Body

New research reveals that only a minority of U.S. Medicare beneficiaries with knee osteoarthritis in 2005-2010 used non-surgical care such as physical therapy and knee injections, and few were treated by rheumatologists, physiatrists, or pain specialists. The study, which is published in Arthritis & Rheumatology, also found that non-surgical care was more common in regions with low rates of knee replacement surgery.

It will be important to examine whether the use of conservative therapies was limited by capacity constraints or underappreciation of their role in the treatment of knee osteoarthritis.

"In addition to its low use overall, conservative care was less commonly used in regions of the country with high rates of knee replacements, suggesting that surgery may more often be substituted for conservative care in these regions," said study author Michael Ward, MD, MPH, of the National Institute of Arthritis and Musculoskeletal and Skin Diseases.

New molecules, developed by researchers at Linköping University, have promising properties as possible drugs against epilepsy. A study published in the journal Epilepsia shows that several of the molecules have antiseizure effects.

In people with epilepsy, the nerve cells in the brain become overactive, causing epileptic seizures.

"More than 60 million people in the world have epilepsy. A third of them still experience seizures despite taking medication, so there is a pressing need for new types of drugs", says Nina Ottosson, principal research engineer in the Department of Biomedical and Clinical Sciences, Linköping University.

Nerve impulses are electrical signals that travel along nerves lightning-fast. Epilepsy and several other conditions arise when the nerves transmit signals far too readily, at times when they should be electrically quiet. The nerve impulses are created when small channels, known as ion channels, located in the membranes of the nerve cells allow electrically charged ions to pass through. When sufficiently many ions have entered a cell, an electrical impulse arises, which is transmitted along a long nerve fibre and subsequently stimulates other nerve cells. The ion channels thus play a key role in epilepsy. Many of the drugs currently used to prevent epileptic seizures act by affecting ion channels.

Previous work by the research group at Linköping University has shown that resin acids, which are found in the resin from pine and spruce trees, can affect certain types of ion channel. The scientists used these natural resin acids as a starting point to develop new, similar molecules. The long-term goal is to create drugs that prevent epileptic seizures.

In the newly published study, the researchers have examined an ion channel that affects how readily a nerve impulse is stimulated. This channel, the potassium ion channel denoted by hKV7.2/7.3, plays an important role in epilepsy. If it is closed, an epileptic seizure can occur, while the seizure can be stopped if the channel opens. One drug, retigabine, can open hKV7.2/7.3, and this was useful in treating severe epilepsy. Retigabine, however, affects other ion channels, in particular channels in the smooth muscle found in, for example, the bladder and blood vessels. This gave undesired effects, such as abnormally low blood pressure and difficulties in urinating. Retigabine was withdrawn a couple of years ago.

The researchers have shown in the study that several of the new resin acid molecules can open hKV7.2/7.3. They also investigated whether the molecules affect a closely related ion channel, hKV7.4, which is opened by retigabine and contributes to its undesired effects. Experiments in tissue from rats demonstrated that the new molecules have less effect on smooth muscle, and it is thus less probable that they give undesired effects on blood vessels and the bladder. The new resin acids influence ion channels using a different mechanism than that used by retigabine. The researchers believe that the difference in the mechanism of action is significant for the effects in different tissues.

"I believe that the mechanism for how our molecules act on ion channels can be extremely important. We hope that through future collaborations we can take our molecules along the complete pathway to a drug in clinical use", says Nina Ottosson.

Another important question is whether the new molecules can prevent seizures in a whole organism. The researchers thus investigated the effect of the molecules in zebrafish larvae in which epileptic seizures were provoked using a special substance.

"Several of the molecules had an antiseizure effect in these experiments when used at the same concentration as retigabine", says Nina Ottosson.

The scientists are now continuing to work towards a detailed understanding of how the resin acid molecules affect ion channels, and how they can be improved such that they can be used as drugs.

"Patients and relatives often contact me, and their stories show how pressing the need for effective treatments is. It would be amazing if some of those affected could be helped in the long term by our research. But at the same time, we must realise how incredibly difficult it is to take a molecule along the complete pathway to a new drug. Our results may also contribute to development by stimulating other research", says Fredrik Elinder, professor in the Department of Biomedical and Clinical Sciences at Linköping University.

applying a thin sheath around the defective vein eliminated the varicose vein problem in over 95 per cent of cases. The research team published their findings in the Journal of International Medical Research on 6 April 2021.

When the blood pools in the leg

Varicose veins are more than just a cosmetic problem: the unsightly bulges might result in serious health problems such as leg ulcers, thromboses or even pulmonary embolisms. The cause of varicose vein disease is usually a weakness in the connective tissue, which causes the vein wall to give way and thus the vein diameter to grow. This process is accelerated by pregnancy or frequent standing and sitting.

The increase in vein diameter impairs the function of the vein valves. The valve leaflets are pulled apart and a leak develops, which is called valve insufficiency. The blood pools in the leg where it leads to an increase in venous blood pressure. This valve insufficiency most often affects the truncal vein, also called the great saphenous vein or great rose vein, which opens in the groin.

Like a second skin

The therapy concepts to date have been based on a radical approach: destruction by laser or by radio wave therapy, or removal of insufficient truncal veins by stripping surgery. "At the RUB Hospital, we have developed an alternative to the radical methods with the procedure of extraluminal valvuloplasty, which adopts an organ-preserving approach," explains Professor Achim Mumme, Director of Vascular Surgery. Venous valves are repaired through a small incision in the groin. A sheath of wafer-thin polyurethane is placed around the dilated vein like a second skin. The sheath acts as a kind of internal compression stocking that returns the vein, which is weak in connective tissue, to its normal diameter.

Use primarily when risk factors for circulatory disorders are present

In a multicentre study, the team tested the effectiveness of the organ-preserving treatment method. "With a success rate of 95.24 per cent, vein repair with the novel polyurethane sheath proved to be an effective therapeutic alternative to radical treatment methods," outlines study supervisor Dominic Mühlberger. "The great advantage of extraluminal valvuloplasty is that the truncal vein is preserved - unlike in radical therapy methods."

This is especially important if circulatory problems occur at a later stage in life. In this case, the presence of suitable bypass material can be decisive for the treatment options. The truncal veins are needed as vascular graft in cardiovascular surgery. Whereas the lack of suitable autologous replacement material worsens the prognosis.

"Vein-preserving therapy for varicose veins should be used above all when risk factors for the development of circulatory disorders are present, such as smoking, high blood pressure, diabetes or lipometabolic disorders," concludes Mühlberger.

Men who suffer sensory loss, particularly hearing loss, are more likely to be physically inactive and obese than women, according to a new study published in the European Journal of Public Health.

Researchers analysed data from more than 23,000 Spanish adults, and examined associations with physical inactivity and obesity in people with vision and hearing loss, and explored differences between men and women.

Results suggest inactive people with hearing loss were 1.78 times more likely to be obese compared to those who did not have any hearing loss. In people who had difficulty seeing, the odds ratio is slightly smaller, with a likelihood of obesity being 1.375 times higher than those who did not report vision loss.

The association between physical activity and obesity was higher in men with hearing loss, who were 2.319 times more likely to be obese than women who reported difficulty hearing. Obesity in those with sight loss was 1.556 times higher in inactive men than women.

Those with combined seeing and hearing difficulties had the highest prevalence of physical inactivity (44.8%) and obesity (26.1%). Analysis showed a significant association between physical inactivity and obesity in men with vision or hearing loss, but not in women.

Around 62% of adults in Spain are overweight, with 26% reporting as obese. In the UK, the figures are broadly similar at around 64% and 28% respectively, suggesting strong similarities between the countries.

A total of 11.04% of the people surveyed self-reported vision loss, 6.96% reported hearing loss, and 3.93% reported suffering both vision and hearing loss.

Lead author Professor Shahina Pardhan, Director of the Vision and Eye Research Institute at Anglia Ruskin University, said: "It is clear from our study that there are significant differences between genders.

"Although women were overall less physically active than men, we found an association between physical inactivity and obesity in men, but not in women. This indicates that, especially in people with vision and hearing losses, exercise and being active has a very important role in preventing obesity for men.

"Adults, especially those with sensory losses, should be encouraged to be as physically active as possible but there are obviously challenges, strongly suggesting that intervention and encouragement would play a very important role.

"An effective strategy to increase the levels of physical activity in this population group would be through targeted intervention programmes based on health awareness on the importance of physical activity."

Systematic literature review provides evidence base for new therapeutic avenues in vasculitis

Researchers have reviewed all clinical trials of targeted drugs used in the treatment of vasculitis. With this, they propose a completely mechanistic categorisation of these diseases, which may in time provide better treatment.

Diseases which cause inflammation of the blood vessels are presently categorised according to the size of the blood vessels involved. But it would make more sense - and ultimately end with better treatment - if the diseases were categorised based on the causes of the inflammation.

This is shown by a systematic literature review of clinical trials in vasculitis, which researchers from Aarhus University are behind.

The new categorisation provides both the opportunity to develop new medicines and to test existing drugs in new ways, says Associate Professor at the Department of Biomedicine Tue Wenzel Kragstrup.

"We're dealing with a group of immune mediated inflammatory diseases that must be treated in very different ways. We've made so much progress with the clinical trials now that we can use them to learn about understanding of diseases and the underlying immunology," he says.

The researchers have reviewed the latest clinical studies for drugs within the group of autoimmune diseases called vasculitis (inflammation of the blood vessels). At present, the group of diseases is divided anatomically according to the size of the blood vessels that are being affected. However, the old classification criterion does not reflect the cause of the disease, which is immunological.

"Some of the diseases that were previously classified as being very similar, actually turn out to be quite different. They affect the same kind of blood vessels but there are significant differences in the response to different treatments," explains Christopher Kirkegaard Torp who is first author on the study.

"Once you know the cause of a disease, it becomes easier to develop new medicines or test existing drugs for the disease in question. The new categorisation can help patients, doctors and researchers to a better understanding and thereby better treatment," Tue Wenzel Kragstrup says.

Effective drugs must be tested on other diseases

The study is limited to the diseases which are treated with an EMA or FDA-approved drug (approved by the European Commission or The Food and Drug Administration of the United States), which means that the researchers have studied ten drugs. Their use has provided new information about the underlying pathogenic mechanisms of five different types of vasculitis.

"We now have a whole catalogue of targeted immunosuppressants in rheumatology, but only a few have been approved for vasculitis. Our review highlights the immunological aspects of different types of vasculitis. This paves the way for clinical trials with other drugs targeting adjacent immunological abnormalities to identify new treatment options for the patients," says Tue Wenzel Kragstrup.

As new research on anaesthesia trainee morale is published, an impassioned plea is today being made in an open letter from the Association of Anaesthetists to the UK's four Health Secretaries: to urgently double the number of training posts for anaesthetists this summer and for subsequent years so that the UK can safely negotiate the current COVID-19 pandemic, any future pandemics, and deal with the huge backlog of surgical procedures that has built up during lockdown.

The Association has sent a separate letter to go to each Health Secretary - Matt Hancock MP in the UK Department of Health, Humza Yousaf MSP in Scotland, Baroness Eluned Morgan MS in Wales, and Robin Swann MLA in the Northern Ireland Assembly.

Association of Anaesthetists President Dr Mike Nathanson and Trainee Committee Chair Dr Roopa McCrossan explain that due a combination of a number of factors, this year there are many more applicants for specialist training in anaesthesia than in previous years. A recent estimate* found there are only around 350 jobs for approximately 1050 candidates, leaving up to 700 trainee anaesthetists without a suitable training post.

The increase in applicants this year results from a number of factors: the introduction of a new curriculum (mandated by the UK General Medical Council) which places an imperative on obtaining a training post before the regulations** change and the 'goal posts' move; the impact of the COVID-19 pandemic on the number of trainees who might otherwise have spent a year abroad to consolidate their learning but who are now unable to travel and wish to remain in the UK; the difficulty in achieving educational targets while re-deployed during pandemic surges; and a desire to complete training without any further interruptions after the unprecedented pressures and challenges of the last 14 months.

Dr Nathanson and Dr McCrossan add: "Providing these young doctors with training posts now will ensure we have a supply of trained senior staff in five years' time, and during their five-year training they will provide significant service, staff many out-of-hours rotas, and ensure the resilience we need for any further surges of the COVID-19 pandemic."

Recent research published in the Association's journal Anaesthesia revealed the pressure that hospitals in the UK have been under across the winter wave. Furthermore, the most recent census published by the Royal College of Anaesthetists has confirmed the findings of previous censuses that there is a very significant shortage of anaesthetists in the UK (over 1000, and almost certainly closer to 2000). The authors say: "At a time of a very significant shortage in the anaesthetic workforce, it is disappointing and surprising that, to date, there has been no increase in the number of training posts. As a result, the workforce gap will continue to grow. The impact of fatigue and stress, leading to more retirements or moves to part-time working, will only further increase the shortage."

Dr Nathanson and Dr McCrossan also point to the Association's own research*** (embargoed to the time above) that has shown a very significant degree of disillusionment in trainee anaesthetists. They say to the four Health Secretaries: "If you do not act, we believe there is a very real risk that many of these doctors in whom we have already invested time and money in training will be lost to the profession forever as they will seek alternative careers or move to work abroad once travel restrictions are lifted."

They suggest that the number of training posts (ST3) is doubled this year from approximately 350 to 700, and remains at that level for the subsequent two years. They explain that Health Trusts (and Boards) have money set aside for creating non-training 'locally employed doctor' (LED) posts this year as they recognise the need for more anaesthetists. The authors also suggest Health Education England already has money set aside to support the education of trainee anaesthetists. They say: "LED posts will not lead to training of qualified specialists, but if the funds we have identified and some additional new money was used to create training posts then there will be a long-lasting improvement in the anaesthetic workforce and the capability to provide more surgical services."

They conclude by giving an open invitation to the four Health Secretaries to discuss the matter further.

Dr Nathanson says: "There is very little time to act if we are to keep these doctors in the NHS. They have already committed to a career in anaesthesia and have spent at least two years training. We urgently need more anaesthetists; the backlog from the pandemic will take some years to clear, yet we risk losing the future workforce we clearly need. There has been a small increase in training posts in Wales. We need the other administrations to act now."

Dr McCrossan adds: "These highly skilled, dedicated anaesthetic trainees have worked tirelessly during the pandemic, providing the workforce needed to expand critical care. Nearly 700 of these trainees now have no job to go to from August 2021 and we risk losing them from our specialty. There is a documented shortage of consultant anaesthetists and nearly 700 doctors wanting to train in anaesthesia.

"By providing these much-needed training posts now, the four nation governments will resolve the anaesthetic workforce shortage, protecting the future surgical and intensive care capacity of the NHS. In short, it is a simple, cost effective, win-win for the governments involved and the NHS."

Age-related macular degeneration (AMD) is the most common cause of vision loss in people over 50. Up to 12 percent of those over 80 have the chronic disease. An estimated 16.4 million adults are affected by retinal vein occlusion (RVO) worldwide, a condition caused by a thrombosis of a retinal vein. It is the second most common cause of blindness from retinal vascular disease after diabetic retinopathy (DR). DR in turn is the leading cause of blindness in developed countries and affects up to 80 percent of people with more than 20 years of diabetes. It can lead to a swelling of the macula (diabetic macular edema, DME), which may cause partial or complete vision loss.

All three conditions are treated by injections of a so-called anti-vascular endothelial growth factor (anti-VEGF) into the eye at intervals to slow down disease progress and prevent blindness. Because with eyesight a central human sense is in jeopardy, patients are eager to know that they are being treated often enough to avoid rapid worsening. And doctors want to make sure they see each patient frequently enough not to miss important developments.

The challenge

With the ageing population, cases of AMD, RVO or DME are globally on the rise, making it hard for specialized eye clinics to keep up with the growing demand for regular treatments. "As doctors, we want to give each patient the necessary attention and treatment frequency that they need", says Sebastian Wolf, Head of the Ophthalmology Department of the Inselspital that currently sees 6000 patients with AMD, RVO and DR. "But it is also an organizational challenge to meet all patients' needs and be able to study all relevant eye imaging data to assess individual disease progression and take treatment decisions in the short time given."

To monitor progression of the chronic eye conditions, Optical Coherence Tomography (OCT), an imaging tool that generates 3D images of the eye at extremely high resolution, is usually applied. In collaboration with the ARTORG Center for Biomedical Engineering Research, the Inselspital has developed automated OCT analysis tools based on artificial intelligence, which can assist eye doctors in the assessment of a whole patient OCT-set in just a few seconds. Together with RetinAI, a startup specialized in AI-based eye care technologies, they now have conducted a retrospective study of patients to assess how well AI can predict anti-VEGF treatment demand from the start.

The setup

The study looked at OCT-data from 340 patients with AMD and 285 patients with RVO or DME, treated with anti-VEGF at the Inselspital between 2014 and 2018. Based on morphological features automatically extracted from the OCT volumes at baseline and after two consecutive visits, as well as patient demographic information, two machine learning models were trained to predict the probability of the long-term treatment frequency demand of a new patient (one for AMD and one for RVO and DME).

Based on the first three visits, it was possible to predict if a patient had a low or a high treatment demand for both the AMD and the RVO & DME groups with similar high accuracy. More importantly, the study revealed that it is possible to predict reasonably well at the initial visit and even before the first injection if a patient will less often require injections.

Three advantages

"We have shown that machine learning classifiers can predict treatment demand when a patient is first diagnosed with a chronic eye disease," says Mathias Gallardo, postdoctoral researcher the ARTORG AI in Medical Imaging (AIMI) lab and member of the new Center for Artificial Intelligence in Medicine (CAIM). "Hence, artificial intelligence may assist in establishing patient-specific treatment plans for the most common chronic eye conditions in the near future."

Planning the ideal treatment frequency for each patient has multiple benefits. Firstly, patients can be sure their disease is being treated in the best way possible without subjecting them to too frequent visits and unpleasant injections into the eye. Secondly, individualized planning can help clinics cope with ever growing patient numbers allowing for the highest possible capacity utilization of specialized medical skills and infrastructure. Thirdly, objectivized on-demand planning helps avoid overprovision and can lead to improved cost-efficiency and less healthcare expenditures.

High-yield confluence of clinical, data science, and industrial research

This study illustrates once more the proven eye-level collaboration between clinicians and data scientists of the Inselspital and the ARTORG Center, which produces technology solutions suitable for everyday use because they were designed directly as a response to clinical needs. A further important aspect to provide a roadmap for the clinical implementation of such technology was the startup RetinAI. "We are extremely happy to apply the EU funding we received to build patient-focused solutions in ophthalmology, making sure that technology can be transformed into products that can really benefit patients and improve treatment at scale," says RetinAI CEO Carlos Ciller. With its headquarters at sitem-insel the startup also is spatially located exactly at the interface between clinic and science. This unique Bernese environment for clinically driven AI technologies will be further capitalized by the new Center for Artifical Intelligence in Medicine (CAIM), combining the best of the three worlds of healthcare, science, and industry for the benefit of patients.

According to estimates from the Children's Bureau, an agency within the U.S. Department of Health and Human Services, there were 673,000 children in or entering foster care in the United States in 2019.

Data from the Minnesota Department of Human Services say that approximately 15,300 children experienced foster care in 2019. Minnesotan children of color were overrepresented compared to the general population, with Native American children 18 times more likely and Black children three times more likely to experience foster care than white children.

Most children in the foster care system have medical and dental coverage through Medicaid. However, despite mandatory state dental coverage, children in foster care face significant barriers to accessing oral health care. One of the largest obstacles is finding a dental provider who takes Medicaid or the Children's Health Insurance Program.

A new study from the University of Minnesota published in The Journal of the American Dental Association compared the self-identified oral health needs and access to dental care among youth who have and have not experienced foster care. The data was drawn from the 2019 Minnesota Student Survey, a statewide survey of public-school students in grades 5th, 8th, 9th and 11th. Youth with a history of foster care were compared to youth with no history of foster care on seven oral health indicators.

Youth were asked whether or not they had experienced five types of dental problems in the past 12 months:

Toothaches or pain;
Decayed teeth or cavities;

Swollen, painful, or bleeding gums;
Could not eat certain foods because of a dental problem;
Missed one or more school days because of a dental problem.

If youth reported any dental problems, they were then asked if this dental health issue was treated by a dentist and when they last had an appointment at a dental office for a check-up, exam, teeth cleaning or other dental work. Finally, they were asked about routine dental care: when was the last time they saw a dentist for a check-up, exam, or teeth cleaning or other dental work.

"To our knowledge, this study is the first in the United States to survey youth with a history of foster care about their oral health care needs using their own words," said study co-author Elise W. Sarvas, a clinical associate professor in pediatric dentistry at the U of M School of Dentistry. "We found that compared to their peers, youth with a history of foster care have self-identified dental needs, including issues with pain, and they have less access to a dentist to address these needs."

Specifically, the study presented that:

Youth with a history of foster care were more likely to report each of the five dental problems and less likely to report receiving dental care, compared to their peers with no history of foster care;
Approximately 44% of youth with a history of foster care reported at least one dental problem, compared to 32.2% of youth with no experience of foster care;
Youth with a history of foster care had lower odds of seeing a dentist for a dental problem (58.2% vs. 71.2%) or for routine dental care (69.6% vs. 84.4%), than their peers with no history of foster care.

"There are likely a number of reasons why youth with a history of foster care have more dental problems relative to their peers," said co-author Rebecca J. Shlafer, an assistant professor in the U of M Medical School. "Compared to their peers, foster youth in this sample were more likely to report living in households experiencing poverty. "Dentists should recognize the oral health concerns of this group of kids in the context of their special health care needs and be prepared to render appropriate care."

JUNE 8, 2021, NEW YORK - A study conducted by researchers at the Ludwig Center at Harvard has demonstrated how a drug screening method known as dynamic BH3 profiling can be used to quickly identify potentially effective combinations of existing drugs for personalized cancer therapy.

"We know that cancer cells and healthy cells have different metabolisms," said Ludwig Harvard investigator Anthony Letai who, with former postdoctoral researcher Veerle Daniels, led the study reported in the current issue of Science Signaling. "Using BH3 profiling, we found a specific metabolic dependency in triple negative breast cancer cells obtained from a patient that we could target with an existing drug, making the cells more susceptible to death and priming them for a second targeted drug that could then trigger their death."

Daniels, Letai and colleagues also showed that the strategy suppresses growth of triple negative breast cancer (TNBC) in mice bearing patient-derived tumors.

Though tumors often have unique metabolic adaptations on which they depend, specifically targeting those vulnerabilities with drugs has proved challenging. Such drugs have often failed in clinical trials because they were poorly targeted or too toxic at the doses required to kill cancer cells when used as single agents.

"We wanted to see which of the drugs known to perturb metabolism would bring the TNBC cells closer to dying, but leave normal cells unaffected," said Daniels. The researchers reasoned that such cells could then be selectively targeted by existing therapies known as BH3 mimetics to push them over the edge. Because the initial priming treatment requires low doses of the drug, this strategy could lower the risk of toxicities that have troubled the development of drugs targeting cancer metabolism.

Therapy often induces in cancer cells a type of programmed death known as apoptosis, which is orchestrated by an elaborate protein machinery. Cells, however, also produce anti-death proteins that inhibit key elements of that machinery. Whether a stressed cell dies or survives depends on the balance of pro-death and anti-death proteins, and cancer cells tend to produce large quantities of the latter to escape apoptosis and resist therapy.

BH3 mimetics inhibit anti-death proteins, tipping the balance in favor of cell suicide. Notably, one BH3 mimetic has already been approved for the treatment of certain blood cancers, and other such drugs are in various stages of development.

Dynamic BH3 profiling (DBP), developed in Letai's laboratory, measures that same balance of pro-death and anti-death proteins to gauge how primed a patient's tumor cells are for apoptosis following exposure to a drug. It thus represents a potentially rapid and unbiased method for screening hundreds of drugs at a time to find those most likely to treat a given patient's tumors.

Daniels, Letai and colleagues used DBP to examine a "library" of 192 compounds that perturb metabolism--developed in the laboratory of Ludwig Harvard Co-Director Joan Brugge--for their effects on normal and TNBC cells. Eight disrupted cancer cell metabolism but left normal cells unperturbed.

Two of these drugs target an enzyme known as NAMPT, which participates in one of three biochemical pathways that produce NAD+, a molecule of critical importance to metabolism. Some sensitive TNBC cell lines, the researchers showed, were dependent on the pathway involving NAMPT. They also ran a DBP screen to find out which specific anti-death proteins the TNBC cells depended on for survival following NAMPT inhibition. They used this information to identify the most effective BH3 mimetic drug to use in combination with NAMPT inhibitors.

Using two mouse models of patient-derived TNBC tumors developed in Brugge's lab, the researchers showed that only the mice bearing NAMPT-dependent tumors responded to a combination of the NAMPT inhibitor and the BH3 mimetic. They propose that the NAMPT inhibitor, which proved too toxic as a single agent, might be repurposed as a combination therapy given at lower doses with BH3 mimetics.

"What we've shown overall is that we can use DBP to find metabolic regulators of apoptotic priming and specific anti-apoptotic dependencies in tumors--and so identify powerful combinations of metabolic compounds and BH3 mimetics for therapy," said Daniels.

Letai's laboratory is using DBP to methodically identify other drug combinations for the treatment of a variety of cancers. Because it is a functional drug screen--examining only whether a given drug primes cancer cells for death--DBP does not require prior knowledge of a cancer's inner workings or genetic aberrations.

"We don't have to be limited to drug targets that are identifiable only by genetic mutations, which are only a tiny fraction of the true targets out there in the cancer world," said Letai.

He and his colleagues are also planning a clinical trial using DBP to identify tailored therapies for individual patients diagnosed with myelogenous leukemia.

Letai and Daniels note that the regular inter-lab meetings and collaborative model of the Ludwig Harvard Center were critical to the conception, design and conduct of the study.

"It was a way of combining a unique set of expertise," said Letai. "I'm good at cell death, not good at metabolism. Veerle is good at metabolism and cell death, but was lacking some key tools to do her initial screening, so we turned to other members of the Ludwig Harvard Center who actually had those tools. We wouldn't have been aware of that expertise if we weren't at the Center because Harvard is a very big place."

Published monthly, the journal CHEST® features peer-reviewed, cutting-edge original research in chest medicine: Pulmonary, critical care, sleep medicine and related disciplines. Journal topics include asthma, chest infections, COPD, critical care, diffuse lung disease, education and clinical practice, pulmonology and cardiology, sleep and thoracic oncology.

The June issue of CHEST includes 95 articles, clinically relevant research, reviews, case series, commentary and more. Each month, the journal also offers complementary web and multimedia activities, including visual abstracts, to expand the reach of its most interesting, timely and relevant research.

"We have a great lineup of original research and review articles in this month's issue," says Editor in Chief of the journal, Peter Mazzone, MD, MPH, FCCP. "As always, I am grateful to the authors of this work, the reviewers who volunteered their time to improve the quality of these submissions and our editorial board for guiding everything that we do."

Included in the June 2021 issue:

Racial disparities in asthma and COPD

Looking deeper into the racial, ethnic and economic disparities in access to care associated with asthma and COPD, National Trends and Disparities in Health-Care Access and Coverage Among Adults With Asthma and COPD: 1997-2018 looks to determine whether health coverage and access to care and medication have improved, and disparities have narrowed, over the past 2 decades. An accompanying visual abstract can be found here.

Inequalities in influenza and pneumonia

Asking whether geographic variation in racial disparity in influenza and pneumonia mortality exists, Geographic Variation in Racial Disparities in Mortality From Influenza and Pneumonia in the United States in the Pre-Coronavirus Disease 2019 Era found age-adjusted mortality rates were higher in non-Hispanic Blacks than in non-Hispanic Whites across age groups. The greatest disparity was seen in two Health and Human Services regions, with disparities greatest in the core of major metropolitan areas. An accompanying visual abstract can be found here.

Obesity and ventilator-associated pneumonia

The first study to evaluate obesity and ventilator-associated pneumonia (VAP), Relationship Between Obesity and Ventilator-Associated Pneumonia: A Post Hoc Analysis of the NUTRIREA2 Trial revealed no statistically significant difference in VAP between obesity and nonobesity. Furthermore, the study found that the 90-day mortality rate was significantly less in the obese group, highlighting the "obesity paradox." The accompanying visual abstract can be found here.

Lung cancer among gender minority individuals

Individuals whose gender identity (man, woman, other) or expression (masculine, feminine, other) is different from their sex (male, female) assigned at birth face unique challenges in cancer diagnosis and care. A research letter, Assessing Disparities in Lung Cancer Incidence for Gender Minority Individuals Using California Cancer Registry Data, describes a unique study looking at gender minorities in lung cancer.

There is a growing body of evidence supporting airborne transmission of SARS-CoV-2, the virus that causes COVID-19. Despite updates from the World Health Organization, the U.S. Centers for Disease Control and Prevention (CDC) and the Public Health Agency of Canada that the virus can be transmitted by short- and long-range aerosols, Canada's public health guidance has not been adequately updated to address this mode of transmission, argue authors of a commentary published in CMAJ (Canadian Medical Association Journal)

Canadian public health guidance and practices should be updated to include more emphasis on the following airborne mitigation measures: ventilation, filtration and better masks.

"Ventilation is a key element in the fight against airborne transmission. We need clear guidelines and funding for the assessment and improvement of ventilation in our indoor spaces, particularly our schools," says Dr. Sarah Addleman, emergency physician, The Ottawa Hospital, Ottawa, Ontario.
Along with ventilation, it is time to revisit Canadian personal protective equipment (PPE) recommendations in health care and other essential settings.

"People who work in close proximity to others (in both health care and other settings) are at higher risk of infection from short-range aerosol inhalation, and better masks (such as N95s) are needed to prevent infection," says coauthor Dr. Victor Leung, infectious disease physician, University of British Columbia, Vancouver, British Columbia.

"It took decades for the medical community to accept that tuberculosis and measles were airborne diseases. The science on airborne transmission of SARS-CoV-2 has, in contrast, moved fast. It is time for Canadian guidance and policies to follow swiftly too," the authors conclude.

A population-based study, published today in JAMA, has found flu vaccination during pregnancy does not lead to an increased risk of adverse early childhood health outcomes.

Although pregnant people are not more susceptible to acquiring influenza infection, they are at an increased risk of severe illness and complications if they get the flu during pregnancy. For this reason, all pregnant people are advised to receive a flu shot each year, yet only 36 percent received it according to a study monitoring four flu seasons in Nova Scotia. Safety concerns are reportedly a leading reason people may not receive influenza vaccination in pregnancy.

Dr. Deshayne Fell, an Associate Professor of Epidemiology in the Faculty of Medicine at uOttawa and a Scientist at the CHEO Research Institute, a pediatric healthcare and research centre, led the study along with researchers in Ontario and at Dalhousie University in Nova Scotia. The study followed over 28,000 children from birth up to an average age of 3 ½ years, with the results suggesting that maternal influenza vaccination during pregnancy was not associated with:

- Immune-related health conditions, such as asthma, ear infections or other types of infection.

- Non-immune-related health problems like neoplasms, sensory impairment.

- Nonspecific health needs such as Emergency Department visits and hospitalizations did not increase.

"This study adds to what we know from other recent studies showing no harmful effects of flu vaccination during pregnancy on the longer-term health of children," says Dr. Fell, whose other recent work includes studying the effectiveness and safety of COVID-19 vaccines during pregnancy. "This is important because we know that getting the flu shot during pregnancy not only protects the pregnant person, but has the added bonus of protecting newborn babies from getting the flu during their first few months of life, which is when they are most susceptible to respiratory infections but still too young to get the flu shot themselves."

The study, Association of Maternal Influenza Vaccination During Pregnancy with Early Childhood Health Outcomes, is published in JAMA.

CHICAGO --- Having trouble falling or staying asleep may leave you feeling tired and frustrated. It also could subtract years from your life expectancy, according to a new study from Northwestern Medicine and the University of Surrey in the United Kingdom (UK).

The effect was even greater for people with diabetes who experienced sleep disturbances, the study found. Study participants with diabetes who experienced frequent sleep disturbances were 87% more likely to die of any cause (car accident, heart attack, etc.) during the 8.9-year study follow-up period compared to people without diabetes or sleep disturbances. They were 12% more likely to die over this period than those who had diabetes but not frequent sleep disturbances.

"If you don't have diabetes, your sleep disturbances are still associated with an increased risk of dying, but it's higher for those with diabetes," said corresponding study author Kristen Knutson, associate professor of neurology (sleep medicine) and preventive medicine (epidemiology) at Northwestern University Feinberg School of Medicine.

But by answering one simple question -- "Do you have trouble falling asleep at night or do you wake up in the middle of the night?" -- people can begin to address sleep disturbances earlier in life and hopefully mitigate this increased risk of death, Knutson said.

"This simple question is a pretty easy one for a clinician to ask. You can even ask yourself," Knutson said. "But it's a very broad question and there are a lot of reasons you might not be sleeping well. So it's important to bring it up with your doctor so they can dive deeper.

"Is it just noise or light or something bigger, like insomnia or sleep apnea? Those are the more vulnerable patients in need of support, therapy and investigation into their disease."

The study will be published June 8 in the Journal of Sleep Research.

"Although we already knew that there is a strong link between poor sleep and poor health, this illustrates the problem starkly," said first study author Malcolm von Schantz, professor of chronobiology from the University of Surrey. "The question asked when the participants enrolled does not necessarily distinguish between insomnia and other sleep disorders, such as sleep apnea. Still, from a practical point of view it doesn't matter. Doctors should take sleep problems as seriously as other risk factors and work with their patients on reducing and mitigating their overall risk."

The authors analyzed existing data of nearly half a million middle-aged participants in the UK Biobank Study. To the scientists' knowledge, it is the first study to examine the effect of the combination of insomnia and diabetes on mortality risk.

"We wanted to see if you have both diabetes and sleep disturbances, are you worse off than just diabetes alone?" Knutson said. "It could have gone either way, but it turns out having both diabetes and sleep disturbances was associated increased mortality, even compared to those with diabetes without sleep disturbances."

Participants had predominately Type 2 diabetes, the most prevalent form, though some had Type 1.

Women who will develop potentially life-threatening disorders during pregnancy can be identified early when hormone levels in the placenta are tested, a new study has shown.

Pregnancy disorders affect around one in ten pregnant women. Nearly all of the organ systems of the mother's body need to alter their function during pregnancy so that the baby can grow. If the mother's body cannot properly adapt to the growing baby this leads to major and common issues including fetal growth restriction, fetal over-growth, gestational diabetes, and preeclampsia - a life-threatening high blood pressure in the mother.

Many of these complications lead to difficult labours for women with more medical intervention and lifelong issues for the baby including diabetes, heart issues and obesity.

Pregnancy disorders are usually diagnosed during the second or third trimester of gestation when they have often already had a serious impact on the health of the mother and baby. The current methods to diagnose pregnancy disorders are not sensitive or reliable enough to identify all at risk pregnancies.

Now scientists have found a way to test hormone levels in the placenta to predict which women will have serious pregnancy complications.

Dr Amanda N. Sferruzzi-Perri, a Fellow of St John's College, University of Cambridge, runs a lab in the Department of Physiology, Development and Neuroscience and is the lead author of a new paper published today (JUNE 8) in Nature Communications Biology.

Dr Sferruzzi-Perri said: "The female body is remarkable and from the moment of conception, a pregnant woman's body needs to change nearly every single organ system so the fetus can develop. The fetus also needs nutrients and oxygen to grow so the mother has to change her metabolism and vascular system so she can provide them.

"We know that the placenta drives many of the changes in a women's body during pregnancy and our study found hormonal biomarkers from the placenta could indicate which women would have pregnancy complications. We found that these biomarkers are present from the first trimester of pregnancy, normally women are only diagnosed with complications during the second or third trimester when disorders may already have had serious consequences for the health of the mother and her developing baby.

"This is a highly important finding given that pregnancy disorders affect around one in ten pregnant women and are often diagnosed too late when the complications are already wreaking havoc on the mother's body and the fetal development."

The placenta is a complex biological organ. It forms and grows from the fertilised egg, and attaches to the wall of the uterus. It allows nutrients and oxygen to flow from mother to baby, and removes fetal waste products. Despite its importance, the placenta is a very understood organ and is notoriously difficult to study in pregnant women. But its ability to function properly is vital as it impacts on pregnancy outcomes and the lifelong health of mother and child.

The placenta develops during pregnancy and connects the developing baby to the mother. It serves as the lungs, kidneys, gut and liver for growing babies and carries oxygen and nutrients to the fetus whilst secreting hormones and discarding waste.

Using mouse models, researchers looked at the proteins made by the placenta and compared them to blood samples from women who had uneventful pregnancies and those who developed gestational diabetes. The team developed new methods to isolate and study the endocrine cells in the mouse placenta because these cells are responsible for secreting hormones during pregnancy.
They profiled the placenta to identify the hormones that are secreted to create a comprehensive map of proteins in the mysterious organ.

The mouse model map of hormonal proteins from the placenta was then compared with datasets from studies of the human placenta and pregnancy outcomes and researchers discovered a lot of biological overlap.

Dr Sferruzzi-Perri said: "We found that around a third of the proteins we identified changed in women during pregnancies with disorders. Using a small study to test if these placental proteins will have some clinical value, we also discovered that abnormal levels of hormones were present in the mother's blood as early as the first trimester - week 12 of gestation - in women who developed gestational diabetes, a pregnancy complication usually diagnosed at 24-28 weeks.

"We also identified several specific transcription factors - proteins within the cell that turn on or off genes - that are likely to govern the production of placental hormones which have important implications for understanding how we may improve pregnancy outcomes."

The scientists explored whether these genetic biomarkers were detectable during pregnancy and used a study that tracked pregnancy outcomes in women at Addenbrooke's Hospital in Cambridge. They found that blood samples showed these biomarkers in early pregnancy which could lead to earlier diagnosis of complications allowing treatment to begin more quickly.

Dr Claire Meek, a diabetes in pregnancy physician and researcher at Addenbrooke's, said: "This pregnancy-induced form of diabetes causes accelerated growth of the baby and complications at the time of delivery. Unfortunately, some women already have signs of a big baby at the time of diagnosis at 28 weeks. This new test might be able to identify gestational diabetes earlier in pregnancy, providing opportunities to prevent the disease, or to protect mums and babies from the most harmful complications."

Dr Sferruzzi-Perri said: "This work provides new hope that a better understanding of the placenta will result in safer, healthier pregnancies for mothers and babies. Our team is now working to assess if these discoveries could improve clinical care in future, either through earlier diagnosis or to provide new opportunities to treat these pregnancy complications by targeting the placenta."

A new study from the University of California, Davis and the Icahn School of Medicine at Mount Sinai confirms that surgical masks effectively reduce outgoing airborne particles from talking or coughing, even after allowing for leakage around the edges of the mask. The results are published June 8 in Scientific Reports.

Wearing masks and other face coverings can reduce the flow of airborne particles that are produced during breathing, talking, coughing or sneezing, protecting others from viruses carried by those particles such as SARS-CoV2 and influenza, said Christopher Cappa, professor of civil and environmental engineering at UC Davis and corresponding author on the paper.

High-efficiency masks such as N95 respirators are designed to have a tight seal to the face, while surgical and most cloth face masks leave small gaps around the sides, which can be reduced when they are worn correctly.

The researchers looked at particles flowing from these gaps by sitting volunteers in front of an instrument that counts airborne particles down to a size of half a micron. The 12 volunteers read aloud or coughed, with and without a surgical mask of the type widely used by the public, either with their mouth directly in front of the funnel of the particle counter, turned to the side or with their head lowered or raised to count particles passing directly through the mask or leaking around the sides.

The researchers found that wearing a mask while talking reduced particles directly through the mask by an average of 93%, from the bottom by 91%, the sides by 85% and the top by 47%, although with substantial variability between individuals. They got similar results for coughing.

Models to measure leakage

The team used simulations to model the overall reduction in particles due to wearing a mask, allowing for leakage around the edges. They calculated that the overall efficiency of masks was about 70% for talking and 90% for coughing.

"While air escape does limit the overall efficiency of surgical masks at reducing expiratory particle emissions, such masks nonetheless provide substantial reduction," Cappa said. "Our results confirm that mask wearing provides a significant reduction in the probability of disease transmission via expiratory particles, especially when both infected and susceptible individuals wear masks."

Masks also redirect the flow of air from a high-velocity plume from the talker or cougher towards anybody in front of them, Cappa said.