creator and caretaker, Sir Ian Wilmut.

Professor Wilmut just months before in 1996 had cloned a sheep from an adult somatic cell, shocking the world. This was the first successful attempt of its kind. All over the world people were wondering: would we be cloning a human being next? We talked science, we talked ethics, and we talked about his creations potential impact on altering the course of human history. I also met and examined the cloned sheep, Dolly, in her stall.

Dolly, named after Tennessees own Dolly Parton, was a Finnish Dorset sheep cloned from a single, adult mammary gland cell. Her creation, birth, and short life were scientific feats that immediately sparked global concern and discourse on the increasingly complex moral and ethical dilemmas posed by a sudden discovery of life-manipulating science.

Wilmut and colleagues published their achievement in February 1997, having kept Dolly secret for seven months. We, as a society, were quickly forced to answer difficult, probing questions. A few months later on the Senate floor, I borrowed a question that the Washington Post editorial board had posed a few years before: Is there a line that should not be crossed even for scientific or other gain, and if so where is it?

Here are my remarks in the Senate chamber in 1998:

So it is vital that our public debate and reflection on scientific developments keep pace, and even anticipate and prepare for new scientific knowledge. The moral and ethical dilemmas inherent in the cloning of human beings may well be our greatest test to date. We do not simply seek knowledge, but the wisdom to apply that knowledge. As with each of the mind-boggling scientific advances of the last century, we know that there is the potential for both good and evil in this technology. Congressional Record February 2, 1998

Years removed, I now reflect back on the confusion, questions, and status quo that Dolly challenged.

Dolly was the first mammal to be successfully cloned from an adult somatic cell, which is any type of bodily cell that is not a reproductive germ cell. The process Wilmut developed is technically called somatic cell nuclear transfer, colloquially known as cloning. It is the process of transferring the nuclear DNA of a donor somatic cell into an enucleated oocyte, followed by embryo development and then transfer to a surrogate recipient, followed by live birth.

Dollys creation in a test tube and eventual birth marked a major milestone in scientific research, suggesting that an animal could be cloned to create an exact replica using genetic material derived from theoretically any type of body cell. It opened the world to staggering new possibilities in reproductive cloning and therapeutic cloning.

Soon after Dollys birth, another parallel and similarly monumental finding was made: in 1998 embryonic stem cells were discovered. These cells are a highly unique type of unprogrammed somatic cell with the exceptional ability to both reproduce unlimited exact copies of themselves and develop into more specialized cell types, such as heart, lung, kidney or skin cells. And though seemingly miraculous in potential, these cells could not be created or programmed from any other type of cell and could only be collected from embryos an ethical dilemma because collection for research required destruction of the embryo itself.

Dolly changed this. Her successful creation paved the way for future scientists to develop a technique to independently produce equally powerful pluripotent stem cells by reprogramming other adult somatic cells, revolutionizing genetic therapy, and completely nullifying the ethical dilemma of collecting embryonic stem cells from embryos. Similarly, Dolly also highlighted the potential for scientists to create new tissues and organs for diseased patients, and to preserve the genetic material of endangered species.

But, along with these positive contributions came widespread concern about the ethics of cloning, especially around potential attempts to clone another human being. Many, including myself, feared this type of technology, if left unregulated, would be misused and abused. Indeed, cloning evoked great scientific power that demanded even greater ethical responsibility, and there were no established ethical guardrails at the time to monitor this duty.

In retrospect, these fears have diminished in part due to proactive measures and to the inherent complexities of the human genome (cloning an entire human being is, after all, a large jump from cloning a sheep). Importantly, legislative and scientific communities have been resolute and unified in their opposition to cloning human beings.

Though a human embryo was indeed successfully cloned in 2013, no known progress has been made when it comes to attempts to clone a human being. Yet the technique to create Dolly has been repurposed widely and has led to numerous scientific innovations.

In 2003, six years after her birth, Dolly became sick and was euthanized. Her decline in health was due to the development of tumors in her chest; some examinations of her cells suggested that she was also aging prematurely.

Despite her relatively short life (the average sheep lifespan is ~10-12 years), Dollys influence on the scientific community has been profound. Not only did she force scientists and researchers to redefine the ethics of their field, but she also laid the foundation for other significant scientific advancements in the fast-evolving new field we know today as regenerative medicine.

One powerful example is gene therapy and editing, where specific genes are targeted, edited, and repaired to protect against disease, cancer, autoimmune disorders, and even rewiring immune system cells for treatment-resistant cancer patients. This revolutionary innovation is made possible by CRISPR technology (the same technology that enabled rapid vaccine development for COVID-19), which is currently celebrating its 10-year anniversary.

Genetic cloning was also made possible thanks to Dolly. This is a type of cloning where scientists create copies of genes within DNA segments to combine with plasmid DNA, or self-replicating genetic material, and then place this new plasmid into a host organism, such as a bacterium, yeast, or mammal cell. This process is used to develop vaccines and antigen tests and is also used to identify useful genetic traits in plants, which can be replicated on a larger scale through the genetic modification of seeds.

Further, cloning techniques have also helped to advance agricultural practices. Farmers can use cloning technology to quickly introduce favored characteristics of prize livestock (such as the ability to produce large amounts of high-quality milk) into a herd by cloning and breeding. These livestock will then further reproduce using traditional breeding or assisted reproductive technology.

Despite advances in genetic cloning and agricultural practices, cloning especially the additional attempts at cloning whole organisms remains variable and highly inefficient.

Successful attempts have been made by companies like Sooam Biotech Research and ViaGen Pets to clone dogs and kittens for wealthy pet owners. But, even today, the success rate of animal cloning is estimated to be less than 30%. In fact, many animal rights activists oppose the practice citing animal welfare. In 2015, the European Union banned the practice of livestock cloning.

Overall interest in cloning slowed as advances in adult stem cell research gained traction in the 2000s. This resulted primarily from scientists newfound ability to take adult human cells, for example skin cells, and reprogram them back into an earlier, more primitive but more powerful embryonic-like, pluripotent cells.

This technique was pioneered by Japanese scientist Shinya Yamanaka in 2006, for which he was awarded the 2012 Nobel Prize in Physiology or Medicine. Yamanakas discovery of reprogramming already specialized adult cells to create induced pluripotent stem cells (IPS) took the ethical issue of destroying embryos for research off the table. Some scientists continue to look to cloning as a way to develop genetically unique stem cells that can be used to reduce the risk of triggering an immune response.

Notes taken shortly after my visit with Dolly.

We have come a long way since my exploratory journey from the Senate floor in Washington, DC, to the stall and research laboratory that housed Dolly in Edinburgh in 1997.

For all the controversy that Dolly sparked during her short life, her contributions to society have been nothing short of remarkable. She forced thought leaders, researchers, and policymakers around the world to confront the ethics of cloning. And, she encouraged us, as a society, to weigh in and engage on the ethical considerations of increasingly frequent scientific discoveries.

On all of these fronts, we worked tirelessly to instill and adhere to a strong scientific code, focusing on the bettering of science, innovation, and technology for societal good. Cloning gave us that first glimpse into the future.

As I said on the floor of the Senate on February 3, 1998:

This cloning debate, I think, maybe for the first time in the history of this body [the US Senate], forces us to address what is inevitable as we look to the future, and that is a rapid-fire, one-after-another onslaught of new scientific technological innovation that has to be assimilated into our ethical-social fabric. Congressional Record February 3, 1998

What I said then still holds true today, Science and ethics must march hand in hand. Congressional Record February 11, 1998

Continue reading here:
Twenty-Five Years After My House Call To Dolly: What Have We Learned About Cloning And How Did We Learn It? - Forbes

Recommendation and review posted by Bethany Smith

The landscape of genetic variation of DENRGs in GC

A total of 48 DENRGs were identified using limma package for further analysis (p<0.05, Fig.1A). Out of 433 GC samples, 147 (33.95%) were showed regulatory mutations associated with necroptosis (Fig.1B) and ATRX (5%) was the highest frequency mutated gene. As loss or gain of function is commonly achieved through DNA mutation or amplification/deletion, we considered both somatic mutation and somatic copy number changes in our analysis. We first summarized the incidence of copy number variations and somatic mutations of 48 DENRGs in GC. The frequency of CNV alterations and found that all 48 DENRGs showed prevalent CNV alterations (Fig.1C). The rates of amplification or deletion for most of DENRGs were relatively low. The altered position of CNVs of DENRGs on chromosome were also scanned and illustrated with visual figure (Fig.1D). In addition, most of the DENRGs were significant increase in tumor tissues (Fig.1E).

The landscape of genetic alterations of DENRGs in GC. (A) Heatmap of DENRGs expression between the normal and tumor samples. Blue represents normal gastric tissue, pink represents tumor tissue; upregulated genes were defined as red, and downregulated genes as blue. (B) Mutation characteristics of DENRGs in the TCGA-GC cohort. The TMB is presented in the barplot at the top of the image; the mutation frequency of each DENRGs is indicated on the barplot right. The barplot on the right represents different mutation types proportions. (C) CNV variants frequency of the DENRGs in the TCGA-GC cohort. Red: amplification frequency. Green: loss frequency. The column represented the alteration frequency. (D) The locations of CNV alteration of DENRGs on 23 chromosomes. (E) Expression of DENRGs between normal gastric tissue and tumor tissue. Blue: normal gastric tissue. Red: tumor tissue. DENRGs, differentially expressed necroptosis-related genes. (*p<0.05; **p<0.01; ***p<0.001).

To further explore the interactions of these DENRGs, we conducted a PPI analysis, and the PPI network was shown in Fig. S1A. In addition, the correlation network containing all DENRGs was presented in Fig. S1B. The network above indicated that there was a very strong correlation among DENRGs. GO-term analysis showed that DENRGs were associated with necrotic cell death, programmed necrotic cell death, necroptotic process and apoptotic signaling pathway (Fig. S2A). KEGG pathway analysis displayed that these DENRGs were involved in multiple tumor-related signaling pathway including necroptosis, apoptosis, TNF signaling pathway, IL-17 signaling pathway, and Toll-like receptor signaling pathway (Fig. S2B).

According to Consensus clustering analysis, when the clustering variable was set to the optimal value (K=2), the intragroup correlations were the highest, and the intergroup correlations were the lowest, indicating that all GC patients could be classified into two molecular subtypes (Figs.2A, S3A and S3B), which were termed as C1 (n=208) and C2 (n=163). The heatmap demonstrated a significant difference between cluster C1 and C2 in clinical factors including tumor grade and T stage (Fig.2B). Result of KaplanMeier curve analysis revealed that the patients in C2 cluster had a poorer prognosis (Fig.2C). The results above indicated that the necroptosis subtypes classified by consensus clustering analysis do well in distinguishing prognosis of those GC patients.

Tumor molecular subtypes related by differentially expressed necroptosis-related genes. (A) Consensus clustering of GC patients for k=2 in the meta-cohort (TCGA-GC and GSE84437). (B) Unsupervised clustering heatmap of top 100 DEGs in GC. Clusters, age, gender, grade and stage were used as patient annotations. Red represents high DEGs expression and blue low DEGs expression. *p<0.05; **p<0.01; ***p<0.001. (C) KaplanMeier curves (Log-rank test, P=0.004) for OS of two necroptosis-related molecular subtypes. Blue line represents cluster C1 (n=208), yellow line represents cluster C2 (n=163). DEGs, differentially expressed genes between various molecular subtypes; OS, overall survival.

Given the clear importance of the TME in tumorigenesis, we further investigated whether the two subtypes showed differential characteristics of immune microenvironment and the main results presented in Fig.3AH. The abundance of immune infiltrating cells, including resting Dendritic cells, resting Mast cells, T cells regulatory (Tregs), Monocytes and M2 macrophages, were found significantly higher in the C2 subtype. And M1 macrophages, T cells follicular helper and activated T cells CD4 memory in C1 subtypes showed greater infiltration. These results suggested that the two molecular subtypes associated with necroptosis had distinct TME infiltration characteristics and prognoses.

TME immune cell infiltration levels between two molecular subtypes. The abundance of Monocytes (A), resting Mast cells (B), M2 macrophages (C), M1 macrophages (D), resting Dendritic cells (E), T cells regulatory (Tregs) (F), T cells follicular helper (G) and activated T cells CD4 memory (H) between the two subtypes (all p<0.05). Blue represents cluster C1, red represents cluster C2. The median value is represented as the thick line, and the interquartile range is represented as the box bottom and top. Scattered dots represent outliers.

To better understand the mechanisms responsible for the prognosis differences in the two above molecular subtypes, we further investigate the functional and pathway and 1101 DEGs associated with necroptosis phenotypes were identified by the limma package. GO analysis showed an enrichment of GO terms for these DEGs, including extracellular matrix organization, collagen containing and extracellular matrix binding (Fig.4A). KEGG pathway analysis for the DEGs showed that genes involved in immune-related pathways were enriched, including ECM-receptor interaction, Focal adhesion, and TGF-beta signaling pathway (Fig.4B). These results reconfirmed a pivotal role of necroptosis in regulating the immune microenvironment.

Functional enrichment analysis of the DEGs. (A) Top 10 enriched GO terms of the DEGs (B) Top 10 enriched KEGG pathways of the DEGs. The box color represents the number of enriched genes. Red represents a large number of genes enriched; blue is the opposite. DEGs differentially expressed genes, BP biological process, CC cellular component, MF molecular function. (all adjusted p<0.05).

Although our results identify a role of necroptosis molecular subtypes in prognosis and regulation of immune infiltration, these analyses are based only on patient groups and cannot be used to predict the necroptosis characteristics in individual GC patients. For this, we next constructed an multigenic prognostic signature associated with prognosis and response to treatment in each GC patient based on differential genes of molecular subtypes. We performed univariate Cox regression analysis on all DEGs and resulted in 84 genes as candidate genes (all P<0.005; Fig.5A). Most of the candidate genes were risk factors for the prognosis of GC except for MYB and RNF43. We then subjected the candidate genes to LASSO Cox regression analysis by narrowing the number of genes for the establishment of the NRGsig (Fig.5B and C). In total, 11 optimal genes (CYTL1, PLCL1, CGB5, ADRA1B, APOD, RGS2, CST6, MATN3, RNF43, SLC7A2 and SERPINE1) were screened (Table 2) and most of the optimal genes were significant differentialexpression between the normal tissue and tumor tissue (Fig. S4). The formula of the risk score was calculated as follow:

$$begin{gathered} Risk; score = CYTL1 {text{exp}}.; times ;0.05351 ; + ; PLCL1 {text{exp}}.; times ;0.06101 ; + ; CGB5 {text{exp}}.; times ;0.1605 hfill \ quad quad quad quad , + ; ADRA1B {text{exp}}.; times ;0.07886; + ;APOD {text{exp}}.; times ;0.03166; + ;RGS2 {text{exp}}.; times ,0.04199, + ;CST6 {text{exp}}. hfill \ quad quad quad quad , times ;0.00119 ; + ;MATN3 {text{exp}}.; times ;0.13379 ; + ;RNF43 {text{exp}}.; times ; - 0.09577; + , SLC7A2 {text{exp}}. times ;0.07123. hfill \ quad quad quad quad , + ;SERPINE1 {text{exp}}.; times ;0.12925 hfill \ end{gathered}$$

The development of NRGsig in the TCGA-GC cohort. (A) The prognostic-related genes determined by univariate Cox-regression analysis. Red represents risk genes; green represents protective genes. (B) LASSO regression of prognostic-related genes. (C) Crossvalidation for tuning the parameter selection.

All GC patients were divided into high- and low-risk score group according to the median risk score value. Next, we investigated whether the prognostic signature could distinguish different risk groups of patients clearly. A clearly discernable dimensions between the two risk groups of patients was observed according to the results of PCA and t-SNE analysis (Fig.6A and B). KaplanMeier curves analysis revealed high-risk group patients had a worse prognosis. (Fig.6C). The time-dependent ROC curves were performed to evaluate the prediction performance of the NRGsig and the areas under the curve for 5-year was 0.743 in the TCGA-GC cohort (Fig.6D). Results above demonstrated NRGsigs advantage as robust tool for prognosis.

Prognosis value of necroptosis-related prognostic signature in the TCGA-GC cohort. (A) Principal component analysis plot. (B) T-distributed neighbor embedding plot. (C) KaplanMeier curves (Log-rank test, P<0.001) for OS of high- and low-risk groups. (D) The AUC of the prediction of 1, 3, 5year survival rate of GC. OS, overall survival.

We externally validated the NRGsig using the GSE84437 dataset, an independent validation dataset, and found a similar prediction performance. Patients were then classified as being high or low risk according to the calculated NRGsig risk score. A clearly two directions between the two risk groups of patients was also observed according to the results of PCA and t-SNE analysis (Fig.7A and B). KaplanMeier curves analysis indicated high-risk group patients had a worse outcome (Fig.7C). This independent validation dataset yielded a prediction performance AUC of 0.623 at 5-year (Fig.7D). As a whole, these results showed a satisfactory prediction performance of the NRGsig in external data.

Validation of the necroptosis-related prognostic signature in the GSE84437 cohort. (A) Principal component analysis plot. (B) T-distributed neighbor embedding plot. (C) KaplanMeier curves (Log-rank test, P=0.005) for OS of high- and low-risk groups. (D) The AUC of the prediction of 1, 3, 5year survival rate of GC. OS, overall survival.

The independence of NRGsig were evaluated by univariate and multivariate Cox regression analysis and the result revealed the NRGsig was an independent prognostic factor of GC (Fig.8A and B). Above analysis were repeated in the GSE84437 cohort and similar results were observed (Fig.8C and D). Furthermore, the clinical features in the different risk groups for TCGA-GC cohort we depicted as a heatmap (Fig.8E). To verify the clinical implications of our NRGsig risk score, we examined the correlation of the risk score with the available clinical features in TCGA-GC cohort. The KaplanMeier curves indicated that risk score remained its independent predictive performance regardless of other clinical features, including age (60 or>60years), sex (female or male), grade (G1-2 and G3), T-stage (T3-4), N-stage (N0 and N1-3), and M-stage (M0) (Fig. S5AL). Survival analysis demonstrated that these 11 optimal genes were all correlation with the OS of GC patients (Fig. S6AK). All the results above illustrated that NRGsig was a satisfactory and reliable prognostic tool and could be as an independent risk factor for GC.

Independent prognosis analysis. (A, B) Univariate Cox regression analysis in the TCGA-GC cohort. (C, D) Multivariate Cox regression analysis in the GSE84437 cohort. (E) Heatmap depicting the clinicopathological characteristics and optimal genes expression between the high- and low-risk groups. Risk, age, gender, grade and stage were used as patient annotations. Red represents high expression and blue low expression. *p<0.05; **p<0.01; ***p<0.001.

After categorizing cases of TCGA-GC cohort into two risk score groups by the median risk score value, we further performed GSEA analysis towards them. The results of GSEA suggested that the KEGG_COMPLEMENT_AND_COAGULATION_CASCADES, KEGG_ECM_RECEPTOR_INTERACTION, KEGG_FOCAL_ADHESION, KEGG_HYPERTROPHIC_CARDIOMYOPATHY_HCM, and KEGG_NEUROACTIVE_LIGAND_RECEPTOR_INTERACTION were the top five most enriched pathways in the high-risk group, while the KEGG_CELL_CYCLE, KEGG_DNA_REPLICATION, KEGG_BASE_ EXCISION_REPAIR, KEGG_RIBOSOME, and KEGG_SPLICEOSOME pathways were most enriched in the low-risk group (Figs. S7A and B).

To make the prognosis tool more convenient and quantitative, we integrated risk score with other clinical features including Age and TNM stage to establish a nomogram followed by a series of performance testing (Fig.9A). The net benefit of nomogram was better than other clinical factors, a clinical value was observed as our expectations (Fig.9B). The ROC curve analysis revealed that nomogram had an advantage over other single predictors. In addition, an excellent consistency with ideal model could be observed in the subsequent calibration plot of nomogram for OS predicting (Fig.9C and D). Furthermore, to evaluate the prediction performance of the NRGsig for clinical applications in the TCGA-GC cohort, we compared our prognostic signature with other GC signatures reported in 2020 (Dai signature, Guan signature, Liu signature and Shao signature, respectively). We adopted similar risk score-estimated method described above towards these four signatures to generate risk score for samples from TCGA-GC cohort. The time-independent ROC curves illustrated that Liu signature, Shao signature and Guan signature exhibited lower AUC values for 1-, 3- and 5-year survival rates than NRGsig. The Dai signature presented similar AUC values with our signature (Fig. S8AE). Similar to our signature, these four signatures could also predict the OS of GC patients except for Liu signature and shao signature (Fig. S8GJ). Moreover, the C-index of the NRGsig was the higher than other four signatures (Fig. S8K). NRGsig evidenced its advantage in long-term survival predicting and risk stratification compared with other four prognostic signatures.

The construction and assessment of nomogram. (A) Nomogram integrating clinical factors and risk score for predicting 1-, 3-, and 5-year OS in TCGA-GC cohort (B) Decision curves of risk score, nomogram, and single clinical factors including T stage, N stage and age. (C) The time-dependent ROC curves of risk score, nomogram and single clinical factors including T stage, N stage and age. (D) The calibration curves for 1-, 3-, and 5-year OS. OS, overall survival.

In line with our aim to increase the response to immunotherapy, we investigated the potential correlates between immune infiltration of tumors and NRGsig risk score. After calculating the infiltrating score of 16 immune cells and 13 immune-related pathways by using ssGSEA, we observed significantly increased antigen presenting function including aDCs, DCs and APC co-stimulation score in the high-risk group, while the activity of APC co-inhibition and MHC class I showed the opposite variation (all adjusted P<0.05). Besides, contents of Treg cells, TIL cells and T helper cells were relatively higher in high-risk group, while the activity of Th2 cells had exactly the reverse results. Those results suggested significant difference in T cell regulation between the two subgroups. Moreover, CCR, mast cells, B cells, macrophages, neutrophils, parainflammation, type I IFN response and type II IFN response were observed to have increasing activities in samples from high-risk group (Fig.10A and B). Similar observational results existed for in the GSE84437 cohort (Fig.10C and D). Taken together, the findings of this study demonstrated that different risk groups have different immune landscape, which affected the prognosis of GC patients.

ssGSEA scores in the high- and low-risk group in the TCGA-GC and GSE84437 cohort. (A, B) TCGA cohort, (C, D) GSE84437 cohort. The scores of 16 immune cells (A, C) and 13 immune-related functions (B, D) are displayed in boxplots.

We next explored potential expression changes of immune checkpoints between high- and low-risk groups. Results showed clear differences between the two patient groups, such as BTLA, CD86, CD200, CD27, and other immune checkpoints (Fig. S9). These results highlighted NRGsig as a therapeutic potential for combination strategies with immune checkpoint blockade (ICB) therapy in GC patients. Beyond ICB therapy, we also investigated sensitivity of chemotherapeutic and targeted therapeutics agents between high- and low-risk score groups in TCGA-GC cohort. Results indicated that IC50 toward eleven chemotherapeutics including A.770041, AS601245, AZ628, Axitinib, Luminespib, Navitoclax, Motesanib, Ponatinib, Rucaparib and Saracatinib, of samples in low-risk group were higher than those of high-risk group except for Veliparib (P<0.05), suggesting that samples in low-risk group were more responsive to those medicine (Fig.11AK). As mentioned already, GSEA analysis revealed that a drug-resistant pathway like KEGG_BASE_EXCISION REPAIR was highly enriched in the low-risk score group, which could partially explain the above results. Drugs sensitivity analysis suggested that high-risk score patients might be more suitable for chemotherapy better response to chemotherapy.

Drugs sensitivity analysis in patients from different risk score groups. The sensitivity to chemotherapeutic drugs was represented by the half-maximal inhibitory concentration (IC50) of chemotherapeutic drugs. (AK) Comparisons of IC50 for chemotherapeutics drugs between two subgroups revealed that the high-risk group was more likely to benefit from the treatments (KruskalWallis test, all p<0.01).

Evidence is growing that high TMB is a feature associated with response to immunotherapy in a variety of tumors, and high TMB levels lead to an increase in tumor neoantigens, which may trigger the immune system to attack the tumor40,41. Thus, we assessed the correlation of risk score with TMB in the TCGA-GC cohort. A negative relationship was observed between them, and the TMB score of the two risk groups were evaluated and significant disparity could be observed. The results illustrated that low-risk group patients had a significantly higher TMB than high-risk group (Fig.12A). The combination of high TMB and low-risk score had the best OS in GC by KaplanMeier curves (Fig.12B).

Correlation of risk score with TMB and predictive value of risk score for immunotherapy response. (A) TMB differences between the high- and low-risk score groups and the scatter plot depicted a positive correlation between risk score and TMB. (B) KaplanMeier curves for patients stratified by risk score and TMB in the TCGA-GC cohort. (CE) Immunophenscore (IPS) between high- and low-risk score groups. Blue represents the low-score group and red the high-score group. The thick line within the violin plot represents the median value. The inner box between the top and bottom represents the interquartile range. (C) IPS score when PD-1 positive; (D) IPS score when CTLA4 positive; (E) IPS score when both PD-1 and CTLA4 positives. TMB, tumor mutation burden; IPS, Immunophenscore. (F) TIDE score differences between the high- and low-risk score groups and the scatter plot depicted a positive correlation between risk score and TIDE and lower risk score may be more likely to benefit from the immunotherapy (Spearman text, p<0.001).

Furthermore, we explored the potential of risk score as predictor for immunotherapy response. We applied two mature algorithms, including IPS and TIDE, to predict the response of GC samples with different risk score to immunotherapy. The result evidenced that the IPS value for CTLA4 or PD1 therapy response was more sensitive in the low-risk group and suggested that the NRGsig has high potentiality for predicting CTLA4 and PD1 blockade therapy (Fig.12CE). On the other hand, the TIDE score was higher in the low-risk group and was also positively correlated with risk score, which indicated the lower risk score might benefit more from immunotherapy (Fig.12F and G). Two distinct algorithms drew consistent results. The results above implied that NRGsig may effectively help predict the response to immunotherapy.

Go here to see the original:
Construction of a novel signature and prediction of the immune landscape in gastric cancer based on necroptosis-related genes | Scientific Reports -...

Recommendation and review posted by Bethany Smith

Editors note: WRAL TechWire today launches a new package of features focusing on innovation. This package will be part of Innovation Thursday.

+++

INNOVATION ROAD TRIP: Part One

Earlier this year, WRAL published a series titled Innovation Road Trip that featured six video and story packages from across North Carolina. Check out part one:

How CRISPR is solving problems through DNA editing

Written by Abbey Slattery, WRAL Digital Solutions

Eradication of certain diseases, increasing crop sizes, reducing pest populations the current and future applications of CRISPR have the potential to change ways of life around the world.

A tool for editing genomes including altering DNA and modifying gene functions CRISPR is short for CRISPR-Cas9 and refers to a string of DNA and the Cas9 enzyme. CRISPR works by finding a specific section of DNA, cutting it, then inserting a mutation or replacing a faulty gene.

Read the full story at this link.

Go here to see the original:
Innovation Thursday: How CRISPR is solving problems through DNA editing - WRAL TechWire

Recommendation and review posted by Bethany Smith

Cell and gene therapies are taking the world by storm. With CRISPR gene-editing technology, the genome is no longer an untouchable sacred text. Instead, genomic DNA is actively manipulated in the laboratory and the clinic. This revolution is changing the bench, the bedside, and the boardroom. As a result, the cell and gene therapy market is valued at USD 4.99 billion and is expected to grow to over USD 36 billionby 2027.

The potential of personalized medicinewhere treatments are specific to an individual's geneticsexplains this exponential growth. Cell therapies, such as CAR-Ts, modify cells outside the patient and reintroduce them as a targeted treatment. In comparison, gene therapies alter the DNA within cells. The final genetic dosage from a cell or gene therapy walks a razor's edge between therapeutic and toxic. This makes the quality control testing of cell and gene therapies absolutely vital. Many turn to qRT-PCR for this task, but this method cannot deliver absolute quantification as each run requires a standard curve, creating inconsistencies.

In this article, we explore how Droplet Digital PCR (ddPCR) technology is revolutionizing quality control for cell and gene therapies, enabling scientists to save time, money, and resources through confident quantification.

Before we dive into how ddPCR assays reimaginethe limits of quality control in cell and gene therapies, lets explore ddPCR technology. Like qRT-PCR, ddPCR technology requires a nucleic acid sample. However, in ddPCR assays, samples are partitioned into 20,000 discrete droplets. Individual PCR reactions occur within each droplet, which on average contains just a single copy of the donor DNA. During PCR cycling, positive droplets that contain the target DNA will produce a fluorescent signal. This digital system results in absolute quantification without the need for standard curves, leading to unparalleled precision, simplified workflows, and removal of PCR bias.

Generating cell and gene therapies is complex, requiring precise quality control. CRISPR, while powerful, does not have a 100% success rate. However, you need 100% certainty in your product. Thats where the absolute quantification from ddPCR technology comes in. Here we explore several instances where ddPCR assays allow scientists to expand cell and gene therapy boundaries.

The ideal quality control assay for gene therapy would simultaneously quantify the transfer of genetic material and changes in expression. In their 2021 publication, Clarner et al. did just that using a one-step RT-ddPCR method. Their method quantified transgene expression and potency with both RNAi and augmentation vectors in vitroand in vivo,using non-human primate models. They noted that the absolute quantification from ddPCR reduced variability and provided a more streamlined workflow.

In a second example, CRISPR can generate knock-ins to increase gene dosage, which is technically challenging because integration efficiency is low. The process of developing knock-ins becomes time and resource-intensive and requires processing many failures.CRISPR SNIPERuses ddPCR technology to quantify knock-ins with precision and efficiency. Because ddPCR assays partition donor DNA into 20,000 droplets, CRISPR SNIPER can accurately measure low-frequency integration events that qRT-PCR simply cannot detect.

Finally, ddPCR methods are excellent for cell therapy transgene quantification. CAR-T cells are generated using viral vectors that insert transgenes into T-cell DNA. However, the number of integrated transgene copies can be variable.Lu et al. used ddPCR technology to accurately measure transgene copy insertion in CAR-T cells with high levels of reproducibility.

Across the board, ddPCR assays are uniquely positioned to catapult cell and gene therapies to the next level, standardizing and safeguarding the production process worldwide. ddPCR methods possess the accuracy, precision, and reproducibility required for cell and gene therapy quality control. Across applications from knock-in generation to CAR-T cell transgene quantification, this technology allows scientists to focus on what they do best: science. Meanwhile, ddPCR technology can take care of quality control.

Learn more about ddPCR applications for cell and gene therapy manufacturing.

Read the original here:
Next-level quality control in cell and gene therapy - BioPharma Dive

Recommendation and review posted by Bethany Smith

Heart disease is the leading cause of death among men in the U.S., according to the Centers for Disease Control and Prevention (CDC). Over 380,000 men die from heart disease annually, accounting for about one in every four male deaths. By now, most of us are aware that various risk factors can make you especially vulnerable to heart-related death: being obese, smoking, or having diabetes or high blood pressure, for example. Now experts are warning men about a little-known risk factor you'd never suspect. Read on to learn why certain men are at an outsized risk of life-threatening heart disease, and the one thing you can do to reduce your chances of a problem.

READ THIS NEXT:Doing This at Night Could Lead to Heart Failure, Study Warns.

Composed of proteins and DNA, chromosomes are structures found within the nuclei of cells that contain your genes. Within each human cell, there are two pairs of 23 chromosomes (a total of 46), two of which can differ depending on biological sex. Women have two X chromosomes, while men have one X and one Y chromosome.

However, experts say many men begin losing their Y chromosomes as they age, a phenomenon known among scientists as hematopoietic mosaic loss of Y chromosome (mLOY). "At least 40 percent of males lose the Y chromosome from some of their blood cells by age 70. And by age 93, at least 57 percent have lost some of it," The New York Times recently reported.

READ THIS NEXT:If This Happens to You in the Bathroom, Get Checked for Heart Failure.

Though researchers have been aware of mLOY for decades, much was still unknown about its impact on the body. Now, they're exploring its link to age-related disease and higher risk of mortality in men.ae0fcc31ae342fd3a1346ebb1f342fcb

To do so, one group of researchers studied genetically engineered male mice, who were "reconstituted with bone marrow cells lacking the Y chromosome." They found that as the mice lost their Y chromosomes, they developed scar tissue on the heart, resulting in "reduced cardiac function," heart failure, and increased mortality from heart disease.

Though the study, published in the Jul. 2022 issue of the journal Science, used mice as subjects, the researchers behind the study believe their findings are applicable to human males. Other studies have supported this notion, having found a causal link between loss of Y chromosomes and chronic illnesses such as cancer and heart disease.

Some scientists say this could help explain the difference in life expectancy between men and women. According to the CDC, women live an average of five years longer than men. According to a 2020 report by the health authority, women live an average of 80 years, while men live an average of 75 years.

A 2014 study on the subject published in the journal Nature Genetics reviewed data from 1,153 men in Sweden. The team discovered that men who were missing the Y chromosome in a large percentage of their blood cells were at notably heightened risk of mortality in the years that followed. "I saw that men with loss of Y in a large proportion of their blood cells survived only half as long, 5.5 years versus 11.1 years," Lars Forsberg, a researcher at Uppsala University and one of the study's lead authors, told the Times.

For more health news sent directly to your inbox, sign up for our daily newsletter.

The New York Times reports that having low testosterone levels is unrelated to loss of Y chromosome, and testosterone supplements do not benefit men with mLOY.

However, experts say there is one known way to reduce your risk of Y chromosome loss: quitting smoking. In fact, according to a separate study published in Science, smokers are up to four times more likely to lose all Y chromosomes in the blood cells, compared with non-smokers.

Addicted to nicotine? Speak with your doctor for tips on how to quitand to learn more about the benefits of doing so.

Go here to see the original:
Men Missing Y Chromosome Have High Heart Disease Risk Best Life - Best Life

Recommendation and review posted by Bethany Smith

Summary: In males, sun exposure activates the p53 protein which signals to the body to produce the appetite-associated ghrelin hormone. In women, estrogen blocks the interaction between p53 and ghrelin, reducing the urge to eat following sun exposure.

Source: Tel Aviv University

A new study from Tel Aviv University reveals that solar exposure increases appetite in males, but not in females. Conducted on lab models, the study unravels the differences between males and females in the activation of the metabolic mechanism.

The researchers explain that in males of both animal species and humans, sun exposure activates a protein called p53, in order to repair any DNA damage in the skin that might have been caused by the exposure. The activation of p53 signals the body to produce a hormone called ghrelin, which stimulates the appetite.

In females, the hormone estrogen blocks the interaction between p53 and ghrelin, and consequently does not catalyze the urge to eat following exposure to the sun.

The groundbreaking study was led by Prof. Carmit Levy and PhD student Shivang Parikh of the Department of Human Genetics and Biochemistry at TAUs Sackler Faculty of Medicine.

It was conducted in collaboration with many researchers in Israel and worldwide, including contributors from Tel Aviv Sourasky (Ichilov), Assuta, Meir, and Sheba Medical Centers, along with Dr. Yiftach Gepner and Dr. Lior Bikovski from TAUs Sackler Faculty of Medicine, and Prof. Aron Weller of Bar-Ilan University.

The paper was published in the prestigious journalNature Metabolism.

The study was based on epidemiological data collected in a year-long survey about the eating habits of approximately 3,000 Israelis of both sexes, including self-reports from students who had spent time in the sun, combined with the results of a genetic study in a lab model.

The findings identify the skin as a primary regulator of energy and appetite (metabolism) in both lab models and humans.

The researchers explain that there is a dramatic metabolic difference between males and females, impacting both their health and their behavior. However, so far it has not been established whether the two sexes respond differently to environmental triggers such as exposures to the suns UV radiation.

Prof. Levy: We examined the differences between men and women after sun exposure and found that men eat more than women because their appetite has increased.

Our study was the first gender-dependent medical study ever conducted on UV exposure, and for the first time, the molecular connection between UV exposure and appetite was deciphered.

Gender-dependent medical studies are particularly complex, since twice the number of participants are required in order to find statistically significant differences.

Prof. Levy concludes: As humans, we have cast off our furand consequently, our skin, the largest organ in our body, is exposed to signals from the environment. The protein p53, found in the skin, repairs damage to the DNA caused by sun exposure, but it does more than that. It signals to our bodies that winter is over, and we are out in the sun, possibly in preparation for the mating season.

Our results provide an encouraging basis for more research, on both human metabolism and potential UV-based therapies for metabolic diseases and appetite disorders.

Author: Noga ShaharSource: Tel Aviv UniversityContact: Noga Shahar Tel Aviv UniversityImage: The image is in the public domain

Original Research: Open access.Food-seeking behavior is triggered by skin ultraviolet exposure in males by Carmit Levy et al. Nature Metabolism

Abstract

Food-seeking behavior is triggered by skin ultraviolet exposure in males

Sexual dimorphisms are responsible for profound metabolic differences in health and behavior. Whether males and females react differently to environmental cues, such as solar ultraviolet (UV) exposure, is unknown.

Here we show that solar exposure induces food-seeking behavior, food intake, and food-seeking behavior and food intake in men, but not in women, through epidemiological evidence of approximately 3,000 individuals throughout the year.

In mice, UVB exposure leads to increased food-seeking behavior, food intake and weight gain, with a sexual dimorphism towards males.

In both mice and human males, increased appetite is correlated with elevated levels of circulating ghrelin.

Specifically, UVB irradiation leads to p53 transcriptional activation of ghrelin in skin adipocytes, while a conditional p53-knockout in mice abolishes UVB-induced ghrelin expression and food-seeking behavior. In females, estrogen interferes with the p53chromatin interaction on the ghrelin promoter, thus blocking ghrelin and food-seeking behavior in response to UVB exposure.

These results identify the skin as a major mediator of energy homeostasis and may lead to therapeutic opportunities for sex-based treatments of endocrine-related diseases.

See the original post:
Going to the Beach? Planning a Hike? Be Prepared: Men Will Be Much Hungrier! - Neuroscience News

Recommendation and review posted by Bethany Smith

The headline of a recent article by Dani Blum, a News Assistant in the Well section of the New York Times, forced me to ask myself, Are we really this misinformed about what contributes to good health and wellness, and the basic actions we can take to improve our chances of aging well and avoiding disease and chronic pain? Blums piece, entitled, You Wont Live Longer by Diet or Exercise Alone, Study Says, began by stating Sprawling new research showed that healthy eating and regular workouts do not, in isolation, stave off later health issues. They need to be done together.

Really? You mean it took Sprawling new research to verify that walking Fido vigorously each morning, then taking him with me for a pancake and whipped cream breakfast seven days a week might not be the best preparation for my senior years? That three-times-a-week to the gym followed by a mocha cookie crumble frappuccino and double-smoked bacon, cheddar and egg croissant sandwich wont necessarily qualify me for the Canada Summer Games next time they swing into Niagara?

Assume my diet is a perfect combination of organic leafy greens, black beans, lentils and gluten-free, hearth-baked bread with natural honey on seaweed crackers for dessert. Does this mean I can sit in an ergonomic chair at work or in front of my home computer all day, then watch four hours of Netflix every evening without risking my long-term health? Of course not. Next up was an article in The Guardian by Linda Geddes, Science Correspondent, entitled, Sunlight may trigger hormone that makes men hungrier, study suggests.

The piece was based on a study by Carmit Levy, a Professor of Human Molecular Genetics and Biochemistry, at Tel Aviv University, examining the effect of sunlight on appetite in male and female people and similar genders of mice.

The substance of the article was that his team had discovered ghrelin levels (a gut hormone which stimulates food intake, fat deposition and growth hormone release in our bodies) rise in males blood after sun exposure, but estrogen appears to block a similar increase in females. The article stated, Analysis of 3,000 people revealed that men, but not women, increased their food intake during the summer months. Okay, but could there possibly be any other reasons than exposure to sunlight?

I dont recall many of my male buds worrying about losing a few pounds to fit into a new bathing suit before hitting the beach and going on a summer crash diet, or blaming sunshine for the need to have a beer or three and plate of fries after playing a round of golf, which is most-often done in the summer. Seems backyard steak and sausage BBQs are more prevalent in the summer than winter too. Could any of these be a factor?

As I completed reading Geddes article, my skepticism was rewarded by a review notation in the second to last paragraph. It read, Dr. Duane Mellor, a dietitian and senior teaching fellow at Aston University (Birmingham, England) was more cautious. What it does show is the potential mechanism of how UVB can influence hormone metabolism, and how this may be associated with an increase in the appetite hormone ghrelin, at least in mice, he said.

The need to evaluate wellness and health advice, as this column generally cautions when it ventures into these topics, through additional corroborating evidence mixed with our own best common sense is clear. Indiscriminately accepting what fits into our preconceived ideas is seldom useful, and understanding the motivation behind conflicting health information is helpful. Those of us born in the two decades immediately following the Second World War remember our mothers constantly telling us to eat carrots by the bunch to improve our vision. Dear mom was aided in this unabashed conspiracy of forced carrot consumption by Bugs Bunny, Warner Bros sassy carrot-chomping wild hare in cartoon after cartoon.

Science later proved that the beta-carotene in carrots does indeed help our bodies produce vitamin A, which increases the ability of our eyes to convert light into signals the brain understands, and reduces cornea degeneration as we age.

Problem is, this carrot and eyesight health link wasnt founded on solid health science in the early 1940s. It seems that the British Royal Air Force had developed radar technology late in the war, suddenly increasing the success of their bombing raids on Germany. In an effort to hide their discovery, the British promoted the myth that their airmen had suddenly become more capable of night vision by eating volumes of carrots. The science came much later than the headlines.

Remember the MSG (monosodium glutamate, a common amino acid with one sodium atom added) scare which began in the late 1960s? Im still afraid of this food additive, or at least I was until I read that MSGs bad rap began in 1968, when an American doctor named Robert Ho Man Kwok wrote a letter to the New England Journal Medicine, calling a medical condition of general numbness and weakness the Chinese restaurant syndrome, citing the MSG used to flavour Chinese food as the culprit. The American Chemical Society, a potentially unbiased stakeholder if ever there was one, swiftly responded with the vague non-statement that MSG can temporarily affect a select few when consumed in huge quantities on an empty stomach, but its perfectly safe for the vast majority of people.

Confused by this conundrum between natural salt and MSG, I personally chose to switch to pink Himalayan salt. Its reputed to contain healthy trace minerals, which worked for me until my son pointed out that the dispenser I was using to grind it had hardened plastic cutting teeth rather than metallic ones. I was in fact ingesting more trace plastic than healthy trace minerals. Now its Pass the sea salt please at our house.

Then theres the five-second rule, the idea that if a piece of food drops on the floor you can safely pick it up and eat it as long as it doesnt sit there for more than five seconds. Apparently Julia Child gets the blame for this one. During one of her TV shows she dropped a potato pancake, promptly returned it to the pan, and continued with her cooking demonstration as if nothing had happened.

The crazy part is that the five-second rule has since been the subject of countless studies which have determined that food on the floor can pick up bacteria quickly, that sticky wet food will collect more potential pathogens than dry morsels, that some floor bacteria are more harmful than others, and that dirty floors are more likely to be unsafe for five second food drops than clean ones. Sure hope our taxes werent funding Health Canada to participate in this research. My personal interpretation of the five-second rule doesnt need scientific guidance. If the food dropped is a cookie or ripe sweet cherry, it will be picked up and eaten. Dropped soggy cooked brussels sprouts go straight to the compost bucket. Pizza is situational. When I bought the last slice of warm pizza at 5:59 PM from the only gas station still open along some desolate road in northern Ontario, after cycling 120 kilometres, then promptly dropped it face-down on the sidewalk, a five-second or five-minute rule wouldnt have saved that pizza slice and a few fresh tiny specs of gravel from being eaten.

Are the natural sugars in honey better for you than processed sugar? Will an apple a day keep the doctor away? Is herbal tea or juice better for detoxing? The list goes on.

As Dani Blum suggested at the beginning of this column, Ill stick with balancing diet and exercise, and do my best research before I intentionally change a wellness habit. In the meantime, I just viewed the beginning of a podcast, and now I really need to find out why Dr. Steven Gundry, MD and best-selling author of nutrition and cookbooks, claims that, Beans are so lethal that five raw kidney beans will kill a human being in five minutes by coagulating their blood.

Go here to see the original:
THE BALANCED LIFE | Use common sense when digesting wellness advice | - The Voice of Pelham

Recommendation and review posted by Bethany Smith

Before its 75th Independence Day, India will have brought back cheetahs to semi-wild conditions in Madhya Pradesh, where cheetah roamed more than 100 years ago.

It will surely be a moment of rejoice but one should remember that these animals may be more of a tourist attraction than add ecological value. It is the worlds first species re-introduction programme and comes at the time when less than 7,000 cheetahs are remaining in the world with their population on decline.

Last Wednesday, India and Namibia signed a historic memorandum of understanding (MoU) on translocation of cheetahs to India for a period of 5 years, which can be renewed for successive 5-year periods, unless either party terminates the agreement. Namibia has promised to provide India eight cheetahs in two batches of four each.

The agreement speaks about biodiversity conservation with specific focus on restoration of the cheetah in its former range areas; sharing expertise and capacities for cheetah conservation in the two countries, wildlife conservation and sustainable biodiversity utilisation and mechanisms of livelihood generation for local communities living in wildlife habitats.

On the face of it, the agreement looks good but wildlife experts point out that the provision on sustainable conservation of biodiversity actually means supporting Namibia at the meetings of Convention on International Trade in Endangered Specials of Wild Flora and Fauna (CITES) to allow trade of wildlife and its body parts. Namibia and several other African countries, which have a huge stockpile of wildlife body parts, have been trying for long to negotiate the trade at CITES, the international wildlife regulator, for their sale in high demand western and West Asian countries.

This is a historic event. After a 75-year gap we will see cheetahs back in India. This will be the first inter-continental wild to wild transfer of cheetahs in the world. Some concerns regarding the agreement were there but those have been resolved now. Negotiations on modalities of translocation are underway. Initially, we may get 8 cheetahs by August, said SP Yadav, head of National Tiger Conservation Authority (NTCA), the national big cat regulatory body.

The Cheetah project

The Supreme Court appointed panel had surveyed 10 sites between 2010 and 2012 to select where the cheetah could be introduced. Based on the International Union for Conservation of Nature (IUCN) guidelines for reintroductions that consider species viability according to demography, genetics and socio-economics of conflict and livelihoods, Kuno Palpur National Park in Shivpuri district of Madhya Pradesh was considered ready for receiving the cheetah. This was because there had been already been a lot of investments in this protected area for introducing Asiatic lions from Gir National Park in Gujarat.

The current carrying capacity for Kuno (748 sq km) is a maximum of 21 cheetahs and it could be enhanced for another 20 by including the remaining part of the Kuno Wildlife Division (1,280 sq km) through prey restoration, the ministry said. It has also provided R10 crore for the project and is sourcing money from private funders. The Wildlife Institute of India (WII) with national and international cheetah experts is providing technical and knowledge support, the ministry said.

According to an environment ministry report on Cheetah Translocation Project, the aim of bringing cheetahs to India is to establish a viable cheetah meta-population in India that allows the cheetah to perform its functional role as a top predator and provide space for the expansion of the cheetah within its historical range.

According to a Ravi Chellam, biodiversity expert and CEO, Metastring Foundation & Coordinator, Biodiversity Collaborative, in March 2022, published a report saying that range of cheetahs extended from Punjab in north to Bihar in the east to Gujarat and Rajasthan in the west and till Western Ghats in south. The last cheetah spotted in India was in Western Ghats and northern Bihar in 1967. Madhya Pradesh where the cheetahs are being brought lost their last this big cat in 1912 and 1932, as per the study.

There are authentic reports of their occurrence from as far north as Punjab to the Tirunelveli district in Tamil Nadu. The cheetahs habitat was also diverse, favouring the more open habitats, scrub forest, dry grasslands, savannas and other arid and semi-arid open habitats, he said in the report.

The consistent and widespread capture of cheetahs from the wild over centuries, its reduced levels of genetic heterogeneity due to a historical genetic bottleneck resulting in reduced fecundity and high infant mortality in the wild, its inability to breed in captivity, sport hunting and bounty killings are the major reasons for the extinction of the Asiatic cheetah in India, Chellam had said.

On the ministry statement that it wants cheetah to perform its functional role as a top predator, Chellam said the role is being done by Asiatic lion and leopards in the country. Moreover, data from African countries show that farm bred cheetahs (which India is getting) are very vulnerable to leopard. In Kuno, where they would be habituated for wild, top predator is leopards with officials estimate their number to be more than 50.

The translocation process

The ministry said cheetahs from Namibia will be first to arrive by August 15 and the animals have been identified there.

According to a University of Pretoria statement, 12 animals are being prepared in South Africa for their new home in Madhya Pradesh. Of them, at least six are expected to be in Kuno by end of 2022, which would by then have four cheetahs from Namibia.

The ministry has made Kuno National Park management responsible for monitoring and protection of cheetahs with the help of Wildlife Institute scientists and international experts from South Africa and Namibia. For people living in and around Kuno, an awareness campaigns is underway with a local mascot named Chintu Cheetah, ministry said.

Cheetahs brought in from Namibia would be soft released (providing wild animals with a gradual transition to the wild during translocation) into a 10 sq km enclosure in Kuno to reduce their tendency to disperse long distances from their site of release, officials said, adding they would be housed in the predator proof fenced enclosures.

Initially, male and female cheetahs would be kept separately in five square kilometre enclosure but adjoining compartments and will be allowed to co-habit as and when indications would be there. The location of the enclosure will be such that the cheetahs can sense the presence of prey and predators before release.

A new study by a United Nations affiliated global wildlife regulator in July 2022 said that cheetahs are notoriously difficult to breed in captivity based on long-time research on cheetah breeding in captive facilities in Africa. Cheetahs are notoriously difficult to breed in captivity for example, North American cheetahs have excellent genetic variation as well as housing and veterinary care, yet only 23 out of 111 females have had offspring, the study said.

The concerns

Experts point out that apart from breeding in captivity concerns, there are also questions over whether Kuno, a Vindhya forest with limited grassland, is a perfect habitat for cheetah, which like vast open spaces for their biological and physical needs. Studies in Africa have shown that female cheetah are solitary and roam vast distances whereas male defends smaller territories and mate when female pass through, creating breeding issues.

Even the national action plan for cheetah translocation released in January 2022 hinted at the animals low reproduction issues saying Kuno has current capacity to sustain 21 cheetahs in 15 years and 36 after 30-40 years.

Wildlife experts also point out to the presence of leopards in Kuno which would make release of the animals in the wild difficult. Studies have shown that in Africa, the leopards have hunted down cheetah as prey, and similar fears are being expressed for Kuno also, which has about 50 leopards in and around the core area, where cheetahs will be housed.

Another pivotal issue is whether a cheetah living in an enclosure and being fed with a prey will be able to hunt in wild on its own. In the past decade or so, not even a single wild big cat such as tiger and lion treated or bred in enclosure have been able to return to life in wild. Sundari, the tigress which returned from Satkosia in Odisha after failed relocation attempt, was finally kept captive for life in Bhopal Zoo. Close to 30 lions kept in an enclosure after CDV outbreak in Gir National Park would go to different zoos in the country.

Anish Andheria, President of Wildlife Conservation Trust, however, rebuffed some concerns. In Africa, cheetahs live alongside other felids like lions and leopards. Cheetah is an intermediate size cat. Male tigers do migrate to Kuno from Ranthambore off and on, but they haven't bred due to the absence of tigresses. So, conflict with tigers is not a major concern. We will have to see how cheetahs cope with leopards, he said.

He also pointed out cheetahs survived in wooded habitats in Africa also and therefore, forest of Kuno should not be a major concern. I agree it is not the best habitat for cheetah. I think the ministry should start exploring other larger, more open habitats in Gujarat and Rajasthan and prepare them for cheetah introduction in 10 years he said.

More than 117 years after the project to rehabilitate lions from Africa failed, the government has readied an enclosure for cheetahs in the dry deciduous forest landscape of Kuno Palpur. In 1905, 10 lions were brought from Africa and of them, seven reached, who were killed by local villagers. Kuno had lost all its lions till 1872 and cheetahs by early 1920s. Getting back cheetah is a milestone in Indias wildlife management history that started in 1973 with declaration of first tiger reserve. The Cheetah project is an experiment worth pursuing to improve forest and wildlife management. Whether it succeeds or fails, the future will tell.

The views expressed are personal

Chetan Chauhan heads regional editions as Deputy National Affairs Editor. A journalist for over 20 years, he has written extensively on social sector with special focus on environment and political economy. ...view detail

Read more from the original source:
Ecostani | Despite concerns, the Cheetah project is worth pursuing - Hindustan Times

Recommendation and review posted by Bethany Smith

IntroductionThis essay explores why people should not be held fully morally responsible for their choices. It first draws from theories developed by scholars in psychology and sociology, then refers to case studies in criminality to explore these ideas. The first part explores the 'just world' fallacy, which explains that people wish to believe the world is just, thus most have a desire for others to be held responsible for their choices. Whilst that may be the case, people's choices are undoubtedly influenced by their environmental and genetic conditions. This suggests that social circumstances and innate factors are the main influencers on our behaviour, which means that people are not fully responsible for their choices. The second and third sections use academic research and case studies in criminogenic literature to explore the extent to which social environment and innate factors influence people's choices and lead some individuals or groups to criminality. Finally, in conjunction with Jung's complex theory, I conclude that poor social conditions and congenital deficiencies can make people more susceptible to mental illness and be more prone to irrational, criminal acts, especially when violence is concerned. This leads me to argue that prisons should rehabilitate criminals rather than punish them. As criminals cant possibly take full moral responsibility for their choices, empathy rather than retribution should be societys focus.Main bodyMelvin J Lerner developed the just world fallacy in the 1960s. This theory puts forth the case that people often think the world is fair only to understand or cope with various injustices.[1]It thus explains why people are keen to attribute the mistakes of others or to their own personal behaviour for a misfortune, as opposed to pointing to the circumstances and other factors beyond their control.[2] Conversely, if one has a positive or beneficial outcome, they often attribute its cause to their own efforts. The key thesis of this concept is that humans need a sense of just deserts in order to make sense of reality. In one study, for instance, Melvin J Lerner asked a group of students to observe a girl receive electric shocks as a punishment for making a mistake on a faux mission.[3] Following the observation, the students disparaged the victim and behaved as if she deserved the harsh punishment she received. At the same time, however, they also recognised that they felt powerless to help the girl. This observation demonstrates that a punishment, especially one carried out by an authority figure, can play in to the just world fallacy and suspend critical thought. The Just World fallacy may also compliment Jung's view that human begins are in state of moral conflict. This is due to our innate awareness that we are imperfect, a realisation that triggers a type of trauma-complex."[4] This forces people to behave irrationally in ways that are not otherwise acceptable to the self, as the confrontation between their ego and this complex disturbs them.[5] Jung, however, believed that everyone was more or less prone to multiple personalities as everyone had complexes.[6] This means that with the right amount of psychological help and understanding of people's 'attitudes' (introversion and extroversion), people are largely able to maintain a healthy state of mind and are less likely to behave in extreme ways. As such, Jung can grant us insights about the issue of moral responsibility as he views our consciousness as far from a singular entity with one narrative. He is, therefore, still of great influence in how we can understand the complexities of personality.Modern psychology, however, now demands more scientifically rigorous studies that explore the complexities of consciousness. Firstly, genes may play a role in determining human behaviour. This is because genes can not only determine ones sex or biological structure of the human body in general, but may also may influence ones psychological characteristics.[7] According to Laura A. Baker, the genes of ones parents can influence an individuals behaviour (including the way they raise their children), and children's genes influence their behaviour in return (including the way they react to their parents).[8] For example, in one controversial study, working-class families and their descendants are more likely to possess genes that predispose individuals to aggressive behaviour. This is because, the study argues, their ancestors were more likely to drink or used drugs which can cause genetic defects. These defected genes then pass on to their offspring, depriving them of what could have been their expected learning abilities and physiological systems. This is called epigenetics, which means people's diseases, behaviours, and other health indicators are inherited from family members a generation or even several generations prior.[9]Notwithstanding, although genes are essential to understanding ones predisposition to certain behaviours, factors such as the political environment and ones socialisation directly also influence thoughts and behaviour. As mile Durkheim famously argued, individuals or social groups who do not follow what is deemed the acceptable rules of the society are deviants.[10] Whilst Durkheim viewed deviants as necessary elements of the social structure, most people arguably suppress their true thoughts and actions in order to conform to the moral maxims that are generally expected of them. This is the case even if it results in them not achieving their personal goals. Jung, once again, is useful to draw from here, as he uses the term "persona" to describe the phenomenon where people choose to hide their true selves in order to form functional relations with society.[11] For example, in Solomon Aschs conformity experiments, fifty students were asked to take a "visual test" in a room alongside several other observers. They did not know, however, whether the other participants were also students. Within this experiment, non-student observers gave wrong answers to 12 of 18 questions. They did this to see if the students would change their answers to match the rest of the group. What the study found was that although the students gave a correct answer at first, they then they gave the wrong answer based on the observer's answer.[12] This demonstrates the powerful effects of peer pressure and socialization on ones actions.According to another study conducted by Paul Willis showed that students from working-class families have a negative attitude towards education.[13] They may, for instance, disrupt class or not follow school rules. Willis argues that the reason why working-class people are more likely to engage in deviant behaviour than the other people from other classes is because of social inequality.[14] As working-class family do not have the financial means to provide quality education for their children as middle-class and upper-class families do, working-class families may expect their children to find work earlier in life to support their families. However, as they are less qualified, they often have to work in factories or manufacturing industries as labourers for very little pay. Conversely, children of other classes have the opportunity to study in higher education, and thus use their knowledge and experience to attain well-paid jobs. Yet when working class children communicate with middle class children during their school years, they realize that they can't get the same treatment and experience as other classes. This, in turn, leads to violence to vent their frustrations. Albert Cohen therefore argued that when students don't get the status they aspire to, they tend to form a criminal subculture.[15] This could explain why working-class children are more likely to commit crimes.Accordingly, if someone commits a moral error such as a crime, its only logical to offer them rehabilitation than handing out punitive punishments. Criminals are not entirely in control of their actions, as they may be influenced by family upbringing or congenital factors that manifest as psychological problems. According to psychologist Thomas Fagan, many prison systems in recent years have finally realised that psychological care for mentally illness in prisons is of great importance.[16] This entails that prisons should be similar in their scope and ethos to mental hospitals, regardless of the difference in damage they may have done to society. In fact, it can be further deduced that all the mental deficiencies of criminals in prison may have even more serious symptoms than those admitted to mental health facilities. Hence, whilst criminals are punished by the law in prison, they undoubtedly also require psychological rehabilitation from doctors.One case study of interest is on conducted by James O. Beasley II on Offender Number Five, one of seven serial murder cases. Offender Number Five is a black male who grew up in a very unstable home and lived with his grandmother.[17]After his grandmother died, he turned to a life of crime and violence. He was arrested for a number of juvenile offenses, namely robbery, sexual assault, murder, and multiple thefts. Following his release from prison, he immediately resumed his murderous activities. His level of brutality was distinctive and shocking, as he robbed his victims of their mobility, sexually assaulted them, and finally beat them to death. One of his surviving victims eventually took him to court and he was sent back to prison.[18] In the interview, the criminal admitted that he had a strong sense of loneliness, yet he refused to communicate with others and chose to digest these feelings on his own.[19] As he got older, however, he found that he couldnt satisfy his sexual desire unless it was accompanied by violence against others.[20] Upon examination, he scored 33 on the psychopathic checklist, which is well above the diagnostic criteria for psychopathy.[21] This means he had little control over his actions and showed little remorse for his violent actions. Accordingly, Offender Number Five is a prime example of how poor socialization in childhood can induce psychopathy and breed criminality.ConclusionTo conclude, this essay has explored the extent to which social environment, genetic predisposition, and mental illness can influence people's choices. It first explored some Jungian psychology, which suggested that ones personality is more complex and multifaceted than it might seem on the surface. This led the essay to modern theories that a poor social environment may lead to epigenetic predispositions that induce psychological problems of inferiority and vulnerability. This chain reaction results in worsening psychological problems, which leads people to lose themselves and engage in extreme behaviour that they do not expect and cannot control. Hence, as there is plenty of evidence that people do not necessarily have control over their actions and choices, it is logically unsound to hold them not responsible for their moral decisions. Therefore, prisons should allocate more resources towards psychological rehabilitation, namely psychological counselling or drug treatment, which may compensate for the psychological defects of the primary socialisation stage and allow them to recover quickly and return to society. Finally, further research into this topic may seek to explore the other extreme of the spectrum. What leads sometimes to a life of joy and success? What factors are present in their upbringing? Perhaps even a comparative study between negative and positive examples may be helpful to illuminate the contrasts. Nevertheless, there is plenty more cases or examples than can be unearthed to grant insights to this question and prove my conclusion further.References

Abrams, D. (2019). Deviance - Sociological perspectives | Britannica. InEncyclopdia Britannica. britannica.com/topic/deviance/Sociological-perspectivesBaker, L. A. (2007). THE BIOLOGY OF RELATIONSHIPS: WHAT BEHAVIORAL GENETICS TELLS US ABOUT INTERACTIONS AMONG FAMILY MEMBERS.De Paul Law Review,56(3), 837846. ncbi.nlm.nih.gov/pmc/articles/PMC4685725/Beasley, J. O. (2004). Serial murder in America: case studies of seven offenders.Behavioral Sciences & the Law,22(3), 405. doi.org/10.1002/bsl.595Benson, E. (2003, July).Rehabilitate or punish?Www.apa.org; American Psychological Association. apa.org/monitor/julaug03/rehabCherry, K. (2019).How the Just-World Phenomenon Explains Victim-Blaming. Verywell Mind. verywellmind.com/what-is-the-just-world-phenomenon-2795304Cherry, K. (2020, April 3).The Asch Conformity Experiments. Verywell Mind; Verywellmind. verywellmind.com/the-asch-conformity-experiments-2794996Gadek, R. (2019).Rehabilitation Versus Punishment in the Adult Justice System. Criminaljusticeonlineblog.com. criminaljusticeonlineblog.com/11/rehabilitation-versus-punishment-in-the-adult-justice-system/Hadberg, A. V. (2006). The methodology of Paul Willis. A review of Learning to Labor: How Working Class Kids get Working Class Jobs.Athenea Digital. Revista de Pensamiento E Investigacin Social,1(9). doi.org/10.5565/rev/athenea.275Khan Academy. (2008).Genes, environment, and behavior. Khan Academy. khanacademy.org/test-prep/mcat/behavior/behavior-and-genetics/a/genes-environment-and-behaviorKreitzer, M. J. (2016).What Impact Does the Environment Have on Us?Taking Charge of Your Health & Wellbeing. takingcharge.csh.umn.edu/what-impact-does-environment-have-usLerner, M. J., & Simmons, C. H. (1966). Observers reaction to the innocent victim: Compassion or rejection?.Journal of Personality and Social Psychology,4(2), 203210. doi.org/10.1037/h0023562Lumen. (2018).Functionalism and Deviance | Introduction to Sociology. Courses.lumenlearning.com. courses.lumenlearning.com/wm-introductiontosociology/chapter/theoretical-perspectives-on-deviance/Mcleod, S. (2020, January 21).Stanford Prison Experiment. Simply Psychology; Simply Psychology. simplypsychology.org/zimbardo.htmlPaul, S., & Repository, S. (2020). The Criminal Behavior of Genes | Role of genes in criminal activity.Www.sciencerepository.org. doi.org/10.31487/sr.blog.14Santa Clara University. (2015).The Just World Theory. @SantaClaraUniv. scu.edu/ethics/ethics-resources/ethical-decision-making/the-just-world-theory/Stein, M. (2017a).Jungs Map of th Soul : an Introduction(K. Zhu, Trans.; p. 143). General distributor of Daiwa Books and Newspapers, Xin Bei Shi. (Original work published 1998)Stein, M. (2017b).Jungs Map of the Soul : an Introduction(K. Zhu, Trans.; p. 70). General distributor of Yamato Books and Newspapers, Xin Bei Shi. (Original work published 1998)Stein, M. (2017c).Jungs Map of the Soul : an Introduction(K. Zhu, Trans.; p. 60). General distributor of Daiwa Books and Newspapers, Xin Bei Shi. (Original work published 1998)Stein, M. (2017d).Jungs Map of the Soul : an Introduction(K. Zhu, Trans.; pp. 5659). General distributor of Daiwa Books and Newspapers, Xin Bei Shi. (Original work published 1998)Stein, M. (2017e).Jungs Map of the Soul : an Introduction(K. Zhu, Trans.; pp. 6667). General distributor of Daiwa Books and Newspapers, Xin Bei Shi. (Original work published 1998)Thompson, K. (2016, May 31).Subcultural Theories of Deviance. ReviseSociology. revisesociology.com/2016/05/31/subcultural-theories-crime-deviance/tutor2u. (2019, April).Classic Texts: Paul Willis Learning to Labour 1977. Tutor2u. tutor2u.net/sociology/reference/classic-texts-paul-willis-learning-to-labour-1977tutor2u. (2020, March 8).Classic Texts: Albert Cohen Delinquent Boys. Tutor2u. tutor2u.net/sociology/reference/classic-texts-albert-cohen-delinquent-boys-1955Weinhold, B. (2006). Epigenetics: The Science of Change.Environmental Health Perspectives,114(3). doi.org/10.1289/ehp.114-a160

[1] Cherry, K. (2019).How the Just-World Phenomenon Explains Victim-Blaming. Verywell Mind. verywellmind.com/what-is-the-just-world-phenomenon-2795304[2] Ibid[3] Lerner, M. J., & Simmons, C. H. (1966). Observers reaction to the innocent victim: Compassion or rejection?.Journal of Personality and Social Psychology,4(2), 203210. doi.org/10.1037/h0023562[4] Stein, M. (2017b).Jungs Map of the Soul: an Introduction(K. Zhu, Trans.; p. 70). General distributor of Yamato Books and Newspapers, Xin Bei Shi. (Original work published 1998)[5] Ibid, pp. 5659[6] Ibid, pp. 6667[7] Baker, L. A. (2007). THE BIOLOGY OF RELATIONSHIPS: WHAT BEHAVIORAL GENETICS TELLS US ABOUT INTERACTIONS AMONG FAMILY MEMBERS.De Paul Law Review,56(3), 837846. ncbi.nlm.nih.gov/pmc/articles/PMC4685725/[8] Ibid, pp. 837-846[9] Weinhold, B. (2006). Epigenetics: The Science of Change.Environmental Health Perspectives,114(3). doi.org/10.1289/ehp.114-a160[10] Lumen. (2018).Functionalism and Deviance | Introduction to Sociology. Courses.lumenlearning.com. courses.lumenlearning.com/wm-introductiontosociology/chapter/theoretical-perspectives-on-deviance/[11] Stein, M. (2017a).Jungs Map of the Soul: an Introduction(K. Zhu, Trans.; p. 143). General distributor of Daiwa Books and Newspapers, Xin Bei Shi. (Original work published 1998)[12] Cherry, K. (2020, April 3).The Asch Conformity Experiments. Verywell Mind; Verywellmind. verywellmind.com/the-asch-conformity-experiments-2794996[13] tutor2u. (2019, April).Classic Texts: Paul Willis Learning to Labour 1977. Tutor2u. tutor2u.net/sociology/reference/classic-texts-paul-willis-learning-to-labour-1977[14] Ibid[15] tutor2u. (2020, March 8).Classic Texts: Albert Cohen Delinquent Boys. Tutor2u. tutor2u.net/sociology/reference/classic-texts-albert-cohen-delinquent-boys-1955[16] Benson, E. (2003, July).Rehabilitate or punish?Www.apa.org; American Psychological Association. apa.org/monitor/julaug03/rehab[17] Beasley, J. O. (2004). Serial murder in America: case studies of seven offenders.Behavioral Sciences & the Law,22(3), 405. doi.org/10.1002/bsl.595[18] Ibid, pp. 405[19] Ibid, pp. 405[20] Ibid, pp. 405[21] Ibid, pp. 405

Continue reading here:
To what extent human beings are morally responsible for the actions they take as a result of their innate and acquired influences - Teen Ink

Recommendation and review posted by Bethany Smith

Do you have healthy hair? Do you suffer from hair fall? Are you trying to grow your hair fast?

Many people do not give a second thought to their hair growth. For them, the growth of their hair is not a matter of concern. But the people who experience hair fall, hair damage, or have extremely thin hair often brood about the growth of their hair and what they can do to attain it. They often wonder how long it will take to reach the desired length or how fast hair grows normally.

Heres everything to know about hair growth, the factors affecting the growth, and how fast hair really grows.

First things first! The growth of everyones hair is not the same. It will always vary due to various factors such as hormone levels, genes, age, etc. If you see your friends hair growing fast doesnt mean your hair will grow at the same frequency or vice versa.

That being said, studies have laid down an average rate of hair growth in humans. According to a scientific report, most peoples hair grows at the rate of half an inch per month. It further depends on how well you care for your hair. It means that if you treat your hair properly and care for it on time, your hair will grow six inches a year.

While some people may experience good growth in their hair, others may not.

If your hair is weaker and more brittle compared to previous years, there may be an imbalance or deficiency in your body, resulting in malnourished hair. The factors such as poor diet and lifestyle, thyroid imbalances, medications, and inflammation from stress often make your hair weak and slow down the process of hair growth. As a result, your hair tends to grow slower than ever.

The speed of your hair growth depends upon many factors ranging from genetic to environmental. We have listed down some of them.

According to a study, your ethnicity defines the growth of your hair to a great extent. For instance, Asian hair grows the fastest at about 411 micrometers a day. This steady growth rate in their hair results in 0.48 inches growth per month.

African hair has a slower growth rate than Asian, around 280 micrometers a day or 0.32 inches a month. The growth for Caucasian hair is somewhere around 367 micrometers a day or 0.42 inches a month.

The growth of your hair is also characterized by your gender. Many studies have determined that male hair grows faster than female hair. It moves through the hair cycle quicker, thus, not getting as long as female hair before shedding and starting over again.

The growth rate in male hair is faster than in females. Compared to the opposite gender, male hair grows 0.5 inches per month, while female hair grows 0.4 inches per month. It is why men need more frequent haircuts and trimming than women.

Your age is one of the primary factors affecting your hair growth rate. The growth of your mane is partially regulated by the hormones, of which your body adjusts production over time. It is found that your hair growth is at the peak between 15 to 30 years of age.

After your thirties, the follicles of your hair stop growing new hairs in their entirety. It means that some hair strands already been shed through the natural hair cycle will not grow back on your scalp. Now you know what causes thinning of hair!

Age-related hair loss is again influenced by genetic and environmental factors. Thus, some people may not experience a noticeable reduction in their hair growth as they age.

One of the essential factors that influence your hair growth is your diet. As your hair is composed of protein, it needs to get enough protein and other forms of nutrition such as amino acids, iron, zinc, niacin, fatty acids, etc. for proper growth. If you are not getting the desired amounts of nutrients, minerals, and vitamins in your diet, the growth of your hair may suffer at large.

People who reduce their calorie count all at once are at a higher risk of thinning their hair.

Your genetics are equally responsible for influencing the growth rate of your hair. Every individuals hair enters a growth or anagen phase. The phase is where the follicles produce new hair cells actively, resulting in longer strands. Your genetics may cause you to have a short anagen phase lasting only 2-3 years, while it could last as long as 6-7 years for others.

The longer your hair is in the anagen phase, the more opportunities it gets to grow before shedding and being replaced by new hair. If you suffer from any genetic disorder, it may affect your hair growth, on the whole, resulting in the conditions such as premature shedding and shorter growth phases.

If you are bothersome about the slow growth of your hair, fret not. Increasing the rate at which your hair grows is possible when you take all the factors affecting your hair growth into consideration. While you cannot alter some factors such as genetics, ethnicity, age, and gender, there are a couple of things that you can do to accelerate your hair growth.

Here are some tips to encourage faster hair growth.

As stated, nutrition plays an integral role in managing your hair. Your hair has a few nutrient requirements that need to be met if you expect hair growth at a proper rate. According to scientists, the below-listed nutrients help you grow hair and prevent hair loss.

Make it a point to consume healthy meals including all the above-listed nutrients to grow your hair and improve your overall health. You can include the food items such as eggs, fish, dairy products, green vegetables, and fruits into your diet. Adding nuts such as almonds and walnuts also helps you grow your hair and improve its quality.

Never take hair supplements without consulting your doctor or nutritionist. Consume proteins in higher amounts to keep hair fall at bay.

A few studies have laid down that regular head massages may help hair grow thicker. More research is required to prove this claim, but massaging your hair regularly may help you in many ways.

Hair massage is known to help ease stress, which is considered one of the biggest triggers of hair fall. Apart from this, massaging your hair always feels great. You can use hair oil and massage your hair weekly. You can also buy a scalp massaging tool from the market. You will feel relaxed immediately.

Sleeping on a silk or satin pillow for hair growth is trending all over social media platforms. While some people do not take it seriously, there are benefits of using this fabric to sleep.

Crisp cotton lines may feel comfortable and good against your skin, but they may not be the best choice if you have fragile hair. Some people wear a satin bonnet to bed or sleep on satin pillowcases. Although this hack doesnt make your hair grow faster, it reduces hair friction, frizz, and breakage.

Do you skip conditioning every time you wash your hair?

If yes, its about time you take this step seriously. Using conditioner every time after shampooing your hair strengthens it. A conditioner also helps your hair behave and look better. A good-quality conditioner protects your hair from harmful UV sun rays. If you have fine hair, applying a conditioner on the bottom of your hair helps avoid weighing it down. A conditioner also helps to nourish fragile hair.

Many studies claim that severe stress is one of the triggers for hair fall. It sends your hair into a resting phase, skipping the stage that coaxes your hair to grow. Stressing too much may also put you at a higher risk for a condition known as alopecia areata. Under this condition, your immune system starts affecting your hair follicles, thus leading to extreme hair loss.

Do not stress too much, and give yourself a break to save your hair from falling.

Bleaching your hair may make you look food and stylish, but do you know it may damage your hair?

Using chemical hair treatments that alter your hair permanently may weaken your hair. Consequently, your hair starts breaking before growing. Do not color your hair too often. Always choose a high-quality product claiming minimal damage to color your hair.

Heat styling may damage your hair in ways you cannot imagine. If you often get blow-outs or use a curling or straightening iron or even a hot comb on your hair, avoid doing it to save it from damage.

If you heat your hair regularly, put on a heat protectant first and use the coolest setting.

We hope that the above-listed article helps you learn everything about hair growth and how you can protect them from damage. Keep in touch for more.

See the article here:
How Fast Does Hair Grow? Know These Easy-Peasy Tips to Grow your Tresses - TheTealMango

Recommendation and review posted by Bethany Smith

Sure, your heart has been warmed by the historic releases of four California condors into our region over the last couple months. But how much do you know about these birds individual personalities?

If you are just realizing that you are woefully unprepared to distinguish your new feathered friends from each other, never fear. The U.S. Fish and Wildlife Services Rebecca Fabbri files the following helpful Prey-go-neesh profiles so you may better grasp the temperaments of the specific majestic creatures soaring over your head:

For the first time in more than a century, endangered Prey-go-neesh (California condors) can now be seen flying over Northern Californias redwoods.

On May 3, 2022, the Yurok Tribe successfully released the first pair of condors, out of a group of four, in Redwood National and State Parks, establishing the northernmost condor release area to date, and reclaiming a significant part of their former historic range, from which theyve been absent since 1892.

This journey towards restoration began in 2003, when a panel of Yurok elders made the decision that Prey-go-neesh was the highest priority land-based animal to return to Yurok ancestral territory due to the Yuroks deep cultural connection to the birds, saidYurok Wildlife Department DirectorTiana Williams-Claussen.

The reintroduction effort builds on over a decades worth of planning and preparation initiated by the Yurok Tribe with support by the U.S. Fish and Wildlife Service, the National Park Service, State and other partners.

For countless generations, the Yurok people have upheld a sacred responsibility to maintain balance in the natural world, saidJoseph L. James, the Chairman of the Yurok Tribe, in the days leading up to release. Condor reintroduction is a real-life manifestation of our cultural commitment to restore and protect the planet for future generations.It is a historical moment in the Yurok Tribe, as we introduce our condors back home, providing that balance for us.Our prayers are answered.

The four condors, including one female and three males, are between two and four years old, an ideal age range where they would leave the care of their parents in the wild. Although it will take several years until these birds are at an age to reproduce in the wild, we believe we have a model for success with future northern reintroduction efforts. Learn a little more about each condor below.

# # #

Poy-we-son

Poy-we-son was the first California condor to take flight into wild. Photo courtesy of Matt Mais/Yurok Tribe

Hatched:Peregrine Funds World Center for Birds of Prey

Wing Tag: A3

Age: 2-year-old male

About me:First out the holding pen, we have Poy-we-son, which literallytranslates to, the one who goes ahead, but also harks back to the traditional name for a headman of a village, who helps lead and guide the village in a good way.

A3 is one of the more dominant birds, and I expect that hell be a leader amongst this flock and for new birds coming in, said Williams-Claussen.

True to his name, Poy-we-son was adventurous right from the start, boldly exploring the area surrounding the release facility for two weeks before returning to the release enclosures. His sojourn will have equipped him with valuable knowledge which he will share with his fellow cohort-members, as the small flock expands across the landscape.

Studbook number:1045

# # #

Nes-kwe-chokw perches outside of the flight pen. Photo courtesy of Patrick Myers/Yurok Tribe

Hatched:Oregon Zoo

Wing Tag: A2

Age: 2 1/2-year-old male

About me: Nes-kwe-chokw, which translates to He returns or He arrives, is a representative of the historic moment we just underwent, and condors return, free-flying, to the Yurok and surrounding landscape, said Williams-Claussen. He is a confident bird, often jockeying with A3 in play, but also to help establish his place in the hierarchy and with the will to do well in the wild.

Also proving true to his nickname, Nes-kwe-chokw initially has stuck more closely to home, the release enclosure, seemingly awaiting the release of the rest of his flock. Though growing increasingly comfortable ranging farther from the release facility, he has largely shown himself content to stay close to the facility, visiting with the birds remaining in captivity and agreeably taking advantage of food proffered by biologists to keep the far-ranging birds interested in the facility, which will be used for ongoing management.

Studbook number:1010

# # #

Ney-gem Ne-chweenkah takes in her new home. Photo courtesy of Patrick Myers/Yurok Tribe

Hatched:Oregon Zoo

Wing Tag: A0

Age: 3-year-old female

About me:Ney-gem Ne-chweenkah which translates to She carries our prayers is the only female of the first released cohort. She represents the creative life-force energy that females bring to the world, said Williams-Claussen. Its powerful. I envision her as the start of a whole new life and possibilities, both for our flock and for condors throughout their range. We also imbue this name with our prayers for her specifically, her cohort brothers and for all condors. She carries those, wherever she goes. We are incredibly grateful that Prey-go-neesh have come home to carry our beliefs, our energy, and our prayers when were asking for the world to be in balance, as a critical part of ecological community.

Though she struggled a bit with the mechanics of flying free in her first forays, as her first time to spread her wings in the wild, shell figure it out soon and has integrated well with both Poy-we-son (A3) and Nes-kwe-chokw (A2). All three are comfortably sharing resources and will continue to learn from and teach each other.

Studbook number:969

# # #

Hlow Hoo-let was the last to join the cohort with his friends, who together will take flight toward reestablishing a California condor population in the Pacific Northwest. Photo courtesy of the Yurok Tribe

Hatched:Peregrine Funds World Center for Birds of Prey

Wing Tag: A1

Age:3-year-old male

About me:A1 has been nicknamed Hlow Hoo-let which means At last I (or we) fly! In line with the heavier names this first cohort carries, said Williams-Claussen. I interpret that as reference to the joyous day that all four of our first cohort fly free together.

On a lighter note, its definitely also a reference to poor A1s extended wait to be let out, due to his faulty transmitter! We welcome Hlow Hoo-let to the skies of Yurok and surrounding lands, and look forward to his journey with us.

On July 14, 2022, he was the last to join the cohort with his friends, who togetherwill take flight toward reestablishing a California condor population in the Pacific Northwest.

Studbook number:973

# # #

Paaytoqin was chosen as a mentor bird because of his calm nature and good disposition. Photo courtesy of Matt Mais/Yurok Tribe

Hatched:Peregrine Funds World Center for Birds of Prey

Age:8-year-old male

About me:His name Paaytoqin (pie-toe-quin) means come back in Nez Perce language because he returned to World Center Birds of Prey, one of the recovery programs captive breeding facilities, after being at Oregon Zoo for three years, saidLeah Esquivelfrom the Peregrine Fund.

Hatched in 2014, he was selected to be held back for captivity based on genetics and is unreleasable.

We do not release captive adults that have never had any wild experience, saidSteve Kirkland, California condor field coordinator for the U.S. Fish and Wildlife Service. He could be paired with a mate in the future, if necessary; however, as for now, his role as a mentor will be an important influence on the younger birds.

Paaytoqin was chosen as a mentor bird because of his calm nature and good disposition.Prior to arriving to the Northern California Condor Reintroduction Program Facility, he proved to be a steady and centering influence onyoung birds, helping them become acclimated to their new regionand with their development ofcritical social behavior before their release.He regularly charges turkey vultures outside of the pen feeding, showing the condors stature in the feeding order.

He will eventually return to captivity to help contribute to the health and vitality of the overall flock as part of the captive breeding program after his stint in Northern California, said Williams-Claussen.

# # #

Poy-we-son and Nes-kwe-chokw spotted exploring their new home. Photo courtesy of the Northern California Condor Restoration Program|Image Details

Comprised of biologists and technicians from the Yurok Tribe and Redwood National Park, the Northern California Condor Restoration Program will collaboratively manage this flock from a newly constructed condor release and management facility in Northern California, near the Klamath River in Redwoods National and State Park.

The return of the condors to the skies over the Redwoods represents a significant milestone in the restoration of this magnificent forest to its former glory, remarked Redwood National and State Park SuperintendentSteve Mietz. This project is a model for listening to and following the lead of the parks original stewards, healing both our relationship with the land and its original people.

With the release of these birds, the Northern California Condor Restoration Program team officially joins the larger California Condor Recovery Program led by the U.S. Fish and Wildlife Service. The recovery efforts include three additional release sites in California, one in Arizona and one in Baja Mexico. Each release site is championed by a partner in condor recovery.

The reintroduction of condors into Northern California is truly a monumental moment, saidPaul Souza, Regional Director for U.S. Fish and Wildlife Services Pacific Southwest Region. This effort builds upon the programs collective knowledge and history of releasing condors and showcases the benefit of partnering with tribes and others to implement recovery of listed species. We are proud to support this collaborative and innovative partnership with the Yurok Tribe and Redwood National Park. Together we can recover listed species for future generations.

PREY-GO-NEESH KEECH KE-ME-YEHL CONDORS HAVE COME HOME.The Yurok Tribe

Visit link:
BETTER KNOW A PREY-GO-NEESH: Up Close and Personal With Your New Condor Neighbors - Lost Coast Outpost

Recommendation and review posted by Bethany Smith

In early June, three 2-year-old lion cub siblings were permanently relocated from the Pittsburgh Zoo to the Alabama Gulf Coast Zoo.

Adjusting to a new home is a feat for anyone, including the three young predators, Chadwick, Regina and Daniel.

Staff members at the zoo in Gulf Shores, Ala., worked hard to prepare for the cubs arrival. They made sure to have a pool in the cats enclosure to help battle the Southern heat.

They were much fluffier when they first got here, Ashlyn Kenwright, one of the zookeepers who interact with the cubs daily, said in mid-July. They quickly shed a ton to try to cool off naturally.

The keepers use other methods to keep the lions cool, such as freezing blocks of blood and giving them to the cats to enjoy like a carnivorous Popsicle.

Its something that they would lie down to eat, said Joel Hamilton, Alabama Gulf Coast Zoo director. They hold the block with their front paws and the ice cools down their arms as their internal temperature lowers with the intake of the cool moisture.

Introductions between the cubs and their keepers were a slow process. They started by helping the cubs get used to the keepers scents. This entailed the keepers entering the feeding building while the cubs were in another room.

In the beginning, doors leading from the feeding room to inside the enclosure were left open so the cats could leave if they felt uncomfortable. That slowly transitioned to the keepers being able to feed the cats inside and clean their enclosure while the cubs ate.

This is the first time that weve taken care of cubs that werent born in our zoo, said Caitland Dallas, another zookeeper who helps care for the lions. This was a new experience for us and the cats. The secret to most cats is not through their hearts, but their stomachs. Once they realized that we usually show up with food, they decided to let us stick around.

The three cubs are closely bonded with each other, especially Chadwick, who calls for his siblings when he cant see them. This usually only happens during feeding time. Sometimes the cat lets his nerves get the best of him and he can only eat a few pounds of meat before he begins to miss his brother and sister.

Keepers have been giving him a smaller diet with the hopes that his hunger will make him fully enter the feeding building, and he can learn that there is a full meal waiting for him there.

The Pittsburgh Zoo described Chad as a little insecure, said Kenwright. Were hoping that he gets more confident in his own skin. Their whole world just got changed, so he just needs a bit more time to get comfortable.

Chadwick was certainly at his brightest on a recent morning once his siblings came out from the feeding building. He bumped heads with Daniel encouraging his brother to play, and followed Regina as she investigated the milk bottle that Dallas gives them as a treat.

Dairy in large amounts can upset a cats stomach, she said. But a small amount like this is a good treat that they enjoy and it helps them cool off.

After the cubs had their fill of the spray-bottle milk, they cuddled in a pile for a nap.

The heat never stops them from sleeping on top of each other, said Kenwright. They could sleep a few feet apart and be much cooler, but they just want to be as close as possible.

The Alabama Gulf Coast Zoo looks to become a bigger part in breeding programs for lions in the Zoological Association of America. Director Hamilton took in the cubs hoping to find a cage mate for the zoos other female lion, Nandi.

African lions were officially put on the vulnerable species list in 2020. In response, ZAA has communicated with zoos around the country to help increase healthy breeding.

For lions to be bred, their family trees need to be mapped to avoid any inbreeding. Each zoo that would like to participate in the program must have their lions genetics mapped.

The whole point is to have a science- based breeding program, where animals are sent or received is all based on genetics, Hamilton said. Looking at who should be paired with who to keep genetic vigor going for several generations is all based on their family trees.

Once the cubs get a bit more settled, the zoo staff will begin the introduction process between Nandi and the male cubs. If she takes a liking to one, their breeding will help bolster the lion population.

Hamilton hopes there will be a successful mating and an opportunity to send the possible cubs to a zoo with eligible mates. With the widespread work of zoos across America, the African lion population will have a chance to increase so that the species is no longer considered vulnerable.

Hayley Daugherty is a contributing writer.

Link:
From the 'Burgh to the Gulf: Lions relocated in zoo breeding program - TribLIVE

Recommendation and review posted by Bethany Smith

Introduction

More than 47% of less than five-year-old deaths globally occur in the neonatal period, resulting in 2.4 million deaths yearly.1 Most of these deaths usually occur in low-income countries, and almost one million deaths are attributed to infectious causes, including neonatal sepsis, meningitis, and pneumonia.1,2 On the other hand, the survivors of neonatal sepsis are vulnerable to short- and long-term neurodevelopmental morbidity.3

Pathophysiology of neonatal sepsis relies on the innate immunity of neonates as their adaptive immune response is not fully developed. A more rigorous evaluation of the possible association between genetic signatures and neonatal sepsis is critical. The related neonatal innate and adaptive immune responses showed impairment of some aspects of innate immunity to bacterial infection, particularly in low-birth-weight infants.46

The recently recognized family of non-coding RNAs, long non-coding RNAs (lncRNAs; >200 nucleotides), has been implicated in several biological processes, including innate immunity.7 The lncRNA Metastasis Associated Lung Adenocarcinoma Transcript 1 (MALAT1) upregulation has demonstrated an independent predictive value as a biomarker for diagnosis, severity, and poor prognosis in adults with sepsis.8,9 Also, the antisense non-coding RNA in the INK4 locus (ANRIL) was implicated in regulating inflammation in rats with uric acid nephropathy,10 and the pro-inflammatory genes, including IL6 and IL8, in human endothelial cells under the control of the nuclear factor-B.11 Gui et al have identified its clinical utility as a biomarker of severity, inflammation, and prognosis in adult sepsis patients.12 Lastly, the lncRNA HOX Transcript Antisense RNA (HOTAIR) was observed to promote sepsis progression by regulating interleukin-6 receptor expression via microRNA-211 in a septic rat model.13 Additionally, it was reported to play a vital role in sepsis-induced acute kidney injury via regulating apoptosis.14,15

Although dysregulated expression of the lncRNAs mentioned above was associated with sepsis etiopathology in adults, no studies have explored their potential clinical utility as diagnostic and/or prognostic biomarkers in neonatal sepsis.16 To this end, the authors were inspired to explore the potential clinical utility of the lncRNAs MALAT1, ANRIL, and HOTAIR in a sample of neonatal sepsis to confirm their rules in this devastating disorder. The results of this work could help in risk stratification for this vulnerable group of population and provide preliminary data for future molecular targeted therapy.

A total of 124 neonates with sepsis (93 early-onset and 31 late-onset sepsis) and 17 healthy controls were enrolled in the current study after taking informed consent from all their parents or legal guardians. Cohorts were recruited from Suez Canal University Hospital, Egypt, between December 2018 and November 2019. Age enrollment starts from the day of life (DOL) 1 at delivery till DOL 7 of suspected neonates with any manifestations that enable physicians to diagnose neonatal sepsis. Neonates 28 weeks gestational age confirmed by New Ballard Score,17 of both sex diagnosed with sepsis (defined as bacteremia presented clinically with dysregulation of response to infection in the first four weeks of life),18 or suspected neonatal sepsis (defined as neonates who are delivered to a mother with risk factors for sepsis, including premature rupture of membrane (PROM) >18 hours, urinary tract infection, genital infections, fever, leukocytosis or chorioamnionitis),19 were enrolled. In addition, neonates presented with clinical indicators (ie, observations and events in the baby) of possible/suspected neonatal sepsis/infection, including red flag clinical indicators and other National Institute for Health and Care Excellence (NICE) guidelines-related clinical indicators, were recruited.20 Exclusion criteria included newborns with gestational age <28 weeks, gross congenital malformation/genetic syndromes, history of perinatal hypoxia, hypoxic-ischemic encephalopathy, maternal drug abuse, or maternal viral hepatitis. The study was executed following the Declaration of Helsinki guidelines and approved by the Ethics Committee of the Faculty of Medicine, Suez Canal University (approval no. 4463).

Early clinical diagnosis of neonatal sepsis is still highly suspected due to the lack of specific signs and symptoms as they are shared with various other neonatal diseases. Blood culture is the gold standard of lab diagnosis but has certain limitations, which delay early identification. Routinely, 713% of neonates are treated empirically for suspected sepsis because of these diagnostic limitations. In this sense, we included all neonates with sepsis, either diagnosed with +ve blood cultures or ve results.6,21

Prenatal maternal history was examined for maternal risk factors such as premature rupture of membrane, maternal diabetes, anemia, hypertension, pre-eclampsia, urinary tract infection, or triple I (intrauterine inflammation, infection, or both). Detailed obstetric history on the mode of delivery, weight at birth, antepartum hemorrhage, maternal antibiotics, or intrapartum fever were obtained. Putative neonatal risk factors were evaluated as preterm, intrauterine growth retardation, receiving total parental nutrition, mechanical ventilation, umbilical venous catheterization and other invasive procedures such as a urinary catheter, chest tubes, or long lines. Symptoms in neonatal sepsis are unspecific, as many non-infected neonates display similar symptoms. There is no single-point assessment of clinical signs to diagnose sepsis; hence, our clinical examination included the following: (1) gestational age assessment, weight, and sex of the full-term neonates, (2) general and systemic examination, including (a) the respiratory system: tachypnea, apnea, increased ventilator support, and oxygen desaturation, (b) the cardiovascular system: bradycardia, pallor, hypotension, persistent pulmonary hypertension (PPHN) and decreased perfusion, (c) metabolic changes: hypothermia, hyperthermia, glucose instability, metabolic acidosis, (d) gastrointestinal system: poor feeding, vomiting, diarrhea, jaundice, feeding intolerance, abdominal distension, and ileus (e) neurologic changes: lethargy, hypotonia, decreased activity, and seizures, (f) hematological: disseminated intravascular coagulopathy, purpura, petechiae, and bleeding.

Qualified nurses collected 5 milliliters of blood on several occasions (ie, not at one time) from a peripheral vein under an aseptic condition from the enrolled neonates upon admission for routine hematological, chemistry, immunological assessment, blood culture, and genetic analysis. Tubes for genetic analysis (1 mL on EDTA tubes) were transferred immediately to the genetic lab within 20 min to be centrifuged with separation of the buffy coat in sterile Eppendorf for the subsequent genetic analysis. Post-treatment samples were withdrawn three days after starting antibiotics (as post-treatment samples) for 43 neonates (only the available samples for comparison).

As blood culture is the gold standard to define neonatal sepsis, a blood culture sample (0.51 mL) taken from a normally sterile site under aseptic measures was taken in pediatric oxoid blood culture bottles and sent to the microbiology lab for cultivation. Blood culture time to positivity (TTP) or turn-around time technique was used. The blood cultures were incubated aerobically at 37C and observed daily for the first three days to identify any visible microbial growth (turbidity). A preliminary report of findings is available within 48 hours. However, even in the absence of turbidity, the blood was subcultured up to the seventh day, and the report depends on the growth result rather than the observation of the bottles. The final report is released after 57 days accordingly.

Extraction of total RNA from the buffy coat separated from the whole blood was carried out using PureLink RNA Mini Kit (Qiagen, Catalog no. 217184) according to the manufacturers instructions. RNA concentration and purity were assessed via NanoDrop ND-1000 spectrophotometer (NanoDrop Tech., Inc. Wilmington, DE, USA). Samples with a 260/280 nm absorbance ratio <1.8 were excluded. RNA was converted to complementary/copy DNA (cDNA) using the high-capacity cDNA Reverse Transcription (RT) Kit (Applied Biosystems, USA), as described in our previous work.22 The RT reactions were carried out in a Mastercycler Gradient Thermocycler (Eppendorf, Hamburg, Germany) at 25C for 10 min, 37C for 120 min, and 85C for 5 min, then held at 4C. No template and no enzyme samples as negative controls were included in each run. Gene expression of MALAT1, ANRIL, and HOTAIR compared to GAPDH was performed using quantitative real-time polymerase chain reaction (qPCR) following the Minimum Information for Publication of Quantitative Real-Time PCR Experiments (MIQE) guidelines.23 The PCR reactions were carried out in duplicate with a final volume of 20 L, including 1 L TaqMan assays (Hs00273907_s1, Hs03300540_m1, Hs05502358_s1, and Hs02786624_g1) that include the pre-designed primer and probe set (Thermo Fisher Scientific) for MALAT1, ANRIL, HOTAIR, and GAPDH, respectively, diluted in RNAse-free water, 1.33 L RT product, and 2 TaqMan Universal PCR Master Mix (Applied Biosystems, Waltham, MA, USA) following the previously described protocols.24 The fold change of the studied lncRNA expressions in each case with sepsis relative to the healthy controls was calculated via the Livak and Schmittgen method based on the quantitative cycle (Cq) value (2Cq); where Cq = (Cq lncRNA Cq GAPDH) sepsis cases (Cq lncRNA Cq GAPDH) healthy neonates.25

Statistical Package for the Social Sciences (SPSS) for Windows software (version 27.0; IBM SPSS Statistics, USA) and GraphPad Prism 9.1.2 software were used for data analysis. Data were presented as the median and interquartile range or frequency and percentage. Chi-square (2), Fishers exact, and MannWhitney U (MW) tests were used. Spearman correlation analysis was carried out to assess lncRNAs co-expression. Cox proportional regression analysis was performed to identify independent predictor risk factors for mortality. Hazard ratio (HR) and 95% confidence interval (CI) were reported. Statistical significance was set at a p-value<0.05. Heatmap, hierarchical clustering, box plots, and correlation matrix were generated using reshape2, scales, RColorBrewer, gplots, psych, factoextra, FactoMineR, and ggpubr R package.

The current study included 124 neonates with sepsis (93 early-onset and 31 late-onset sepsis). Two-thirds of them (65.3%) were males, and in-hospital mortality was reported in 29%. Table 1 demonstrates a comparison between 88 survivors of neonates with sepsis and 36 non-survivors. The non-survivors were more likely to be delivered by cesarean section (66.7% vs 46.6%, p=0.049), preterm (63.9% vs 34.1, p=0.002), with inserted umbilical venous catheter (44.4% vs 9.1%, p<0.001). Higher prevalence of deceased neonates presented with hypoxia (86.1% vs 65.9%, p=0.027) and respiratory distress syndrome (55.6% vs 30.7%, p=0.014). Mothers were more likely to have premature rupture of membranes (52.8% vs 28.4%, p=0.010), pre-eclampsia (13.9% vs 0%, p<0.001), and received amoxicillin (27.8% vs 8.0%, p=0.003). Higher frequency of non-survivors neonates required ventilation (63.9% vs 29.5%, p<0.001) and surfactant therapy (33.3% vs 10.2%, p=0.001). Non-survivors neonates were more likely to develop complications (75% vs 13.6%, p<0.001), such as pulmonary hemorrhage (16.7% vs 0%, p<0.001), air leak syndrome and pneumothorax (19.4% vs 3.4%, p=0.002), respiratory failure (22.2% vs 1.1%, p<0.001), necrotizing enterocolitis (11.1% vs 0%, p=0.002), and multiple organ failure (22.2% vs 0%, p<0.001).

Table 1 Characteristics of Sepsis Patients According to Survival

Compared to normal neonates, the three tested lncRNAs expression signatures were upregulated in the circulation of neonates presented with sepsis. Their median levels were as follows: median = 1.71, IQR: 0.5 to 3.27 for MALAT1, median = 1.09, IQR: 0.89 to 1.30 for ANRIL, and median = 1.83, IQR: 1.44 to 2.41 for HOTAIR (Figure 1A). Co-expression analysis showed a direct correlation between the three lncRNAs ranged from weak (r = 0.37) to moderate (r = 0.42 and 0.61) correlations (all p-values <0.001) (Figure 1B). Hierarchical cluster analysis classified patients into two clusters: the first cluster was characterized by high expression of all lncRNAs, and almost all patients died, while the second cluster, including those who survived, exhibited downregulation of at least one of the markers (Figure 1C). On comparison of gene expression levels of the studied lncRNAs pre- and post (three days)-treatment after initiating the antibiotic therapy, there was no observed significant change in their expression signature (Figure S1).

Figure 1 The expression level of long non-coding RNAs in plasma of neonatal sepsis compared to normal neonates. (A) Box plot for fold change (log-transformed). All the three studied lncRNAs were upregulated in neonates with sepsis relative to controls. Mann-Whitney U-test was used. Cases are plotted compared to controls (set at zero line). All p-values were <0.001. (B) LncRNAs co-expression analysis. A direct correlation between the three studied lncRNAs was identified. The correlation coefficient (r) text color aligns with the degree of correlation. Spearman correlation analysis was employed. All p-values were <0.001. (C) Heatmap showing expression pattern in patients. Ward.D2 method and Euclidean distance measure were utilized. Hierarchical cluster analysis categorized cases into two distinct clusters: high expressors of all lncRNAs and those who exhibited downregulation of at least one of the studied lncRNAs.

The transcriptomic pattern of MALAT1 (p=0.93), ANRIL (p=0.69), and HOTAIR (p=0.98) did not show a significant difference between early-onset and late-onset sepsis groups. However, overall and stratification by sex revealed significantly higher levels of the three lncRNAs in deceased neonates compared to the survivor group (all p-values <0.001) (Figure 2AC). Analysis of the association of the three studied lncRNAs with other comorbidities in the study groups is presented in Table S1. Running a principal component analysis showed a clear demarcation between the two groups of cohorts in males and females (Figure 3A).

Figure 2 Association of long non-coding RNA expression with survival and gestational age in neonates with sepsis. (AC) Boxplots comparing non-survivors and survivors groups. Higher levels of the three lncRNAs in non-survivor neonates compared to the survivor group were observed. (D) The association between gestational age in neonates with sepsis and survival. Fold change was estimated using the formula of delta Cq = (Cq lncRNA Cq GAPDH) sepsis cases (Cq lncRNA Cq GAPDH) healthy neonates. The median and interquartile range are shown to the left of the corresponding boxplots. Mann-Whitney U-test was applied.

Figure 3 Multivariate analysis for predicting mortality. (A) Principal component analysis for data exploration showing clear demarcation between survivor and deceased infants based on the three lncRNAs. The expression levels of the three lncRNAs, demonstrated by the direction of their corresponding arrows, were pointing towards the cluster of the Died group. In contrast, the gestational age (GA) arrow pointed towards the Alive group, indicating that the higher the GA, the better survival. The length of the arrows indicates the weight of the variables. All points (round and triangle) represent each study subject and are of equal size. A large circle and triangle represent the centroid of the cluster. (B) Cox hazard proportional regression analysis was performed. Data are represented as hazard ratio (HR) and 95% Confidence intervals (CI). Non-survivor neonates were significantly more likely to be males and have upregulated circulating ANRIL and HOTAIR levels. Significant data with p-values less than 0.05 are red.

Abbreviations: LBWB, low birth-weight baby; ARDS, acute respiratory distress syndrome; PROM, Premature rupture of membrane.

As depicted in Figure 3B, Cox regression analysis revealed that non-survivor neonates were more likely to be male (HR = 6.43, 95% CI = 1.3115.7, p = 0.022) and presented with early-onset sepsis (HR = 4.18, 95% CI = 1.0511.6, p = 0.043). Cohorts with upregulated ANRIL (HR = 4.21, 95% CI = 1.1510.4, p=0.030) and HOTAIR (HR = 2.49, 95% CI = 1.026.05, p = 0.044) were at higher risk of mortality. On the contrary, higher gestational age, more than 33.5 weeks, were less likely to die (HR = 0.79, 95% CI = 0.640.96, p=0.020), and those who received surfactant therapy conferred protection (HR = 0.21, 95% CI = 0.060.76, p=0.017).

Neonatal sepsis contributes to global neonatal morbidity and mortality worldwide, with a higher burden, in particular, in low- and middle-income countries.26 The current study included 124 neonates with sepsis, two-thirds of them were males, and the non-survivor neonates were more likely to be male, as revealed by Cox regression analysis. This male predominance aligns with previous studies that revealed that females have a less exaggerated immune reaction to pathogens than males due to hormonal and genetic/epigenetic modifiers contributing to the observed immunological and survival rate differences.27,28 Also, Cox regression analysis revealed that non-survivor neonates were more likely to be presented with early-onset sepsis. This finding is congruent with recent Fleischmann et als meta-nalysis conclusion that in the overall time frame, estimated incidence and mortality was higher in early-onset than late-onset neonatal sepsis cases based on 26 studies from fourteen countries.26

In comparison between 88 survivors of neonates with sepsis and 36 non-survivors, the non-survivors were more likely to be delivered by cesarean section, preterm, and have a history of an inserted umbilical venous catheter. Their mothers were more likely to have premature rupture of membranes, pre-eclampsia, and received amoxicillin. Also, non-survivor neonates were more likely to develop complications such as pulmonary hemorrhage, air leak syndrome and pneumothorax, respiratory failure, necrotizing enterocolitis, and multiple organ failure as expected.

On exploring the association of the tested inflammation-related lncRNAs expression signature with neonatal sepsis and outcome, our results demonstrated that the three lncRNAs, MALAT1, ANRIL, and HOTAIR, were markedly increased in the plasma of cases with neonatal sepsis compared to healthy neonates. On correlating the expression signatures of the studied lncRNAs to the clinical features and outcome of the neonatal cases, we found significantly higher levels of the three lncRNAs in deceased neonates than in the survivor group. Furthermore, the cohorts with upregulated ANRIL and HOTAIR were at higher risk of mortality, as revealed by Cox regression analysis.

Given the high blood stability and detection sensitivity of lncRNAs in plasma compared with several traditional protein biomarkers,29 circulating lncRNAs show promising roles as adjunct diagnostic/prognostic epigenetic biomarkers in several disorders, including inflammatory conditions.3032 In the last years, the circulatory MALAT1 expression profile was screened mainly in adults with sepsis. Pellegrina et al identified that deregulated MALAT1 expression might contribute to gene expression changes associated with the poorer outcome of elderly patients with sepsis.33 In the present study, the expression signature of this lncRNA is uncovered for the first time in neonatal sepsis. Our finding could be supported by the vital role MALAT1 plays in regulating the lipopolysaccharide-induced inflammatory response via its interaction with nuclear factor (NF)-kappa B.34 It was also implicated in regulating the hyperglycemia-induced inflammatory process.35 Recent findings by Liu et al, in addition, confirm the substantial value of MALAT1 as part of the MALAT1/miR-125 axis in discriminating adult sepsis cases from a healthy population and demonstrate a significant correlation with disease severity, organ injury, and inflammation level.36

Several in vivo and in vitro studies suggested that ANRIL might mediate the inflammatory and immune responses associated with various diseases, including sepsis.10,12,37,38 In line with our findings, recently, Gui et al found overexpression of ANRIL in plasma of non-survivor patients with sepsis than survivors, and the accumulating survival was worse in patients with ANRIL high expression. They proposed that this action could be mediated via enhancing multiple signaling pathways, such as increasing NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) inflammasome by regulating the miR-122-5p/BRCC3 (BRCA1/BRCA2-Containing Complex Subunit 3) axis.12

The lncRNA HOTAIR was upregulated and associated with neonatal survival in the present cohort. This finding aligns with the previous experimental studies that revealed the implication of HOTAIR in sepsis progression and outcomes.14,15 Through acting as a microRNA-211 sponge with subsequent interleukin-6 receptor induction, HOTAIR has been found to promote inflammation response, inhibit monocyte proliferation and induce monocyte apoptosis in the mice model of sepsis.13 Furthermore, Shen et al showed that HOTAIR could promote cell apoptosis via the microRNA-22/high mobility group box 1 (HMGB1) pathway in vivo and in vitro.15

Although this study is the first, up to the authors knowledge, to explore the implication of the studied lncRNAs in neonatal sepsis, some limitations should be considered. First, the relatively limited sample size, in particular, the healthy control group; Second, the short follow-up duration of hospitalized neonates and absence of testing multiple samples to unravel the stability of the studied lncRNAs in the blood along the progression of the disease. Third, the exploratory nature of the present study lacks explaining the molecular mechanisms by which the studied lncRNAs increase the risk of sepsis or are associated with poor prognosis/survival. Fourth, the specificity of the studied lncRNAs for other neonatal pathological entities is questionable. In this sense, further future studies in large-scale cohorts with long outcome evaluations and molecular experiments are required to unravel the biological significance of these lncRNAs and their potential target genes in neonatal sepsis and the precise underlying molecular mechanisms. Furthermore, replication studies in other neonatal pathological entities, and including pathological controls with multiple sample testing during the disease progress, are recommended to validate the studied lncRNAs specificity in neonatal sepsis.

The present results show upregulation of circulatory lncRNA MALAT1, ANRIL, and HOTAIR in neonatal sepsis compared to healthy neonates. The lncRNAs ANRIL and HOTAIR may have potential prognostic utility as biomarkers for survival in neonatal sepsis.

All data generated or analyzed during this study are included in this submitted article.

The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Ethics Committee of the Faculty of Medicine, Suez Canal University (approval no. 4463). Informed consent was obtained from all included neonates parents or legal guardians before participating in the study.

The authors thank all the parents who agreed to let their infants join the study.

This research received no external funding.

The authors declare no conflicts of interest in relation to this work.

1. Sharrow D, Hug L, Liu Y, You DZ. Levels & Trends in Child Mortality Report, 2020. Estimates Developed by the UN Inter-Agency Group for Child Mortality Estimation United Nations Inter-Agency Group for Child Mortality Estimation (UNIGME). World Health Organization; 2020.

2. Li Z, Karlsson O, Kim R, Subramanian SV. Distribution of under-5 deaths in the neonatal, postneonatal, and childhood periods: a multicountry analysis in 64 low-and middle-income countries. Int J Equity Health. 2021;20(1):111. doi:10.1186/s12939-021-01449-8

3. Cai S, Thompson DK, Anderson PJ, Yang JY. Short- and long-term neurodevelopmental outcomes of very preterm infants with neonatal sepsis: a systematic review and meta-analysis. Children. 2019;6(12):131. doi:10.3390/children6120131

4. Levy O, Martin S, Eichenwald E, et al. Impaired innate immunity in the newborn: newborn neutrophils are deficient in bactericidal/permeability-increasing protein. Pediatrics. 1999;104(6):13271333. doi:10.1542/peds.104.6.1327

5. Levy O. Innate immunity of the human newborn: distinct cytokine responses to LPS and other toll-like receptor agonists. J Endotoxin Res. 2005;11(2):113116. doi:10.1179/096805105X37376

6. Esposito S, Zampiero A, Pugni L, et al. Genetic polymorphisms and sepsis in premature neonates. PLoS One. 2014;9(7):e101248. doi:10.1371/journal.pone.0101248

7. Ho J, Chan H, Wong SH, et al. The involvement of regulatory non-coding RNAs in sepsis: a systematic review. Crit Care. 2016;20(1):383. doi:10.1186/s13054-016-1555-3

8. Geng F, Liu W, Yu L. Potential role of circulating long noncoding RNA MALAT1 in predicting disease risk, severity, and patients survival in sepsis. J Clin Lab Anal. 2019;33(8):e22968. doi:10.1002/jcla.22968

9. Chen J, He Y, Zhou L, Deng Y, Si L. Long noncoding RNA MALAT1 serves as an independent predictive biomarker for the diagnosis, severity and prognosis of patients with sepsis. Mol Med Rep. 2020;21(3):13651373. doi:10.3892/mmr.2020.10923

10. Hu J, Wang D, Wu H, Yang Z, Yang N, Dong J. Long non-coding RNA ANRIL-mediated inflammation response is involved in protective effect of rhein in uric acid nephropathy rats. Cell Biosci. 2019;9:11. doi:10.1186/s13578-019-0273-3

11. Zhou X, Han X, Wittfeldt A, et al. Long non-coding RNA ANRIL regulates inflammatory responses as a novel component of NF-B pathway. RNA Biol. 2016;13(1):98108. doi:10.1080/15476286.2015.1122164

12. Gui F, Peng H, Liu Y. Elevated circulating lnc-ANRIL/miR-125a axis level predicts higher risk, more severe disease condition, and worse prognosis of sepsis. J Clin Lab Anal. 2019;33(6):e22917. doi:10.1002/jcla.22917

13. Chen J, Gu X, Zhou L, et al. Long non-coding RNA-HOTAIR promotes the progression of sepsis by acting as a sponge of miR-211 to induce IL-6R expression. Exp Ther Med. 2019;18(5):39593967. doi:10.3892/etm.2019.8063

14. Jiang ZJ, Zhang MY, Fan ZW, Sun WL, Tang Y. Influence of lncRNA HOTAIR on acute kidney injury in sepsis rats through regulating miR-34a/Bcl-2 pathway. Eur Rev Med Pharmacol Sci. 2019;23(8):35123519. doi:10.26355/eurrev_201904_17717

15. Shen J, Zhang J, Jiang X, Wang H, Pan G. LncRNA HOX transcript antisense RNA accelerated kidney injury induced by urine-derived sepsis through the miR-22/high mobility group box 1 pathway. Life Sci. 2018;210:185191. doi:10.1016/j.lfs.2018.08.041

16. Wang W, Yang N, Wen R, Liu CF, Zhang TN. Long noncoding RNA: regulatory mechanisms and therapeutic potential in sepsis. Front Cell Infect Microbiol. 2021;11:563126. doi:10.3389/fcimb.2021.563126

17. Martin RJ, Fanaroff AA, Walsh MC. Fanaroff and Martins Neonatal-Perinatal Medicine E-Book: Diseases of the Fetus and Infant. Elsevier Health Sciences; 2019.

18. Molloy EJ, Wynn JL, Bliss J, et al. Neonatal sepsis: need for consensus definition, collaboration and core outcomes. Pediatr Res. 2020;88(1):24. doi:10.1038/s41390-020-0850-5

19. AbdAllah NB, Toraih EA, Al Ageeli E, et al. MYD88, NFKB1, and IL6 transcripts overexpression are associated with poor outcomes and short survival in neonatal sepsis. Sci Rep. 2021;11(1):13374. doi:10.1038/s41598-021-92912-7

20. Rodgers A, Singh C. Specialist neonatal respiratory care for babies born preterm (NICE guideline 124): a review. Arch Dis Child Educ Pract Ed. 2020;105(6):355357. doi:10.1136/archdischild-2019-317461

21. Bhandari V. Effective biomarkers for diagnosis of neonatal sepsis. J Pediatric Infect Dis Soc. 2014;3(3):234245. doi:10.1093/jpids/piu063

22. Toraih EA, Abdelghany AA, Abd El Fadeal NM, Al Ageeli E, Fawzy MS. Deciphering the role of circulating lncRNAs: RNCR2, NEAT2, CDKN2B-AS1, and PVT1 and the possible prediction of anti-VEGF treatment outcomes in diabetic retinopathy patients. Graefes Arch Clin Exp Ophthalmol. 2019;257(9):18971913. doi:10.1007/s00417-019-04409-9

23. Bustin SA, Benes V, Garson JA, et al. The MIQE guidelines: minimum information for publication of quantitative real-time PCR experiments. Clin Chem. 2009;55(4):611622. doi:10.1373/clinchem.2008.112797

24. Fakhr-Eldeen A, Toraih EA, Fawzy MS. Long non-coding RNAs MALAT1, MIAT and ANRIL gene expression profiles in beta-thalassemia patients: a cross-sectional analysis. Hematology. 2019;24(1):308317. doi:10.1080/16078454.2019.1570616

25. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2 (-delta delta C (T)) method. Methods. 2001;25(4):402408. doi:10.1006/meth.2001.1262

26. Fleischmann C, Reichert F, Cassini A, et al. Global incidence and mortality of neonatal sepsis: a systematic review and meta-analysis. Arch Dis Child. 2021;106(8):745752. doi:10.1136/archdischild-2020-320217

27. Shepherd R, Cheung AS, Pang K, Saffery R, Novakovic B. Sexual dimorphism in innate immunity: the role of sex hormones and epigenetics. Front Immunol. 2020;11:604000. doi:10.3389/fimmu.2020.604000

28. Everhardt Queen A, Moerdyk-Schauwecker M, McKee LM, Leamy LJ, Huet YM. Differential expression of inflammatory cytokines and stress genes in male and female mice in response to a lipopolysaccharide challenge. PLoS One. 2016;11(4):e0152289. doi:10.1371/journal.pone.0152289

29. Shi T, Gao G, Cao Y. Long noncoding RNAs as novel biomarkers have a promising future in cancer diagnostics. Dis Markers. 2016;2016:9085195. doi:10.1155/2016/9085195

30. Gu Z, Shen HQ, Fu PH, Chen M. Screening of long non-coding RNAs markers in plasma of children with chronic gastritis. Chronic Dis Transl Med. 2020;6(1):6268. doi:10.1016/j.cdtm.2020.01.001

31. Hashemian SM, Pourhanifeh MH, Fadaei S, Velayati AA, Mirzaei H, Hamblin MR. Non-coding RNAs and exosomes: their role in the pathogenesis of sepsis. Mol Ther Nucleic Acids. 2020;21:5174. doi:10.1016/j.omtn.2020.05.012

32. Wang C, Liang G, Shen J, et al. Long non-coding RNAs as biomarkers and therapeutic targets in sepsis. Front Immunol. 2021;12:722004. doi:10.3389/fimmu.2021.722004

33. Pellegrina DVDS, Severino P, Barbeiro HV, et al. Insights into the function of long noncoding RNAs in sepsis revealed by gene co-expression network analysis. Noncoding RNA. 2017;3(1):Jan. doi:10.3390/ncrna3010005

34. Zhao G, Su Z, Song D, Mao Y, Mao X. The long noncoding RNA MALAT1 regulates the lipopolysaccharide-induced inflammatory response through its interaction with NF-B. FEBS Lett. 2016;590(17):28842895. doi:10.1002/1873-3468.12315

35. Puthanveetil P, Chen S, Feng B, Gautam A, Chakrabarti S. Long non-coding RNA MALAT1 regulates hyperglycaemia induced inflammatory process in the endothelial cells. J Cell Mol Med. 2015;19(6):14181425. doi:10.1111/jcmm.12576

36. Liu W, Geng F, Yu L. Long non-coding RNA MALAT1/microRNA 125a axis presents excellent value in discriminating sepsis patients and exhibits positive association with general disease severity, organ injury, inflammation level, and mortality in sepsis patients. J Clin Lab Anal. 2020;34(6):e23222. doi:10.1002/jcla.23222

37. Qiao C, Yang L, Wan J, et al. Long noncoding RNA ANRIL contributes to the development of ulcerative colitis by miR-323b-5p/TLR4/MyD88/NF-B pathway. Biochem Biophys Res Commun. 2019;508(1):217224. doi:10.1016/j.bbrc.2018.11.100

38. Hu J, Wu H, Wang D, Yang Z, Dong J. LncRNA ANRIL promotes NLRP3 inflammasome activation in uric acid nephropathy through miR-122-5p/BRCC3 axis. Biochimie. 2019;157:102110. doi:10.1016/j.biochi.2018.10.011

See more here:
Long Non-Coding RNAs ANRIL and HOTAIR Upregulation is Associated with | IJGM - Dove Medical Press

Recommendation and review posted by Bethany Smith

Just three short weeks ago the bee parasite Varroa destructor was detected in Newcastle, NSW. Beekeepers and government bodies have sprung into action to establish eradication, surveillance, and notification zones for areas surrounding colonies with identified mites.

At the time of writing, more than 38 premises had been identified, bee hives in large areas of the state have been locked down, and hundreds of colonies comprised of millions of bees have been destroyed.

If poorly managed, the forthcoming spring and subsequent migratory pollination could turn this outbreak into varroa superspreader events that will devastate the nations honey bee population and the livelihoods of the people who depend on them.

What are these dreaded mites, why are they so feared and now that theyre here, possibly to stay, how can beekeepers deal with them?

Varroa destructor (and related species)are parasites of the eastern honey bee, Apis cerana. Their long-standing relationship means Apis cerana has evolved a number of defences against varroa, but during the 20th century, on at least two occasions, the Varroa destructor mite switched hosts to the economically important and more familiar western honey bee, Apis mellifera. Humanitys love of honey and dependence on the western honey bee for crop pollination means theyve spread to six continents. And following close behind are the varroa mites. Some territories, especially islands such as Hawaii and New Zealand, avoided the mite for some time, leaving Australia as the only country without varroa. Until now.

The impressive parasitising ability of varroa comes from the two main components to its life cycle reproduction and dispersal. The varroa sex life is pretty wild it features a lot of incest and a communal faecal pile but the important thing is that a single female mite, known as a foundress, can produce an impressive number of offspring. And over a few short generations that single mite can propagate into thousands.

Varroa mites feed on the fat stores of developing larvae and pupae of the honey bees. In doing so they rob the developing bee of energy stores, while also serving as a vector for damaging viruses such as deformed wing virus and acute bee paralysis virus.

Varroa mites feed on the fat stores of developing larvae and pupae of the honey bees. In doing so they rob the developing bee of energy stores, while also serving as a vector for damaging viruses

As Apis mellifera has not evolved defences to varroa, or the viruses they carry, the colony can be overwhelmed, both by the mites feeding and the viruses they carry, leading to sick bees and a collapse of the colonys population. Unfortunately, the death of the resident bees often spells trouble for other nearby colonies, as they come to rob the failing colony of the precious honey stores and pick up waiting varroa mites at the same time. This dispersal phase is just one way the mites can spread, as they can hitch a ride from colony to colony on the male drone bees, or through hopping from one foraging worker bee to another on flowers.

The experience of beekeepers in New Zealand gives an indication of what the introduction of varroa can do to the honey bee population. Losses of feral colonies were estimated at 90% in the first few years of the incursion, and 2021 figures compiled for the Ministry of Primary Industries showed annual managed colony losses at around 13%, with the losses directly attributed to varroa growing annually. And beekeepers have to do a lot of work to keep losses this low.

Get an update of science stories delivered straight to your inbox.

The challenges posed by the mites has necessitated the development of a number of chemical treatments. Organophosphorus and organofluorine compounds such as coumaphos and fluvalinate were commonly used as miticides, and they were initially very successful treatments. These molecules are highly fat soluble, and over time they accumulate in the wax that forms the structural matrix of the colony. The low-level persistence of these treatments in the colony has provided the opportunity for the rapidly reproducing varroa mites to evolve resistance. The miticides are also retained in the processed wax, contaminating downstream products such as cosmetics, food-wraps, candles and more. The miticides can also be spread to untreated colonies, as beeswax is commonly recycled as foundation hexagonally patterned sheets that are used inside other hives as a template for honeycomb production. Another synthetic miticide called Amitraz remains in common use, but resistance is also on the rise.

Many beekeepers want to keep bees as naturally as possible, and a number of bio-related miticide treatments such as thymol (found in many herbs) and beta hop acids (from hops used in brewing beer) have been developed. These compounds are appealing as they have known botanical sources, and established breakdown pathways in the environment. Beekeepers are also treating for varroa using small organic acids found in nature. Formic acid most associated with ant bites is quite volatile and can kill varroa mites on developing brood. The volatility of formic acid means it must be used within strict temperature ranges, and it can have a negative impact on queen bees, frequently leading to their replacement by the colony. Oxalic acid commonly associated with rhubarb and other plants is a less volatile option that can be applied in a sugar solution, or through a specialised piece of equipment that sublimes the solid acid to a gas at temperatures above 157C. The mechanism of action for these organic acids is thought to involve pH changes inside of the mite, which is considered less likely to promote resistance.

These treatments add to the cost and effort of beekeeping, and are not without safety hazards. Organophosphates are well-known neurotoxins, while the volatile formic acid and sublimed oxalic acid are hazardous to the skin, eyes and lungs and require specialised respirators for their safe use. At the time of writing only two chemical treatments for varroa have been approved by the Australian Pesticides and Veterinary Medicines Authority amitraz and thymol. One would hope that the current emergency will expedite the approval of other treatments so they are (legally) available to beekeepers for the upcoming season.

While chemical treatments can offset the worst of varroa in managed colonies, they are not a long-term solution. The best outcome is for Apis melifera to evolve to deal with the mite and its associated viruses. The devastation experienced by feral colonies has provided an extreme selection pressure for these colonies to evolve resistance. Commercially and backyard managed colonies are not under the same evolutionary selective pressures, and are often bred for gentle behaviour and honey production. So, the unintended consequence of the interventional chemical treatments is the perpetuation of poor varroa-resistant honey bee genetics in the environment.

Three main behaviours have been observed in varroa-resistant colonies. The first is grooming, where adult bees physically damage or kill varroa, preventing a foundress mite infesting a new larval cell. Bees with this trait can even request to be groomed by another worker by performing a long vibrating dance. The second is hygienic behaviour, where bees can detect diseased or dead young in their cells, and the third is varroa sensitive hygienic behaviour, where the bees are able to distinguish brood infested with multiple female mites or those with high numbers of viruses and uncap their cell. Foundress mites only carry a limited number of sperm, so if the bees can break their reproductive cycle they can limit their proliferation.

Beekeepers who are actively breeding for varroa resistant traits have had mixed success. A study in Sweden found that only 7% of colonies of an isolated population survived without treatment, but with the potentially negative consequence of significant inbreeding. And attempts to breed varroa resistance in commercial colonies is made difficult by the mating habits of queen bees as they fly long distances and mate with multiple drones from uncontrolled or genetically undesirable colonies. The heritability of certain honey bee traits are strongly linked to the drone colony genetics, making it more difficult to select for desirable traits without controlling both the queen and the drone genetics.

The best outcome is for Apis melifera to evolve to deal with the mite and its associated viruses.

Commercial beekeeper and entomologist Randy Oliver has publicly shared his own experiences through his website and online presentations, and annually takes some 1,500 colonies through selection trials for mite resistance. His own success rate of less than 1% at the beginning of his trials in 2017 has steadily increased towards 20% through annual selective breeding. It should be noted that this selective breeding doesnt mean that poorly performing colonies are left to wither and die. The weak colonies can be combined with resistant colonies, or requeened with more favourable genetics, helping the beekeeper to maintain their stock and continue to seek a profit through honey production or pollination contracts.

Regardless of whether the current outbreak is contained, varroa mites are coming. Australian beekeepers need to be ready to rapidly adjust the ways they look after their hives. Fortunately, they have available the scientific tools of chemistry in the short term, and the evolutionary biology for the long-term survival of their bees.

The biggest news, in detail, quarterly. Buy a subscription today.

More:
Varroa and the threat of bee decimation has now arrived. What have we learned from other nations' - Cosmos

Recommendation and review posted by Bethany Smith

In short, stem cells initiate the production of new tissue cells, which can then replace their diseased counterparts.

Mesenchymal stem cells (MSCs) are adult stem cells found in many areas of the body such as bone marrow. The unique thing about these cells is their compatibility with a range of tissues such as bone, cartilage, muscle, or fat. MSCs respond to injury or disease by migrating to these damaged areas, where they restore tissue function by replacing the damaged cells.

Sign up to our Opinion newsletter

It has recently been shown that the success of MSCs relies on their ability to release cell signals their mechanism to initiate tissue regeneration. These signals are packaged into extracellular vehicles (EVs) which are essentially bubbles of information. These are released by MSCs and taken up by the injured or diseased tissue cells to kickstart their inbuilt process of regeneration.

Through funding from the Royal Society of Edinburgh, research has started into the development of artificial EVs as a viable alternative to cell therapy. These EVs will contain the key molecules released by stem cells when they are responding to injury cues in the body.

The power to induce tissue regeneration would provide a significant new tool in biomedical treatment, such as incorporating EVs into synthetic hydrogels within a wound dressing to encourage and accelerate healing.

Within the lab setting, we have been able to manipulate stem cell cultures to produce EVs with different signal make-ups, and accurately identify their properties.

Controlling and identifying the different make-ups contained in EV signals which in turn induce different cell responses is crucial if we want to operationalise their use in medicine.

We now aim to synthesise artificial vesicles, or bubbles, for different clinical problems, such as, for example, bubbles with potent wound-healing properties that would help our ability to use new artificial stem cell therapy.

The research is underway and it is showing promise that we may be able to harness the regenerative power of stem cells in the near future.

An artificial EV-based approach also has several advantages over stem cell-based therapies, such as having increased potency and greater consistency in treatment, and at a lower cost to carry out.

Both inside and on the surface of the body, we would have the ability to induce a process vital to medical treatment we work with every day and, in turn, open a whole new avenue of possibilities in biomedical science.

Dr Catherine Berry is a reader in the Centre for the Cellular Microenvironment at the University of Glasgow, and a recipient of the Royal Society of Edinburghs personal research fellowship in 2021. This article expresses her own views. The RSE is Scotland's national academy, bringing great minds together to contribute to the social, cultural and economic well-being of Scotland. Find out more at rse.org.uk and @RoyalSocEd.

Here is the original post:
Stem cells: Could we gain the power to induce cell regeneration? Dr Catherine Berry - The Scotsman

Recommendation and review posted by Bethany Smith