Body

COLUMBIA, Mo. - Humans and animals are made up of trillions of cells, and each cell contains DNA specific to that individual. Therefore, identifying DNA that causes genetic disorders gives researchers and clinicians a better understanding of how to treat inherited diseases and possibly prevent the diseases from being passed down to future generations.

Now, researchers at the University of Missouri have located a specific mutation in the gene responsible for causing Chédiak-Higashi syndrome, a rare condition that weakens the immune system and leaves the body more vulnerable to infections. In their new study, Leslie Lyons, a professor of comparative medicine at the MU College of Veterinary Medicine, and Reuben Buckley, a postdoctoral fellow, found the answer by creating a DNA map of a domestic cat with the syndrome.

"Different treatment options target different parts of the gene, so we needed to know which part of the gene was messed up in order to target therapies to the appropriate place," Lyons said. "Similar to finding a specific address, we knew we had the right street but we needed to find the exact house, and modern DNA sequencing helped us find it."

Collaborating with reproduction specialists at the Cincinnati Zoo and Botanical Gardens, Lyons worked with Smokey, a 16-year-old male cat who served as the last biomedical cat model for Chédiak-Higashi syndrome before passing away. Through in vitro fertilization, Lyons was able to use semen from Smokey to resurrect the previously extinct feline disease model. Learning if cats are genetic carriers of a certain disease can be useful so that breeders are aware of which cats to avoid breeding together in order to prevent their offspring from being affected.

Lyons' research team is also studying genetic mutations that cause other diseases, such as polycystic kidney disease, a common inherited disorder that affects hundreds of thousands of people each year and can lead to kidney failure. She highlights the value of translational medicine in her research.

"All mammals tend to have very similar genes, so if we find out what causes a disease in cats, then whatever therapies can be used to help cats can potentially be translated to help humans suffering with the same disease," Lyons said. "Likewise, human research can potentially be translated to help animals as well."

In addition to translational medicine, Lyons' research is also an example of precision medicine, or tailoring specific treatments for a patient according to their individual genetic makeup. Precision medicine will be a key component of the NextGen Precision Health Initiative by helping to accelerate medical breakthroughs for both patients in Missouri and beyond.

Breastfeeding is associated with benefits for children and their mothers. However, when mothers take medications there is a potential for adverse side effects in the infant.

In a recently published study in JAMA Neurology, a University of Minnesota-led research team looked at antiepileptic drug (AED) exposure in infants who were breastfed by mothers with epilepsy.

For mothers with epilepsy, there is no consensus within the medical community on if breastfeeding while taking antiepileptic drugs could have adverse side effects on their children. While previous studies examined breast milk concentrations of antiepileptic drugs, it did not account for the amount of antiepileptic drugs metabolized by the child. U of M researchers found that the antiepileptic drug concentrations in blood samples of infants who were breastfed were substantially lower than maternal blood concentrations.

They accomplished this by analyzing samples from breastfed infants and their mothers between five to 20 weeks after birth. The amount of AED concentrations was measured from blood samples taken from both mother and child. These mothers and infants were enrolled in the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study.

"We measured the drug concentrations directly in infants that reflected overall drug exposure to the infant through breast milk," said Angela Birnbaum, a professor in the College of Pharmacy. "Our study supports breastfeeding for mothers with epilepsy who are taking antiseizure medications. This means that primary care providers can have more informed conversations with recent and expecting mothers about the possibilities of breastfeeding their child."

WASHINGTON, D.C.-- New research in the January edition of Annals of Emergency Medicine reveals that cooling with running water is the best initial treatment for a child's burn. Researchers found that cool running water can reduce the odds of needing a skin graft, expedite healing and lessen the chance that a young burn victim requires admission to the hospital or an operating procedure.

"If a child is burned, the first course of treatment should be 20 minutes of cool running water," said Bronwyn R. Griffin, PhD, honorary senior fellow at the University of Queensland Child Health Research Centre (Australia) and study co-author. "Cool running water is most effective immediately after a burn occurs, but evidence suggests it remains beneficial for up to three hours following an injury."

The study shows children who received adequate first aid involving 20 minutes or more of cooling with running water had the odds of skin grafting reduced by more than 40 percent. Providing any amount of cool running water was associated with reduced odds of hospital admission by 35.8 percent and reduced the odds of requiring treatment in an operating room by 42.4 percent.

Among patients who did not require grafting, the speed of healing was faster with the administration of any cool running water. This is important because faster healing reduces the risk of scarring, the authors note.

Study results confirm that burns cooled with running water fared better than those that received no first aid or an alternative to cool running water, such as aloe, gels, compresses, toothpaste, butter or egg whites, for example.

The study, "Cool Running Water First Aid Decreases Skin Grafting Requirements in Pediatric Burns," analyzed the treatment of 2,495 children at a children's hospital with the median age of two years old. Patients in the study cohort were treated most frequently for scalds, liquid or steam burns, on or near their arms or legs. These types of mild to moderate burns commonly occur at home.

The optimal duration of cool running water therapy remains under discussion. The Australian Burn Association, British Burn Association and European Burns Association all recommend 20 minutes of cool running water. The American Burn Association calls for five or more minutes and the British Red Cross and St. John Ambulance (UK) both prescribe 10 minutes or more. This study lends further support to the recommendation of a full 20 minutes, the authors note.

"Whether you are a parent or paramedic, administering 20 minutes of cool running water to a child's burn is highly recommended. This is the most effective way to lessen the severity of tissue damage from all thermal burns," said Dr. Griffin.

U.S. birth weights have fallen significantly in recent decades due to soaring rates of cesarean deliveries and inductions which have shortened the average pregnancy by about a week, new CU Boulder research shows.

"Our data indicate that there has been a dramatic shift in birth timing in this country, it is resulting in birthweight decline, and it is almost entirely due to changes in obstetric practices," said Ryan Masters, a social demographer with the Institute of Behavioral Science and senior author of the study published January 29 in the journal Demography.

Previous research has shown that, after decades of rising, birth weights began to fall in 1990, a trend that has puzzled scientists and alarmed public health officials well aware of the long-term adverse health effects that can arise from low birthweight.

Masters and lead author Andrea Tilstra, a PhD candidate in the Department of Sociology, set out to pinpoint what's driving the trend, using records from the National Vital Statistics System.

They analyzed more than 23 million single births to healthy mothers from 1990 to 2013, using demographic techniques to plot: birthweight; week at which each birth occurred; and whether the baby was born via vaginal delivery, induced vaginal delivery, cesarean delivery, or induction and cesarean.

Then they ran a simulation to see what would have happened if cesarean and induction rates hadn't increased.

"We found that the decline in birth weight would not have happened if it were not for the rapid increase in these obstetric interventions," said Tilstra. "In fact, birth weights would have gone up."

Medical interventions on rise

Among the study population, the incidence of cesarean deliveries grew from 25% in 1990 to 31.2% in 2013, with rates rising fastest among healthy women in weeks 37 to 39. Labor induction more than doubled from 12% of deliveries to 29%.

Meanwhile, the average length of pregnancy decreased from 40 weeks to 39 weeks, and overall births became increasingly concentrated between 37 and 39 weeks, with far fewer stretching into 42.

About 18% of births in 2013 would have happened later, via a vaginal delivery that was not induced, had they occurred in 1990. That matters, the researchers note, because a fetus can put on significant weight in the final weeks of pregnancy.

Over the 23 years, the average weight of a baby born in the United States declined 67 grams (about 2.4 oz). Had rates of interventions stayed level, the average birth weight would have risen by 12 grams.

"By intervening in the pregnancy instead of allowing it to reach its natural finality we are shifting when birth happens, and that can have public health consequences," said Tilstra, noting that low birth weight has been linked to poorer long-term health and lower educational attainment.

The authors stress that inductions and cesarean deliveries are, in many instances, medically necessary. But they raise concerns that the greatest rise in such interventions is among healthy women who are at full-term yet not overdue.

Because U.S. physicians have more latitude than in other areas of the world to determine whether a cesarean delivery is necessary, they suspect cultural and institutional factors, including financial incentives at the hospital or insurance level, are driving the trend.

"The American College of Obstetricians and Gynecologists guidelines permit physicians and/or birth attendants a great deal of discretion in their decision to obstetrically intervene in a pregnancy, whereas the international guidelines form the World Health Organization use strong langue to discourage it," they wrote.

Tilstra stresses that she is in no way telling clinicians not to perform cesarean deliveries or inductions or advising mothers to decline them. But she hopes her study offers new information that helps both practitioners and parents weigh costs and benefits.

"I hope it prompts physicians to take a step back and realize there can be broader public health impacts from these individual decisions, and I hope it reminds mothers that they have more autonomy in the birth process than they sometimes feel they do," she said. "If something is not obviously medically necessary it is important to ask why it's happening."

PHILADELPHIA - Some cancer cells refuse to die, even in the face of powerful cellular immunotherapies like CAR T cell therapy, and new research from the Abramson Cancer Center of the University of Pennsylvania is shedding light on why. In a new study, researchers describe how a death receptor pathway in the cancer cell itself plays a central role in determining its response to CAR T cells. It's the first study to show that natural cancer features can influence response to CAR T cells, and that cancer cells can drive the development of CAR T cell dysfunction. The findings may provide guidance for future immunotherapies in patients whose blood cancers are resistant to CAR T therapy. The findings published today in Cancer Discovery, a journal of the American Association for Cancer Research.

CAR T cell therapy modifies patients' own immune T cells, which are collected and reprogrammed to potentially seek and destroy cancer cells. After being infused back into patients' bodies, these cells both multiply and attack, targeting cells that express a protein called CD19. In acute lymphoblastic leukemia (ALL), between 10 and 20 percent of patients have disease that is resistant to CAR T cells, but until now, researchers did not understand why.

"Most theories have centered around a defect in the T cells, but what we've shown here is that the problem originates in an important death signaling pathway in the cancer cell itself, which prevents the T cell from doing its job," said the study's co-senior author Marco Ruella, MD, an assistant professor of Hematology-Oncology in the Perelman School of Medicine at the University of Pennsylvania and a member of the Center for Cellular Immunotherapies in Penn's Abramson Cancer Center. Ruella's co-senior author is Saar Gill, MD, PhD, an assistant professor of Hematology-Oncology at Penn.

Researchers first performed a genome-wide CRISPR/Cas9-based screen of an ALL cell line known as Nalm6 to isolate pathways associated with resistance. CRISPR is a gene-editing tool that can effectively target specific stretches of genetic code, as well as modify DNA at precise locations for experiments and in some instances treatment. Cells were edited for loss of function of single genes and combined with CAR T cells for 24 hours to identify the pathway driving the primary resistance.

The team discovered that in ALL cells resisting CAR T attack, there was depletion of genes involved in activating the cell death pathway (FADD, BID, CASP8 and TNFRSF10B) and enrichment of genes required for resisting the cell death pathway (CFLAR, TRAF2 and BIRC2). When they tested this in animal models, the effect was even greater than what they had observed in vitro. The researchers were initially mystified by this discrepancy, prompting them to study the effect of the cancer on the T cells trying to kill it. This led them to the discovery that prolonged survival of cancer cells led to T cell dysfunction.

The team then explored the clinical relevance of these findings using pediatric patient samples from previous CAR T trials by analyzing the genes in leukemia cells and in T cells - pre- and post- infusion - from responders and non-responders. They found that the previously identified signaling pathways in cancer cells were directly associated with responses to CAR therapy in the patients from two clinical trials, further suggesting that death receptor signaling is a key regulator of primary resistance to CAR T cell therapy in ALL.

"We now know that resistance occurs in two phases: the cancer cells' initial resistance to death, followed by the cancer's ability to impair T cell function," said co-first author Nathan Singh, MD, MS, who led the work while he was a post-doctoral researcher with Carl June, MD, the Richard W. Vague Professor in Immunotherapy and director of the Center for Cellular Immunotherapies. Singh is now an assistant professor of Medicine at Washington University School of Medicine in St. Louis and a research member of Siteman Cancer Center. "Together, this leads to CAR T cell failure that allows the disease to progress."

Researchers say these findings suggest the use of heathy donor T cells for CAR T manufacturing may face the same barriers as cells used from the patient.

"This will also inform future research investigating new and improved CAR T cells that have the ability to overcome this resistance, along with therapies that target the defective signaling pathway in cancer cells," Gill said.

Developing a therapy to combat cancer remains one of the most difficult challenges in medical research. Cancer owes its notorious identity to the fact that the cancer cells use the host's own immune system to grow and spread, ultimately becoming deadly. Immune cells like macrophages, which ordinarily fight to protect normal cells, are hijacked by malignant cancer cells, and populate the environment around the tumors, becoming tumor-associated macrophages (TAMs). In fact, it was found that the cancerous tissue of patients for whom immunotherapy was not successful was indeed rich in macrophages, confirming the link between the cancer and the TAMs. It is these TAMs that produce signaling proteins like chemokines and trigger the inhibitory immune checkpoint releases that create an immunosuppressive tumor environment, which protects the cancer cells and allows their accelerated growth. Since it is the TAMs that facilitate the spreading of cancer cells, regulating them as a therapeutic strategy for combating cancer has gained attention in recent years.

A research group led by Yuya Terashima from the Tokyo University of Science saw this as an opportunity to explore the realm of developing novel anti-cancer drugs. Their seminal work in Nature Immunology 2005 reported the discovery of a new target protein called FROUNT, which is linked to regulation and movement of the TAMs. Since FROUNT amplified "chemokine signaling," a type of cellular communication, an integral process for TAM accumulation and activity, it was therefore linked directly to TAM regulation.

The team decided to expand on these findings, in order to investigate whether a therapeutic strategy can be formulated and have published their findings in Nature Communications. Through animal experiments, the researchers found that by regulating FROUNT expression in TAMs, cancer growth could be suppressed.

Then, in order to reduce any side effects, the team also developed an independent strategy of limiting the effect of FROUNT on chemokine signaling by inhibiting the interaction between the two. The team screened 131,200 compounds and zeroed in on disulfiram, a drug used to treat alcoholism, and known for its potential as an anti-cancer drug. This drug was found to directly bind to the FROUNT site, making FROUNT unavailable for interaction with the components of chemokine signaling. Reflecting on the results, Terashima explains, "When tested on mice, disulfiram inhibited the movement of macrophages and suppressed the growth of cancer cells. Therefore, our findings present a new cancer treatment strategy that can suppress the growth of cancer cells that are difficult to respond to by immune checkpoints when used in combination with disulfiram."

The team is now further pushing the boundary of the finding and has started clinical research at the National Cancer Center Hospital East. Illustrating the outline for further research, Terashima comments, "since macrophages pose as a problem in various types of diseases, the indications for FROUNT inhibitors for a wide range of diseases may be considered." Indeed, the team expects this this to be the first therapeutic strategy to regulate TAMS, and are hopeful that a better understanding of the correlation between the inhibition of the target protein FROUNT and TAMs paint a promising picture for the future of novel therapeutic strategies.

Mason, OH - Thursday, January 30, 2020 - Undiagnosed chest pain sends 8-10 million Americans to Emergency Departments annually, making it the second most common complaint. Emergency physicians must rapidly identify patients whose chest pain is cardiac-related. A new pilot study has found that a resting 90-second magnetocardiography (MCG) scan shows promise in evaluating emergency department observation unit (EDOU) chest pain patients for Acute Coronary Artery Syndrome. The publication also indicates that CardioFlux MCG may provide additional information to support the usual clinical pathway of Stress Testing and Coronary Angiography.

Genetesis, Inc. today announced the publication of the company's initial pilot study of its CardioFlux FAC Magnetocardiograph, conducted by a team of emergency medicine physicians at a major cardiac hospital in Detroit, MI. CardioFlux MCG is a novel medical device that can now non-invasively measure and visualize the well-studied electromagnetic function of the heart. A CardioFlux scan is performed at rest and without the use of radiation or pharmaceuticals to record the magnetic field map generated by the electrical activity of the myocardium. These fields have previously been shown to change with cardiac ischemia due to dysfunction of the ion channels responsible for repolarization and depolarization of the myocardium. The study titled "A 90-second Magnetocardiogram Using a Novel Analysis System to Assess for Coronary Artery Stenosis in Emergency Department Observation Unit Chest Pain Patients" was published online by the International Journal of Cardiology Heart and Vasculature on January 8th, 2020.

Only a small minority of patients will ultimately be diagnosed with Acute Coronary Syndrome yet most are still placed in an observation unit for additional tests and monitoring. This leads to longer hospital stays, a higher cost of care, and unnecessary downstream tests that expose patients to radiation and pharmaceuticals. CardioFlux has the potential to substantially reduce cost and wait times while improving patient experience and outcomes.

"Having a non-invasive diagnostic test that can be performed rapidly with almost no patient preparation in the emergency department observation unit or possibly incorporated into the ER workflow would be a game-changer in the evaluation of ED patients presenting with chest pain" says Dr. Margarita Pena, lead author of the pilot study. "This has a lot of potential to screen patients out [for] Coronary Artery Disease, not to mention the benefits of avoiding risks to the patient associated with radiation, adverse reactions to pharmacologic and contrast agents, as well as risks associated with hospitalization."

In the prospective emergency department observation unit clinical study, 101 low-intermediate risk chest pain patients were administered a 90-second noninvasive heart scan using the CardioFlux MCG. Cardioflux identified different magnetic field maps for patients with and without myocardial ischemia diagnosed via standard of care evaluation. CardioFlux performed competitively relative to stress testing and coronary angiography, with a demonstrated specificity of 78.3% and a negative predictive value (NPV) of 92.3%. These results are the beginning of a robust set of data demonstrating that CardioFlux shows promise as a "feasible and comparable testing option" relative to standard of care stress testing. The data were previously presented at the American College of Emergency Physicians Scientific Assembly in October 2018.

Dr. Pena notes that further research on CardioFlux is underway. "Now they're looking at the high-risk population of patients that get [catheterized] so that we can see how this compares to catheterization," says Pena.

"While previous studies of magnetocardiography have yielded promise in the detection of coronary artery disease, this is the first time a scalable iteration of this technology has been made available to emergency medicine in their difficult task of diagnosing ACS," Dr. Alisa Niksch, Genetesis Chief Medical Officer, stated. "This data has given Genetesis the momentum to expand research into other populations at risk for ischemic heart disease."

All type 2 diabetes patient subgroups are likely to achieve cardiovascular protection from the use of SGLT2 inhibitors, according to a large multi-study review published in the Journal of the American Heart Association.

Lead author and Senior Research Fellow at the George Institute for Global Health Dr Clare Arnott said that while previous studies of SGLT2 inhibition in type 2 diabetes (T2DM) have shown cardiovascular benefits, it was primarily in those with established cardiovascular disease (CVD) or renal disease.

"In this meta-analysis of large event-driven SGLT2 inhibitor outcome trials we found SGLT2 inhibitors protected against cardiovascular disease and death in diverse subsets of patients with type 2 diabetes regardless of their cardiovascular disease history," she said.

"While the extent of this protective effect may vary across patient types, the consistency of the ?ndings suggests signi?cant and broad cardiovascular protection can be achieved from use of this drug class."

Sodium-glucose cotransporter 2 or SGLT2 inhibitors were developed to lower glucose levels for people with diabetes. Early studies showed they reduced levels of protein in the urine leading to great hopes they would protect against kidney failure. Since then, several large studies have been designed to examine whether SGLT2 inhibitors also prevented heart attack, stroke and kidney disease. These studies showed a clear reduction in CVD events in established atherosclerotic CVD, but whether that translated to those without CVD was still uncertain.

George Institute for Global Health researchers conducted a review and meta-analysis, pooling data from four major randomised controlled trials to de?ne the cardiovascular bene?ts and the effects on key safety outcomes of SGLT2 inhibition, overall and separately among participants with and without established CVD, reduced kidney function, or heart failure.

Four studies involving 38,723 patients with T2DM which assessed three SGLT2 inhibitors - canagliflozin, empagliflozin, and dapagliflozin - were included in the meta-analyses. Overall there were 3,828 major adverse cardiac event (MACE) outcomes, 1,192 hospitalizations for heart failure, 1,506 cardiovascular deaths, and 2,612 deaths from any cause. The results showed that those treated with an SGLT2 inhibitor compared with placebo achieved:

an overall 12% proportional reduction in MACE

an overall 17% relative reduction in cardiovascular death

a 32% relative reduction in hospitalisation for heart failure

consistent cardiovascular benefits regardless of baseline history of cardiovascular disease, heart failure or reduced kidney function

a possible reduction in stroke events in those with reduced kidney function.

Type 2 diabetes mellitus is a global pandemic, with an estimated 370 million people currently affected. It is a major risk factor for both cardiovascular disease and chronic kidney disease, with CVD the leading cause of death in people with T2DM.

"Our study has shown that we have a class of drug in our treatment arsenal that could potentially have a significant impact on the cardiovascular complications of type 2 diabetes," said Dr Arnott.

Chronic lymphocytic leukemia (CLL) is the most common form of blood cancer (leukemia) in the Western world, affecting approximately 1.2% of all cancer patients. This type of cancer starts with the lymphocytes (a type of white blood cells) that are produced in the bone marrow. CLL is characterized by the proliferation of abnormal lymphocytes (B cells) that fail to mature and grow out of control. These abnormal cells accumulate in the bone marrow and lymph nodes, taking the place of other healthy cell types and impeding their normal development. Finding the most suitable therapy for each patient poses a challenge due to the clinical and molecular heterogeneity of this disease, with some patients facing slow disease progression, whereas others face rapid progression and require quick medical response.

The cancer drug ibrutinib, a Bruton tyrosine kinase (BTK) inhibitor, has remarkable efficacy in most patients with CLL. It is becoming the standard of care for most patients requiring treatment due to its clinical efficacy and mostly tolerable side effects. However, it does not cure the disease, and patients must undergo prolonged periods of treatment. Christoph Bock and his group at CeMM investigated the molecular program with which CLL cells and other immune cells response to ibrutinib treatment in patients with CLL. Their goal was to learn the epigenetic and transcriptional patterns that predict how swiftly the treatment is having an effect on the CLL cells and how long it takes for the disease to respond in each individual patient.

In previous studies, scientists had investigated only specific aspects of the molecular response to ibrutinib, focusing largely on genetic drug resistance or the transcriptome response of cancer cells. For the first time, CeMM researchers provide a comprehensive genome-scale, time-resolved analysis of the regulatory response to this drug in primary patient samples. The authors used a combination of immunophenotyping, single-cell transcriptome profiling (scRNA-seq) and chromatin mapping (ATAC-seq) to jointly monitor the activity, regulation and expression of the CLL cells and other cell types of the immune system. Importantly, they performed this analysis at eight pre-defined time points during the ibrutinib therapy, following seven individual patients over a standardized 240-day period after the start of the treatment.

Through integrative bioinformatic analysis of the resulting dataset, the authors were able to describe at high resolution how ibrutinib induces a very consistent chain of events on cancer cells over time across all patients. They found that ibrutinib first acts right at the center of the CLL cells' activity, causing the genes that establish the cancer cell identity of the CLL cells to shut down, and then puts them in a dormant state. This means that the cancer cells stop dividing but quiescently survive, waiting for the right environment conditions to begin proliferation once again.

The present study by André Rendeiro, Thomas Krausgruber and colleagues is the result of cross-disciplinary collaborations with researchers from the Department of Hematology and Stem Cell Transplantation of the National Institute of Hematology and Infectious Diseases at the Central Hospital of Southern Pest, and the Department of Pathology and Experimental Cancer Research of the Semmelweis University in Budapest (Hungary). It constitutes one of the first high-resolution, multi-omics time series of the molecular response to targeted therapy in cancer patients, and it establishes a broadly applicable approach for analyzing drug-induced regulatory programs, identifying molecular response markers for targeted therapy. Finally, the study could help stratify patients into fast and slow responders based on characteristic molecular markers and open up new directions for the development of ibrutinib-based combination therapies for CLL.

Claudio Franceschi, a world-renowned scientist, professor at the University of Bologna (Italy) and head of the Research Laboratory for Systems Medicine of Healthy Aging at Lobachevsky University, together with other members of an international research team, has described the mechanisms underlying chronic inflammation and identified several risk factors leading to disease. As noted in the paper "Chronic inflammation in the etiology of disease across the life span" published in the journal Nature Medicine (journal impact factor 30,641), these include infections, physical inactivity, diet, environmental factors, industrial toxicants and psychological stress.

Professor Claudio Franceschi's many years of research have resulted in the theory of "inflamm-aging", according to which aging is a general inflammatory process that involves the whole body and provokes diseases associated with age: Alzheimer's disease, atherosclerosis, cardiovascular disease, type II diabetes and cancer.

"Today, chronic inflammatory diseases are at the top of the list of death causes. There is enough evidence that the effects of chronic inflammation can be observed throughout life and increase the risk of death. It's no surprise that scientists' efforts are focused on finding strategies for early diagnosis, prevention and treatment of chronic inflammation," says Claudio Franceschi.

One of the serious results obtained to date has been the concept of immune aging, which enables researchers to characterize the immune function of an individual and to predict the causes of mortality much more accurately than by relying only on chronological age. In addition to well-known inflammation biomarkers, such as C-reactive protein, interleukins 1 and 6, tumor necrosis factor, scientists note the need to study additional biomarkers of the immune system, which differ very much from person to person, in particular, the subgroups of T- and B-lymphocytes, monocytes, etc.

Scientists have identified certain factors (social, environmental and lifestyle factors) that contribute to systemic chronic inflammation. Taken together, such factors are the main cause of disability and mortality worldwide.

Some of the most powerful tools in research of aging processes are genomic, transcriptomic and proteomic analyses (collectively referred to as "omics"). However, although the trajectory of human aging can be established as early as at the moment of fetal development in the womb, the factors influencing the whole life cycle also have a strong influence. Professor Franceschi insists that the lifestyle, the effects of stressors, the history of vaccinations, as well as the social and cultural characteristics of each individual starting from the first days of life to adulthood should be determined in as much detail as possible and taken into account.

An integrative approach to the study of mechanisms of systemic chronic inflammation is being adopted by a growing number of scientists. Research is continuing, and scientists have a long way to go to fully understand the role of chronic inflammation in aging and mortality, and to be able to predict changes in a person's health throughout life.

Research results open up new strategies for early diagnosis, prevention and treatment of a wide range of diseases associated with systemic chronic inflammation. It is expected that prevention and treatment of inflammatory processes will serve to slow down aging and prolong life.

Under the guidance of Professor Franceschi, the megagrant project "Digital Personalized Medicine for Healthy Aging" is being implemented at the Lobachevsky University of Nizhny Novgorod where a unique Center for Healthy Aging and Active Longevity has been established with the aim of making a breakthrough in the search for aging markers, early diagnosis of age-related diseases and, ultimately, achieving active longevity.

The adoption of children is a fundamental method of building families. However, adoptees may face subsequent adaptive challenges associated with family stress at the time of birth and during the adoption process.

It should be no surprise, then, that adoptees have a small but well-known increased risk for depression, anxiety and other mental health disorders. The health effect has been attributed to stressful early childhoods. But genetics also plays a role, according to a large new study published in Biological Psychiatry, published by Elsevier.

"We found adopted individuals on average had a somewhat higher genetic risk for mental health problems, but the effects are quite small," said lead author Kelli Lehto, PhD, a postdoctoral researcher at Karolinska Institute in Stockholm. "Overall, the main message here is that both environment and genetics are important."

Psychiatric disorders, including depression, anxiety and schizophrenia are, to varying degrees, heritable. Genome-wide association studies (GWAS) have identified a growing number of genetic markers associated with the risk for most major psychiatric disorders so that a 'polygenic risk score' for these disorders may be estimated.

Dr. Lehto and colleagues analyzed the genomic and health information data of 243,797 participants in the UK Biobank, a major health resource established by the Wellcome Trust and others, including a group of 3,151 who were adopted as children within Britain, mostly in the 1950s and 1960s.

Overall, the adoptees in the study reported being happy and satisfied with their lives. When compared to the general population, they were more likely to be male, to smoke, have less education, attain a lower income, and to experience more stressful life events. Adoptees also had slightly more mental health problems, such as depressive symptoms, bipolar disorder, higher neuroticism and loneliness.

The researchers found a slightly elevated genetic risk of depression, schizophrenia and neuroticism among adoptees. They did not find however, any evidence of interaction between genetics and adoption on mental health. Thus, while children put up for adoption were at increased genetic risk for developing symptoms of mental illness, the adoption process did not appear to increase the impact of this genetic risk.

"Basically, genetic risk and adoption each are predictors of psychiatric problems," explained Dr. Lehto. "It's important to highlight that adoption and genetic risk each only contributed a small amount to the individual differences in mental health. That indicates many more factors contribute to the development of mental health problems."

"There are many complicated issues to consider in these findings," John Krystal, MD, Editor of Biological Psychiatry. "But the most straightforward implication is that adopted children may face both special environmental and genetic risks for adjustment problems and mental illness. Awareness of these risks increases the importance of programs aimed at early detection and intervention for these children."

The findings of this study of people with UK-based ancestry pertain only to people of European ancestry and the results might be different in other groups. Scientists note significant racial and ethnic differences in the findings from genome-wide association studies (GWAS).

"It would be important to study resilience factors as well as risk factors, Dr. Lehto said.

"The differences between adoptees and the rest of the population are very small. Generally, adoptees are doing well." The findings may apply to other types of childhood adversity and adult mental health outcomes among non-adoptees, she added.

Tuberculosis (TB) is one of the world's most vexing public health problems. About 1.5 million people died from this bacterial lung infection in 2018, and the World Health Organization (WHO) estimates that one-quarter of the world's population -- some 2 billion people, mostly in developing countries -- are infected with the bacteria that causes TB.

For decades, scientists have been studying the deadly disease in mice and other animal models to develop drug therapies and vaccines to treat or prevent the infection. But findings in animals with TB don't always translate well to people with the disease, leaving scientists puzzled by the discrepancies.

Now, a new study led by Washington University School of Medicine in St. Louis offers a genetic road map detailing the similarities and differences in immune responses to TB across three species -- mice, macaques and humans. According to the researchers, the insight into the immune pathways that are activated in diverse models of TB infection will serve as a valuable tool for scientists studying and working to eradicate the disease.

The research, appearing Jan. 29 in the journal Science Translational Medicine, is a collaboration between Washington University; the Texas Biomedical Research Institute in San Antonio; and the University of Cape Town in South Africa.

"For many years, scientists have been frustrated by the fact that animal models of TB -- especially the genetically identical mice so often studied -- don't really reflect what we see in people with TB infections," said co-senior author Shabaana A. Khader, PhD, a professor of molecular microbiology at Washington University. "This study is important because now we show in great detail where these animal models overlap with humans with TB and where they don't."

Unlike many previous mouse studies, the new research involved genetically diverse mice that more closely recapitulate the wide range of TB infection severity in humans: Some infected individuals show no symptoms; others show intermediate degrees of severity; and still others develop extreme inflammation of the lungs.

With co-author Deepak Kaushal, PhD, at the Texas Biomedical Research Institute, the researchers compared the genetic and immune responses to TB infection in these diverse mice with the responses of TB-infected macaques in the Kaushal lab. And with co-author Thomas J. Scriba, PhD, of the University of Cape Town, the research team analyzed blood samples from adolescents in Western Cape, South Africa, who are enrolled in a clinical trial investigating TB infection. The samples from people allowed the researchers to analyze and compare data from the mice and macaques with a range of responses to TB infection in young people.

Past research from this long-running clinical trial identified a group of 16 genes whose activation patterns predicted the onset of TB disease more than a year before diagnosis. These genes -- called a human TB gene signature -- differed significantly in their activation patterns between young people who developed symptoms of TB and those who didn't.

In macaques, primates closely related to humans, scientists have long assumed that TB infection closely resembles such infection in people.

"Our data demonstrate that 100% of the genes previously identified as a human TB gene signature overlap in macaques and people," said co-senior author Makedonka Mitreva, PhD, a professor of medicine and of genetics at Washington University and a researcher at the university's McDonnell Genome Institute. "It's important to have the definitive data showing it to be true."

There was significant overlap between humans and mice as well, according to the researchers, including co-first authors Mushtaq Ahmed, PhD, an assistant professor of molecular microbiology in Khader's lab; Shyamala Thirunavukkarasu, PhD, a staff scientist in Khader's lab; and Bruce A. Rosa, PhD, an assistant professor of medicine in Mitreva's lab. But they also identified genetic pathways that differed between mice and humans, providing detailed analysis of areas where TB in mice is unlikely to point to meaningful insight into human TB infection.

"Until now, we have studied mouse models to understand TB disease progression, not knowing where the mouse disease translates to human disease and where it doesn't," Khader said. "Now, we have shown that many areas do translate but that there are important aspects of TB infection that don't. If you are using mouse models to develop TB vaccines or other therapeutics that target areas that don't overlap, you likely won't succeed."

Added Mitreva, "Our study will inform researchers when they may need to move to a different animal model to study their genetic or molecular pathways of interest."

The researchers studied in detail the genes that increase in expression in people who develop severe TB disease. Of 16 such genes identified in people, they were able to study 12 in mice. Four of the genes could not be studied because mice don't have equivalent versions of such genes or, when such genes were eliminated, the mouse embryos died during development.

The scientists found that the 12 genes fall into three categories: those that provide protection against TB infection; those that lead to greater susceptibility to TB infection; and those that had no effect either way. Such information will be useful in seeking future therapeutics that could, for example, boost effects of protective genes or shut down harmful ones.

According to Khader and Mitreva, their team plans to use the new knowledge to better understand TB infections that have become drug-resistant, a growing problem in places where the disease is endemic. In addition, they will harness the information to help understand why the TB vaccine often administered to high-risk groups of people works well in some individuals but not others.

With the study's raw data publicly available, Khader and Mitreva said they are hopeful it will serve as a valuable resource to TB research and immunology communities worldwide.

This is the finding of a team of international scientists, led by Imperial College London, and including researchers from the University of California and University of Florida.

The Imperial team, based at J-IDEA, the Abdul Latif Jameel Institute for Disease and Emergency Analytics, created the first ever global map of dengue transmission intensity - which is a measure of how easily dengue is transmitted from person to person.

Using this map, the researchers predicted the global effectiveness of two interventions to combat dengue - vaccination and the release of 'infected' mosquitoes unable to transmit the virus between people.

Scientists infect mosquitoes in the laboratory with a type of naturally-occurring bacteria called Wolbachia, which prevents the virus replicating in the insect. In carefully-controlled trials, releasing these modified mosquitoes in areas heavily affected by dengue has been linked to a 70 per cent reduction in cases, though scientists caution this has to be confirmed in larger trials.

The study was published in the journal Science Translational Medicine, and funded by the Medical Research Council, National Institute for Health Research, the National Institute of General Medical Sciences, and the Department for International Development.

The new map is online and freely-available.

Dr Lorenzo Cattarino, lead author of the research from the MRC Centre for Global Infectious Disease Analysis, said: "Dengue is a leading cause of illness and death among children across the globe. Our research not only produces the first world map of dengue transmission, but can act as a tool to inform the World Health Organisation, local governments and policy makers on the effectiveness of prevention strategies, such as the release of Wolbachia-infected mosquitoes and vaccination programmes."

Dengue is a viral infection that infects over 100 million people each year. According to the latest estimates, around half of the world's population are thought to be at risk. The virus is spread by mosquitoes, and causes fever, headache, muscle and joint pain. In some cases, it can lead to a life-threatening condition called haemorrhagic fever which is a leading cause of death and serious illness among children in some Asian and Latin American countries.

There is no specific treatment for the disease, and prevention centres around avoiding mosquito bites - for instance using insecticides and reducing areas of standing water where the insects can breed, such as plastic containers.

However two methods of preventing infections have recently emerged that show promise of combatting the disease. A vaccine is now licensed for use against dengue, which works by reducing the intensity of subsequent dengue infections. There are four different types of dengue and therefore people can catch the disease four times. However, the vaccine can only be used in people previously infected with dengue (and thus requires people to be tested for dengue first). This is because the vaccine may prime a person's immune system to 'over-react' to a subsequent dengue infection if they haven't encountered the virus before, making the disease more severe.

Another method of prevention is disabling mosquitoes' ability to transmit the virus, by infecting them with the bacteria Wolbachia.

This bacteria is found naturally in around 60 per cent of insect species, including some mosquitoes, butterflies and moths.

Previous laboratory research has shown mosquitoes infected with Wolbachia do not transmit dengue, as the bacteria stops the virus replicating inside the insect.

In carefully controlled trials, scientists are now purposefully infecting the mosquito species that carry dengue - called Aedes aegypti - with Wolbachia, and releasing them into areas infected with dengue.

The trials suggest the bacteria does not pose a threat to animals or people in the areas where the mosquitoes are released.

Using data from these laboratory and mathematical modelling studies, the scientists behind the latest study used their map to predict this approach could eliminate nearly all dengue cases worldwide.

They also modelled the effectiveness of the Sanofi Pasteur dengue vaccine if used in all areas affected by dengue, and found the number of dengue cases could be reduced by up to 30 per cent. This is because the vaccine reduces the probability of becoming severely ill, rather than virus transmission.

The team highlight caveats in their study. The predictions assume the effectiveness of the mosquitoes in small-scale trials will be replicated on a global scale, and that the diagnostic test for dengue screening, which is recommended before the vaccine can be administered, is 95 per cent accurate. The researchers add that the two interventions were modelled separately.

Professor Neil Ferguson, co-lead author of the research, and head of Imperial's Department of Infectious Disease Epidemiology said: "Until now, gauging the effectiveness of control strategies for dengue, such as vaccine and Wolbachia-infected mosquitoes, has been limited by the lack of data on transmission across large geographical regions. The creation of this freely available global map of transmission, and the likely impact of control measures, will help identify strategies to reduce the number of people affected by the disease. The cost-effectiveness of these strategies can also be assessed, which is particularly important when most areas affected by dengue are in lower income nations."

January 29, 2020 - Used for facial rejuvenation, dermal fillers do more than just fill in wrinkles. According to a new study in the February issue of Plastic and Reconstructive Surgery®, the official medical journal of the American Society of Plastic Surgeons (ASPS), they also restore a more youthful pattern of facial movement and expressiveness.

Using 3D digital stereophotogrammetry, the study suggests that hyaluronic acid (HA) dermal filler treatment can restore a more youthful pattern of facial expressiveness. "The strain reduction following filler treatment objectively conveys a dermal tightening effect, likely secondary to the volumization of treated areas," writes ASPS member Ivona Percec, MD, PhD, of University of Pennsylvania, Philadelphia, who led the study.

With further analysis, Dr. Percec and co-authors believe that quantitative dynamic strain analysis could aid in planning and optimizing the outcomes of facial rejuvenation treatments.

Injectable dermal fillers provide a minimally invasive approach to reduce facial lines and wrinkles while restoring volume and fullness in the face. Nearly 2.7 million dermal filler injection procedures were performed in 2018, according to the most recent ASPS statistics.

To be truly effective though, these treatments must do more than just fill out facial lines and sagging - they must also produce a more youthful-appearing pattern of facial movements. "Facial expressions convey emotions as well as signal characteristics such as age and quality of life," Dr. Percec and colleagues write.

How do dermal fillers affect the face in motion? Using a technique called 3D digital stereophotogrammetry, Dr. Percec and colleagues obtained precise measurements of facial stretch and compression in 30 women, aged 41 to 65 years. All patients were to undergo HA dermal filler treatment for facial lines and wrinkles in the lower face.

Specifically, the women were treated for moderate to severe nasolabial folds (NLF), the lines running from the corners of the nose to the corners of the mouth; and "marionette lines" (ML), running from to mouth to the chin. The scans were performed first before HA filler treatment, then repeated six weeks later.

The facial dynamic strain results were compared with those in a group of 20 younger (aged 25 to 35), untreated women. In scans performed before dermal filler treatment, heat maps showed significantly higher "stretch profiles" in the NLF and ML areas in the older women, compared to the younger women.

In the follow-up scans after HA treatment, the older women had significant reductions in stretch and strain, across the full range of facial expressions. "That finding provides objective evidence that HA dermal filler treatment of facial lines in middle-aged women results in stretch levels more like those of younger women, in areas prone to the effects of facial aging," said Dr. Percec.

Facial movement reflects the complex interplay of the skin and underlying soft tissue, skeletal volume, and muscle activity. "Facial dynamics should be central to the evaluation of rejuvenation treatments to produce natural-looking results," according to the authors. Assessment of facial movement is especially important in the area around the mouth, which is especially mobile and prone to facial lines and volume loss.

Click here to read "An objective, quantitative dynamic assessment of hyaluronic acid fillers that adapt to facial movement."
DOI: 10.1097/PRS.0000000000006461

A new analysis, published in The Lancet, includes 99 patients with laboratory-confirmed 2019 novel coronavirus (2019-nCoV) who were transferred to Jinyintan Hospital, an adult infectious disease hospital admitting the first 2019-nCoV cases from hospitals across Wuhan, between January 1 and January 20, 2020. The study includes the first 41 cases from Wuhan reported in The Lancet last week [1].

The authors combined clinical records, laboratory results, and imaging findings with epidemiological data. Most patients were middle-aged (average age 55.5 years) and male (67 patients), and around half had a history of exposure to the Huanan seafood market (49 patients)--most of whom (46 patients) worked at the market as managers or salespeople.

Around half of cases (50 cases) occurred in people with underlying chronic diseases including cardiovascular and cerebrovascular diseases (40 patients) and diabetes (12 patients). All patients admitted to hospital had pneumonia--most were infected in both lungs (74 patients). The majority also had fever (82 patients), cough (81), and a third experienced shortness of breath (31). Five critically ill patients also experienced coinfections with bacteria (1 patient) and fungi (4).

Most patients were treated with antivirals (75 patients), antibiotics (70), and oxygen therapy (75), and had a good prognosis. However, 17 patients developed acute respiratory distress syndrome (ARDS), 11 of whom died of multiple organ failure.

More than half of patients (57 patients) are still in hospital, and almost a third (31 patients) have been discharged, as of 25 January, 2020.

The authors point out that while this is the largest study of its kind, involving 99 confirmed cases of 2019-nCoV, larger studies including patients from other cities and countries are needed to obtain a more comprehensive understanding of this novel coronavirus.