Body

Vitamin B12 is essential for proper functioning of the nervous system and blood cells and also plays an important role in DNA synthesis in all our cells. Vitamin B12 deficiency causes fatigue, muscle weakness, headaches, and sometimes even serious neurological symptoms. Usually, the necessary amounts of B12 are absorbed from food in our digestive tract; however, in 0.1-2% of individuals, the epithelial lining of the stomach fails to produce a glycoprotein intrinsic factor that is needed for proper absorption of B12. This leads to vitamin B12 deficiency and a certain type of anemia called pernicious anemia. Pernicious anemia is most commonly caused by the fact that autoimmune reactions destroy the cells that are responsible for the production of the intrinsic factor.

Previously it was known that people with pernicious anemia and their relatives often also have other autoimmune diseases, which points to a genetic predisposition. At the same time, the genetic risk factors for pernicious anemia were unknown, since the condition is very rare and there were no sufficiently large cohorts for conducting genetic studies. "We used large population-based biobank data in our study, which allowed us to study gene variants throughout the genome in a very large number of individuals to find the genetic risk factors of pernicious anemia, " explained Triin Laisk, the first author of the paper and an Associate Professor at the Institute of Genomics.

The study found pernicious anemia risk is associated with genetic variants that regulate our immune system and that are involved in several other autoimmune diseases. Additionally, the results show some of the genetic risk factors have a larger effect on men. The authors also described associations between pernicious anemia and other autoimmune diseases, gastritis, stomach cancer, intestinal malabsorption, and irritable bowel syndrome, which all reflect the risk factors and autoimmune background of pernicious anemia. "The more we know about associations between diseases, the better we become at counselling patients regarding potential comorbidities," added Professor Reedik Mägi, who coordinated the study.

This is the first study of such a scale that evaluates the genetic determinants of pernicious anemia. Future studies should focus on the more specific mechanisms of how the identified risk factors lead to the condition. "Although such large-scale genetic studies allow us to take a glimpse at the potential genetic risk factors of a disease, it is still merely the first step to fully understand the biological background and mechanisms," concluded Laisk.

The authors analysed the genetic data from 150,000 Estonian Biobank participants together with data from other population-based biobanks, bringing the total sample size to 660,000.

Drugs routinely used during fertility treatments to release eggs do not increase the risk of developing breast cancer, new research has shown.

Researchers from King's College London, in partnership with King's Fertility, analysed studies involving 1.8 million women undergoing fertility treatments. These women were followed up in studies for an average period of 27 years and had no increase in the risk of developing breast cancer.

The research, published today in Fertility and Sterility journal, is the largest study to date assessing whether commonly used fertility drugs are for a cancer risk for women.

Fertility treatments can range from using medications to boost the release of an egg in a women's natural cycle to more complex treatment such as IVF which involves stimulating a patient's ovarian cycle, extracting eggs from their ovaries, fertilising them with sperm in a laboratory, then transferring the embryo into the womb to develop.

Fertility drugs to stimulate ovaries to release eggs have been used to treat infertility since the early 1960s. Drugs that are used to stimulate the ovaries increase oestrogen hormone production and can act on breast cells. There has been concern that this could turn the cells cancerous, which has led to an uncertainty about the potential risk of infertility drugs causing breast cancer.

The review looked at studies from 1990 to January 2020. Women of all reproductive ages were included in this study and followed up for an average of 27 years following their fertility treatment. 'Researchers found no significant increase in risk to women exposed to treatment versus untreated women, and untreated women who were infertile.

Study author Dr Yusuf Beebeejaun from King's College London and King's Fertility said: "Fertility treatment can be an emotional experience. Patients often ask us if taking ovarian stimulating drugs will put them at increased risk of developing cancers, including breast cancer. To answer that important clinical question, we undertook this review that reports data from nearly 2 million people.''

Dr Sesh Sunkara, senior-author of the paper, from King's College London and King's Fertility said ''Our study showed that the use of drugs to stimulate ovaries in fertility treatment did not put women at increased risk of breast cancer. This study provides the evidence needed to reassure women and couples seeking fertility treatments.''

Katy Lindemann, a patient advocate with lived experience of fertility treatment said: "So much of the fear, stress and anxiety associated with fertility treatment is rooted in navigating uncertainty. This study not only gives patients peace of mind at an emotional level, but also enables us to make more informed decisions about treatment risks and benefits at a rational level."

Dr Kotryna Temcinaite, Senior Research Communications Manager at Breast Cancer Now, said: "Each year around 55,000 UK women get the terrible news that they have breast cancer. We urgently need to learn more about what factors contribute to someone's risk of developing the disease and stop women dying from breast cancer.

"Previously it was unclear whether fertility drugs affect breast cancer risk, and we do receive calls to our Helpline from women who are concerned that their breast cancer has been caused by fertility treatment. While this analysis of existing published studies does provide welcome reassurance that fertility treatment is unlikely to increase breast cancer risk, further long-term and detailed studies are now needed to confirm these findings.

"Anyone seeking breast cancer information and support can speak to our expert nurses by calling our free Helpline on 0808 800 6000."

A study by the University of Liverpool has shown that while asymptomatic COVID-19 testing in Liverpool was popular, significant inequalities were evident between those who got tested and those who didn't.

Published in the journal The Lancet Regional Health - Europe, the study found that 43% of residents aged over 5 years (n = 214 525) took up the offer of free testing for people without symptoms of COVID-19 between 6th November 2020 and 31st January 2021. A total of 1.3% of tests were positive, meaning that 5192 individuals who did not know they had the virus were notified of the need to self-isolate, potentially breaking chains of transmission.

However, the research identified significant inequalities in who got tested. It found that uptake was lower in the most deprived areas of the city located in North Liverpool (from Everton across to Walton) with 32% of people getting tested compared to 53% of people in the least deprived areas such as Woolton and Allerton. It also found that there was lower uptake of testing amongst Black, Asian and other non-White ethnic groups, and areas classified with high digital exclusion.

In addition, these groups were also more likely to have tested positive for COVID-19. Lateral flow testing found more positive cases in the most deprived areas with 1.74% cases positive in the most deprived compared to 1.04% of tests in the least deprived areas. Among Black groups this was 1.96% and among other non-White ethnic groups it was 3.28% compared to 1.27% in White groups.

The Liverpool 'mass testing' pilot in November 2020 was the first of its kind in the World, designed to evaluate a programme providing free, drop-in voluntary testing for COVID-19 to all residents over the age of 5 years without symptoms in a large city. Findings from the pilot have gone onto inform the national roll-out of testing across the UK and strategies in other countries including the US.

Dr Mark Green, lead author of the paper, said: "The response in Liverpool towards getting tested during the 'mass testing' pilot was brilliant and we thank the people of Liverpool for helping to make it a success.

"Demand for testing was also particularly high after the pilot finished with long queues just before Christmas, as well as into the January lockdown. However, significant inequalities were evident across Liverpool in who did and didn't get tested. Those communities and populations who have been most affected by COVID-19 were also less likely to get tested. Learning how to effectively minimise inequalities in testing behaviours, including the mechanisms and barriers underpinning the relationships we identify, is critical if we are going to be able to effectively manage COVID-19 and future pandemics.

"We also found strong digital inequalities in testing patterns, with areas that were less confident in using the Internet also having lower uptake."

Professor Matt Ashton, Director of Public Health for Liverpool, said: "This paper demonstrates how important it is to consider inequalities in both the design and delivery of local and national public health interventions.

"Despite a strong comms and engagement strategy, and specific mitigation measures designed to encourage uptake in our most disadvantaged communities, there was still a significant difference in testing uptake across different communities in Liverpool. In particular it is essential to consider financial barriers to access alongside physical barriers to access, many of which may require additional financial support."

Professor Iain Buchan, Dean of the Institute of Population Health and lead for the evaluation of Liverpool community testing pilot, said "This research demonstrates why testing in a pandemic is much more than a technical exercise of implementing a test as if it were a clinical test in a hospital.

"Public health testing is a complex social and technical exercise, with important and expected inequalities to address. The lower uptake of testing and higher rates of infection among disadvantaged and BAME groups was predicted and responded to by our local public health teams who understand their communities. Locally-guided implementation of testing and nationally-backed financial support for those isolating on low incomes are important."

The authors of the paper make several recommendations including making sure test site locations were accessible and walkable, ensuring non-digital routes for testing, communicating about the benefits of testing beyond the Internet, and providing sufficient financial support to allow low-income groups to isolate so that they feel comfortable getting tested.

A blood test that can detect tiny amounts of circulating cancer DNA may be able to identify risk of cancer recurrence and guide precision treatment in bladder cancer following surgery, according to a clinical study led by Professor Tom Powles from Queen Mary University of London and Barts Health NHS Trust. The findings from the study, published in Nature, may change our understanding of cancer care following surgery.

The study found that patients with urothelial cancer who had a particular cancer DNA marker in their blood following surgery to remove their tumour had a higher likelihood of cancer relapse. These patients could benefit from subsequent treatment with an immunotherapy called atezolizumab.

Globally, there were approximately 573,000 cases of and 212,000 deaths from bladder cancer in 2020. Surgery is often among the first treatments for advanced bladder cancer that has grown into the muscle layer of the bladder wall (muscle-invasive). However, relapse rates after surgery are high as some cancer cells can be left behind when the tumour is removed. These remaining cancer cells, known as molecular residual disease (MRD), increase the chances of a patient's cancer reoccurring as the cells can spread and establish tumours elsewhere in the body.

This study, funded by F. Hoffmann-La Roche Ltd./Genentech, Inc, and Barts Cancer Institute/Queen Mary University of London evaluated treatment outcomes in a subgroup of patients (comprising 581 individuals) who were enrolled onto a randomised phase III trial (IMvigor010) and a phase II study (ABACUS) which investigated whether the drug atezolizumab could reduce cancer recurrence in high-risk muscle-invasive urothelial carcinoma.

To identify patients with increased likelihood of MRD following surgery, a blood test was used to detect the presence or absence of circulating tumour DNA (ctDNA) - tumour-derived fragments of genetic material that can escape into the bloodstream and are considered to be indicative of MRD. The team found that patients with ctDNA-positive blood tests after surgery were at higher risk of cancer recurrence than those who were ctDNA-negative.

Treatment with atezolizumab did not significantly improve disease-free survival (DFS; the length of time after treatment during which no sign of cancer is found) nor overall survival (OS) in the whole IMvigor010 study population; however, in the ctDNA-positive subgroup of patients evaluated in this study, treatment with atezolizumab compared with observation alone significantly improved DFS (5.9 vs 4.4 months) and OS (25.8 vs 15.8 months). The outcomes in patients who were ctDNA-negative did not appear to differ whether they received atezolizumab or not.

Lead researcher, Tom Powles, Professor of Genitourinary Oncology at Queen Mary's Barts Cancer Institute and Director of Barts Cancer Centre at Barts Health NHS Trust, said:

"These novel findings demonstrate ctDNA as a marker for residual disease and response to atezolizumab. We also found ctDNA measurement to be more accurate than traditional radiology at identifying disease relapse. These findings may change our understanding of post-surgical cancer care and, if validated in this setting as well as across tumour types, they may also change clinical practice."

It is difficult to determine which patients harbour MRD and which are cured after surgery. As a result, many patients who are cured by surgery are unnecessarily exposed to toxicities from additional treatments, and other patients with residual disease may not receive potentially beneficial treatment until disease progression is detectable by imaging. The findings from this study suggest that detection of ctDNA shortly after surgery may overcome these clinical limitations by enabling early identification of patients harbouring MRD.

Initiating personalised treatment based on the identification of MRD rather than treating unselected patients or waiting for relapse would be a significant change in cancer treatment. Further studies will now be required to validate and expand the clinical utility of this method, and to determine whether ctDNA measurement could aid in directing post-surgical treatment to those who need it.

Biologists at the Universities of Bath and Vienna have discovered 71 new 'imprinted' genes in the mouse genome, a finding that takes them a step closer to unravelling some of the mysteries of epigenetics - an area of science that describes how genes are switched on (and off) in different cells, at different stages in development and adulthood.

To understand the importance of imprinted genes to inheritance, we need to step back and ask how inheritance works in general. Most of the thirty trillion cells in a person's body contain genes that come from both their mother and father, with each parent contributing one version of each gene. The unique combination of genes goes part of the way to making an individual unique. Usually, each gene in a pair is equally active or inactive in a given cell. This is not the case for imprinted genes. These genes - which make up less than one percent of the total of 20,000+ genes - tend to be more active (sometimes much more active) in one parental version than the other.

Until now, researchers were aware of around 130 well-documented imprinted genes in the mouse genome - the new additions take this number to over 200.

Professor Tony Perry, who led the research from the Department of Biology & Biochemistry at Bath in the UK, said: "Imprinting affects an important family of genes, with different implications for health and disease, so the seventy-plus new ones add an important piece of the jigsaw."

THE IMPORTANCE OF HISTONES

Close examination of the newly identified genes has allowed Professor Perry and his colleagues to make a second important discovery: the switching on and off of imprinted genes is not always related to DNA methylation, where methyl groups are added to genomic DNA- a process that is known to repress gene activity, switching them off). DNA methylation was the first known type of imprint, and was discovered around thirty years ago. From the results of the new work, it seems that a greater contribution to imprinting is made by histones - structures that are wrapped up with genomic DNA in chromosomes.

Although scientists have known for some time that histones act as 'dimmer' switches for genes, fading them off (or back on), until now it was thought that DNA methylation provided the major switch for imprinted gene activity. The findings from the new study cast doubt on this assumption: many of the newly identified genes were found to be associated with changes to the histone 3 lysine 27 (H3K27me3), and only a minority with DNA methylation.

WHY IMPRINTING MATTERS

Scientists have yet to work out how one parental version of a given gene can be switched (or faded) on or off and maintained that way while the other is in the opposite state. It is known that much of the on/off switching occurs during the formation of gametes (sperm and egg), but the precise mechanisms remain unclear. This new study points to the intriguing possibility that some imprinted genes may not be marked in gametes, but become active later in development, or even in adulthood.

Although it only involves a small proportion of genes, imprinting is important in later life. If it goes wrong, and the imprinted gene copy from one parent is switched on when it should be off (or vice versa), disease or death occur. Faulty imprinted genes are associated with many diseases, including neurological and metabolic disorders, and cancer.

"We may underestimate how important the relationship between imprinting and disease is, as well as the relationship of imprinting to the inheritance of parentally-acquired disease, such as obesity," said Professor Perry. "Hopefully, this improved picture of imprinting will increase our understanding of disease."

Fat biomolecules in the blood, called "serum lipids," are necessary evils. They play important roles in the lipid metabolism and are integral for the normal functioning of the body. However, they have a darker side; according to several studies, they are associated with various cancers. The medical community has fathoms to go before truly understanding the implications of different serum lipid levels in cancer.

As a major step in this direction, a group of scientists from the Key Laboratory of Carcinogenesis and Translational Research, Laboratory of Genetics, Peking University Cancer Hospital and Institute; Hua County People's Hospital; and Anyang Cancer Hospital, have successfully determined that a family history of esophageal cancer modifies the association between serum lipids and risk of developing cancerous esophageal lesions, according to a pioneering study published in Chinese Medical Journal.

Many individuals undergo routine lipid profile checkups, but most people and doctors only focus on the risk of cardiovascular diseases, and unwittingly fail to look deeper into the results. What if the change in serum lipid levels is an sign of the risk of having malignant esophageal lesions?

To answer this question, Chinese medical researchers analyzed data from the "Endoscopic Screening for Esophageal Cancer in China" trial. The trial included analysis of serum lipids like total cholesterol (TC), triglycerides, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol from 211 individuals with malignant esophageal lesions, and 2101 "control" individuals who didn't have the lesion.

Although the team's initial analysis of data showed that there is no consistent association between serum lipid levels and risk of developing malignant esophageal lesions, a simple family history check--and deeper analysis--told a different story. Particularly for cases with a family history of esophageal cancer, high levels of TC and LDL-C were linked to a significantly higher risk of developing malignant esophageal lesions. Also, when such family history was not identified, there was a notable negative association between the same parameters. Better to know late, than never, right?

Professor Yang Ke from Key Laboratory of Carcinogenesis and Translational Research, Laboratory of Genetics, Peking University Cancer Hospital and Institute, Beijing, who is also one of the lead scientists of the study, thinks so. In this regard, Professor Ke jubilantly says, "We found that the association of serum lipids and malignant esophageal lesions might be modified by esophageal cancer family history. This finding provides population-level evidence in research at the interface of serum lipid biology and esophageal carcinogenesis."

Further, the findings of this study shed light on the importance of considering a 'stratified' analysis on such population-based studies. A relevant example is a stratification this study proposes, in terms of those with and without esophageal cancer family history. This stratification helped the researchers have a better understanding of the data from the trial considered. Moreover, Dr. Meng-Fei Liu, from Laboratory of Carcinogenesis and Translational Research, and the other corresponding author of this study, thinks that this research is far from its endpoint. He says, "The stratified analysis would be crucial for population-based studies investigating the association of serum lipids and cancer. However, the mechanism by which a family history of esophageal cancer modifies this association warrants further investigation."

Overall, this study has paved the way for a better understanding of the role of serum lipids in esophageal carcinogenesis in cases involving esophageal cancer family history. While the medical community continues to look for further advances, which could be translated into future clinical applications in such population-based cancer research, this study has definitely given us much to think about; the signs of cancer may be in our blood, in more ways than one!

June 21, 2021 -- A new study published in Nutrients investigated the effect of increased dietary potassium from a whole food source--baked/boiled potatoes and baked French fries--or a potassium supplement on blood pressure and other cardiovascular disease risk factors compared to a 'typical American' control diet (lower potassium intake) among 30 pre-hypertensive to hypertensive men and women. Results showed that including baked/boiled potato consumption as part of a typical American diet had the greatest benefit on reducing sodium retention, even more than the supplement, and resulted in a greater systolic blood pressure reduction compared to the control diet. Further, despite commonly held misbeliefs about French fries and their role in heart-healthy lifestyles, the authors observed that a 330-calorie serving of baked French fries, when eaten as part of a typical American diet, had no adverse effect on blood pressure or blood vessel function.

"While significant emphasis is often placed on reducing dietary sodium intakes to better control for blood pressure and cardiovascular disease risk, that's only half of the story," says Connie Weaver, PhD, the primary investigator. "Potassium plays just as an important role, and perhaps the ratio of potassium to sodium is most important in the context of the entire food matrix, as the potato meal resulted in a greater reduction of sodium retention than the potassium supplement alone."

Evidence on the effect of increased dietary potassium on blood pressure from clinical trials is extremely limited, and this is one of the first known controlled feeding interventions investigating dietary potassium as the primary variable of interest.

"It's important to establish clinical trials that follow observational research to establish a causal link between diet and health," notes Weaver. "For example, in this clinical study baked French fries had a null effect on blood pressure, which counters observational findings, at least in the short term, and helps to prioritize the importance of focusing on a total diet approach for maintaining health versus one that overemphasizes avoidance of any single food or food group."

Potatoes comprise roughly 20 percent of the vegetable intake in the American diet and help fill several nutrient gaps, including dietary fiber and potassium.1 Eating just one medium potato meets approximately 10 percent of an adult's daily potassium needs. According to the 2020-2025 Dietary Guidelines for Americans, potassium is an essential nutrient of concern, indicating most Americans aren't consuming enough. The mineral has been linked to improvements in cardiovascular and other metabolic health outcomes - including decreased blood pressure in those with hypertension. Overall, potatoes and French fries represent about 7 percent and 3 percent of potassium intake, respectively, in the United States.1

"Considering Americans fall significantly short in meeting daily potassium intakes, these findings show the importance of promoting, not restricting, whole food good-to-excellent sources of potassium in Americans' diets, like potatoes," Weaver said.

A Closer Look at the Study Methodology, Strengths and Limitations

Participants were randomly assigned to one of four 16-day dietary potassium interventions:

Control diet including 2300 mg potassium/day (reflective of typical intake, considered to be 'low potassium')

Control diet + 1000 mg of potassium from potatoes (baked, boiled, or pan-heated with no additional fat)

Control diet + 1000 mg from baked French fries

Control diet + 1000 mg from a potassium-gluconate supplement

Each diet was tailored to participants' specific caloric needs while all other nutrients were kept constant. Blood pressure was measured across multiple visits of each phase, and participants also collected daily urine/stool samples to assess potassium and sodium excretion and retention.

The strengths of the study include a highly controlled diet, cross-over design, and excellent compliance. However, the researchers note a few limitations as well, including the study's relatively small sample size, poor retention in study participation and relatively short study duration.

"All clinical studies are faced with limitations; however, despite those found in this study, the rigor of the study design is strong and unlike any other studies that have investigated the effect of a whole food - and potassium - on high blood pressure," Weaver notes. "Through our carefully controlled balance study, we could determine the mechanism by which potatoes reduced blood pressure. Overall, we concluded that boiled or baked potatoes can help reduce systolic blood pressure - and baked French fries have no adverse effects on blood pressure and can be included as part of an overall healthy diet."

The research manuscript, "Short-term randomized controlled trial of increased dietary potassium from potato or potassium gluconate: effect on blood pressure, microcirculation, and potassium and sodium retention in pre-hypertensive-to-hypertensive adults," is published in Nutrients (doi: https://doi.org/10.3390/nu13051610). Authors include Michael Stone, Berdine Martin and Connie Weaver of Purdue University. Funding was provided by the Alliance for Potato Research and Education.

COVID-19 therapies made from antibodies often are given to patients who are at high risk of severe illness and hospitalization. However, there have been nagging questions about whether such antibody therapies retain their effectiveness as worrisome new virus variants arise.

New research at Washington University School of Medicine in St. Louis suggests that many, but not all, therapies made from combinations of two antibodies are effective against a wide range of variants of the virus. Further, combination therapies appear to prevent the emergence of drug resistance.

The study, in mice and hamsters, tested all single and combination antibody-based therapies authorized for emergency use by the Food and Drug Administration (FDA), or that are being evaluated in late-stage clinical trials, against a panel of emerging international and U.S. variants of SARS-CoV-2, the virus that causes COVID-19.

The findings, published June 21 in the journal Nature, suggest that COVID-19 drugs made of two antibodies often retain potency as a therapy against variants even when in vitro studies -- experiments conducted in a dish -- indicate that one of the two antibodies has lost some or all ability to neutralize the variant.

"We knew how these antibodies were behaving in vitro, but we don't give people drugs based solely on cell culture data," said senior author Michael S. Diamond, MD, PhD, the Herbert S. Gasser Professor of Medicine. "When we looked in animals, there were some surprises. Some of the combinations performed better than we thought they would, based on in vitro data. And there was no drug resistance to combinations whatsoever, across all of the different variants. We're going to have to continue to monitor the effectiveness of antibody therapy as more variants arise, but combination therapy is likely needed for treating infections with this virus as more variants emerge."

So-called monoclonal antibodies mimic those generated by the body to fight off the virus that causes COVID-19. Administration of antibody therapies bypasses the body's slower and sometimes less effective process of making its own antibodies. At the time this study began, there were two dual-antibody combination therapies and a single antibody therapy authorized by the FDA for emergency use. The FDA withdrew authorization for the single antibody therapy, bamlanivimab, in April on the grounds that it was not effective against the variants circulating at that time. In May, the FDA authorized the single antibody sotrovimab as a treatment for COVID-19.

In all, the researchers evaluated antibodies corresponding to the FDA-authorized ones made by Eli Lilly and Co., Regeneron and Vir Biotechnology/GlaxoSmithKline, as well as the antibodies currently under development by AbbVie, Vir and AstraZeneca that are in clinical trials.

The researchers -- led by co-first authors Rita E. Chen, an MD/PhD student, Emma S. Winkler, an MD/PhD student, and Brett Case, PhD, a postdoctoral researcher -- tested the antibodies against a panel of virus variants containing key mutations in their spike genes. The SARS-CoV-2 virus uses spike protein to invade cells. All monoclonal antibody-based COVID-19 therapies work by interfering with the interaction between spike protein and cells.

The panel included mutations found in three of the four variants that have been designated "variants of concern" by the World Health Organization -- Alpha (first identified in the United Kingdom), Beta (South Africa) and Gamma (Brazil) -- as well as an emerging variant from India similar to the Delta variant of concern. They also tested variants from New York and California. The researchers used a mix of virus samples originally obtained from people with COVID-19 and laboratory strains genetically engineered to contain key mutations.

The researchers evaluated the antibodies in hamsters and two strains of mice. The researchers first gave the animals antibodies -- singly or in the same combinations in which they are given to treat patients -- a day before infecting them with one of the virus variants. The researchers monitored the animals' weight for six days and then measured the amount of virus in their noses, lungs and other parts of the body.

Although some single antibodies showed reduced or no ability to neutralize virus variants in a dish, low doses of most of the antibody combinations protected against disease caused by many of the variants. The researchers sequenced viral samples from the animals and found no evidence of drug resistance in viruses from any of the animals that had been treated with combination therapies.

"Dual therapy seemed to prevent the emergence of resistant viruses," said co-author Jacco Boon, PhD, an associate professor of medicine, of molecular microbiology and of pathology & immunology. "Resistance arose with some of the monotherapies, but never with combination therapy."

Since antibody-based COVID-19 therapies primarily are used to treat people who already are infected, the researchers also evaluated how well the antibody combinations performed when given after infection with the Beta variant. The Beta variant was chosen because it has been shown to be most likely to escape neutralization in laboratory-based experiments and has the most resistance to COVID-19 vaccines. The antibody cocktails corresponding to those from AstraZeneca, Regeneron and Vir were all effective at reducing disease caused by the Gamma variant; the one from AbbVie only was partially protective, and the one from Lilly showed no efficacy at all.

"It's going to be useful going forward to understand how these monoclonal antibodies are going to behave as variants continue to emerge," said Diamond, who also is a professor of molecular microbiology and of pathology & immunology. "We need to think about and generate combinations of antibodies to preserve our ability to treat this disease. And we'll need to monitor for resistance -- although, in my opinion, the use of specific combinations will make this less of an issue."

In a new study published today in the American Journal of Human Genetics, researchers announced the development of a new method to increase the utility and equity of large genetic databases. The research was conducted by Audrey Hendricks, an associate professor of statistics at the University of Colorado Denver (CU Denver).

Summix, the new method developed by Hendricks and her team of CU Denver undergraduate and graduate students, estimates the genetic ancestry in databases and adjusts the information to match the ancestry of a person or sample of people. This method leads large genetic databases to become more useful for people of various ancestries such as African American or Latinx, as they are underrepresented in genetic databases and studies. Hendricks compares this method to translating a book from English to another language.

"Think of DNA as the words of our body," says Hendricks. "All of the words of our body make the instruction book that makes each of us up. Right now, it's like the DNA books are only written in English so the information in the library is not as useful for people who don't speak English. We're working to create books in the library that are more universal."

According to Hendricks, individuals and samples from understudied populations, such as African American and Latnix, are the most likely to lack large public resources with precisely matched ancestry data. As a result, researchers working with those populations often resort to the closest, but still poorly matched ancestral group. This leads to biased results in the very populations where high-quality research is needed the most.

The team showed the effectiveness of Summix in over 5,000 simulation scenarios and in the widely used Genome Aggregation Database (gnomAD), a publicly available genetic resource. They found Summix's estimates of ancestry proportions to be highly accurate (within 0.001%) and the ancestry-adjusted genetic information to be less biased. The Summix method is available in open access software increasing the utility of the method and its applications.

"Most people are a combination of multiple continental (e.g. African and European) or finer scale (e.g. Italian and German) ancestries," said Hendricks. "As healthcare moves forward with precision medicine, matching the unique ancestral make-up of each person will become increasingly important. The ability of Summix to update a genetic resource to match the ancestry of an individual is an important step in this direction and helps to increase the utility and equity of genetic summary data."

Every day, our bodies face a bombardment of UV rays, ozone, cigarette smoke, industrial chemicals and other hazards.

This exposure can lead to free-radical production in our bodies, which damages our DNA and tissues. A new study from West Virginia University researcher Eric E. Kelley--in collaboration with the University of Minnesota--suggests that unrepaired DNA damage can increase the speed of aging.

The study appears in the journal Nature.

Kelley and his team created genetically-modified mice with a crucial DNA-repair protein missing from their hematopoietic stem cells, immature immune cells that develop into white blood cells. Without this repair protein, the mice were unable to fix damaged DNA accrued in their immune cells.

"By the time the genetically-modified mouse is 5 months old, it's like a 2-year-old mouse," said Kelley, associate professor and associate chair of research in the School of Medicine's Department of Physiology and Pharmacology. "It has all the symptoms and physical characteristics. It has hearing loss, osteoporosis, renal dysfunction, visual impairment, hypertension, as well as other age-related issues. It's prematurely aged just because it has lost its ability to repair its DNA."

According to Kelley, a normal 2-year-old mouse is about equivalent in age to a human in their late 70s to early 80s.

Kelley and his colleagues found that markers for cell aging, or senescence, as well as for cell damage and oxidation were significantly greater in the immune cells of genetically-modified mice compared to normal, wild-type mice. But the damage was not limited to the immune system; the modified mice also demonstrated aged, damaged cells in organs such as the liver and kidney.

These results suggest that unrepaired DNA damage may cause the entire body to age prematurely.

When we are exposed to a pollutant, such as radiation for cancer treatment, energy is transferred to the water in our body, breaking the water apart. This creates highly reactive molecules--free radicals--that will quickly interact with another molecule in order to gain electrons. When these free radicals interact with important biomolecules, such as a protein or DNA, it causes damage that can keep that biomolecule from working properly.

Some exposure to pollutants is unavoidable, but there are several lifestyle choices that increase exposure to pollution and thus increase free radicals in the body. Smoking, drinking and exposure to pesticides and other chemicals through occupational hazards all significantly increase free radicals.

"A cigarette has over 10 to the 16th free radicals per puff, just from combusted carbon materials," Kelley said.

In addition to free radicals produced by pollutant exposure, the human body is constantly producing free radicals during a process used to turn food into energy, called oxidative phosphorylation.

"We have mechanisms in the mitochondria that mop free radicals up for us, but if they become overwhelmed--if we have over-nutrition, if we eat too much junk, if we smoke--the defense mechanism absolutely cannot keep up," Kelley said.

As bodies age, the amount of damage caused by free-radical formation becomes greater than the antioxidant defenses. Eventually, the balance between the two tips over to the oxidant side, and damage starts to win out over repair. If we are exposed to a greater amount of pollutants and accumulate more free radicals, this balance will be disrupted even sooner, causing premature aging.

The issue of premature aging due to free-radical damage is especially important in West Virginia. The state has the greatest percentage of obese citizens in the nation and a high rate of smokers and workers in high-pollution-exposure occupations.

"I come from an Appalachian background," Kelley said. "And, you know, I'd go to funerals that were in some old house--an in-the-living-room-with-a-casket kind of deal--and I'd look at people in there, and they'd be 39 or 42 and look like they were 80 because of their occupation and their nutrition."

Many West Virginians also have comorbidities, such as diabetes, enhanced cardiovascular disease, stroke and renal issues, that complicate the situation further.

Although there are drugs, called senolytics, that help to slow the aging process, Kelley believes it is best to prevent premature aging through lifestyle change. He says that focusing on slowing the aging process through preventive measures can improve the outcome for each comorbidity and add more healthy years to people's lives.

"The impact is less on lifespan and more on healthspan," he said. "If you could get people better access to healthcare, better education, easier ways for them to participate in healthier eating and a healthier lifestyle, then you could improve the overall economic burden on the population of West Virginia and have a much better outcome all the way around."

In two separate articles in the Annals of Neurology, clinicians in India and England report cases of a rare neurological disorder called Guillain-Barre? syndrome after individuals were vaccinated against COVID-19.

Both reports describe an unusual variant of Guillain-Barre? syndrome characterized by prominent facial weakness. Seven cases were reported from a regional medical center in Kerala, India, where approximately 1.2 million people were vaccinated with the AstraZeneca COVID-19 vaccine. Four cases were reported from Nottingham, England, in an area in which approximately 700,000 people received the same vaccine. All eleven cases were among people who had received that vaccine 10-22 days earlier.

The frequency of Guillain-Barre? syndrome in these areas was estimated to be up to 10 times greater than expected.

"If the link is causal it could be due to a cross-reactive immune response to the SARS-CoV-2 spike protein and components of the peripheral immune system," wrote the authors of the report from England.

The authors of both articles stress that clinicians should be vigilant in looking for this rare neurological syndrome following administration of COVID-19 vaccines.

DARIEN, IL - A new position statement from the American Academy of Sleep Medicine emphasizes that sleep is a biological necessity, and insufficient sleep and untreated sleep disorders are detrimental for health, well-being, and public safety.

Published online in the Journal of Clinical Sleep Medicine, the statement notes that sleep is vital for health and well-being in children, adolescents, and adults. While awareness of the value of sleep has risen in the last decade, there is a significant need for greater emphasis on sleep health in education, clinical practice, inpatient and long-term care, public health promotion, and the workplace.

"Healthy sleep is as important as proper nutrition and regular exercise for our health and well-being, and sleep is critical for performance and safety," said AASM President Dr. Kannan Ramar. "It is the position of the AASM that sleep is essential to health, and we are urging educators, health care professionals, government agencies, and employers to prioritize the promotion of healthy sleep."

The statement was written by the members of the 2020 - 2021 AASM board of directors, comprising 11 sleep medicine physicians and a clinical psychologist. In recognition of sleep's significant and multi-faceted connections to health and chronic disease, the authors outlined the following positions:

- Sleep education should have a prominent place in K-12 and college health education, medical school and graduate medical education, and educational programs for other health professionals.

- Clinicians should routinely inquire about sleep habits and symptoms of sleep and circadian rhythm sleep-wake disorders during patient encounters, and hospitals and long-term care facilities should optimize sleep conditions.

- Healthy sleep should be targeted by public health and workplace interventions to improve health-related outcomes, and behaviors that help people attain healthy sleep should be actively promoted.

- More sleep and circadian research is needed to further elucidate the importance of sleep for public health and the contributions of insufficient sleep to health disparities.

"Education about sleep and sleep disorders is lacking in medical school curricula, graduate medical education, and education programs for other health professionals," said Ramar. "Better sleep health education will enable our health care workforce to provide more patient-centered care for people who have common sleep disorders such as obstructive sleep apnea and insomnia."

According to the authors, chronic insufficient sleep and untreated sleep disorders are linked to increased health and safety risks such as cardiovascular disease, diabetes, obesity, workplace accidents, and motor vehicle crashes. Data from surveys conducted by the Centers for Disease Control and Prevention and the Maternal and Child Health Bureau show that 34.1% of children, 74.6% of high school students, and 32.5% of adults in the U.S. fail to get a sufficient duration of sleep on a regular basis. Therefore, helping people get enough sleep is one of the goals of Healthy People 2030, which provides 10-year, measurable public health objectives for the U.S.

The AASM position statement declaring that sleep is essential to health has been endorsed by more than 25 medical, scientific, patient, and safety organizations:

Alliance of Sleep Apnea Partners

American Academy of Cardiovascular Sleep Medicine

American Academy of Dental Sleep Medicine

American Academy of Neurology

American Academy of Otolaryngology--Head and Neck Surgery

American Academy of Physician Assistants

American Association of Clinical Endocrinology

American Association of Sleep Technologists

American College of Preventive Medicine

American Geriatrics Society*

American Society for Metabolic and Bariatric Surgery

American Society of Addiction Medicine

American Society of Anesthesiologists*

American Thoracic Society

Circadian Sleep Disorders Network

International REM Sleep Behavior Disorder Study Group

National Safety Council

National Sleep Foundation

Obesity Action Coalition

Project Sleep

Restless Legs Syndrome Foundation

Sleep Research Society

Society for Research on Biological Rhythms

Society of Anesthesia and Sleep Medicine

Society of Behavioral Sleep Medicine

Start School Later

Wake Up Narcolepsy

World Sleep Society

*The American Geriatrics Society supports the general principles in the document and believes it is of general benefit to its membership. The American Society of Anesthesiologists' Administrative Council approved support for the position statement with qualifications; since the document has neither been presented to nor approved by either the ASA Board of Directors or House of Delegates, it is not an official or approved statement or policy of the Society. Variances from the recommendations contained in the document may be acceptable based on the judgment of the responsible anesthesiologist.

Learn more about the AASM at aasm.org.

To request a copy of, "Sleep is essential to health: An American Academy of Sleep Medicine position statement," or to arrange an interview with an AASM spokesperson, please contact the AASM at 630-737-9700 or media@aasm.org.

NEW YORK, NY--COVID vaccine surveillance efforts are a global priority, but safety monitoring for vaccines should not reflect a single population. The largest, most extensive international study of the background rates of adverse events of special interest (AESI) that are being tracked in vaccine surveillance efforts show that adverse event rates vary substantially by age, sex, and method of data capture.

Led by researchers at Oxford University, Columbia University, Erasmus MC, UCLA, and Janssen, an international team of collaborators from the Observational Health Data Sciences and Informatics (OHDSI) network provided a timely reference of the background rates of AESIs in a new study published June 14 in The BMJ.

The researchers found significant differences in the observed rates of AESIs based on the age groups and sex of more than 126 million people across four continents and 13 databases. Differences were also observed among people within databases.

"We knew regulators would be monitoring a long list of events for the surveillance of COVID vaccines safety," said co-senior author Dani Prieto-Alhambra MD MSc PhD, Professor of Pharmacoepidemiology at the University of Oxford. "To do this, they need robust estimates of the background rates of these events in historical data. These results can be used as benchmark for the monitoring of these potential safety events and for any upcoming COVID-19 vaccines."

There were 15 prespecified adverse events studied, matching those being monitored by the U.S. Food and Drug Administration and similar to those used by other regulatory agencies, including heart attack, stroke, and blood clotting. Incidence rates were classified by age groups and gender across the databases, though the outcomes of those groups vary by database.

"We found significant heterogeneity in background rates between age and sex," said co-lead author Xintong Li, DPhil candidate and Clarendon scholar at the University of Oxford. "If we compare these rates regardless of age or sex group, we may either find a false signal or neglect a real safety signal while monitoring vaccine surveillance.

"The observed and expected rates comparison should also be conducted within the same health database whenever possible," Li added. "While we understand that is not possible for all surveillance systems or vaccine safety studies, choosing a similar population and stratifying or standardizing by age and sex is highly recommended."

Heart attack, for example, was observed as a very rare (

"If a vaccinated population is older than an unvaccinated population, and we do not adjust for it, we may see a false increased risk of events following vaccination," said co-lead author Anna Ostropolets, MD, a PhD candidate in the Columbia University Department of Biomedical Informatics.

The variability between different databases could reflect numerous factors, ranging from the process of data capture to population differences such as socioeconomic status and comorbidities.

"The observed heterogeneity between databases was more than I expected," Prieto-Alhambra said. "As a consequence, vaccine safety surveillance should be conducted using the same database for both post-vaccine and background rates."

This multinational network cohort study used deidentified electronic health records and health claims data, all of which were mapped to the OMOP common data model, which allows for the systematic analysis of different observational databases. All rates of adverse events, as well as the protocol and study codes, are available in the publication.

Patients with brain injury (caused by stroke or trauma) primarily rely on rehabilitation therapy for recovery, as there are no other known effective treatment methods. The rate of recovery from brain injury observed in adults is significantly slower (or the recovery is impossible) than that observed in young children. The consensus among researchers is that the number of excess neural stem cells capable of restoring brain functions is lower in a mature brain than that in the brain of young children.

A Korean research team reported a novel mechanism to describe the brain injury recovery process. The researchers reported that when the animal model experiment was conducted, the time taken to recover from a brain injury could be controlled by regulating the proteins. The Korea Institute of Science and Technology (KIST) has released an announcement that a team led by Dr. Eun Mi Hwang of the Brain Science Institute, KIST collaborated with another team led by Prof. Kyoungho Suk of the School of Medicine, Kyungpook National University and reported the presence of a novel interaction between proteins (hevin-calcyon); this interaction plays a critical role in the brain injury recovery process in adults. The researchers also revealed that this interaction plays an important role in the early stages of recovery.

The researchers working at KIST identified the calcyon protein as a novel interaction partner of hevin, a protein secreted by the glial cells present in the brain. They also reported that the interaction between the proteins played a critical role in the recovery process of neuronal cells present in an injured adult brain. As neurons are cells that directly influence brain activity, it is believed that brain diseases can be cured when they are recovered and/or treated.

*Glial cells : Cells that support the tissues of the central nervous system, provide nutrients to neurons inside the brain and spinal cord, and create a chemical environment suitable for the activities of neurons

The results from the experiments revealed that an increase in the number of hevin-calcyon interactions in the brain could promote synaptic contacts and reorganization, which could help in the early recovery of the impaired brain. The hevin-calcyon interaction and the expression of these proteins were confirmed by studying healthy brain tissues. It was also observed that the number of interactions in patients suffering from the condition of traumatic brain injury was significantly reduced.

Researchers at the Kyungpook National University studied the recovery process of brain injury by studying the hevin and calcyon interaction using a brain injury animal model. They reported that the neuroinflammatory response-induced proteases formed in the early stages of brain injury resulted in the fragmentation of hevin. This also impeded the generation of the hevin and calcyon interaction. Experiments were conducted using an animal model of brain injury. It was observed that the recovery time could be reduced to approximately 2 to 3 weeks (from 4 weeks) if an inflammatory response inhibitor was administered directly to the injured region of the brain. The rate of recovery could be further slowed by administering an additional inflammatory protein.

The joint research team reported that the absence of the hevin-calcyon interaction in the early stages (a critical period in the recovery process of brain injury) of the recovery process might negatively impact the effective recovery process. The reported result is the outcome of the five years of persistent efforts by the team led by Dr. Eun Mi Hwang of KIST (this team identified the novel interaction between proteins), team led by Dr. Hoon Ryu of KIST (this team investigated human traumatic brain injury), and team led by Prof. Kyoungho Suk of the Kyungpook National University (this team studied the properties of inflammation using various animal models). Each team contributed to the findings based on their area of expertise.

Dr. Eun Mi Hwang of KIST said, "The hevin-calcyon interaction can potentially help in treating brain diseases as brain injury and neurodegenerative diseases can result in the generation of inflammatory responses." She also added, "The findings can potentially help in the development of procedures for treating refractory brain diseases caused by impaired synaptogenic activity."

Globally, an estimated 10 million people develop tuberculosis (TB) each year and the disease remains a leading cause of death from a single infectious agent. Standard short-course anti-TB treatment still requires a regimen of at least six months of antimicrobial drugs, and drug-resistant TB is an increasing public health threat. Even after the traces of TB disease are quashed, patients often suffer from significant sequelae, such as lung scarring. TB survivors have approximately three to four times greater mortality than their local population.

In pulmonary TB, the most common form of active TB disease, the Mycobacterium tuberculosis bacteria causes the formation of sites of high bacterial load, known as cavities. These cavities are poorly penetrated by TB drugs. After TB treatment is complete, there is likely to be tissue damage within the lungs that can lead to further lung problems such as permanent respiratory dysfunction leading to difficulty in breathing, stiffness in the lungs and bronchiectasis, which can make people cough up blood.

Researchers from NUS Yong Loo Lin School of Medicine's Infectious Diseases Translational Research Programme have discovered that the use of a common antibiotic, doxycycline, in combination with TB drug treatment, reduces the size of lung cavities and accelerates markers of lung recovery.

In the Phase 2 double-blind trial conducted at the National University Hospital and TB Control Unit, the treatment was found to be safe, with side effects similar to patients on placebo pills. The study shows promise in delivering a new standard-of-care which can potentially prevent long term complications and the study team is seeking funds for a fully-powered larger scale Phase 3 trial to verify these findings.

"Pulmonary TB patients tend to suffer from lung damage after TB, which is associated with mortality, and poorer quality of life. Doxycycline is a cheap and widely available antibiotic that can decrease lung damage, and potentially improve quality of life for these patients," said Assistant Professor Catherine Ong, Principal Investigator of the study and member of the Infectious Diseases Translational Research Programme (TRP) at NUS Medicine. The study findings were published in the Journal of Clinical Investigation.

Professor Paul Tambyah, who was also involved in the study and is Deputy Director of the Infectious Diseases TRP commented, "While we have been able to successfully treat most cases of TB for the last few decades, we have seen many people suffer the complications of the lung damage from the original TB infection. If this common drug, doxycycline, can help prevent the complications of "Long TB" (to use a term currently in vogue), this will really help a lot of patients in Singapore and worldwide."

The Infectious Diseases TRP aims to provide a holistic, patient-centric approach to infectious diseases that are relevant to Singapore and the region. The Programme focuses on programmatic research areas including pathogen evolution and transmission, host-microbe interactions and vaccine and therapeutics development.