Body

Seasonal fluctuations drive the dynamics of many infectious diseases. For instance, the flu spreads more readily in winter. Two scientists from the University of Nantes* and the CNRS** in Montpellier have developed a mathematical model to predict the risk of the emergence of an epidemic, depending on the time of the year at which the pathogen is introduced. Their theoretical predictions, which accounts for random factors acting on the birth and death rates of the pathogen, highlight an interesting temporal dynamic when these pathogens have a "winter" period. This is not necessarily the season of the same name, but a period which is less favourable to them (when the birth rates is lower than the death rate). According to their research, a pathogen introduced just before this "winter" has a much lower probability of escaping extinction and causing a large epidemic. The scientists have called this the "winter is coming" effect. Their theoretical model, it is thought, will make it possible to develop better strategies to act on seasonal epidemics. Intervention at the right time could amplify this effect and would thereby generate unfavourable conditions for the emergence of an epidemic.

This research is published in PLOS Computational Biology.

Individuals with genetic risk factors for dementia can still reduce their risk by improving their cardiovascular health.

A new Boston University School of Public Health (BUSPH) and School of Medicine (BUSM) study finds that genes and cardiovascular health can both raise or lower risk of dementia.

Published in the journal Neurology, the study finds that dementia-associated common gene variants or the APOE ?4 genotype can more than double dementia risk, but that good cardiovascular health can halve dementia risk. These effects are additive, meaning genes and cardiovascular health can independently add to or subtract from a person's risk of developing dementia.

"Just because you have a high genetic risk of dementia doesn't mean that you can't lower your risk by adopting a healthier lifestyle," says study lead author Dr. Gina Peloso, assistant professor of biostatistics at BUSPH.

Peloso and colleagues used data from 1,211 participants in the offspring cohort of the BU-based Framingham Heart Study, the longest-running cardiovascular disease study in the U.S. (The study began in 1948, and the offspring cohort are the original participants' children and their spouses.) The analysis included genetic information, cardiovascular health data from 1991-1995, and data from the Framingham Heart Study's regular dementia screenings beginning in 1998-2001.

The researchers found that participants with a high genetic risk score based on several common gene variants were 2.6 times more likely to develop dementia than participants with a low genetic risk score. The researchers also looked separately at the dementia-associated APOE ?4 genotype, found in 10-15% of the general population, and found that participants with at least one APOE ?4 allele were 2.3 times more likely to develop dementia than participants without one.

Previous research has suggested that cardiovascular health affects a person's risk of dementia and Alzheimer's. For this study, the researchers scored participants on the American Heart Association's seven components of cardiovascular health: physical activity, cholesterol, healthy diet, blood pressure, weight, blood glucose, and smoking status. They found that participants with a favorable cardiovascular health score were 55% less likely to develop dementia than participants with an unfavorable score.

The researchers did not find any interaction between genetic risk score or APOE ?4 and cardiovascular health, indicating that these risk factors independently affect dementia risk.

"We have long maintained that genetics is not destiny, that the impact of your family history and genetic risk can be lowered by healthy lifestyle choices. This is true for persons with low genetic risk and also for persons with high genetic risk of dementia, so it is never too soon and never too late to adopt a 'heart-healthy lifestyle," says study senior author Dr. Sudha Seshadri, founding director of the Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases at The University of Texas Health Science Center at San Antonio. She is also a professor of neurology at BUSM and the Framingham Heart Study's principal investigator in neurology.

The adage "all things in moderation" applies not to just to food and drink, but also to the legions of bacteria inside our guts helping us digest that food and drink. It turns out the rule may also extend to the lesser understood bacteriophages, which are viruses that infect the bacteria living inside us.

Like Russian nesting dolls, our bodies host close to 100 trillion bacterial cells that make up our microbiomes--and those bacterial cells have their own inhabitants.

"We're appreciating more and more that the most abundant microbial entities in the human gut are actually viruses," says Eric Martens, Ph.D., associate professor of microbiology and immunology at the University of Michigan's Medical School.

His team has been exploring the puzzling way bacteria and their viruses appear to coexist inside the human gut. The secret may lie in a hairy-looking sugar coating bacteria used to defend not only against attacks from the human immune system, but also from various viruses seeking a way in.

Using a common gut bacteria Bacteroides thetaiotaomicron, or BT for short, Martens' team began to look at the complex interaction between BT and viruses, by pitting them against each other in the lab.

When challenged with viruses, or phages, collected from waste water, some of the bacteria were able to resist infection while some were not. "When a particular phage comes along that can kill certain members of the population, it does so and the resistant bacteria quickly grow out," says Martens.

However, instead of permanently altering the receptor that allowed the viral penetration, and potentially harming itself, some of the bacteria temporarily turn on a resistant state through a reversible process called a phase variation. But some of members of the bacterial population, unaware of the phage's continued presence, turn off this resistance switch, leaving them susceptible to infection...and on and on.

The team genetically engineered the BT strain to express just one of eight chemically-distinct capsules and a version with no coating at all. In all cases, infection could be blocked by some, but not all, of the capsules. Surprisingly, the researchers noted that the bald bacteria were also able to evade infection. "We were intrigued to see we could take away all of the capsules and still infect it with these phages and the bacteria could still survive, which necessitates that they have a backup mechanism in place," Martens says.

The interplay between the gut microbiome and their phages could have implications for human disease. "One of our hypotheses is that individuals carry different types of viral loads in their guts. Some could be more or less immunogenic, interacting with our immune system to cause inflammation. But they also might modify the physiology of the bacteria that are there by forcing them to express certain functions/capsules that we also know interact with the immune system," says Martens.

He says the study helps explain this age old observation that these bacteria coexist with their viruses. Notes Martens, "Neither side necessarily wins out over the other." As such, bacterial viruses could offer a way of beneficially altering the gut microbiome for the treatment of disease.

Researchers at The Rockefeller University in New York have developed new tools to rapidly test the ability of antibodies to neutralize SARS-CoV-2, the novel coronavirus responsible for the COVID-19 pandemic. The approach, described today in the Journal of Experimental Medicine (JEM), will help researchers understand whether patients are susceptible to reinfection by SARS-CoV-2 and assess the effectiveness of experimental vaccines, as well as develop antibody-based therapies against the disease.

People infected with SARS-CoV-2 produce neutralizing antibodies that prevent the virus from infecting cells by binding to the spike protein on the virus’s surface. Early studies have suggested that the strength of this antibody response varies greatly between patients, and it remains unknown how long any such neutralizing antibodies persist in the blood to provide protection against reinfection.

Meanwhile, efforts are under way to treat and prevent COVID-19 using either purified antibodies or whole blood plasma collected from convalescent patients who produce large amounts of neutralizing antibodies. Moreover, any successful vaccine against SARS-CoV-2 will have to induce the production of neutralizing antibodies.

“Whether elicited by natural infection or vaccination, or administered as convalescent plasma or in recombinant form, neutralizing antibodies will likely be crucial for curtailing the global burden of COVID-19 disease,” says Paul D. Bieniasz, a professor at The Rockefeller University and investigator at the Howard Hughes Medical Institute. “For this reason, the availability of rapid, convenient, and accurate assays that measure neutralizing antibody activity is crucial for evaluating naturally acquired or artificially induced immunity against SARS-CoV-2.”

Antibody tests using the SARS-CoV-2 virus itself are labor intensive and must be carried out in biosafety level 3 facilities, limiting their widespread application. Bieniasz and colleagues therefore developed a number of safer, surrogate viruses that can be used in place of SARS-CoV-2 to test the neutralizing activity of antibodies targeting the coronavirus spike protein.

The surrogate viruses are versions of either the human immunodeficiency virus type-1 (HIV-1) or vesicular stomatitis virus (VSV) that produce the SARS-CoV-2 spike protein instead of their own surface proteins. Some of these surrogate viruses are unable to replicate, making them even safer to use in the laboratory. Moreover, the viruses are engineered to generate fluorescent or luminescent infected cells, making it easy for researchers to track infection and measure how well this process is blocked by potential neutralizing antibodies.

Bieniasz and colleagues tested the ability of convalescent patient plasma samples and purified antibodies to block the entry of the surrogate viruses into human cells grown in the laboratory. “Each of the surrogate virus-based assays generated quantitative measurements of neutralizing activity that correlated well with neutralization measured using authentic SARS-CoV-2,” says Theodora Hatziioannou, a research associate professor at Rockefeller who co-directed the study with Bieniasz. “In just a few weeks, we have already used these assays to determine the neutralizing potencies of hundreds of plasma samples and monoclonal antibodies in a biosafety level 2 laboratory.”

Bieniasz adds, “Automation and additional miniaturization is certainly feasible to further increase throughput—a notable consideration given the sheer number of vaccine candidates in the development pipeline. We think that these surrogate viruses and assays will be of significant use in curtailing the COVID-19 pandemic.”

A USC-led team of scientists has found that a fasting-mimicking diet combined with hormone therapy has the potential to help treat breast cancer, according to newly published animal studies and small clinical trials in humans.

In studies on mice and in two small breast cancer clinical trials, researchers at USC and the IFOM Cancer Institute in Milan -- in collaboration with the University of Genova -- found that the fasting-mimicking diet reduces blood insulin, insulin-like growth factor 1 (IGF1) and leptin. In mice, these effects appear to increase the power of the cancer hormone drugs tamoxifen and fulvestrant and delay any resistance to them. The results from 36 women treated with the hormone therapy and fasting-mimicking diet are promising, but researchers say it is still too early to determine whether the effects will be confirmed in large-scale clinical trials.

The research was published in the journal Nature.

"Our new study suggests that a fasting-mimicking diet together with endocrine therapy for breast cancer has the potential to not only shrink tumors but also reverse resistant tumors in mice," said Valter Longo, the study's co-senior author and the director of the Longevity Institute at the USC Leonard Davis School of Gerontology and professor of biological sciences at the USC Dornsife College of Letters, Arts and Sciences. "We have data that for the first time suggests that a fasting-mimicking diet works by changing at least three different factors: IGF1, leptin and insulin."

The researchers say the two small clinical trials are feasibility studies that showed promising results, but they are in no way conclusive. They believe the results support further clinical studies of a fasting-mimicking diet used in combination with endocrine therapy in hormone-receptor-positive breast cancer.

The scientists also contributed to a recent clinical study of 129 breast cancer patients conducted with the University of Leiden. The results, published last month in Nature Communications, appeared to show increased efficacy of chemotherapy in patients receiving a combination of chemotherapy and a fasting-mimicking diet.

In the two new small clinical trials -- one of which was directed by the study co-corresponding author Alessio Nencioni -- patients with hormone-receptor-positive breast cancer receiving estrogen therapy along with cycles of a fasting-mimicking diet seemed to experience metabolic changes similar to those observed in mice. These changes included a reduction in insulin, leptin and IGF1 levels, with the last two remaining low for extended periods. In mice, these long-lasting effects are associated with long-term anti-cancer activity, so further studies in humans is needed.

"Some patients followed monthly cycles of the fasting-mimicking diet for almost two years without any problems, suggesting that it is a well-tolerated intervention," Nencioni said. "We hope this means that this nutritional program that mimics fasting could one day represent a weapon to better fight cancer in patients receiving hormone therapy without serious side effects."

"The results in mice are very promising. And the early clinical results show potential as well, but now we need to see it work in a 300- to 400-patient trial," Longo explained.

The data also suggest that in mice, the fasting-mimicking diet appears to prevent tamoxifen-induced endometrial hyperplasia, a condition in which the endometrium (or the lining of the uterus) becomes abnormally thick. The study authors believe this potential use of the fasting diet should be explored further, given the prevalence of this side effect of tamoxifen and the limited options for preventing it.

Approximately 80% of all breast cancers express estrogen and/or progesterone receptors. The most common forms of hormone therapy for these breast cancers work by blocking hormones from attaching to receptors on cancer cells or by decreasing the body's hormone production. Endocrine therapy is frequently effective in these hormone-receptor-positive tumors, but the long-term benefits are often hindered by treatment resistance.

Several clinical trials, including one at USC on breast cancer and prostate patients, are now investigating the effects of the fasting-mimicking diets in combination with different cancer-fighting drugs.

"I like to call it the nontoxic wildcard for cancer treatment," Longo said. "These clinical studies we have just published -- together with the many animal studies published in the past 12 years -- suggest that cycles of the fasting-mimicking diet has the potential to make standard therapy more effective against different cancers, each time by changing a different factor or nutrient important for cancer cell survival."

DES PLAINES, IL -- While the history and physical examination is important, only a few key signs and symptoms significantly change the underlying likelihood of community-acquired pneumonia (CAP). That is the conclusion of a study published in the July 2020 issue of Academic Emergency Medicine (AEM), a journal of the Society for Academic Emergency Medicine (SAEM).

The lead author of the study is Mark H. Ebell MD, MS, assistant professor in the department of emergency medicine at the University of Massachusetts Medical School-Baystate. The findings of the study are discussed with the author in a recent AEM podcast, "What's the Signs and Symptoms of Pneumonia?"

The history and physical examination is a critical component of the evaluation of patients with acute cough; however, many individual signs and symptoms have limited value (especially when absent) and only a few key signs and symptoms significantly change the underlying likelihood of community-acquired pneumonia.

The study suggests that knowledge of the signs and symptoms most predictive of CAP can help physicians focus their evaluation and avoid inappropriate antibiotic use. The authors suggest that teaching and performing these high value elements of the physical examination be prioritized, with the goal of better targeting chest radiographs and ultimately antibiotics.

The authors further recommend that future research should be performed to validate promising clinical prediction rules and to integrate signs, symptoms, and point-of-care tests such as C-reactive protein and to explore novel approaches to the development and validation of these rules.

Pulmonary arterial hypertension (PAH) is an insidious disease. Symptoms may begin slowly, and even before they appear, extensive damage has caused the obstruction of small arteries leading to increased blood pressure in the lungs. By the time symptoms -- most notably, shortness of breath -- become severe enough for someone with PAH to seek care and obtain a definitive diagnosis, the patient's chances of survival at five years are slightly better than 50 percent on currently available treatments.

Paul B. Yu, MD, PhD, a cardiovascular medicine specialist at Brigham and Women's Hospital, has been studying PAH for more than 15 years to better understand the fundamental process in which blood vessels in the lungs are lost to the disease. In a paper published in Science Translational Medicine, members of Yu's lab and co-authors at Brigham and Women's Hospital and Acceleron Pharma illuminate the underlying biological pathways that may lead to vessel destruction. Their results provide a biological explanation for why proteins called activins and growth and differentiation factors (GDFs) might contribute to pulmonary vascular disease, and provide an explanation of how the activin/GDF-blocking drug sotatercept, currently in clinical trials, may help treat patients with pulmonary arterial hypertension.

"We were delighted to contribute to the pre-clinical validation of sotatercept, and improve our understanding of the signaling molecules that drive pulmonary arterial hypertension." said Yu. "We hope these advances will lead to new treatment options for this incredibly vexing disease."

Currently, PAH is treated with vasodilators to widen lung blood vessels and increase blood flow. Yu and his team have uncovered biological insights that may help to affect the underlying disease process more directly. Previous studies have shown that there are heritable forms of PAH -- mutations in certain genes may impact the development, maturation and remodeling of arterial circulation. These genes are involved in two pathways: bone morphogenetic protein (BMP) signaling and transforming growth factor-β (TGFβ) signaling. It was thought that BMP was protective and higher levels TGF-β were destructive, but the specific mechanisms involved remain unclear. There were also indications that two other closely related ligands, known as GDFs and activins, were involved. These play important roles in reproductive biology, but what were they doing in the context of PAH?

In their Science Translational Medicine paper, Yu and colleagues present data from both human and rodent models to cohesively connect these various protein players. The team found increased levels of activin A, GDF8, and to a lesser degree GDF11 in lung lesions from patients with PAH and rodent models of the disease. The team then tested what would happen when they added a "ligand trap" -- a fusion protein that captures GDF and activin, blocking their activity. The team found that the fusion protein was more effective than vasodilators at treating PAH and preventing blood vessel remodeling, by restoring a more normal balance between proliferation and cell death of the cells that make up blood vessel walls. When mouse models were treated in the later stages of severe disease, the treatment increased the number of open lung vessels despite previous damage, in contrast to vasodilators which did not have this effect.

"It was unexpected to find such a prominent role for GDF and activin in PAH, but if they are helping to drive pulmonary vascular disease, it may help explain why a therapy that targets these ligands may be effective against PAH. Our research demonstrates that this central genetic pathway of PAH is tractable and can be exploited as a drug target," said co-lead author Peiran (Brian) Yang, PhD, a senior member of Yu's group at Brigham.

The ligand trap is currently under investigation as a treatment for PAH. The human version of this trap, known as sotatercept, was recently granted both Orphan Drug and Breakthrough Therapy designation by the United States Food and Drug Administration (FDA).

Acceleron Pharma, the manufacturers of sotatercept, recently announced the results of PULSAR, a phase 2 trial in patients with PAH. Patients treated with sotatercept experienced a statistically significant reduction in pulmonary vascular resistance (PVR), the trial's primary endpoint, compared to placebo. A second Phase 2 trial, SPECTRA, sponsored by Acceleron and led in part by Brigham investigators, will continue assessing the efficacy and safety of sotatercept in patients with PAH. The SPECTRA trial is ongoing and currently recruiting patients.

"There are still many unanswered questions, but with the clinically relevant degree of change seen in the clinical trial, coupled with our deeper understanding of the biology of the disease, the story of what drives this disease and how we may be able use that knowledge to treat are coming together in a way that is coherent," said Yu.

By André Julião | Agência FAPESP – Researchers affiliated with the University of São Paulo’s Ribeirão Preto Medical School (FMRP-USP) in Brazil have demonstrated the potential of a leukemia drug, arsenic trioxide, to treat medulloblastoma, a type of brain cancer most common in children. When they tested arsenic trioxide on cells taken from one of the most aggressive subgroups of this type of tumor, they obtained promising results in terms of tumor cell death. The drug also made the tumor cells more sensitive to radiation therapy.

The study, published in Scientific Reports, was supported by FAPESP.

“Twelve medulloblastoma subgroups are currently recognized according to their molecular characteristics, which also indicate the prognosis. One of the subgroups with the worst prognosis is known as SHH. This tumor has a somatic mutation in gene TP53, and it’s treated with chemical and radiation therapy,” said Paulo Henrique dos Santos Klinger, first author of the article, written as part of his master’s research at FMRP-USP, and supported with a scholarship from the National Council for Scientific and Technological Development (CNPq).

The study was part of the project “Interactions between emerging therapeutic targets and developmental pathways associated with tumorigenesis: emphasis on pediatric malignancies”, which is led by Luiz Gonzaga Tone, a professor at FMRP-USP.

“The project focuses on an in-depth investigation of dysregulation of the signaling pathways that control normal embryonic development and its link to the onset and progression of pediatric cancer,” Tone said.

Radiotherapy can have severe adverse effects on a child’s brain, causing cognitive, endocrine and motor problems. Hence, the importance of developing therapeutic strategies that reduce or eliminate the need for radiation is important.

In the study, the researchers selected different SHH tumor cell lines and tested different doses of arsenic trioxide, a medication used to treat acute myeloid leukemia. They also tested different doses of radiation in conjunction with the administration of the drug.

On its own, arsenic trioxide proved capable of killing tumor cells and preventing the formation of new tumor cell colonies. The effects were enhanced when the drug was combined with radiation therapy. The drug was not found to be significantly toxic when applied to healthy cells.

Moreover, arsenic trioxide alone could be used to treat pediatric medulloblastoma patients as old as three years, possibly in conjunction with the chemotherapy drugs typically used to treat this type of cancer. Children in this age group with brain cancer cannot be treated with radiation therapy since it may cause irreversible damage to the central nervous system.

Mutation

The drug was chosen because it is a well-known blocker of the SHH signaling pathway in leukemia. The SHH pathway is essential to human embryonic development and is deactivated when embryogenesis is complete. If the pathway is reactivated for some reason, which are currently unknown, then cancer can develop, including some types of skin cancer and various types of leukemia and medulloblastoma.

“Another advantage of arsenic trioxide is its capacity to cross the blood-brain barrier, which protects the central nervous system from circulating toxins or pathogens. Previous studies showed this penetration to be reasonable in medulloblastoma,” said Elvis Terci Valera, last author of the published paper. Valera is an attending physician at the teaching hospital (Hospital das Clínicas) operated by FMRP-USP and a professor at the institution’s child health program.

The prognosis for SHH-type medulloblastomas is typically intermediate, with 50% of patients responding well to treatment. However, the prognosis is worse when a somatic mutation occurs in TP53 because this gene plays a key role in cell division control via the SHH pathway and can counteract alterations that can lead to cancer.

“The germline mutation of this gene points to Li-Fraumeni syndrome, characterized by several clinical factors but generally involving the loss of function of TP53 and increasing the likelihood of various types of tumors,” Klinger said.

Li-Fraumeni syndrome (LFS) confers an inherited familial predisposition to a range of cancers. In children, it entails an augmented risk of the occurrence of medulloblastomas, especially those of the SHH subgroup.

The researchers now plan to test the drug in animal models to determine whether the results are the same as those of the cell experiments. If they are the same, then the treatment may subsequently tested in humans.

Race and ethnicity did not affect pregnancy and birth outcomes in women with SARS-CoV-2 infection who gave birth at two hospitals in northern Manhattan during the height of the pandemic in New York City, according to a preliminary report from researchers at Columbia University Irving Medical Center and NewYork-Presbyterian.

The study - one of the first to examine the impact of race and ethnicity on pregnancy and birth outcomes in women with COVID-19 during the height of the pandemic in New York City -- was published in Obstetrics & Gynecology.

"We did not detect an impact on obstetric complications and symptoms of COVID-19 in different groups of women, though we need to look at a larger group to make more definitive conclusions," says the report's first author Ukachi N. Emeruwa, MD, MPH, a postdoctoral clinical fellow in obstetrics and gynecology at NewYork-Presbyterian/Columbia University Irving Medical Center.

Racial and ethnic disparities in health care delivery and outcomes

Racial and ethnic disparities in healthcare delivery and outcomes have been well-described in most areas of medicine.

Such disparities have become a flash point during the COVID-19 pandemic, with several studies showing that ethnic minorities, including Blacks and Hispanics, have disproportionately higher infection rates and worse outcomes compared with other groups.

However, previous studies have not determined whether obstetric outcomes for pregnant women with COVID-19 vary by race and ethnicity.

What the researchers found

Between March 13 and April 23, 2020, 673 women gave birth at NewYork-Presbyterian Morgan Stanley Children's Hospital or NewYork-Presbyterian Allen Hospital.

Among the first 100 women who tested positive for SARS-CoV-2, 73 identified themselves as Hispanic, 10 as non-Hispanic Black, 13 as non-Hispanic white, and 4 as other.

Among these patients, Hispanic women were more likely to have SARS-CoV-2: 18% tested positive compared to nearly 13% of Black women and 9% of white women.

All of the groups had fairly similar rates of conditions like gestational diabetes and preeclampsia and complications including bacterial infections, preterm delivery, and postpartum bleeding. There were no differences in neonatal outcomes.

Close follow-up care

"Our medical center was among the first in New York City to implement universal SARS-CoV-2 testing among women admitted for delivery and provide more frequent follow-up care for women and newborns with COVID-19," says the study's senior author Cynthia Gyamfi-Bannerman, MD, MSc, the Ellen Jacobson Levine and Eugene Jacobson Professor of Women's Health in Obstetrics and Gynecology at Columbia University Vagelos College of Physicians and Surgeons, and a maternal-fetal medicine expert at NewYork-Presbyterian/Columbia University Irving Medical Center. "These measures may explain why we found similar birth outcomes across all ethnic groups, including those from economically disadvantaged neighborhoods."

Emeruwa and Gyamfi-Bannerman are now conducting a larger study that will compare birth outcomes in women with and without COVID-19 from different ethnic and racial groups.

San Juan Capistrano, Calif. - A new study shows significant benefits of the Ellipsys® Vascular Access System in easily and safely creating durable vascular access for end-stage renal disease (ESRD) patients who require hemodialysis. It also offers a standardized process for using the minimally invasive technology that other physicians can follow to reproduce the results, which "will make it easier for more practitioners to adopt this patient-friendly approach to dialysis access," explained lead author Alexandros Mallios, MD, a vascular surgeon at Institut Mutualiste Montsouris of Paris, France.

Hemodialysis requires access to the patient's bloodstream, which is often created by establishing a permanent connection between an artery and a vein in the arm known as an arteriovenous fistula (AVF). Traditionally, fistulas are created during an open surgical procedure by suturing the artery and vein together. In contrast, the Ellipsys System uses a small needle puncture and catheter to create a percutaneous AVF (pAVF) without an implant or suture, leaving the vessels and tissue around the AVF undisturbed.

Published in the Journal of Vascular Surgery (JVS), this marks the largest study of any pAVF technique to date. Of the 232 patients who had an Ellipsys pAVF created between May 2017 and July 2019, there were no adverse events and 96 percent still had fully functioning fistulas with strong blood flow after a year. That "patency rate" is higher than published rates for surgically created fistulas, which average about 60% after one year.

"Vascular access is quite literally the lifeline for dialysis patients," said Dr. Mallios. "The advantages of the percutaneous Ellipsys fistula are that it is a very safe, simple and reproducible way to create a fistula that will function for a long time with minimal interventions."

In addition, the study reported that patients were able to begin using their pAVF for dialysis an average of four weeks after creation, with six percent of fistulas becoming functional (or "mature") in as little as two weeks. Such rapid maturation can have a significant impact on patient safety, as it avoids the use of a central venous catheter (CVC) if they need to begin dialysis quickly. Compared to fistulas, CVCs are associated with significantly higher rates of complications, including infection and even death.

One of the most important aspects of the study, Dr. Mallios added, is that it offers a protocol for fistula creation, maturation and maintenance--which should make it easier for other physicians to adopt the relatively new procedure. For example, the study shows the benefit of adding a new step to the procedure--performing balloon angioplasty immediately after a fistula is created. That improves blood flow and speeds maturation, and could improve patency rates without increasing the need for additional maintenance procedures.

"Dr. Mallios' results are very exciting, particularly with such a large patient population, as it adds to the growing body of evidence that this approach offers a safe and effective way to quickly create a functional percutaneous fistula," said Mark Ritchart, President and CEO of Avenu Medical. "He also uses his valuable experience as a guide to enable more widespread use of percutaneous fistulas, which may improve patient safety by reducing reliance on riskier vascular access options."

In April, JVS published a case report by Dr. Mallios that featured a 3-D rendering of the Ellipsys pAVF on the cover of the publication. Dr. Mallios also co-authored two recent papers in the Journal of Vascular Access that discussed patient eligibility for Ellipsys and the similarities between an Ellipsys pAVF and a surgical AVF, the current standard of care.

In addition, recently published long-term Ellipsys data showed a functional patency rate of 92 percent at two years. The study also found high levels of patient satisfaction with the procedure.

Cleared by the FDA in 2018 for patients with end-stage kidney disease, Ellipsys is the first significant innovation in AVF creation in over 50 years. It transforms a complex surgery into a minimally invasive procedure that can be performed in a hospital outpatient setting or ambulatory surgery center. Since 2015, more than 1,800 patients worldwide have had the Ellipsys procedure.

A scientific analysis of more than 2,000 brain scans found evidence for highly reproducible sex differences in the volume of certain regions in the human brain. This pattern of sex-based differences in brain volume corresponds with patterns of sex-chromosome gene expression observed in postmortem samples from the brain's cortex, suggesting that sex chromosomes may play a role in the development or maintenance of sex differences in brain anatomy. The study, led by researchers at the National Institute of Mental Health (NIMH), part of the National Institutes of Health, is published in Proceedings of the National Academy of Sciences.

"Developing a clearer understanding of sex differences in human brain organization has great importance for how we think about well-established sex differences in cognition, behavior, and risk for psychiatric illness. We were inspired by new findings on sex differences in animal models and wanted to try to close the gap between these animal data and our models of sex differences in the human brain," said Armin Raznahan, M.D., Ph.D., study co-author and chief of the NIMH Section on Developmental Neurogenomics.

Researchers have long observed consistent sex-based differences in subcortical brain structures in mice. Some studies have suggested these anatomical differences are largely due to the effects of sex hormones, lending weight to a "gonad-centric" explanation for sex-based differences in brain development. However, more recent mouse studies have revealed consistent sex differences in cortical structures, as well, and gene-expression data suggest that sex chromosomes may play a role in shaping these anatomical sex differences. Although the mouse brain shares many similarities with the human brain, it is not clear whether these key findings in mice also apply to humans.

To explore the neurobiological basis of sex differences in the human brain, Raznahan, lead author Siyuan Liu, Ph.D., and colleagues first analyzed neuroimaging data collected as part of the Human Connectome Project (HCP). The data, obtained from 976 healthy adults between the ages of 22 and 35, revealed consistent sex differences in the volume of certain cortical structures. On average, females had relatively greater cortical volume in the medial and lateral prefrontal cortex, orbitofrontal cortex, superior temporal cortex, and lateral parietal cortex. Males, on average, had relatively greater cortical volume in ventral temporal regions and occipital regions, including the temporal pole, fusiform gyrus, and primary visual cortex.

Liu and colleagues then used two complementary approaches to determine whether these findings were reproducible. First, the researchers conducted 1,000 split-half comparisons by randomly splitting the HCP dataset in half and comparing results in the two halves. The results of these split-half comparisons indicated that the pattern of sex-based differences in cortical volume was highly stable. Second, the researchers quantified the reproducibility of the HCP findings in an unrelated neuroimaging dataset from the UK Biobank. Although the datasets had notable demographic and methodological differences, the researchers found that the overall pattern of sex-based differences in cortical volume was highly consistent.

Liu and co-authors then cross-referenced their anatomical findings with publicly available maps of gene-expression in the brain, which are based on 1,317 postmortem tissue samples from six human donors. The results indicated that the spatial pattern of sex differences in cortical volume was similar to the spatial pattern of sex-chromosome gene expression in the cortex. Specifically, regions of the cortex with relatively high expression of sex-chromosome genes tended to have greater cortical volume in males than females.

This correspondence with cortical expression of sex-chromosome genes is also consistent with findings from earlier mouse studies, suggesting that sex differences in brain anatomy may be due, at least in part, to genetic mechanisms that have been conserved throughout mammalian evolution. These findings suggest that sex differences in cortical volume may be influenced by genes located on the X and Y sex chromosomes.

"Males and females differ on many genetic and environmental factors that could all potentially influence brain development. Because it is challenging to experiment in humans, we often rely on observational data to infer potential genetic or environmental drivers of brain sex differences," said Raznahan. "The fact that we observed a very high level of reproducibility of anatomical sex differences across different groups of males and females, and a link between these differences and sex chromosome gene expression, suggests these differences are likely not primarily the result of environmental effects alone."

The researchers also compared the anatomical findings with data from more than 11,000 functional neuroimaging studies. The results indicated spatial overlap between areas of the brain that showed sex-based differences in cortical volume in the HCP dataset and areas of the brain associated with face processing in functional neuroimaging studies.

Taken together, these findings shed light on the mechanisms that may contribute to sex-based differences in brain anatomy and point to genetic factors that may contribute to sex-based differences in brain disease and behavior. With these correlational findings as a roadmap, future research can more efficiently investigate the causes and consequences of sex differences in the human brain.

Scientists at Sanford Burnham Prebys Medical Discovery Institute have shown that the blood protein vitronectin is a promising drug target for dry age-related macular degeneration (AMD), a leading cause of vision loss in Americans 60 years of age and older. The study, published in the Proceedings of the National Academy of Sciences (PNAS), also holds implications for Alzheimer's and heart disease, which are linked to vitronectin.

"Our findings suggest that vitronectin, which is shaped like a sticky propeller, orchestrates the formation of the spherical deposits that accumulate and cause dry AMD," says Francesca Marassi, Ph.D., director of the Cancer, Molecules and Structures Program at Sanford Burnham Prebys and senior author of the study. "With this information, we can look for drugs that prevent the deposits from forming and help people retain their sight for as long as possible."

More than 11 million Americans have AMD; and this number is expected to double by 2050 as the U.S. population ages. Of the two types of macular degeneration--wet and dry--the dry form is the most common, making up approximately 80 to 90% of cases. While the progression of dry AMD can be slowed with lifestyle changes, such as taking vitamin supplements, eating healthy, and not smoking, no pharmaceutical treatment exists.

New insights into deposit formation

Dry AMD is caused by the progressive accumulation of drusen, pebble-like deposits at the back of the eye, which results in blurry vision and, over time, vision loss. While scientists knew that these deposits contain cholesterol, fats (lipids), proteins such as vitronectin, and a mineralized form of calcium phosphate called hydroxyapatite--the same material that forms teeth and bone--how these deposits form was unknown.

In the study, Marassi and her team used the structure of vitronectin--which was solved by Marassi last year--and various sophisticated biophysical tools to prove that the propeller top tightly clasps calcium and hydroxyapatite. These findings suggest a mechanism by which vitronectin drives the formation of the abnormal deposits--and reveal how this process might be interrupted.

"We know that these deposits have a cholesterol-rich lipid core that is surrounded by a shell of hydroxyapatite and a final topcoat of vitronectin," says Marassi. "Our study suggests that vitronectin brings all these pieces together in one place to build up this complex assembly. With this information, we can start to figure out how to disrupt these interactions and break up this deposit."

Forging ahead to drug development

Marassi is already working with scientists at the Institute's Conrad Prebys Center for Chemical Genomics to identify vitronectin-targeting compounds that can stop drusen from forming. This drug candidate would hold promise as a treatment that slows the progression of dry AMD and potentially other plaque-related conditions. Vitronectin is also a major component of the amyloid plaques linked to Alzheimer's disease and the cholesterol-rich plaques that cause heart disease.

"For diseases such as dry AMD and Alzheimer's that have no effective treatment, the need for innovative science is painfully clear," says Diane Bovenkamp, Ph.D., vice president of Scientific Affairs at BrightFocus Foundation, a nonprofit that advances research on macular degeneration, Alzheimer's and glaucoma. "We are hopeful that these findings on how disease-associated proteins bind together will help scientists to design better drugs that could lead to treatments for one or more of these diseases with unmet clinical needs."

A new nanoparticle vaccine for SARS-CoV-2, the virus that causes COVID-19, has shown hints of protection and immunity in a preclinical study, safely eliciting the production of antibodies and antiviral T cell responses in mice and pigtail macaques. The vaccine generated robust immune responses with a single injection in mice - an important goal for vaccine researchers. Although more studies are needed to establish its protection, the vaccine represents a promising candidate for a badly needed, practical vaccine for COVID-19. To be successful in the field, any COVID-19 vaccine would need to protect people from disease after only one or two doses and would incorporate ingredients that can be easily manufactured and distributed. Here, Jesse Erasmus and colleagues formulated a vaccine for SARS-CoV-2 based on repRNAs, molecules that tend to generate stronger immune responses compared with the mRNAs used in more conventional vaccines. Their vaccine, named repRNA-CoV2S, includes repRNAs based on sequences from the SARS-CoV-2 spike protein - which allows the virus to enter human cells - alongside an emulsion of nanoparticles that enhance the vaccine's immunogenicity and stability. The authors saw that a single injection produced large amounts of antibodies against SARS-CoV-2 in mice and adding a booster injection heightened the vaccine's effects in older rodents and generated strong responses from T cells in the spleen and lungs. Both the single-shot and booster approaches were safe and produced similar responses in macaques that lasted for at least 70 days. Furthermore, antibodies from the macaques neutralized quantities of the SARS-CoV-2 virus similar to the concentrations observed in the serum of people recovering from infection. The authors note they plan to begin clinical development of the vaccine under the name HDT-301.

BOSTON - When prostate cancer progresses to a more-dangerous metastatic state, it does so by resurrecting dormant molecular mechanisms that had guided the fetal development of the prostate gland but had been subsequently switched off, say scientists from Dana-Farber Cancer Institute.

The study, an international collaboration with The Netherlands Cancer Institute, was published in Nature Genetics. "It shows that particular programs that were operative during prostate fetal development become reactivated during metastatic disease," said Matthew Freedman, MD, a Dana-Farber medical oncologist and co-corresponding author of the report. "The reactivation of these programs is presumably important for the spread of the disease, and if we could understand it better, and potentially block or inhibit the process, it may help us to suppress metastatic prostate disease."

The insight, gained from one of the largest studies of charting the epigenetic landscape in normal, cancerous, and metastatic prostate tissues, could lay the groundwork for identifying ways of slowing or preventing the initiation and spread of prostate cancer, the investigators say. The comprehensive study of epigenetic changes in prostate cancer, the authors propose, "is foundational for understanding the mechanisms underlying tumor progression" and identifying viable therapeutic targets and vulnerabilities.

The discovery reflects the crafty, efficient nature of cancer's survival strategies. The investigators showed that cells in a localized prostate tumor need not adopt a new mechanism to acquire the characteristics that enable them to migrate away from their origin and travel around the body. Rather, they reactivate a molecular pathway which, in the developing embryo and fetus, had enabled cells to move about and invade tissues to form the prostate gland in fetal development. Then, no longer needed, the pathway was shut down in the mature prostate gland. Although silenced, the molecular "memory" of the mechanism remained present in the epigenome of the prostate cells.

"As the cancer cell searches for ways to grow and metastasize, it appears to access and hijack the program that is most easily 'visible' - the bookmarked developmental site," explained Mark Pomerantz, MD, co-first author of the report. He is a medical oncologist in the Lank Center for Genitourinary Oncology at Dana-Farber. "Development is a time of great movement and a time of great invasion - similar traits that are used by tumor cells to metastasize," explained Freedman.

"We were amazed to see this was a universal phenomenon, shared by all metastatic prostate tumors we studied," said Wilbert Zwart, PhD, of the Netherlands Cancer Institute and co-corresponding author of the study.

Prostate cancer can be viewed as an epigenetic disease. Epigenetics literally means "above" or "on top of" genetics and refers to modifications that turn genes "on" or "off" without changing the DNA sequence.

The investigators say that the study produced the largest epigenomic dataset in prostate biology spanning normal, prostate tumors, as well as metastatic prostate disease. "It's a landscape that will serve as a foundation for countless other investigators to utilize these data within their own experiments," said Pomerantz.

The researchers analyzed 268 sets of epigenetic data from patient-derived samples related to the transition of normal prostate tissue to localized prostate tumors, and from localized tumors to metastatic disease. They integrated the datasets to identify thousands of sites across the prostate genome that regulate expression of nearby and faraway genes. The specific reconfiguration of these gene regulatory elements is implicated in prostate tumor formation and progression. To demonstrate the broad utility of the data, the researchers also noted that the DNA code within these regulatory elements, "were strongly associated with prostate cancer risk heritability" - that is, these regions harbored genetic variants that increase the likelihood of someone developing prostate cancer.

"This work has been the result of many years of intense international collaboration and a prime example of how international teamwork pushes the field forward to better understand cancer," said Zwart.

A new study shows that genetic pre-screening could reduce the number of screening tests needed to identify individuals at risk for osteoporotic fractures. Douglas P. Kiel, M.D., M.P.H., director of the Musculoskeletal Research Center in the Hinda and Arthur Marcus Institute for Aging Research at Hebrew SeniorLife, is an author on the report published this month in PLOS (Public Library of Science) Medicine.

Osteoporosis is a common and costly condition that increases the risk for bone fractures in those with the disease. Fractures, which lead to significant morbidity, mortality and expense, are a large public health concern. Annual costs associated with fractures exceed $19 billion in the United States.

Dual-energy X-ray absorptiometry (DXA), which measures bone mineral density (BMD), has been considered the clinical standard for determining fracture risk, along with the Fracture Risk Assessment Tool (FRAX). A FRAX assessment considers factors such as age, gender, weight, alcohol use, smoking history, and fracture history. Screening programs are generally designed to identify those whose risk is great enough to require intervention. However, assessment takes time and DXA accessibility has declined. Usually only a small proportion of individuals who undergo screening is found to be at high risk, indicating that much of the screening expenditure is spent on individuals who will not qualify for treatment.

The potential exists to improve the efficiency of osteoporosis screening programs using genetic markers to assess fracture risk. The purpose of this study was to understand if genetic pre-screening could reduce the number of screening tests needed to identify individuals at risk of osteoporotic fractures. It used genetic data from more than 300,000 participants from the UK Biobank to calculate the genetically predicted bone ultrasound measure. This was then compared with the commonly used FRAX score and standard BMD measured by DXA as to its ability to predict the risk for fracture.

By building a polygenic risk score and validating its utility in fracture risk screening in five separate cohorts totaling more than 10,000 individuals, study researchers determined that genomics-enabled fracture risk screening could reduce the proportion of people who require BMD-based testing by 41 percent, while maintaining a high ability to correctly determine appropriate treatment for those at risk. While these findings are not meant to be prescriptive, they indicate the possible utility of polygenic risk scores in screening programs that are dependent on heritable risk factors.

"Someday everyone will know their genetic predispositions to various diseases and traits because genetic typing has become so inexpensive," said Dr. Kiel. "When available, these genetic markers can be used to predict diseases to help health care providers screen and treat patients tailored to their genetic predisposition to a given disease. Using genetic risk scores to guide screening for osteoporosis may result in disease screening strategies that are more thoughtful and personalized than the one-size-fits-all approach currently in place within medical practice."