Body

Scientists at the Walter Reed Army Institute for Research (WRAIR) have recently demonstrated that cathepsin B, a well-studied protein important to brain development and function, can be used as biomarker, or indicator of severity, for traumatic brain injury.

Traumatic brain injury (TBI) or brain trauma results from blows to the head, leading to life-changing disruption of the brain and a cascade of long-term health conditions. A leading cause of disability and death worldwide, TBI may occur due to an open-skull injury, like a gunshot wound, a fall, or an automobile accident. Athletes, the elderly, children, and military service members are particularly vulnerable.

Biomarkers are a source of great interest to researchers due to their potential to dramatically improve both the diagnosis and categorization of severity of TBI. Furthermore, they have the potential to validate treatment strategies by indicating whether drugs have reached their proposed targets and achieved therapeutic benefits.

In their publication in the Journal of Neurotrauma, the researchers showed that levels of cathepsin B were increased in areas of the injured brain relevant to controlling the senses, language, memory and other critical executive functions. In healthy cells, cathepsin B has a range of roles, including helping to eliminate damaged cells, maintaining metabolic homeostasis, and degrading improperly produced proteins. When the level of cathepsin B is not tightly controlled, it is linked to inflammation and tissue death. This publication reports the first results demonstrating the ability to use cathepsin B as a blood-based biomarker to capable of identifying TBI severity within different brain regions as well as cerebral spinal fluid.

"Biomarker tests that accurately reflect the extent and severity of injury can dramatically improve the standard of care, minimizing the need for resource-intensive diagnostics like CT or MRI scans in favor of more portable tests," said Dr. Angela Boutte, lead author and section chief of molecular biology and proteomics within the Brain Trauma Neuroprotection Branch at WRAIR. "This would allow for early, accurate detection of TBI, whether at the side of the road after an accident or, most importantly, on the battlefield to help guide medical decisions."

Future research is planned to further characterize the role of cathepsin B in TBI.

DALLAS, July 13, 2020 -- Women taking beta blockers for hypertension with no prior history of cardiovascular disease (CVD) have a nearly 5% higher risk for heart failure than men when they present to hospital with acute coronary syndrome, according to new research published today in Hypertension, an American Heart Association journal.

Beta blockers are medications that reduce high blood pressure and are prescribed for adults with hypertension, a leading cause of CVD. In this study, researchers analyzed the effects of beta blockers on men and women with hypertension and no history of CVD after presenting with acute coronary syndromes. Following incidence of heart failure was recorded to determine if the medication caused different outcomes depending on biological differences.

"Past research on the effects of beta blockers included a majority of participants who were men, so we sought to examine how sex/gender plays a role in the patient outcomes," said Raffaele Bugiardini, M.D., professor of cardiology at the University of Bologna and lead author of the study. "Women are historically underrepresented in most clinical studies on hypertension. It's important to include an equal split of male and female patients in future research, which could shed light on disparities and actionable treatments."

The study analyzed information from the International Survey of Acute Coronary Syndromes (ISACS) Archives, the ISACS-TC and the EMMACE-3X clinical registries from October 2010 to July 2018. The research included data from 13,764 adults in 12 European countries who had hypertension and no prior history of cardiovascular disease. Patients were classified by sex/gender and then separated into two groups: those taking beta blockers and those who were not.

Researchers found that among the participants taking beta blockers:

women had a 4.6% higher rate of heart failure than men when presenting to the hospital with acute coronary syndrome;

the mortality of both men and women with heart failure was approximately seven times that of patients with acute myocardial infarction and no heart failure complications;

women who had ST-segment elevation myocardial infarction (STEMI) were 6.1% more likely to have heart failure than men with STEMI, a serious form of heart attack in which a coronary artery is completely blocked and a large part of the heart muscle is unable to receive blood; and,

men and women not taking beta blockers had approximately the same rate of heart failure.

"What we found presents a solid case for re-examination of the use of beta blocker therapy for women with hypertension. For women who have no history of cardiovascular disease and only hypertension, we think it is incredibly important for them to regulate their blood pressure through diet and exercise," Bugiardini noted. "It's possible that the increased risk of heart failure for women is due to an interaction between hormone replacement therapy and beta blockers, though this information was not collected or tested in our study. This and other potential factors need to be investigated in more depth."

Researchers noted some limitations. Since the study was observational, results may have some variance and additional data is needed for confirmation. However, a randomized controlled trial of beta-blocker therapy in patients with hypertension may not be considered ethical since it would be designed to confirm risk and not benefit. The study did not include, nor have information for, the length of time patients used a previous treatment or dosing of beta blockers.

Through its signature women's initiative, Go Red for Women®, the American Heart Association has advocated for increased representation of women in cardiovascular research studies for nearly two decades. Go Red for Women's Research Goes Red empowers women to contribute to health research. The initiative has built a community of women scientists, researchers, and medical and health professionals to further raise awareness around women's heart health by closing gender disparity gaps in research and clinical trials. In light of the COVID-19 pandemic, Research Goes Red expanded their reach and impact through a COVID-19 survey. This survey assesses the top concerns women have related to the health, social, economic and emotional impact COVID-19 has had on their lives.

For decades, family caregiving has been thought to create a type of chronic stress that may lead to significant health risks or even death, alarming potential caregivers and presenting a guilt-ridden obstacle for those needing help. Now, Johns Hopkins researchers have studied people as they transitioned to becoming caregivers for loved ones. Beyond the normal increases from aging, they found that caregivers didn't have significantly greater inflammation over a nine-year period. Such increases would have indicated that chronic stress from caregiving may have harmed their health.

A report on the findings was published online June 24 by the Proceedings of the National Academy of Sciences of the United States of America.

"The main takeaway point is that caregiving, while stressful in some situations, is not associated with clinically meaningful increases in inflammation," says David Roth, Ph.D., professor of medicine at the Johns Hopkins University School of Medicine, director of the Johns Hopkins Center on Aging and Health, and study co-author. "Our main goal for our research was to challenge past study findings, address potential caregivers' concerns about the toll on their health, and provide hope and relief to people needing or wanting to help."

"Family caregiving," Roth says, "appears to have minimal effects on physical health for most caregivers, and may even be associated with some health benefits similar to those sometimes attributed to volunteerism, such as a lower mortality rate."

As the number of people engaged in family caregiving grows, this news should come as a relief to those worried about a burden on their health.

In the United States alone, it is estimated that at least 17 million and perhaps as many as 40 million people are informal or dedicated family caregivers for older adults. Many assert that family caregiving is a mutually beneficial arrangement, but for some the extra stress may feel like a significant burden that may impact their health.

To investigate whether caregiving harms caregivers, the Johns Hopkins Medicine Transition to Family Caregiving study team examined data on 239 participants in the University of Alabama at Birmingham's ongoing Reasons for Geographic and Racial Differences in Stroke project who became caregivers. They were age 45 or older, and were compared to matched noncaregiving controls who were also assessed over the same time period. The controls were matched for seven factors: age + 5 years, sex, race, education level, marital status, self-rated health and self-reported history of serious cardiovascular disease. Of the caregivers and controls, 65% of each were women. The researchers looked at changes over time on six inflammation biomarkers often associated with loneliness, depression, suppressed immunity, cancer and increased mortality. The biomarkers included high sensitivity C reactive protein (CRP), D-dimer, tumor necrosis factor-alpha receptor 1 (TNFR1), and interleukin (IL)-2 IL-10 and IL-6. Researchers examined biomarkers in blood samples.

All participants were free of caregiving activities prior to the first blood sample taken. Participants completed a baseline interview and an initial in-home assessment. Blood samples were taken at that time. About nine years later, each participant was interviewed again, and trained examiners conducted another in-home assessment, at which time phlebotomists gathered updated urine and blood samples.

The Johns Hopkins Medicine Transition to Family Caregiving study team found general increases in inflammation biomarker levels over a nine-year period across both caregivers and noncaregiving controls, such as would be found in normal aging, but caregivers did not show greater elevations over time compared to the controls. Of the six biomarkers examined, only TNFR1 showed a significantly greater increase, of 0.14 standard deviation units among caregivers compared to controls. The researchers interpreted these findings as being consistent with other population-based studies that suggest minimal systemic inflammation in response to chronic caregiving stress.

"This study is one of the first population-based longitudinal studies to capture data on biomarkers of inflammation from individuals before and after they took on family caregiving responsibilities," says Roth. The researchers say this is an improvement over previous "convenience sample" studies, which surveyed small amounts of people who were simply available -- and were therefore vulnerable to report bias. By contrast, population health studies more accurately reflect a large and diverse group of people.

When COVID-19 forced schools and daycares to shut down and millions of Americans to transition to working from home, some suggested the pandemic might equalize certain aspects of gender equality as men increased their household contributions.

Four months later, however, new research from Washington University in St. Louis finds early evidence that the pandemic has exacerbated -- not improved -- the gender gap in work hours, which could have enduring consequences for working mothers.

"Our findings indicate mothers are bearing the brunt of the pandemic and may face long-term employment penalties as a consequence," said Caitlyn Collins, assistant professor of sociology in Arts & Sciences and co-author of the study.

Between March and April, mothers' work hours fell four to five times as much as fathers', according to the study first published online in Gender, Work and Organization in July.

While mothers scaled back their work hours by about 5%, or two hours per week, fathers' work hours remained largely stable. The impact was greatest among mothers of primary school-aged children or younger children for whom caregiving and homeschooling demands are most intense.

Collins and co-authors -- Liana Christin Landivar at the Maryland Population Research Center; Leah Ruppanner at the University of Melbourne; and William Scarborough at the University of North Texas -- used data from the U.S. Current Population Survey to assess how dual-earner heterosexual married couples with children adjusted their work during the pandemic from February through April. The monthly labor statistics survey includes information from approximately 60,000 households across the United States.

They also examined a subset of households in which both mothers and fathers are employed in telecommuting-capable occupations. They found across all models, fathers' predicted work hours did not fall below 40 hours per week, indicating that while the pandemic had a major toll on all aspects of society, most fathers in heterosexual, dual-earner households continued to put in a full work week.

"Even among households in which both parents are able to work from home and are directly exposed to childcare and housework demands, mothers are scaling back to meet these responsibilities to a greater extent than fathers. Ultimately, our analyses reveal that gender inequality in parents' work hours has worsened during the pandemic," Collins said.

The cause of this inequity is unclear. Collins said it's possible in times of crisis families revert to more traditional gender roles in the household division of labor. Or, it could be that financial stress and the need to protect primary earners -- most often fathers -- caused mothers to assume more of the unpaid domestic work.

What remains clear to the researchers, however, is that this inequity can have long-term, disastrous effects on women's careers.

"Scaling back work is part of a downward spiral that often leads to labor force exits -- especially in cases where employers are inflexible with schedules or penalize employees unable to meet work expectations in the face of growing care demands," Collins and her co-authors wrote.

"We are also concerned that many employers will be looking for ways to save money and it may be at the expense of mothers who have already weakened their labor market attachment," they wrote.

Another potential consequence for the workplace: Future merit-based promotions and pay raises may disproportionately benefit men whose work commitments remained high during the pandemic.

The situation is not expected to improve in the near term as states reopen and onsite work resumes. Initially, telecommuting may have prevented some mothers from more extensive job loss as schools and daycares closed, Collins said. However, with summer camps closed, daycares operating at limited capacity and uncertainty about the coming school year, dual-earner households will be faced with tough choices on how to navigate paid work and family life.

"Flexibility is key right now," Collins said. "By easing work demands and allowing flexibility where possible in the coming months, employers can prevent long-term losses in women's labor force participation. And fathers should be encouraged to provide more hours of care for their children, even if it means sacrificing paid work hours to do so."

Black men in the United States are known to suffer disproportionately from prostate cancer, but few studies have investigated whether genetic differences in prostate tumors could have anything to do with these health disparities.

Now, in the largest study of its kind to date, researchers from Boston University School of Medicine (BUSM), UC San Francisco (UCSF), and Northwestern University have identified genes that are more frequently altered in prostate tumors from men of African ancestry compared to other racial groups, though the reasons for these differences is not known, the authors say. None of the individual tumor genetic differences that were identified are likely to explain significant differences in health outcomes or to prevent Black Americans from benefiting from a new generation of precision prostate cancer therapies, the authors say, as long as the therapies are applied equitably.

The newly identified gene variants could potentially lead to precision prostate cancer therapies specifically focused on men of African ancestry, and will inform broader efforts by the National Cancer Institute's RESPOND study to link gene variants to health outcomes in an even larger cohort of Black patients nationwide.

Despite declines in mortality related to cancer in the U.S., disparities by race have persisted. One in every six Black Americans will be diagnosed with prostate cancer in their lifetime, and these men are twice as likely to die from the disease as men of other races. But it is not yet clear to researchers whether differences in prostate cancer genetics contribute to these health disparities in addition to the social and environmental inequities known to drive poorer health outcomes across the board.

To date, studies trying to figure out what genes are commonly mutated in prostate cancers often have had very few samples from racial/ethnic minority groups despite the greater burden of prostate cancer in these populations. In May, the FDA approved a class of drugs known as PARP inhibitors as a therapy for men with prostate cancers driven by specific genetic mutations, but it is not known how prevalent these mutations are in people of African descent. As more genetic health studies are performed in minority populations, it has become clear that other genetically targeted therapies that have been developed based on studies of patients of European descent are at times much less effective, and in some cases cause dangerous side-effects, in other racial and ethnic groups.

In the new study, published July 10, 2020 in Clinical Cancer Research, a journal of the American Association for Cancer Research, the research team set out to better understand differences in the mutations driving prostate cancer tumors in Black Americans compared to European Americans, and whether any such differences could influence disease outcomes or the effectiveness of PARP inhibitors or other targeted therapies.

The researchers collected and analyzed DNA sequencing data from previously published studies and from a commercial molecular diagnostics company. In total, they examined mutational patterns in prostate cancers from more than 600 Black men, representing the largest such study of this population to date.

The team found that the frequency of mutations in DNA repair genes and other genes that are targets of current therapeutics are similar between the two groups, suggesting that at least these classes of current precision prostate cancer therapies should be beneficial in people of both African and European ancestry, according to corresponding author Franklin Huang, MD, PhD, an assistant professor in UCSF's Division of Hematology/Oncology and member of the UCSF Helen Diller Family Comprehensive Cancer Center, UCSF Institute for Human Genetics, and UCSF Bakar Computational Health Sciences Institute.

While the researchers found no significant differences in frequencies of mutations in genes important for current prostate cancer therapies, they did identify other genes, such as ZFXH3, MYC, and ETV3, that were more frequently mutated in prostate cancers from Black men.

"These results reinforce the idea that there can be biological differences in prostate cancers between different ancestral groups and that samples from Black Americans need to be included in future molecular studies to fully understand these differences," said co-corresponding author Joshua Campbell, PhD, assistant professor of medicine at BUSM.

"The poorer health outcomes we see in Black men with prostate cancer are not easily explained by any of the distinct gene mutations we identified in prostate tumors from men of African ancestry. This highlights the need to examine the environmental and social inequities that are well known to influence health outcomes across the board," Huang added. "On the other hand, our tumor genomic analysis also showed that current precision medicine approaches ought to be as effective in Black Americans as they have been for other groups -- if we can ensure that these drugs are applied equitably going forward."

Developing a comprehensive understanding of how tumor genomics and other biological factors interact with social and environmental inequities to drive poorer clinical outcomes for Black prostate cancer patients should be an important priority for the efforts to improve precision medicine for these patients, the researchers say.

"These types of studies will remain important to understand when certain therapies may preferentially benefit Black patients, who continue to remain underrepresented in clinical trials," Campbell said.

In particular, the results will inform the efforts of the NCI-funded RESPOND Study. RESPOND provided funding for the new UCSF-BUSM-Northwestern study to guide its efforts to perform targeted gene sequencing in tumors from an even larger cohort of Black prostate cancer patients, said Huang, who leads RESPOND's tumor genetics studies based at UCSF. Through partnerships with Black communities across the country, RESPOND aims to recruit 10,000 Black prostate cancer patients in an effort to better understand the drivers of the disease's outsize burden among Black Americans.

"Previous studies have looked in isolation at different biological, social and environmental drivers of well-known racial disparities in prostate cancer," Huang said. "RESPOND is a nationwide effort to integrate all these components and ultimately identify specific steps that can be taken to eliminate prostate cancer's unequal burden in Black communities."

Genova (Italy), 10th July 2020 - Researchers at IIT-Istituto Italiano di Tecnologia (Italian Institute of Technology) discovered a novel chemical compound, which has the potential to became a new drug for the treatment of core symptoms of brain disorders like Down syndrome and autism. These results are obtained in preclinical models where the new compound ameliorated difficulties in cognitive tasks, as well as social interactions and repetitive behaviors, which are present in neurodevelopmental and possibly neurological disorders. Researchers now aim to create a dedicated start-up company with the support of interested investors in order to further develop this compound and make it a treatment for patients. The study has been published in the scientific journal Chem: https://www.cell.com/chem/fulltext/S2451-9294(20)30298-9

These breakthrough findings are the result of a joint effort of two Italian research teams guided by Laura Cancedda and Marco De Vivo, at the Istituto Italiano di Tecnologia in Genova (Italy). Laura Cancedda is head of the IIT's Brain Development and Disease Laboratory and also an assistant scientist at the Dulbecco Telethon Institute. Marco De Vivo is the head of the IIT's Molecular Modeling and Drug Discovery Laboratory. The research study has been funded by Fondazione Telethon and partially benefited of a grant of the European Research Council (ERC).

The two groups worked on complementary aspects of the research study: the De Vivo's group designed the new molecules with the aid of computational methods, and synthetize them whereas the Cancedda's lab focused on extensive biological tests of such compounds. The final result represents the development of a promising chemical compound, which is usually referred in pharmaceutical industry to as 'drug candidate' because of its potential to become a clinical drug in the forthcoming years.

Co-first authors of the research article are Annalisa Savardi (Cancedda's Lab) and Marco Borgogno (De Vivo's lab) who worked synergistically to identify the novel chemical compounds and investigate their biological consequences in the brain of preclinical models of neurodevelopmental disorders. Such models are the first experimental steps to verify the benefits and safety of the new drug.

In particular, researchers focused on the effect of the molecules on the protein NKCC1, a very promising target for drugs to treat brain disorders. NKCC1 is a transporter of chorine (and other) ions in the brain, and the correct concentration of such ions is crucial for brain function. In several brain disorders like Down syndrome, autism and epilepsy, the concentration of such ions in the brain is dysregulated due to NKCC1 abnormal function. These newly discovered compounds can potently and selectively block NKCC1, without undesired side effects (excessive diuresis) caused in fact by other existing drugs which are non-selective NKCC1 inhibitors.

"This study and exciting results come at a time where neuroscience drug discovery in industry struggles to deliver novel breakthrough classes of effective molecules. As a matter of fact, therapeutic options for most of neurodevelopmental disorders have remained scant, or not highly effective over the last decades. This is mainly due to a poor understanding of the mechanisms underlying these challenging pathological conditions. This discovery follows several years of work on NKCC1 function and inhibition at IIT and will possibly bring us closer to the development of sustainable therapeutics for the treatment of a number of brain disorders" - comments Laura Cancedda.

"At this point, our most promising compound could enter into clinical tests in hospitals in less than two years from now. This additional step toward making of this compound an approved drug, however, requires further work and more funds. For this reason, we plan to launch a new start-up company dedicated to this project. It would be wonderful to see our discovery impacting on those in needs" - adds Marco De Vivo.

The newly discovered and promising drug candidate is now undergoing advanced preclinical studies to move it forward and hopefully reach soon clinical studies. Additional studies will allow defining the overall safety profile of the molecule and other key parameters, such as pharmacokinetics, formulation and dosing, necessary to fulfill the regulatory requirements to access clinical studies.

The scientists analysed five full matches played by nine teams from a German Bundesliga season. They employed a tool borrowed from statistical physics, the directional correlation techniques, that describes how similar the motion of the players is to each other in terms of their directions. From this the scientists created a metric - the HCS (highly correlated segments) - which reveals how players perform together within their group and against the opponent players. So rather than analysing only individual performance metrics, for example how much or how fast a player runs in a game, the study examined cooperation and coordination among players in order to reveal collective strategies associated with team performance.

Published by an interdisciplinary research team, from the Research Center in Sports Sciences, Health Sciences and Human Development in Portugal, the Cluster of Excellence "Centre for the Advanced Study of Collective Behaviour" at the University of Konstanz and the co-located Max Planck Institute of Animal Behaviour in Germany, the study can aid football teams in identifying talent and can give extra value for assessment for coaching staff.

CHAPEL HILL, NC - July 10, 2020 - Pregnant women are among those most in need of safe and effective preventives and treatments for HIV and co-infections. Yet because they are commonly excluded from research, they are among the least likely to have robust, timely evidence to inform decisions around the use of medications.

"The resulting evidence gaps and delays are significant," said senior author and PHASES Principal Investigator Anne Drapkin Lyerly, MD, professor of social medicine at the UNC School of Medicine and associate director of the UNC Center for Bioethics, "and they put pregnant women and their children in harm's way. Ethically, we must work together to give pregnant women the evidence base they deserve."

Changing practices in the HIV/co-infections research community so that women, providers, and policy makers can make evidence-informed decisions around the use of medications during pregnancy is the goal of the new report, Ending the Evidence Gap for Pregnant Women around HIV and Co-infections: A Call to Action, issued today by the Pregnancy and HIV/AIDS: Seeking Equitable Study (PHASES) Working Group - an international and interdisciplinary team of 26 experts in bioethics, public health, law, obstetrics and maternal-fetal medicine, pediatrics, HIV research, infectious disease, and pharmacology, as well as community advocates for women living with HIV.

Led by faculty at the University of North Carolina School of Medicine, Georgetown University, and Johns Hopkins University, the PHASES Project - with funding from the U.S. National Institutes of Health - conducted extensive research with affected women and engagement with the HIV research community to inform the report. The guidance, presented this week at the AIDS 2020: Virtual conference, has been endorsed by the International Community of Women Living with HIV Global and East Africa.

"The HIV research and advocacy communities have increasingly recognized the importance of protecting pregnant women through responsible research. But there are still a lot of misconceptions and other barriers to doing this work. Our guidance aims to clear an ethical pathway forward for research to improve the health and safety of women and the children they bear," said Lyerly.

The guidance puts forth 12 concrete, actionable recommendations, which include:

- Formalize a global network for advocacy and resources. The global HIV/co-infections research and advocacy communities, supported by funders, should formalize a network to develop and share a portfolio of resources to empower the HIV research community to advance needed research with pregnant women.

- Design for inclusion. Researchers designing trials addressing HIV/co-infections should integrate pregnant women wherever possible and optimize opportunities to gather pregnancy-specific data.

- Ensure equitable research on pregnant women's own health. Agenda setters in HIV/co-infections research should commit to promoting the study of pregnant women's own health needs as a key pillar of effort and funding. Research into fetal safety outcomes should be matched by relevant maternal outcomes assessments.

- Enhance post-approval safety evaluations. The HIV/co-infections research community should commit to a more robust and regularized structure of postapproval safety evaluations to ensure both adequate pharmacovigilance and pregnant women's timely access to important drugs.

- Contextualize risk findings. Those conducting HIV/co-infections research with pregnant women should anticipate possible adverse events and proactively develop communication strategies for adequately contextualizing them against baseline rates of such events. Communication of overall findings should contextualize potential risks of an intervention against its potential benefits and the risk-benefit profiles of alternatives.

PHILADELPHIA (July 10, 2020) - As of May 2020, nursing home residents account for a staggering one-third of the more than 80,000 deaths due to COVID-19 in the U.S. This pandemic has resulted in unprecedented threats--like reduced access to resources needed to contain and eliminate the spread of the virus--to achieving and sustaining care quality even in the best nursing homes. Active engagement of nursing home leaders in developing solutions responsive to the unprecedented threats to quality standards of care delivery is required.

In an article published in the Journal of Aging and Social Policy, two researchers from the University of Pennsylvania School of Nursing (Penn Nursing) offer a framework, designed with the input of nursing home leaders, to facilitate internal and external decision-making and collective action to address these threats.

"Nursing home residents are arguably the most vulnerable population to the human devastation wrought by this pandemic. Nursing home leaders cannot be left '. . . alone in this battle' in providing residents with the quality of care they need and deserve," write the authors Liza L. Behrens PhD, RN, a post-doctoral research fellow at the NewCourtland Center for Transitions and Health and Mary D. Naylor, PhD, RN, FAAN, the Marian S. Ware Professor in Gerontology and the Director of the NewCourtland Center. "Our framework provides a path for nursing home leaders to guide quality assurance, informed decision-making, and collaboration and coordination among governmental agencies and key stakeholders during adverse events like COVID-19."

The article outlines the framework, which provides an ethically sound path forward to better position nursing home leaders and their teams to achieve these goals. The article also offers ideas for its use by decision-makers, both internal and external to nursing homes, and suggests policy opportunities to advance widespread use of this roadmap to assure acceptable levels of care quality throughout and beyond COVID-19.

New research from Wuhan, China shows that, in patients with COVID-19 but without a previous diagnosis of diabetes, abnormally high blood sugar is associated with more than double the risk of death and also an increased risk of severe complications. The study is by Dr Yang Jin, Union Hospital and Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China, and colleagues. The study is published in Diabetologia (the journal of the European Association for the Study of Diabetes [EASD]).

Previous studies have established that hyperglycaemia (abnormally high blood sugar) is associated with an elevated risk of mortality in community-acquired pneumonia, stroke, heart attacks, trauma and surgery, among other conditions. A number of studies have also shown links between diabetes and poor outcomes in COVID-19 patients. However, direct correlation between fasting blood glucose (FBG) level at admission to hospital and clinical outcomes of COVID-19 patients without diagnosed diabetes has not been well established. In this new study the authors examined the association between FBG on admission and the 28-day mortality of COVID-19 patients without previously diagnosed diabetes in two hospitals.

The retrospective study assessed all consecutive COVID-19 patients with a known outcome at 28-days and FBG measurement at admission from 24 January 2020 to 10 February 2020 in two hospitals based in Wuhan, China. Demographic and clinical data, 28-day outcomes, in-hospital complications and CRB-65 scores of COVID-19 patients in the two hospitals were analysed. The CRB-65 score is an effective measure for assessing the severity of pneumonia and is based on four indicators: level of confusion, respiratory rate (over 30 breaths per min), systolic blood pressure (90 mmHg or less) or diastolic blood pressure (60 mmHg or less), and age (65 years or over).

A total of 605 COVID-19 patients were enrolled, including 114 who died in hospital. The median age of participants was 59 years and 322 (53.2%) were men. A total of 208 (34%) had one or more underlying conditions (but not diagnosed diabetes), of which high blood pressure was the most common. Almost one third (29%) of patients fell into the highest category of FBG on admission (7.0 mmol/L) which if found consistently would result in a diagnosis of type 2 diabetes. A further 17% were in the range that would be considered pre-diabetic (6.1-6.9 mmol/L), while more than half (54%) were in the 'normal' FBG range of 6.0 mmol/L or below.

The results showed that patients in the highest FBG group were 2.3 times more likely to die than those in the lowest, a statistically significant result. Those in the middle (pre-diabetic) FBG group were 71% more likely to die than those in the lowest group, although this result only had borderline statistical significance. The data also showed that men were 75% more likely to die than women; and that patients with higher CRB65 scores (and thus worse pneumonia) were also at higher risk of death: those with a score of 3-4 were more than 5 times more likely to die than those with a score of 0, while for those with a score of 1-2 there was a 2.7 times increased risk.

When looking at FBG and CRB65 scores together, the patients in the highest FBG group had an increased risk of death compared to the lowest, regardless of whether or not the CRB65 score was zero or higher, further underlining that FBG independently increases the risk of death in COVID-19 patients. However, the increased risk of death for the highest FBG group was lower in patients with CRB65 scores of above zero compared with those with a CRB65 score of zero. The risk of complications was also found to be 4 times higher in the highest FBG group compared to the lowest, and 2.6 times higher in the middle (pre-diabetic) group compared to the lowest.

The authors say: "This study shows, for the first time, that elevated FBG (?7.0 mmol/l) at admission is independently associated with increased 28-day mortality and percentages of in-hospital complications in COVID-19 patients without previous diagnosis of diabetes... we have also shown that FBG of 7.0 mmol/l or higher is associated with increased mortality, regardless of whether the patient has pneumonia that is more or less severe."

They add: "These results indicate that our study included both undiagnosed diabetic patients and non-diabetic patients with hyperglycaemia caused by an acute blood-glucose disorder, since the 29% found in the highest FBG group is much higher than the estimated prevalence of diabetes in the Chinese population at 12%. Similarly to what was found in a previous study, COVID-19 patients might suffer from high blood sugar brought about by other conditions, and critically ill patients may develop acute insulin resistance, manifested by high levels of blood sugar and insulin levels. Patients with conditions not related to diabetes, such as severe sepsis, systemic inflammatory response syndrome (SIRS) and traumatic brain injury tend to have abnormally high blood sugar."

The authors note several limitations with their study. First, this was a retrospective study. Second, they did not analyse glycated haemoglobin (HbA1c), a long-term blood sugar control indicator that helps distinguish patients with poor long-term blood sugar control from those with stress hyperglycaemia. Also, they did not have sufficient data to study the effect of glucose-lowering treatment (e.g. insulin, metformin) on the outcome of the patients in their study. However, they believe that acute hyperglycaemia is more important than long-term glycaemic control in predicting the prognosis of hospitalised COVID-19 patients.

The authors suggest that possible mechanisms for this increased mortality include hyperglycaemia-induced changes in coagulation (clotting), worsening of endothelial function (the function of the walls of blood vessels), and overproduction of inflammatory cytokines produced by the immune system (the so-called cytokine storm).

The authors conclude: "In conclusion, a fasting blood glucose level of 7.0 mmol/l or higher at admission is an independent predictor for 28-day mortality in patients with COVID-19 without previous diagnosis of diabetes. Blood sugar testing and control should be recommended to all COVID-19 patients even if they do not have pre-existing diabetes, as most COVID-19 patients are prone to glucose metabolic disorders. During a pandemic of COVID-19, measuring fasting blood glucose can facilitate the assessment of prognosis and early intervention of hyperglycaemia to help improve the overall outcomes in treatment of COVID-19."

Leading health disparities experts hope health institutions will take advantage of a new cancer health equity research volume recently released that curates the latest developments in how researchers can best address health disparities so all patients receive good quality care.

"This volume is important because it uses a health equity approach to focus on factors associated with cancer disparities research, and it identifies potential solutions to those disparities," said Marvella Ford, Ph.D., professor of Public Health Sciences and associate director of population sciences and cancer disparities at the Hollings Cancer Center at the Medical University of South Carolina. "It brings together a spectrum of research from the basic sciences to the population sciences to address cancer health equity."

Ford also is the SmartState Endowed Chair of Cancer Health Equity Research at South Carolina State University. She coedited the volume with Nestor F. Esnaola, M.D., of Houston Methodist, and Judith D. Salley, Ph.D., of South Carolina State University. Two of Ford's studies were included in the recently released book, which is the edited journal volume, Cancer Health Equity Research (Volume 146 -Advances in Cancer Research).

Chapters three, four, six and seven of the volume represent Hollings' studies by Ford and other colleagues. She also wrote the preface in Health Equity Research. The journal includes research that highlights the importance of including diverse populations in cancer research and suggestions for effective recruitment strategies. These studies are what Ford hopes will lead to better health outcomes for cancer patients, especially those who are disproportionately affected by cancer.

"Researchers can take this information, and they can design and implement their own interventions to reduce cancer disparities and promote cancer health equity," Ford said.

Studies in the book reveal how better solutions can be found. One of the studies is part of Ford and Salley's National Cancer Institute U54 PACHE or Partnerships to Advance Cancer Health Equity program and ties to the South Carolina Cancer Disparities Center grant. This research shows the impact of lifestyle on breast cancer risk. The study, originally published in Advances in Cancer Research, found that known breast cancer risks such as a higher body mass index, lower rates of physical activity and a type of cancer called hormone receptor-negative breast cancer appear to be more prevalent in African Americans without Sea Island/Gullah ancestry than in Sea Islanders.

Her other study published in Advances in Cancer Research, led by Hollings Cancer Center researcher David P. Turner, Ph.D., showed that mammary gland development is linked to breast cancer disparity, perhaps mediated through socioeconomic status and childbearing patterns, such as the age at which a young woman starts menstruating.

Ford said the newly released volume is important because these studies help researchers to pinpoint areas where specific health interventions could be developed.

"Cancer disparities are a major public health problem in the United States. The goal of cancer disparities research is ultimately to reduce and eliminate these disparities," Ford said. "The synergy among the chapters is shown by their emphasis on the multiple factors that contribute to cancer disparities, ranging from social factors to biological factors."

Leading firearm violence prevention researchers are first to use data to show differences in gun culture across the country, identifying gun cultures around recreation, self-defense, and politics.

A new Boston University School of Public Health (BUSPH) study published in the Nature journal Humanities & Social Sciences Communications, shows that gun ownership means very different things in different parts of the United States.

Previous researchers have proposed two strands of gun culture: one focused on recreational use and a second on self-defense. But this study identifies a third, of people who do not view the defense of the Second Amendment as a means to an end, but as necessary to any freedom in this country. The study finds that this "Gun Culture 3.0" has increased the most in states that have strengthened their gun laws to the greatest degree, suggesting it may be grounded in fear of perceived threats by the government.

"The NRA has been spreading insurrectionist rhetoric for the past few decades, undermining Americans' trust in their legislators and the federal government, while passing for a patriotic organization. The result is a few million people who are convinced that any genuine firearm violence prevention effort is the first step in a scheme to take away all of their rights and disenfranchise them," says study lead author Claire Boine, a research scholar in community health sciences at BUSPH.

Using data on gun-related behaviors including hunting, NRA membership, magazine subscriptions, handgun and long gun purchases, and certain gun laws, the researchers show that American gun owners vary widely in the symbolic meaning they find in firearms and how they use them.

Over the last 20 years, at the national level, firearm recreation has dwindled and self-defense has expanded, even as a distinct culture of Second Amendment political advocacy has sprung up, the researchers found.

They also identified wide variation between states. Certain states, such as New York and Massachusetts, have very low recreational and self-defense gun cultures but very high Second Amendment activism. In contrast, states such as South Dakota have high recreational and self-defense cultures and little Second Amendment activism. Other states, such as Florida, have a high degree of self-defense gun culture and less recreational and Second Amendment gun culture.

The researchers found more emphasis on recreation in politically conservative states with large rural areas, little racial diversity, and few firearm regulations, while emphasis on self-defense is more common in politically conservative states that have enacted few new firearm laws in the last 20 years, have large rural areas, and are experiencing higher unemployment levels. The Second Amendment-focused "Gun Culture 3.0" is most common in liberal states, states where more of the population lives in an urban setting or is Hispanic, and states with stronger firearm regulations.

The researchers explain that the study shows only a marginal part of American gun culture is political, and the ability to measure gun culture empirically, as demonstrated by this study, will help better account for this variation in future studies of how gun policy affects gun use and violence.

"No longer can we speak about gun culture as if it is a single entity. There are positive aspects to gun culture that bring recreation, enjoyment, or a feeling of security to many people, and there are also some negative elements," says Dr. Michael Siegel, professor of community health sciences at BUSPH.

"Those of us in public health must acknowledge the positive aspects of that culture and stop blaming law-abiding gun owners for the problem of firearm violence," he says. "Instead, we need to address one very specific aspect of gun culture that the NRA has created that does not represent the overwhelming number of gun owners in this country."

NEW YORK, NY (July 10, 2020) -- After only a few days caring for critically ill COVID-19 patients at the start of the outbreak in New York City, Aakriti Gupta, MD, realized that this was much more than a respiratory disease.

"I was on the front lines right from the beginning. I observed that patients were clotting a lot, they had high blood sugars even if they did not have diabetes, and many were experiencing injury to their hearts and kidneys," says Gupta, one of the first Columbia cardiology fellows to be deployed to the COVID intensive care units at Columbia University Irving Medical Center.

In early March, there wasn't much clinical guidance on the non-respiratory effects of COVID-19, so Gupta decided to coalesce findings from studies that were just beginning to appear in the literature with what the physicians were learning from experience.

Gupta, along with senior author Donald Landry, MD, PhD, chair of medicine at Columbia University Vagelos College of Physicians and Surgeons, organized senior co-authors, and Gupta, along with two other colleagues, Mahesh Madhavan, MD, a cardiology fellow at CUIMC, and Kartik Sehgal, MD, a hematology/oncology fellow at Beth Israel Deaconess Medical Center/Harvard Medical School, mobilized clinicians at Columbia, Harvard, Yale, and Mount Sinai Hospital, among other institutions, to review the latest findings on COVID-19's effect on organ systems outside the lungs and provide clinical guidance for physicians.

Their review--the first extensive review of COVID-19's effects on all affected organs outside the lungs--was published today in Nature Medicine.

"Physicians need to think of COVID-19 as a multisystem disease," Gupta says. "There's a lot of news about clotting but it's also important to understand that a substantial proportion of these patients suffer kidney, heart, and brain damage, and physicians need to treat those conditions along with the respiratory disease."

Blood Clots, Inflammation, and an Immune System in Overdrive

"In just the first few weeks of the pandemic, we were seeing a lot of thrombotic complications, more than what we would have anticipated from experience with other viral illnesses," says Sehgal, "and they can have profound consequences on the patient."

Scientists think these clotting complications may stem from the virus's attack on cells that line the blood vessels. When the virus attacks blood vessel cells, inflammation increases, and blood begins to form clots, big and small. These blood clots can travel all over the body and wreak havoc on organs, perpetuating a vicious cycle of thromboinflammation.

To combat clotting and its damaging effects, clinicians at Columbia, many of whom are co-authors on this review, are conducting a randomized clinical trial to investigate the optimal dose and timing of anticoagulation drugs in critically ill patients with COVID-19.

The untempered inflammation can also overstimulate the immune system, and though doctors initially shied away from using steroids to globally suppress the immune system, a recent clinical trial has found that at least one steroid, dexamethasone, reduced deaths in ventilated patients by one-third. Randomized clinical trials are underway to target specific components of thromboinflammation and the immune system, such as interleukin-6 signaling.

"Scientists all over the world are working at an unprecedented rate towards understanding how this virus specifically hijacks the normally protective biological mechanisms. We hope that this would help in the development of more effective, precise, and safer treatments for COVID-19 in the near future," says Sehgal.

Straight to the Heart

Clots can cause heart attacks, but the virus attacks the heart in other ways, one author says.

"The mechanism of heart damage is currently unclear, as the virus has not been frequently isolated from the heart tissue in autopsy cases," says Gupta.

The heart muscle may be damaged by systemic inflammation and the accompanying cytokine release, a flood of immune cells that normally clears up infected cells but can spiral out of control in severe COVID-19 cases.

Despite the degree of heart damage, physicians were not able to utilize the diagnostic and therapeutic strategies, including heart biopsies and cardiac catheterizations, that they would normally use during the early stages of the pandemic given the need to protect personnel and patients from viral transmission. This has changed as the disease prevalence has gone down in New York CIty.

Kidney Failure

Another surprising finding was the high proportion of COVID-19 patients in the ICU with acute kidney damage.

The ACE2 receptor used by the virus to gain entry into the cells is found in high concentrations in the kidney and could likely be responsible for the renal damage. Studies in China reported renal complications, but in New York City, clinicians saw renal failure in up to 50% of patients in the ICU.

"About 5 to 10% of patients needed dialysis. That's a very high number," Gupta says.

Data regarding long-term renal damage are currently lacking, but a significant proportion of patients will likely go on to require permanent dialysis.

"Future studies following patients who experienced complications during hospitalizations for COVID-19 will be crucial," notes Madhavan.

Neurological Effects

Neurological symptoms, including headache, dizziness, fatigue, and loss of smell, may occur in about a third of patients.

More concerning, strokes caused by blood clots occur in up to 6% of severe cases and delirium in 8% to 9%.

"COVID-19 patients can be intubated for two to three weeks; a quarter require ventilators for 30 or more days," Gupta says.

"These are very prolonged intubations, and patients need a lot of sedation. 'ICU delirium' was a well known condition before COVID, and the hallucinations may be less an effect of the virus and more an effect of the prolonged sedation."

"This virus is unusual and it's hard not to take a step back and not be impressed by how many manifestations it has on the human body," says Madhavan.

"Despite subspecialty training as internists, it's our job to keep all organ systems in mind when caring for the patients in front of us. We hope that our review, observations, and recommendations can help other clinicians where cases are now surging."

PHOENIX, Ariz. -- July 10, 2020 -- A drug known as SP-2577 could help enable the body's own immune system to attack ovarian cancer, according to a study led by the Translational Genomics Research Institute (TGen), an affiliate of City of Hope.

Published today in the scientific journal PLOS ONE, the study builds on years of research led by Dr. Jeffrey Trent, TGen President and Research Director, into a type of ovarian cancer known as Small Cell Carcinoma of the Ovary, Hypercalcemic Type (SCCOHT), an aggressive and deadly cancer that usually strikes girls and young women.

Clinical trials already are on the horizon to test SP-2577 in combination with another proven immunotherapeutic compound for the first time in patients with SCCOHT.

"Immunotherapy is the future of cancer treatment. Our combination of drugs should promote an immune response in an ovarian cancer that usually does not respond well to immunotherapies," said Dr. Raffaella Soldi, a TGen Research Associate Professor and the lead author of the study. "One drug opens a biological gate, while the other drug helps push immune cells through the gate to attack the cancer."

SP-2577, also known as Seclidemstat, was developed in the laboratory of Dr. Sunil Sharma, TGen Deputy Director of Clinical Sciences, and senior author of the study. Seclidemstat has already shown to be a promising drug in clinical trials against a bone cancer known as Ewing sarcoma.

Dr. Sharma, who also is Director of TGen's Applied Cancer Research and Drug Discovery Division, explained that Seclidemstat works by inhibiting LSD1, a protein that is abundant in SCCOHT ovarian cancer. LSD1 also is implicated in initiating and aggressively accelerating many other types of cancer.

"We suggest in this paper that LSD1 inhibition should improve the immune-therapy response in these tumors," Dr. Sharma said. "This treatment is exquisitely dependent on the mutation found by Dr. Trent and his group. Without that mutation, this treatment would not work."

In 2014, Dr. Trent led and international team of investigators discovered that a single mutation in a gene called SMARCA4 triggered SCCOHT. The SMARCA4 gene -- previously associated with lung, brain and pancreatic cancer -- was the only recurrently mutated gene in the study's ovarian cancer samples, a finding that at the time Dr. Trent likened to "a genetic superhighway."

"Many genetic anomalies can be like a one-lane road to cancer; difficult to negotiate. But these findings indicate a genetic superhighway that leads right to this highly aggressive disease," Dr. Trent said at the time of his team's discovery. "The correlation between mutations in SMARCA4 and the development of SCCOHT is simply unmistakable."

The study published today in PLOS ONE -- The novel reversible LSD1 inhibitor SP-2577 promotes anti-tumor immunity in SWItch/Sucrose-NonFermentable (SWI/SNF) complex mutated ovarian cancer -- is based on TGen laboratory findings.

In an upcoming clinical trial for those with SCCOHT ovarian cancer, patients will receive Seclidemstat plus another drug, Pembrolizumab, a proven immunotherapy treatment that prevents cancer from hiding from the body's immune system. It uncloaks the tumor so immune cells can see the cancer and attack it.

The study was led by the International Rescue Committee (IRC), the London School of Hygiene & Tropical Medicine (LSHTM), and Action Against Hunger. It was supported by the No Wasted Lives Coalition, the Ministries of Health in Kenya and South Sudan, UNICEF and WFP, with funding from the U.S. Office of Foreign Disaster Assistance (OFDA) and Children's Investment Fund Foundation (CIFF).

The research team tested a simplified, combined protocol for the treatment of malnutrition in young children (6-59 months) through a cluster randomised control trial in Kenya and South Sudan. The research team found that this streamlined protocol, involving a single diagnostic criteria and a single therapeutic food product, led to similar proportions of children recovering from malnutrition as the standard approach. Moreover, it was more cost-effective -$123 cheaper per child recovered.

This is important as nearly 50 million children suffer from acute malnutrition at any given time yet only 25% get access to potentially life-saving treatment.

Malnutrition contributes to the deaths of approximately three million children under the age of five each year.

Experts anticipate a rise in the number of malnourished children in 2020 as a result of COVID-19. The World Food Program recently projected that the pandemic could double the number of people suffering acute hunger to more than a quarter of a billion by December 2020.

Currently, severe and moderate acute malnutrition (SAM and MAM) are treated with separate products and protocols, in separate programs managed by separate UN agencies.

Lead author Jeanette Bailey, Nutrition Research and Innovation Lead at the IRC and London School of Hygiene & Tropical Medicine researcher, said: "The current system for treating acute malnutrition is complex and costly, and fails to reach the majority of children. Many children are diagnosed only after they have deteriorated to the most severe and deadly forms of acute malnutrition. Simplified approaches could encourage earlier detection and treatment, and ultimately save lives."

Dr. Charles Owubah, CEO of Action Against Hunger, said: "The world needs a better way to deal with malnutrition, and research like this is key to creating it. By innovating with easier, more cost-effective treatment delivery, we can reduce the burdens on health systems and maximise scarce resources."

The treatment of SAM is currently supported by UNICEF and provides ready-to-use therapeutic foods (RUTF) for medically uncomplicated cases in outpatient therapeutic programs. This involves weekly visits, often on foot, to a health centre to receive rations of RUTF and essential medicines.

Treatment of MAM is supported by The World Food Programme which provides ready-to-use supplementary foods or fortified blended flours for use in additional feeding programs which sees children bi-weekly.

In this study, the treatment for children aged 6-59 months was unified into one protocol, with simplified diagnostic criteria and a single therapeutic food product. Between May 2017 and March 2018, more than 4,000 children were enrolled in the study, approximately half received standard treatment, half received combined protocol treatment.

At the end of the trial period the research team assessed nutritional recovery defined as children having a mid-upper arm circumference measurement of more than 12?5cm and no edema for two consecutive visits (weekly for SAM and bi-weekly for MAM).

The research team found nutritional recovery in the combined protocol (76.3%) matched that seen through standard treatment (73.5%). No difference was also seen in the number of deaths, children who didn't respond to treatment, children who were transferred to another facility for more treatment and children stopping treatment early by missing visits.

To assess cost-effectiveness, the researchers calculated costs using accounting data, interviews with key informants, and survey questionnaires given to a subset of staff and all caregivers.

The amount of ready-to-use food required for a child with severe malnutrition to reach full recovery was less in the combined protocol (122 vs 193 sachets), and the combined protocol was $123 less per child recovered ($918 v $1,041).

Dr Marko Kerac from LSHTM and study senior author said: "Prolonged and severe emergencies like the COVID-19 pandemic risk increasing global food insecurity and malnutrition and add further strain to already fragile health systems. This study is an important step towards protecting young lives in states affected by crises or conflict, now and in the future."

These results provide new evidence to support recent moves by key actors within the UN system encouraging governments and humanitarian agencies to use this simplified protocol in nutrition programs affected by COVID-19.

The authors acknowledge limitations of their study including the combination of two different contexts in a single estimate of effectiveness, a study population that was primarily between 6-24 months thereby limiting generalizability to older children, and high defaulting caused by contextual factors that affected both arms of the trial equally.

The researchers say further research is now needed to test this new protocol in different contexts for managing acute malnutrition.