Body

A geneticist from RUDN University studied the effect of Bifidobacterium (intestinal bacteria) on the inflammatory process and discovered that their surface protein is capable of stopping excessive or uncontrollable inflammation, like the one observed in COVID-19 patients. A fragment of this protein can be used as an anti-inflammatory medication when treating coronavirus and other diseases. The results of the study were published in the Anaerobe journal.

When in danger, the cells of our body send out an SOS signal that is received by other cells and causes an immune response. This is how inflammation starts. This call to action is transmitted by special peptides known as anti-inflammatory cytokines. Sometimes there are too many of them, and a so-called cytokine storm occurs. This dangerous and sometimes deadly reaction is observed in severe cases of COVID-19. However, some pathogenic bacteria know how to trick our body's protective systems: they use special proteins to capture cytokines and reduce inflammation. Until recently scientists had been unaware whether bifidobacteria--useful symbiotic microorganisms that live in our intestines--have the same effect on the inflammatory process. A geneticist from RUDN University was the first to demonstrate this mechanism.

The researchers conducted an experiment to study how FN3, a surface protein of Bifidobacterium longum, blocks or binds cytokines. FN3 helps cells attach to different surfaces, including intestinal walls covered in mucus. Moreover, it has two protein-carbohydrate moieties (fibronectin domains) that are similar to human cytokine receptors. The experiment showed that FN3 is able to bind TNF-α, one of the main cytokine storm factors.

To find out what specific cytokines are bound by FN3, the team used a method called ELISA (Enzyme-Linked ImmunoSorbent Assay) and applied it to a protein fragment with a fibronectin domain. First, antibodies that react only with FN3 were secured on a base. Then, a fragment of FN3, cytokines, and antibodies to them bound with a fluorescent tag were added. As a result, the team built a sandwich-like structure: antibody-FN3-cytokine-antibody.

Of four cytokines that belonged to different classes, only the tumor necrosis factor TNF-α showed effective binding. The fact that bifidobacterial surface proteins were able to recognize specific classes of cytokines supported the team's theory: these bacteria are also capable of regulating our immune response.

Studies like this are especially important for understanding the processes of immune development in newborn babies, as their intestinal microbiome almost entirely consists of bifidobacteria. Biologists also believe that the tumor necrosis factor-specific fragment of FN3 can reduce the levels of cytokine storm in COVID-19 patients.

"Studies of cytokine-binding properties of microorganisms have become extremely important recently in view of the current epidemiological situation. Uncontrollable inflammation or cytokine storm is one of the most prominent elements of COVID-19 pathogenesis. Selective binding of TNF-α, one of the key factors of inflammation, with a fragment of the FN3 protein of Bifidobacterium longum opens a prospect for developing new medicinal drugs that would slow down the cytokine reaction. It has already been agreed that a preclinical trial of a new FN3-based anti-inflammatory medication should be conducted as quickly as possible," said Prof. Valery Danilenko, a PhD in Biology from RUDN University.

Tokyo, Japan -- Patches seem to be all the rage these days. There are birth control patches, nicotine patches, and transdermal medicinal patches, just to name a few. Now, a team of researchers led by Beomjoon Kim at the Institute of Industrial Science, The University of Tokyo have developed a patch of needles connected to a paper sensor for diagnosing conditions such as prediabetes. Luckily, this patch doesn't multiply the pain and discomfort of a single hypodermic needle. In fact, these microneedles are painless and biodegradable.

Researchers have been trying to develop a practical way to use microneedles--tiny needles less than 1 mm in length--for routine do-it-yourself medical monitoring. Microneedles are so short that they stay within the skin and do not make contact with any neurons, meaning that they cause no pain. Rather than extracting blood, they draw up fluid in the skin that contains most of the important biomarkers that blood tests look for. Several types of microneedles exist, but until now, making a practical device that quickly analyzes the fluid has proved elusive. "We have overcome this problem by developing a way to combine porous microneedles with paper-based sensors," says Kim. "The result is low-cost, disposable, and does not require any additional instruments."

To make the patch, the researchers first made the microneedles by pouring a melted mixture of a biodegradable polymer and salt into the cone-shaped cavities of a micro-mold while applying heat. Then they flipped the mold and needles upside down and placed them on top of a piece of paper, this time applying high pressure from above. The high pressure forced the mixture into the pores of the paper, securing the attachment and allowing fluid drawn through the needles to pass effortlessly into the paper. After removal from the mold, the needles were cooled in a solution that sucked out all the salt, leaving behind thousands of holes, or pores, which are what the fluid flows through on its way to the paper. The salt concentration was a key factor they needed to optimize, testing several concentrations of salt to determine how porous the microneedles should be. To finish the patch, they used double-sided tape to attach a paper glucose sensor onto the paper base of the needle array.

The team tested the patch on an agarose gel in which glucose had been dissolved. Fluid from the gel flowed from the gel into the porous microneedles, and from there into the paper and the sensor layer. The glucose concentration was accurately recorded as color changes in the paper.

The patches are disposable, biodegradable, and using them does not require any medical expertise or training. They are also biocompatible, meaning that there is no problem if any remain in the skin when the patch is removed.

"Of course, prediabetes testing is just one application of the technology," says first author Hakjae Lee. "The paper-based sensor can vary depending on the biomarker you wish to monitor."

After this success, the next step will be to test the practicality of the device with human participants and to develop configurations for monitoring other substances, and in turn, determining the presence of other conditions.

What The Study Did: This study investigated the use of cardiac magnetic resonance imaging in competitive college athletes who recovered from COVID-19 to detect myocardial inflammation that would identify high-risk athletes for return to competitive play.

Authors: Saurabh Rajpal, M.B.B.S., M.D., of Division of Ohio State University in Columbus, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jamacardio.2020.4916)

Editor's Note: The articles includes conflict of interest disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, conflict of interest and financial disclosures, and funding and support.

Scientists at St. Jude Children's Research Hospital are investigating the inherited genetics of childhood leukemia and how particular gene variations can affect treatment outcomes. The research showed that an inherited variation in the GATA3 gene strongly influences early response to chemotherapy and is linked to relapse in children with acute lymphoblastic leukemia (ALL). The work was published as an advance online publication this week in the Journal of the National Cancer Institute.

Minimal residual disease (MRD) checks for the presence of minute numbers of cancer cells after induction therapy, the first stage of ALL treatment. MRD is one of the strongest predictors of relapse risk for young ALL patients.

"We know there is substantial variability in the way patients respond to ALL therapy. Certain mutations in leukemia cells are associated with drug response, but they certainly do not explain the full spectrum of the observed variability. This is when we realize we need to look at inherited genetic variants as well," said corresponding author Jun J. Yang, Ph.D., of St. Jude Pharmaceutical Sciences and Oncology.

The team conducted a genome-wide association study on children in Children's Oncology Group clinical trials for high-risk B-ALL. This cohort was large enough for the scientists to look for associations between the inherited genetics and end-of-induction MRD levels for 863,370 single nucleotide polymorphisms.

Results of the study showed that an inherited GATA3 variant strongly influenced how patients responded to therapy. This variant is also associated with relapse. GATA3 is known by scientists to encode a crucial transcription factor for the development and differentiation of T cells.

"This variant isn't completely new to us; we've previously found it to be associated with susceptibility to Philadelphia chromosome-like ALL, a rare but high-risk subtype," Yang said. "These new findings about the relationship between the GATA3 variant and MRD solidify the potential utility of inherited variants in how we assess newly diagnosed patients for risk-stratified therapy."

Osteoporosis, a bone disease linked to ageing, is characterised by a loss of bone density, micro-architectural deterioration of the bones and an increased risk of fractures. With one third of postmenopausal women affected, it is a major public health problem. Through epidemiological analyses, laboratory experiments and state-of-the-art metagenomic and metabolomics tools, a research team from the University of Geneva (UNIGE), in Switzerland, has observed that exposure to warmer ambient temperatures (34 °C) increases bone strength, while preventing the loss of bone density typical of osteoporosis. Moreover, this phenomenon, linked to a change in the composition of gut microbiota triggered by heat, could be replicated by transplanting the microbiota of mice living in a warm environment to mice suffering from osteoporosis. Indeed, after the transplant, their bones were stronger and denser. These results, to be discovered in Cell Metabolism, make it possible to imagine effective and innovative interventions for prevention and treatment of osteoporosis.

Many biologists are familiar with Allen's Rule, from 19th-century naturalist Joel Asaph Allen, according to which animals living in warm areas have a larger surface area in relation to their volume than animals living in colder environment. Indeed, a larger skin surface allows better evacuation of body heat. "In one experiment, we placed newborn mice at a temperature of 34 °C in order to minimise the heat shock associated with their birth. We found that they had longer and stronger bones, confirming that bone growth is affected by ambient temperature," explains Mirko Trajkovski, Professor at the Department of Cell Physiology and Metabolism and at the Diabetes Centre of the UNIGE Faculty of Medicine, who led the study. But what about adulthood?

Consistent epidemiological data

By placing several groups of adult mice in a warm environment, the scientists observed that while bone size remained unchanged, bone strength and density were largely improved. They then repeated their experiment with mice after an ovariectomy modelling post-menauposal osteoporosis. "The effect was very interesting", says Claire Chevalier, then a researcher in Professor Trajkovski's laboratory and the first author of this work. "The simple fact of warming the living environment of our mice protected them from the bone loss typical of osteoporosis!"

What about human beings? The research team analysed global epidemiological data on the incidence of osteoporosis in relation to the average temperature, latitude, calcium consumption and vitamin D levels. Interestingly, they found that the higher the temperature, the fewer hip fractures --one of the main consequences of osteoporosis-- regardless of other factors. "We found a clear correlation between geographical latitude and hip fractures, meaning that in the northern countries the incidence is higher compared to the warmer south", says Mirko Trajkovski. "Normalising the analysis of the known players such as vitamin D or calcium did not modify this correlation. However, when we excluded the temperature as the determinant, the correlation was lost. This is not to say that calcium or vitamin D do not play a role, either alone or in combination. However, the determining factor is heat -or lack thereof."

How the microbiota adapts

Specialists in the microbiota, the Geneva scientists wanted to understand its role in these metabolic modifications. To this end, they transplanted the microbiota of mice living in a 34° environment to osteoporotic mice, whose bone quality was rapidly improved. "These findings may imply an extension to Allen's rule, suggesting elongation-independent effects of the warmth, which predominantly favours bone density and strength during adulthood through microbiota alterations", says Mirko Trajkovski.

Thanks to the state-of-the-art metagenomic tools developed in their laboratory, the scientists then succeeded in understanding the role played by microbiota. When adapts to heat, it leads to a disruption in the synthesis and degradation of polyamines, molecules that are involved in ageing, and in particular in bone health. "With heat, the synthesis of polyamines increases, while their degradation is reduced. They thus affect the activity of osteoblasts (the cells that build bones) and reduce the number of osteoclasts (the cells that degrade bones). With age and menopause, the exquisite balance between the osteoclast and osteoblast activity is disrupted," explains Claire Chevalier. "However, heat, by acting on the polyamines, which we found to be partly regulated by the microbiota, can maintain the balance between these two cell groups." These data therefore indicate that exposure to warmth could be a prevention strategy against osteoporosis.

Developing new treatments

The influence of microbiota on metabolism is being better understood. However, in order to be able to use this knowledge to develop therapeutic strategies, scientists must identify precisely the role of particular bacteria in particular diseases. In the context of their work on osteoporosis, Professor Trajkovski's team has been able to identify certain important bacteria. "We still need to refine our analyses, but our relatively short-term goal would be to identify candidate bacteria, and develop several 'bacterial cocktails' to treat metabolic and bone disorders, such as osteoporosis, but also to improve insulin sensitivity, for example," the authors conclude.

The CA125 antigen, a plasma membrane glycoprotein found in the tissues of the female reproductive tract, is commonly used for the detection of ovarian cancer but works poorly on its own in identifying early stage cancers. The cancer specificity can be improved significantly when CA125 detection is combined with targeting aberrant sugar structures in the tumour.

The goal of the research group led by Professor Kim Pettersson at the University of Turku, Finland, is to develop novel tests that use the detection of modified sugar structures from the cancer tissue. The recently published article describes how the research group developed this rapid and sensitive point-of-care diagnostic test that can detect ovarian cancer from the patient's blood sample.

Aberrant sugar structures can be used in early cancer diagnostics

With the easy-to-run and rapid test developed in the study, ovarian cancer can be more accurately detected from a blood sample in 30 minutes. The technologies of the Biotechnology unit at the Department of Biochemistry, as well as their expertise in label technology and rapid tests, were widely used in this study.

"When compared with the conventional CA125 diagnostics, the sensitivity of the new test was 4.5 times higher in detecting ovarian cancer," says Doctoral Candidate Sherif Bayoumy, the first author of the study.

The aim is to expand further on these promising results to cover a larger group of patients and other cancers. The goal is to develop rapid tests for clinical use to facilitate to proceed to further examinations and treatment options.

"The received results are extremely promising for early cancer diagnostics. We are currently studying the functionality of similar approaches in other cancers. Detecting the disease as early as possible is extremely important when it comes to, for example, pancreatic cancer," describes Professor Kim Pettersson.

New research shows improving the lifestyle of women with obesity during pregnancy could mean long-term cardiovascular benefits for their children.

The study, led by King's College London and supported by the British Heart Foundation and Tommy's charity, examined how an antenatal diet and physical activity intervention in pregnant women with obesity could positively influence the health of the women and their children three years after giving birth.

The UPBEAT trial is a randomised controlled trial which aims to improve the diet and physical activity of obese pregnant women across the UK. Women who were given a diet and exercise intervention were compared to women in a control group, who made no changes to their lifestyle during pregnancy.

Follow-up examinations three years after birth showed that the children born to the intervention arm of the trial had a lower resting heart rate of -5 bpm than children treated with standard care. A higher resting heart rate in adults is associated with hypertension and cardiovascular dysfunction.

The study also showed that mothers in the intervention arm maintained a healthier diet three years after birth.

While women reported lower glycaemic load, maternal energy and saturated fatty acids intake, and higher protein intake three years after delivery, there were no differences in self-reported physical activity or in measures of body composition.

Lead author Kathryn Dalrymple from King's College London said: "This research shows that an lifestyle intervention in pregnant women, which focused on improving diet and increasing physical activity, is associated with improved cardiovascular function in the child at three-years of age and a sustained improvement in the mothers diet, three years after the intervention finished. These findings are very exciting as they add to the evidence that pregnancy is a window of opportunity to promote positive health and lifestyle changes which benefit the mother and her child."

Senior author Professor Lucilla Poston, Tommy's Chair for Maternal and Fetal Health, said: "Obesity in pregnancy is a major problem because it can increase the risk of complications in pregnancy as well as affecting the longer-term health of the child. This study strengthens my resolve to highlight just how important it is that we give children a healthy start in life."

Tommy's Research and Policy Director, Lizzie D'Angelo, said: "Pregnancy can be higher risk for women who are obese, but trying to lose lots of weight while pregnant is not advised, so our research focuses on finding new ways to make pregnancy safer for these families. It's very reassuring to see that our researchers have been able to improve mothers' diets and children's heart health in the long term, helping to give these babies the best start in life."

Tracy Parker, Senior Dietitian at the British Heart Foundation, said: "Keeping physically active and maintaining a balanced diet are both important ways of keeping our hearts healthy. This research shows that for pregnant women, the benefits don't end there. A healthy diet before, during and after pregnancy can have positive long-term health benefits for both mother and child."

The team of researchers will follow-up these children again at 8-10 years of age to see if this improvement in cardiovascular function is maintained through childhood.

In an editorial for the American Journal of Public Health, faculty from the CUNY Graduate School of Public Health and Health Policy (CUNY SPH) led by Dean Ayman El-Mohandes highlight the long-standing public health-related inequities among people of color in the United States--which have only been exacerbated by the COVID-19 pandemic--and call upon New York City lawmakers to put forth policies to achieve a more equitable distribution of basic necessities such as employment, food, health care, housing, and education.

The authors discuss the COVID-19 tracking survey conducted by CUNY SPH and Emerson Polling between March and May 2020, which revealed that the COVID-19 pandemic and subsequent economic fallout had a particularly deleterious effect on access to health care, employment, housing, food, and education for Black and Latinx New Yorkers. This disparate effect could have been avoided, they say, if city lawmakers had addressed the widening racial/ethnic gaps in income, health care, and food access before the pandemic as well as the risk that they will continue to undermine health equity after the pandemic ends.

"In our opinion, the COVID-19 pandemic highlights the importance of addressing these disparities immediately; otherwise, the gaps will undoubtedly widen further, even beyond where they stood before the pandemic," the researchers warn.

In the wake of the COVID-19 outbreak, the authors conclude, city lawmakers should embrace the data and rely on proven programs that address these growing disparities with holistic, cross-sectoral, community-based strategies that focus on the interconnectedness of health, social, and economic risks that confront our most vulnerable communities.

CHICAGO --- Severely ill COVID-19 patients on ventilators are placed in a prone (face down) position because it's easier for them to breathe and reduces mortality. But that life-saving position can also cause permanent nerve damage in these vulnerable patients, reports a newly accepted study from Shirley Ryan AbilityLab and Northwestern University Feinberg School of Medicine.

Scientists believe the nerve damage is the result of reduced blood flow and inflammation. Other non-COVID-19 patients on ventilators in this position rarely experience any nerve damage.

The study has been accepted by the British Journal of Anaesthesia. It can be viewed as a preprint.

"It's shocking how big a problem it is," said lead investigator Dr. Colin Franz, a physician-scientist at Shirley Ryan AbilityLab and an assistant professor of physical medicine and rehabilitation and neurology at Northwestern's Feinberg School of Medicine. "This is a much higher percentage of patients with nerve damage than we've ever seen in any other critically ill population. Ordinarily, very sick people can tolerate the position that helps their breathing. But COVID patients' nerves can't tolerate the forces other people can generally bear."

Based on this study and another that came out after Franz's, 12% to 15% percent of the most severely ill COVID-19 patients have permanent nerve damage. Based on the number of COVID patients worldwide, Franz estimated thousands of patients have been impacted.

"It's underappreciated, if you take our numbers and extrapolate them," Franz said. So far, he and colleagues have seen 20 patients from seven different hospitals with these injuries.

The injury has been missed because people who have been critically ill are expected to wake up with some generalized, symmetric weakness because they have been bedridden, Franz said. But the pattern of weakness in the COVID-19 patients caught the researchers' attention during rehabilitation since quite often an important joint such as the wrist, ankle or shoulder would be completely paralyzed on one side of the body.

As a result of the findings, physicians are modifying the prone position protocol for COVID-19 patients at Northwestern Memorial Hospital in order to prevent nerve damage.

"We noticed patients are getting a lot of pressure at the elbow or at the neck, so we've made some adjustments to the way we position the joints as well as putting extra padding under the elbow and the knee where there is the most pressure," Franz said.

The most common injuries are wrist drops, foot drops, loss of hand function and frozen shoulder. Some patients had as many as four distinct nerve injury sites. Some people who are dragging a foot need assistance with walking such as a wheelchair, brace or cane.

Franz and colleagues have been doing some therapeutic nerve stimulation, which has shown in other work to help regrow nerves. Franz collaborates on this line of research with John Rogers, biomedical engineer at Northwestern's McCormick School of Engineering, and Dr. Sumanas Jordan, an assistant professor of surgery at Feinberg and a Northwestern Medicine plastic surgeon.

But many patients have pre-existing conditions that interfere with nerve regeneration, such as diabetes mellitus, so they are less likely to recover full function.

"This could mean permanent difficulties with walking or critical hand functions like writing or operating a computer or cell phone," Franz said.

The multidisciplinary team of scientists at Northwestern and Shirley Ryan AbilityLab are working on a pressure map of hot spots for nerve sensitivity, radiology imaging to document the injury and skin sensors to help identify better "prone" position strategies.

Cancer immunotherapy is the manipulation of the immune responses naturally present in the human body to fight cancer. Often, these immune responses are blocked by cells or molecules that prevent them from killing cancer cells, and the tumour is able to establish itself and grow.

In 2004, Sophie Lucas, researcher at the University of Louvain de Duve Institute, began studying the blocking of immune defences in tumours in order to understand the functioning of cells that are said to be 'immunosuppressive' (which block the body's immune responses). The goal was to identify and remove them, thus stimulating antibodies to act against the tumour. The identified culprits are regulatory T lymphocytes (Tregs): highly immunosuppressive cells in cancer patients. In 2009, Prof. Lucas discovered GARP, a molecule located on the surface of Tregs.

In 2018, Prof. Lucas finally managed to understand the role of GARP: the molecule acts as a messenger for Tregs, by sending signals that block immune responses. She is developing a tool (anti-GARP antibodies) to neutralise and prevent the messenger from sending its blocking signals. This important discovery was published in the journal Science.

In August 2020, Nature Communications published the results of the first tests carried out by Prof. Lucas and her team. The tests are very promising: UCLouvain scientists succeeded in neutralising Tregs in cancerous mice using anti-GARP antibodies. If the messenger is neutralised, immune responses are not blocked and can again eliminate cancer cells. The tumour regresses quickly provided the anti-GARP antibodies are combined with another proven immunotherapy (anti-PD1 antibodies). Thus the UCLouvain team combines two complementary immunotherapy approaches, acting in different ways on the immune system, to increase the effectiveness of cancer treatment. And it works!

What's next? Conducting these same tests on humans to provide a more effective therapeutic solution in the fight against cancer.

SALT LAKE CITY - Newly published research has reversed our understanding of an aspect of kidney tumor growth. Researchers at Huntsman Cancer Institute (HCI) at the University of Utah (U of U) discovered that two key proteins have opposite roles than what was previously believed. The proteins HIF-1α and HIF-2α regulate the response to regions of low oxygen (hypoxia) in a solid tumor. Hypoxia is known to increase the aggressiveness of tumors, which is caused by the activation of the hypoxia inducible factor (HIF) proteins. Researchers used tissue from clear cell renal cell carcinoma, the most common and aggressive form of kidney cancer. This study was published in the journal Clinical Cancer Research.

"Prior research in kidney cancer suggests a paradigm in which HIF-1α plays an anti-tumor role, whereas HIF-2α plays a pro-tumor role, but this was determined primarily using cell lines and animal models," said Mei Koh, PhD, an HCI investigator and assistant professor in the Department of Pharmacology and Toxicology at the U of U. The current study tested tissue obtained from human patients.

Researchers gathered tissue from more than 380 patients to analyze the relationship between levels of HIF proteins, tumor grade, stage, and patient outcome. These findings were validated using tissue samples from 72 additional patients.

Findings showed that HIF-1α was associated with more aggressive, or high-grade, tumors. The protein was also linked to tumors that spread to other regions in the body (metastasized), as well as to decreased patient survival and increased resistance to therapy. Conversely, HIF-2α was associated with less aggressive, or low-grade, tumors, lack of metastasis, and longer life.

"The entire team was surprised that our findings were almost exactly opposite to what we had expected," Koh said. "Our view of the HIFs in kidney cancer may need to be revised. We found that HIF-1α, the presumed tumor suppressor, was an indicator of poor patient outcome. HIF-2α, the presumed tumor driver, was significantly associated with better patient outcome. Of note, HIF-1α was detected mainly in tumor-associated macrophages, which are immune cells of the patient, but not within the cells of the tumor. This suggests that these immune cells could play an important role in tumor progression. HIF-2α was detected exclusively within tumor cells."

A multidisciplinary group of researchers from HCI and other institutions conducted this study. "Diversity in collaborators helped reduce bias, whether conscious or unconscious, in data acquisition and interpretation. It also increased the number of well-annotated tissue samples available to us," Koh said. Koh also acknowledged the critical work of Sophie Cowman, postdoctoral research associate in the Department of Pharmacology and Toxicology at the U of U. Cowman was first author for this study.

Researchers from The University of Texas Medical Branch at Galveston have found that while the 30-day readmission rate for patients with chronic obstructive pulmonary disease has decreased, the mortality rate has increased.

The UTMB researchers analyzed data from a nationwide cohort of more than 4.5 million Medicare beneficiaries with COPD to learn more about the impact of a federal program designed to reduce the number of people needing hospitalization within the first 30 days after being released from the hospital for a COPD-related illness.

The findings, said first author Daniel Puebla Neira, UTMB Pulmonary & Critical Care Fellow, are concerning in that some hospitals, in seeking to avoid financial penalties by reducing readmissions, may inadvertently affect minority and disadvantaged patients - people who may have a higher risk of dying.

The findings are currently available in the American Journal of Respiratory and Critical Care Medicine.

COPD is the third leading cause of death in the United States, affecting 12.7 million Americans and about 800,000 patients are hospitalized with COPD each year. Of these, 1 in 5 patients are readmitted after being discharged from the hospital, which is linked with poor outcomes and costs about $13 billion annually. In order to improve the patients' long-term health and control rising healthcare costs, the Patient Protection and Affordable Care Act created the Hospital Readmissions Reduction Program, or HRRP, in March 2010. The program began penalizing hospitals for higher than expected 30-day readmissions rates for non-COPD conditions.

Since the creation of the program, hospitals have reduced their readmission rates. However, it was also suspected that the program may be associated with an increase in the 30-day risk of post-discharge mortality rates for some groups of patients currently participating in the program.

"The benefits of the HRRP to improve health, prevent unnecessary hospitalizations, and control Medicare spending have been widely discussed and debated," said senior author Dr. Gulshan Sharma, director of the Division of Pulmonary Critical Care & Sleep Medicine. "An important concern is the current penalties for readmission do not to take into consideration the impact on mortality. Reducing readmissions may inadvertently affect minority and disadvantaged patients. These patients are not only at higher risk for readmission, they may also be at higher risk of dying."

The research team analyzed data from 4,587,542 Medicare fee-for-service beneficiaries with COPD who were 65 years and older. The study period from 2006 to 2017 covers the creation of HRRP and the introduction of COPD to the program. The data revealed that while the program does decrease the 30-day hospital readmission rate, it also significantly increases in the risk-standardized 30-day post-discharge mortality rates across the nation.

"Further research is needed to confirm our findings and identify factors contributing to the increased mortality seen in patients with COPD in the Centers for Medicare & Medicaid Services readmission reduction program," said Puebla Neira.

Public confidence in vaccines varies widely between countries and regions around the world, with signs that public trust may be improving in parts of Europe, whilst several countries experiencing political instability and religious extremism are seeing growing scepticism that vaccines are safe, and the spread of misinformation online is threatening vaccination programmes worldwide.

The new research mapping global trends in vaccine confidence across 149 countries between 2015 and 2019, published in The Lancet, is based on data from over 284,000 adults (aged 18 years and older) surveyed about their views on whether vaccines are important, safe, and effective.

Public trust in immunisation is an increasingly important global health issue, with WHO declaring vaccine hesitancy as one of the top ten threats to global health in 2019. Declining confidence can result in vaccine delays or refusals, which is contributing to a rising number of vaccine preventable disease outbreaks including measles, polio, and meningitis worldwide.

"It is vital with new and emerging disease threats such as the COVID-19 pandemic, that we regularly monitor public attitudes to quickly identify countries and groups with declining confidence, so we can help guide where we need to build trust to optimise uptake of new life-saving vaccines", says Professor Heidi Larson from the London school of Hygiene & Tropical Medicine, UK, who led the research. [1]

She continues, "One of the main threats to the resilience of vaccination programmes globally is the rapid and global spread of misinformation. When there is a large drop in vaccination coverage, it is often because there's an unproven vaccine safety scare seeding doubt and distrust. Sometimes there is a genuine small risk that gets rapidly spread and amplified to appear to be a much larger risk. There are also cases where vaccine debates have been purposefully polarised, exploiting the doubting public and system weaknesses for political purposes, while waning vaccine confidence in other places may be influenced by a general distrust in government and scientific elites." [1]

Although immunisation coverage is reported across the world, no comparable global estimates and monitoring of vaccine confidence are available. The Vaccine Confidence Project (VCP) was founded a decade ago to help plug the gap, providing a systematic approach to monitoring public attitudes to vaccines and to inform policymakers of the changing trends and determinants of vaccine confidence around the world.

In this study, researchers analysed data from 290 nationally representative surveys conducted between September 2015 and December 2019--combining previously published data from nearly 250,000 survey responses with 50,000 additional interviews from 2019. Modelling was used to estimate trends in public perceptions about the safety and effectiveness of vaccines, and the importance of vaccinating children. They also modelled the relationship between vaccine uptake in each country and demographics (ie, age, sex, religious beliefs), socioeconomic factors (eg, income, education), and source of trust (eg, family, friends, health professionals). Estimates of vaccine confidence for some countries includes wide confidence intervals reflecting lower numbers of recent data--for these countries, the estimates are a weighting of the countries' overall trend and the trend of the whole continent.

More recent changes in vaccine safety perceptions were evaluated for the EU, where a higher frequency of surveys has been conducted per country, on average, compared with the rest of the world (figure 3 and "EU recent changes" excel sheet).

Across the European Union recent significant losses in confidence in vaccine safety were detected in Poland (a dip from 64% strongly agreeing vaccines are safe in Nov 2018 to 53% by Dec 2019), reflecting the growing impact of a highly organised local anti-vaccine movement. However, confidence in vaccine safety is increasing in several countries, including Finland, France, Italy, and Ireland (as well as the UK). In France, where confidence in vaccines has been persistently low, there has been a marked rise in confidence, from 22% of those surveyed strongly agreeing vaccines are safe in Nov 2018, to 30% in Dec 2019. In the UK, confidence in vaccine safety rose from 47% in May 2018 to around 52% in Nov 2019 (figure 3A and Appendix 2 "EU recent changes" excel sheet).

In contrast, six countries (Afghanistan 2% of those surveyed strongly disagreeing vaccines are safe in 2015 rising to 3% in 2019, Azerbaijan 2%-17% , Indonesia 1%-3%, Nigeria 1%-2%, Pakistan 2%-4%, and Serbia 4%-7%) have witnessed substantial increases in people strongly disagreeing vaccines are safe (ie, not just being less convinced, but actively against vaccines) between 2015 and 2019, in what researchers describe as a "worrying trend", with negative attitudes mirroring trends in political instability and religious extremism.

The analysis suggests that overall confidence in vaccines--including safety, effectiveness, and importance--fell in Indonesia, the Philippines, Pakistan, and South Korea between November 2015 and December 2019 (figure 2). For example, risks of a dengue vaccine (Dengvaxia) in the Philippines in 2017 led to a dramatic drop in public confidence in vaccine safety and impacted the uptake of routine vaccines--causing the Philippines to drop out of the top 10 countries with the highest overall vaccine confidence in 2015 (82% of those surveyed strongly agreeing that vaccines safe, 92% important, 81% effective), to ranking no higher than 70th in 2019 (58% those surveyed strongly agreeing that vaccines safe, 70% important, 57% effective; figure 3C). In South Korea, online mobilisation efforts against childhood immunisation by communities such as ANAKI (Korean abbreviation of 'raising children without medication'), have been identified as key barrier to vaccination.

Indonesia has witnessed one of the largest falls in public trust worldwide between 2015 and 2019 (absolute difference in perception of safety fell 14% [from 64% to 50%], importance 15% [75% to 60%], effectiveness 12% [59% to 47%]). The authors say negative attitudes may have been partly triggered by Muslim leaders questioning the safety of the measles, mumps, and rubella (MMR) vaccine, and issuing a fatwa (religious ruling) claiming that the vaccine was haram (forbidden) and contained ingredients derived from pigs, as well as local healers promoting natural alternatives to vaccines.

The analysis suggests that confidence in the importance of vaccines (rather than in their safety or effectiveness) is most strongly linked with vaccine uptake. By December 2019, the majority of European countries were displaying increased levels of confidence in the importance of vaccination than in their safety and effectiveness (figure 2).

"Our findings suggest that people do not necessarily dismiss the importance of vaccinating their children even if they have doubts about how safe vaccines are", says co-lead author Clarissa Simas from the London School of Hygiene & Tropical Medicine, UK. "The public seem to generally understand the value of vaccines, but the scientific and public health community needs to do much better at building public trust in the safety of vaccination, particularly with the hope of a COVID-19 vaccine." [1]

In 2019, Iraq (95%), Liberia (93%), and Senegal (92%) had the highest proportion of respondents who agreed that it is important for children to be vaccinated, while Hong Kong (36%), Russia (34%), and Albania (26%) reported the lowest proportion strongly agreeing on the importance of vaccines.

The study also found that being male or less educated were linked with a lower chance of vaccine uptake, whilst trusting health-care workers the most for medical or health advice, rather than family, friends, and other non-medical sources for health advice was associated with increased chances of vaccine uptake (figure 4). Researchers found a weaker association between minority religious groups (or those refusing to provide their religious belief) and lower likelihood of vaccine uptake.

The researchers note some important limitations of the study, including wide confidence intervals, and a lack of consistency between survey responses, that meant vaccination beliefs were pooled into extreme categories of "strongly agree" or "strongly disagree", potentially masking key information. They also note that vaccination status was based on parental recall, and that the findings do not reveal whether attitudes were related to specific vaccines.

Writing in a linked Comment, lead author Dr Daniel Salmon (who was not involved in the study) from John Hopkins Bloomberg School of Public Health, USA, says that most vaccine scares are not supported by scientific evidence, adding that, "Vaccines have a remarkable safety record, based on rigorous processes of phased randomised controlled trials and on licensure requirements, which have ensured that the benefits of vaccination outweigh the risks. Situations such as Dengvaxia are exceedingly rare."

He concludes that global investment in vaccine safety and communication infrastructure is much needed: "[...] without substantial global investment in active vaccine safety surveillance, continuous monitoring of public perceptions, and development of rapid and flexible communication strategies, there is a risk of SARS-CoV-2 vaccines never reaching their potential due to a continued inability to quickly and effectively respond to public vaccine safety concerns, real or otherwise. With every crisis comes opportunity; it should not be ignored."

A blood test that can identify a variety of mutations in advanced breast cancer can reliably match women to effective targeted treatments, early results of a major clinical trial reveal.

The plasmaMATCH trial provides the strongest evidence yet that simple blood tests known as 'liquid biopsies' can benefit women with breast cancer by tracking their disease as it evolves and directing them to the most effective treatments.

Researchers showed that the blood test is now reliable enough to be offered to patients on the NHS once it has passed approval, raising the prospect of a major reshaping of care that could speed up access to the best available drugs.

A team at The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust, analysed blood samples from more than 1,000 women with breast cancer that had recurred after treatment or spread to another part of the body. The aim was to see whether the blood test could help improve treatment for the significant proportion of women whose breast cancer is caused by one of a variety of rarer mutations - as opposed to better-known defects like BRCA mutations.

The plasmaMATCH trial was largely funded by Stand Up To Cancer, a joint fundraising campaign from Cancer Research UK and Channel 4, with additional support from AstraZeneca, Breast Cancer Now and Puma Biotechnology, and the new findings are published in The Lancet Oncology today (Thursday).

Researchers at The Institute of Cancer Research (ICR) and The Royal Marsden were able to reliably detect mutations found in tumour DNA that had been shed into the bloodstream of women with advanced breast cancer. They then went on to match patients to targeted treatments according to the specific mutations in the tumour DNA.

The researchers looked at three targetable defects in genes called HER2, AKT1 and ESR1, which are known to drive breast cancer. A total of 142 women with these detectable mutations were then given experimental drugs targeted against the specific characteristics of their cancer.

Women with ESR1 mutations were treated with fulvestrant, while women with HER2 mutations received neratinib on its own or with fulvestrant. Women with AKT1 mutations were split into two groups, according to whether their cancer was oestrogen receptor positive or not, and were treated with capivasertib plus fulvestrant, or with capivasertib on its own.

Researchers found that some women with HER2 and AKT1 mutations responded to the treatments assigned to them - suggesting that liquid biopsies can successfully match patients with certain rare forms of advanced breast cancer to more effective treatments.

Five out of 20 women with rare HER2 mutations who were matched to neratinib saw a beneficial response - meaning cancer growth was slowed or stopped, or tumours were shrunk.

Meanwhile, four out of 18 patients with AKT1 mutations responded to capivasertib. However, the treatment targeting the ESR1 mutation was not found to be effective.

Researchers also validated the findings by checking tissue samples from the patients to confirm that the liquid biopsies had correctly identified the presence or absence of the mutations in over 93% of cases - sufficiently accurate to implement in routine care.

The team believes that findings from the plasmaMATCH trial will help make a strong case for the adoption of liquid biopsies into clinical practice for patients with advanced cancer - a case strengthened by the fact that liquid biopsies are easier to take, faster to analyse and less painful for patients than standard tissue biopsies.

Liquid biopsies also offer a more dynamic alternative that could keep track of cancers as they evolve over time and their range of mutations changes.

For the targeted drugs that have shown initial promise in this study, the next step is to carry out larger clinical trials to assess whether they are better than existing treatments. The hope is that larger trials will lead to more targeted treatments being approved, providing new treatment options for patients with rare subtypes of breast cancer.

Study leader Professor Nick Turner, Professor of Molecular Oncology at The Institute of Cancer Research, London, and Head of the Ralph Lauren Centre for Breast Cancer Research at The Royal Marsden, said:

"Our findings show that simple blood tests can quickly and accurately tell us the genetic changes present in a patient's cancer, and use that information to select the most suitable available treatment.

"Using a liquid biopsy could be particularly important for patients with advanced breast cancer, to help select the most appropriate treatment.

"Tests that detect tumour DNA in the blood have huge potential and could transform how doctors select targeted therapies for patients with advanced cancer. Our study shows that these liquid biopsies can pick up the mutations that drive a patient's breast cancer, and can successfully match patients with the best available precision medicine for their cancer."

Study co-leader Professor Judith Bliss, Professor of Clinical Trials at The Institute of Cancer Research, London, and Director of its Cancer Research UK-funded Clinical Trials and Statistics Unit, said:

"The plasmaMATCH trial platform has allowed us to look at the activity of various different treatments at the same time. This efficient trial set-up has been a success and it is already starting to bring patients closer to new targeted treatments."

Professor Paul Workman, Chief Executive of The Institute of Cancer Research, London, said:

"It's exciting to see the first results emerging from the pioneering plasmaMATCH trial. The findings demonstrate the powerful potential of liquid biopsies to pick up mutations that although individually rare can collectively play an important role in causing many breast cancers. Crucially, the study shows that matching women to the best available precision medicine for their tumour, using a blood test rather than an invasive tissue biopsy, can have real clinical benefits.

"These findings should lay the foundation for liquid biopsies to become a standard part of patient care for patients with breast cancer, and help accelerate women's access to the best available precision medicines."

Michelle Mitchell, Chief Executive of Cancer Research UK, said:

"Our Stand Up To Cancer initiative allows us to quickly transform any promising discoveries made in the lab into new tests and treatments for people with cancer. So it's absolutely fantastic that we are looking at the possibility of using a simple blood test to quickly match the best treatments for women with advanced breast cancer. It's results like these that will help us see 3 in 4 people survive their cancer by 2034."

Knowledge may be critical for personalized medicine

Information could be used for diagnostics, drug development, predicting outcomes

Genes found for women's breast cancer progression, male balding patterns

CHICAGO --- Biological sex has a small but ubiquitous influence on gene expression in almost every type of human tissue, reports a new study from Northwestern Medicine, the University of Chicago and the Centre for Genomic Regulation in Barcelona. Gene expression is the amount of product created by a gene for cell function.

These sex differences are observed for genes involved in many functions, including how people respond to medication, how women control blood sugar levels in pregnancy, how the immune system functions, and how cancer develops.

The study will be published September 10 in Science.

Sex also has a weaker but important effect on how genetic variation between individuals impacts their gene expression levels. The scientists discovered 369 instances where a given genetic variant present in males and females impacted gene expression to a different degree in each sex. This enabled the scientists to discover 58 previously unreported links between genes and complex traits such as blood pressure, cholesterol levels, breast cancer and body fat percentage.

"These discoveries suggest the importance of considering sex as a biological variable in human genetics and genomics studies," said project leader Barbara Stranger, an associate professor of pharmacology at Northwestern University Feinberg School of Medicine.

By taking an approach that specifically looks for differences between males and females, the scientists discovered previously unknown links between specific genes and specific human traits that were missed by approaches that considered males and females as a single group. Furthermore, the study reported a portion of previously reported gene-trait links were true only for a single sex.

"The significance of this is if specific genes or genetic variants contribute differentially to a given trait in males and females, it could suggest sex-specific biomarkers, therapeutics and drug dosing," Stranger said. "In the future, such knowledge may form a critical component of personalized medicine or may reveal disease biology that remains obscured when considering males and females as a single group."

Sex differences exist for many human traits and disease characteristics (e.g., age of onset, severity, response to treatment) and have been previously attributed to hormones, sex chromosomes and differences in behavior and environmental exposures. But the molecular mechanisms and underlying biology remain largely unknown.

In this study, scientists investigated sex differences in the human transcriptome, which is the sum of all RNA transcripts in a cell, from 44 types of healthy human tissue from 838 individuals. For each gene, the scientists tested whether the average amount of gene expression in females differed from the amount in males.

They discovered more than a third of all human genes (37%) were expressed at different levels in males and females in at least one type of tissue. Although these effects were abundant, the amount that gene expression differed was mostly small.

The genes with differential expression between males and females represented diverse molecular and biological functions, including genes relevant to disease and clinical traits, many of which had not been previously associated with sex differences.

All of these gene-trait associations suggest a causal link between specific genetic variants and a trait.

"Finding these links helps us to understand the biology underlying the trait," Stranger said. "If we understand the biology of a trait, we can try to use that information for diagnostics, drug development and predicting outcome."

In women, the genetic regulation of CCDC88 expression is strongly associated with the progression of breast cancer. The finding could motivate researchers to assess whether gene expression of CCDC88 is a useful biomarker for cancer progression in women, Stranger noted.

HKCD1 was associated with birth weight in women. Researchers hypothesize that HKDC1 may impact birth weight through altering glucose metabolism in the liver of a pregnant woman.

In men, DPYSL4 was associated with body fat percentage and CLDN7 with birth weight.

The genetic regulation of C9orf66 in males was associated with balding patterns in males. Prior to this study, little was known about the gene. With this discovery, investigators can design experiments to better characterize the role of this gene in balding patterns in males.

The study has some limitations. The researchers note despite extensive sex differences at the transcriptome level, the majority of human biology at all levels is shared between males and females. The findings are based on a snapshot of mostly older individuals. The analysis also does not account for sex differences that occur during different developmental stages or in specific environments.