Body

Columbus, Ohio - A new study led by researchers at The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC - James) reveals how a clotting protein and blood platelets can promote cancer progression and suppress immune responses to cancer.

The findings show how thrombin, a clotting protein in the blood, causes blood platelets to release transforming growth factor-beta 1 (TGF-b1), which is known for promoting disease progression in breast, prostate, colorectal and other cancers, and for suppressing immune-system responses to cancer.

Additionally, TGF-b1 is a leading cause for the failure of immune therapies such as PD1 inhibitors in cancer patients. This study may offers a new explanation for what causes tumors to resist immune therapies and become sensitive to the therapeutic agents.

The researchers used animal models to show that inhibiting thrombin activity prevents the release of TGF-1b and makes tumors that were resistant to anti-PD-1 immunotherapy susceptible to these agents.

The findings are reported in the journal Science Translational Medicine.

"In this study, we describe a direct connection between thrombin and TGF-b1, a cytokine that promotes tumor progression and suppresses the ability of immune cells to attack the tumor," says principal investigator Zihai Li, MD, PhD, a professor in the Division of Medical Oncology at Ohio State and the founding director of the Pelotonia Institute for Immuno-Oncology (PIIO) at the OSUCCC - James. Li also holds the Klotz Memorial Chair in Cancer Research at The Ohio State University College of Medicine

"We also show that systemically interfering with this mechanism prevents the release of TGF-1b and leads to changes in the tumor microenvironment that are favorable to anticancer immune responses," says Li, who is a member of the OSUCCC - James Translational Therapeutics Program.

Li notes that cancer is similar to an unhealed wound that constantly activates the coagulation pathway and generates high concentrations of thrombin in and around a tumor. That, in turn, causes chronic platelet activation and release of TGF-1b.

"TGF plays important roles in cancer development," Li says. "Specifically, TGF-b1 alters the tumor microenvironment in ways that protect cancer cells from attack by immune cells."

Research has shown that inhibiting TGF-b1 enhances cancer immunotherapy, Li adds. "If we can effectively inhibit TGF-b1 maturation or function, it should open new avenues for cancer therapy."

For this study, Li and his colleagues used blood samples from cancer patients, genetic analyses, cell lines and animal models to investigate the mechanism underlying the release of mature TGF-1b and the implications of blocking that release as a means of cancer immunotherapy.

Key findings include:

Thrombin cleaves a molecule called GARP (glycoprotein A repetitions predominant) that is found on the surface of platelets;

GARP cleavage leads to the release of mature TGF-1b from platelets;

This cleavage is required to activate platelet TGF-b1;

Blocking thrombin using the inhibitor dabigatran etexilate greatly altered the tumor microenvironment and increased the number and activity of tumor-infiltrating T cells, natural killer cells and neutrophils.

"Overall, our study reveals a mechanism of cancer immune evasion that involves thrombin-mediated GARP cleavage and the release of TGF-b1 by platelets," Li says. "It also suggests that blocking GARP cleavage could be an effective therapeutic strategy for overcoming cancer's resistance to immunotherapy."

A new study in the journal Family Practice, published by Oxford University Press, shows that there remains a meaningful gender gap between the number of biomedical papers written by women and those written by men.

The medical profession has changed significantly in recent decades, with a growing proportion of women physicians. In many countries, half of the students entering medical schools are women. However, women physicians face enormous barriers throughout their career: they receive lower salaries and less funding, have more difficulty publishing their research and have slower career progression than their male counterparts. The publication of scientific articles is crucial for all researchers, as it plays a major role in the process of promotion and career advancement. The quantification of women's publication activity can be considered as an indicator of their successful integration into science. Gender inequalities in publishing may be among the main reasons why men still outnumber women in academic leadership positions.

Many studies have examined gender inequalities in research, but only limited data are available for general biomedical journals. Researchers here assessed the prevalence of female first authorship in general biomedical journals and examined its variations across a number of author, article and journal characteristics.

The researchers retrieved 767 randomly selected articles published in 2016 in high impact factor primary healthcare and general internal medicine journals. They extracted the following data: author (gender, number of publications and affiliation of the first author), paper (number of authors, number of participants and study design) and journal characteristics (journal discipline and 2015 impact factor).

Overall, the female first authorship proportion was 48% (366 articles), but the figure was significantly higher for primary health care journals than for general internal medicine journals (63% vs. 33%). In multivariate analysis, women published fewer articles, were more often affiliated with institutions in the Western world (55% vs. 45%) and were more likely to publish qualitative studies (vs. systematic reviews or experiments).

The female first authorship proportion found in this study for primary health care journals (63%) compares favorably with the existing literature, while for general internal medicine (33%) this figure is lower than the proportion found in many disciplines, except gastroenterology. The finding (at least for primary health care journals) may be partially explained by a decrease of gender gap in time, as showed by several authors. The proportion of articles with a woman as the first author increased for example from 27% in 1994 to 37% in 2014 for six high-impact medical journals, from 9% in 1992 to 29% in 2012 for gastroenterological journals, from 12% in 1976 to 48% in 2006 for dermatological journals, from 30% in 1989 to 52% in 2009 for pharmacological journals, and from 40% in 2001 to 58% in 2016 for pediatric journals.

Researchers here found that women used qualitative methods for their research three times more often than men (women 25% vs. men 8%). Researchers also found that women were less prone to publish trials (women 7% vs. men 13%). This may be due to the fact that women receive fewer and lower research grants and are therefore less likely to be the principal investigator and/or first author of these costly studies.

There were also significant regional differences in the study. In particular, the researchers found small proportions of female authors in Asia (the results for South America and Africa are more difficult to interpret due to the low number of observations).

Although the findings about female authorship of papers in primary health care journals are encouraging in terms of integration of women scholars, the under representation of women in articles published by general internal medicine journals, in articles coming from some parts of the world (mainly Asia), and in systematic reviews and trials concerned this study's researchers.

(New York, NY - January 14, 2020) - Responders who worked at the World Trade Center site after the attacks on September 11, 2001, have an increased overall cancer incidence compared to the general population, particularly in thyroid cancer, prostate cancer, and, for the first time ever reported, leukemia, according to a Mount Sinai study published in JNCI Cancer Spectrum in January.

Following the attacks on the World Trade Center, 50,000 workers were involved in rescue and recovery, with many of them caught directly in the dust cloud from the collapsing towers. From then until cleanup of the site ended in June 2002, workers were potentially exposed to an array of toxins later shown to cause adverse health effects, including cancer.

This study examined cancer incidence in responders including law enforcement, construction, and telecommunications workers, and found an increased overall cancer incidence, with the greatest elevation in thyroid cancer. It is the first to show an increase in leukemia, which is known to occur after exposure to occupational carcinogens, including benzene fuel and other sources that existed at the World Trade Center site, in some cases at low levels of exposure and with a latency of several years from exposure.

Researchers also found that neither the length of time that first responders and recovery workers worked on the World Trade Center site, nor the intensity of their exposure, had any bearing on the development of the elevated cancers. However, some risk factors--such as responders' age on September 11, their gender, and whether they were smokers at the time--were associated with increased cancer risk, underlining the need for continued surveillance of World Trade Center rescue and recovery workers.

"This study showed increased incidence of several cancer types compared to previously conducted studies with shorter follow-up periods," said Susan Teitelbaum, PhD, Professor of Environmental Medicine and Public Health at the Icahn School of Medicine at Mount Sinai and one of the lead authors. "Because of the long latency period of many types of cancer, it is possible that increased rates of other cancers, as well as World Trade Center exposure health issues, may emerge after longer periods of study."

Researchers studied post-September 11 cancer incidence among 28,729 rescue and recovery workers via cancer registry data from New York, New Jersey, Connecticut, Pennsylvania, Florida, and North Carolina from 2002 through 2013. Although the incidence of certain cancers, such as lung, was not elevated in this study's findings, researchers believe that may be due to the long time periods over which these cancers develop.

January 13, 2020 (Toronto) - Research led by the Centre for Addiction and Mental Health (CAMH) published in the Journal of Clinical Investigation points to a groundbreaking discovery about a new potential treatment and prevention for post-traumatic stress disorder (PTSD).

The research team, led by Dr. Fang Liu, Senior Scientist and Head of Molecular Neuroscience in CAMH's Campbell Family Mental Health Research Institute, and Professor and Co-director of Division of Neuroscience and Clinical Translation, Department of Psychiatry at the University of Toronto, recently identified a protein complex that is elevated in PTSD patients. The researchers also developed a peptide to target and disrupt the protein complex. They found that the peptide prevented recall or encoding of fear memories in early tests. This suggests that the peptide could treat PTSD symptoms or prevent them entirely.

"The discovery of the Glucocorticoid Receptor-FKBP51 protein complex provides a new understanding of molecular mechanisms underlying PTSD," said Dr. Liu. "We believe this protein complex normally increases after severe stress, but in most cases, levels soon go back to baseline levels. However, in those who develop PTSD, the protein complex remains persistently elevated, and so this could be a blood-based biomarker for PTSD as well as being a target for pharmacological treatment. In addition, the peptide we developed could be given after a traumatic event, and could possibly prevent the patient from developing PTSD. This is a completely new approach to PTSD and for psychiatric disorders in general."

PTSD occurs in some people after experiencing or witnessing traumatic events, such as sexual assault or military combat. Patients can suffer from debilitating flashbacks, nightmares and anxiety which can severely impact quality of life. There are currently no laboratory diagnostic tests for PTSD, and existing treatments have limited efficacy. According to a recent study published in the British Journal of Psychiatry, Canada has the highest prevalence of PTSD among 24 examined countries, and 9.2 per cent of Canadians will develop PTSD in their lifetimes.

"We are thrilled this CAMH-led discovery can potentially help millions of people put trauma behind them," added Dr. Liu.

The study has been supported by CIHR and the CAMH Discovery Fund. CAMH has filed a patent for the peptide and diagnostic aspect of Dr. Liu's invention. Dr. Liu and her team will conduct further testing and refining of the peptide before conducting human clinical trials.

Patients with acutely life-threatening health conditions who were treated in the innovative Critical Care Resuscitation Unit (CCRU) received faster treatment and had better health outcomes, including a 36 percent lower risk of dying than those who were transferred from a hospital's emergency department then evaluated and treated in a traditional intensive care unit, according to a recent study in the Journal of Emergency Medicine conducted by researchers at the University of Maryland School of Medicine (UMSOM).

Critically ill patients who experience a sudden life-threatening condition like a stroke, ruptured aneurysm, or a massive pulmonary embolism (blood clot in the lung) are often first brought to the emergency department of the closest hospital and then transferred to a larger institution if their condition is deemed to be beyond the scope of the hospital's level of care. The process of evaluating and transferring these patients, however, is generally ad hoc and fragmented, which results in delays of patients getting time-sensitive care that could save their lives or prevent permanent disability.

To improve access to care for critically ill patients, the University of Maryland R Adams Cowley Shock Trauma Center, in conjunction with the Program in Trauma at UMSOM, established the CCRU in 2013 as the first resuscitation unit in the nation. The recent study demonstrated for the first time that utilization of the CCRU not only helped double the number of transferred patients from other hospitals' emergency departments, but also led to faster access to critical care resources and definitive surgical treatment, which decreased a patient's risk of dying from their illness.

"We have provided an important validation of the CCRU model, showing that it significantly improves patient outcomes," said Quincy Tran, MD, PhD, Assistant Professor of Emergency Medicine at UMSOM who led the study. "Now that we have the data on the lifesaving potential of the CCRU, we hope to see other hospitals creating similar models."

The study analyzed medical records from 1565 critically ill patients with 644 treated in the CCRU at the University of Maryland Medical Center (UMMC) during the first year of its operation in 2013. The rest served as control groups who were transferred directly from other hospitals' emergency department to traditional intensive care units at UMMC during the year 2012 before the CCRU opened, and the year 2013 after the CCRU was opened.

The researchers found that the average time to get into an intensive care unit after a transfer request was filed was 108 minutes for CCRU patients, compared to 158 minutes for the control group of patients who were transferred and treated in 2012 before the CCRU opened, and 185 minutes for those in 2013. CCRU patients requiring emergency surgery received that surgery about 3.5 hours on average after they arrived at UMMC compared to 6 to 7 hours after arrival for those in the control group.

After controlling for variations in the severity of disease and care, the researchers found that the CCRU patients were 36 percent more likely to survive than those in the control group, which was a statistically significant finding.

"The CCRU is modeled after the highly-effective Trauma Resuscitation Unit at the UM R Adams Cowley Shock Trauma Center. It relies on efficient communication and consultation with referring facilities and intra-hospital transport providers in order to facilitate prompt transfer of patients requiring specialized care to the University of Maryland Medical Center," said co-author Daniel Haase, MD, Assistant Professor of Emergency Medicine at UMSOM, and Medical Director of the CCRU. "Our job is to collaborate with our specialists to deliver immediate resuscitation of patients with time-sensitive emergencies."

Procedures performed in the CCRU include massive blood transfusions, continuous renal replacement therapy (dialysis) for patients with malfunctioning kidneys, continuous EEG monitoring of the brain, and organ support with a heart-lung machine.

"We are leading the way in critical care medicine by having the first dedicated Critical Care Resuscitation Unit in the nation," said UMSOM Dean E. Albert Reece, MD, PhD, MBA, University Executive Vice President for Medical Affairs and the John Z. and Akiko K. Bowers Distinguished Professor. "Having the data to demonstrate improved patient outcomes will hopefully convince other hospitals to consider adopting this model of care."

When surgery is delayed, people don't get full benefit of new knee

When surgery is premature, patients assume unnecessary risk and may need a second replacement

Nearly 1 million knee replacement procedures are performed in the U.S. each year

CHICAGO --- The timing of knee replacement surgery is critical to optimize its benefit. But 90% of patients with knee osteoarthritis who would potentially benefit from knee replacement are waiting too long to have it and getting less benefit. In addition, about 25% of patients who don't need it are having it prematurely when the benefit is minimal, reports a new Northwestern Medicine study.

This is believed to be the first study to prospectively examine the timeliness of knee replacement among a large number of patients with knee osteoarthritis who could benefit from the surgery. Few prior studies have quantified timeliness of surgery but only among patients who already had knee replacement, and these studies generally were in smaller cohorts of patients.

"People are waiting and waiting to have the procedure and losing the most benefit," said lead investigator Hassan Ghomrawi, associate professor of surgery at Northwestern University Feinberg School of Medicine.

African-Americans delayed knee replacement surgery more than Caucasians, the study found.

"When people wait too long, two things happen," Ghomrawi said. "The osteoarthritis causes deterioration of their function. Some of them wouldn't be able to straighten out their legs, affecting their walking and mobility. When you can't get exercise, you can start to develop other health problems such as cardiovascular problems. You may also become depressed. The overall impact can be huge."

The second problem with delaying surgery is less benefit. "You don't get as much function back when you wait too long; your mobility is still reduced versus somebody who had it in a timely fashion," Ghomrawi said.

The ideal timing of knee replacement surgery is based on an algorithm that factors in pain, joint function, radiographic assessment and age to determine if a person will benefit from surgery.

Getting knee replacement surgery too early based on the algorithm means patients are having major surgery with risk of complications and getting minimal benefit. They may also need a revision (second surgery) later in life, which is a much more difficult surgery with poorer outcomes than the original surgery.

The study will be published Jan. 13 in the Journal of Bone and Joint Surgery.

Nearly 1 million knee replacement procedures are performed in the U.S. each year with projections of a rapid increase by 2030, the paper reports.

"As the number of surgeries rises, we need to make sure the timing is optimal for patients to obtain the most benefit and to keep health care costs down," Ghomrawi said. "Because knee replacement is an elective procedure, the timing of surgery is susceptible to not just clinical factors but also demographic, socioeconomic and sociocultural ones. We need to develop a better understanding of these factors to improve timing of surgery."

The Northwestern study was based on 8,002 participants who had or were at risk for knee osteoarthritis and were followed for up to eight years as part of two diverse multicenter trials, the Osteoarthritis Initiative and Multicenter Osteoarthritis.

Scientists at the Centro Nacional de Investigaciones Cardiovasculares (CNIC) have discovered a 'disarmament' mechanism that protects our bodies against uncontrolled activity of the immune system. This newly identified immune control system is located in one of the most important cell types of the immune system, the neutrophil. The findings, published in Nature Immunology, could have major implications for the understanding and treatment of conditions such as myocardial infarction, stroke, and acute inflammation.

The immune system is composed of a great variety of cells tasked with defending the organism against external and internal threats. To do this, explained lead investigator Andrés Hidalgo, "they patrol all corners of our bodies, searching for and finding anything alien or out of place and taking appropriate action, usually causing the death of the invading or wayward cells. When it works correctly, this system eliminates not only the innumerable and varied pathogens that constantly attack us, but also internal 'errors' that arise in our own cells, making them malignant, as occurs in cancer."

However, the immune system is a double-edged sword. If immune cells carry out their functions too enthusiastically, they can act in the wrong place or at the wrong time and thus damage healthy tissues. "For this reason, the immune system must be exquisitely regulated," said Hidalgo. Failed immune regulation underlies human diseases such as cancer and cardiovascular, autoimmune, and neurodegenerative diseases. It is therefore essential to understand the mechanisms that control immune action.

The study published today in Nature Immunology identifies a new immune control mechanism located within one of the most important cell types in the immune system, the neutrophil. Neutrophils are the first immune cells to arrive at sites of infection or inflammation and attempt to remove the source of the problem. "Neutrophils are the most abundant circulating immune cells in humans and are the first responders to threats."

Nevertheless, neutrophils are very destructive, and if they are activated in the wrong place or at the wrong time, the same mechanisms that serve to eliminate invading pathogens end up damaging healthy tissues.

The antimicrobial actions of neutrophils are enacted by a 'defensive armory' of proteins stored in granules and that when released induce the formation of neutrophil extracellular traps (NETs). However, the toxicity of these structures is especially threatening to highly vascular tissues such as the lungs.

The new study identifies an intrinsic cell mechanism that modifies the protein content of circulating neutrophils, leading to the progressive loss of the toxic contents of the granules and therefore a reduced capacity to form NETs. This program thus undermines the main offensive mechanism of neutrophils. The study shows that this disarmament program is driven by the receptor CXCR2 and regulators of circadian rhythms.

The findings show that neutrophils possess "an innate system that gradually reduces their capacity to mount a toxic attack, so that as they age, neutrophils disarm themselves before they can damage healthy tissues. There are many diseases that cause more or less damage according to the time of day, and this disarmament program helps to explain the origin of these clinical differences," explained the researchers.

First author Jose María Adrover commented that, thanks to this disarmament program, "neutrophils self-limit their capacity to damage healthy tissues. Moreover, in partnership with the Hospital Clínic de Barcelona we have discovered that this mechanism directly affects the severity of acute pulmonary injury."

The study authors believe that their findings could have major implications for health care. "Once we understand how this process operates naturally, we can attempt to manipulate it to obtain a clinical benefit," said co-author Alejandra Aroca. "We are already working on this and have obtained promising results in preclinical models of acute myocardial infarction."

New experimental therapy may offer hope for rare genetic disorders,
as well as more common diseases

BOSTON - Researchers at Massachusetts General Hospital (MGH) have developed a new way to alleviate problems caused by dysfunctional mitochondria, which are the "powerhouses" that produce energy in cells. Their discovery, reported in the journal Nature Biotechnology on January 13, could lead to a new treatment for rare diseases caused by "broken" mitochondria, but could also be used to develop novel therapies for more common age-associated disorders.

All cells have mitochondria. "Mitochondria take electrons from the food we eat and transfer them to oxygen," explains Vamsi Mootha, MD, investigator in the Department of Molecular Biology at MGH, and senior author of the Nature Biotechnology paper. Mootha compares this process to a river flowing down a mountain, with water wheels that harness the flow to produce energy.

However, mitochondrial disorders act like a dam by blocking this smooth flow and causing a pileup of electrons, known as a redox imbalance, and stalling vital chemical reactions inside the cell. "We think toxicity is coming from the fact that the 'waterwheel' is no longer spinning," says Mootha. The excess electrons eventually spill into blood circulation in the form of lactate, a molecule that serves as a marker for the disease occurring inside the cells.

Malfunctioning mitochondria cause more than 300 rare genetic disorders, such as Leigh syndrome (a crippling neurological disease that can present early in infancy) and MELAS (which causes muscle weakness, diabetes, and strokes, with onset usually before age 40). However, a gradual fall-off in mitochondrial function also occurs in Parkinson's disease and other more common disorders. "Even the aging process itself, absent disease, is associated with a decline in mitochondrial activity," says Mootha.

To address the problem, Mootha and his colleagues created a synthetic enzyme (called LOXCAT) by combining two bacterial proteins, lactate oxidase (LOX) and catalase (CAT). His team added LOXCAT to a medium of cultured human cells with defective mitochondria and found that the artificial enzyme converts lactate to pyruvate, which enters cells and picks up electrons, relieving the pileup. Pyruvate in turn converts to lactate, which is released from the cell. LOXCAT reconverts the lactate to pyruvate, which starts the process anew, creating a cycle.

"Our new therapeutic directly targets circulating lactate as a means of safely dissipating excess electrons. Redox balance is restored and flow inside the cell resumes," says Mootha. "What's conceptually new here is that our enzyme doesn't have to enter the cell--it operates on the incoming and exiting chemicals to benefit the cell's inner workings."

Mootha notes that more engineering remains to be done before LOXCAT is ready for testing in humans. But he feels this research, which was funded by the Marriott Foundation, could have a profound impact. "Right now, we have very few, if any, ways of dealing with the consequences of mitochondrial dysfunction," says Mootha. "This novel approach will potentially help a lot of diverse genetic conditions whose common final endpoint is redox imbalance."

The lead author of the Nature Biotechnology paper is Anupam Patgiri, PhD, a research fellow in the Department of Molecular Biology at MGH. Senior author Vamsi Mootha, MD, directs the Mootha Laboratory, which is based at MGH's Department of Molecular Biology. He is also a professor of Systems Biology at Harvard Medical School, an investigator at the Howard Hughes Medical Institute, and a member of the Broad Institute, in Cambridge, Massachusetts.

(Boston)--Researchers have found a way to help make chemotherapy more effective in treating colon cancer. They identified a new pathway (RICTOR/mTORC2) as a biological target for the disease. Targeted inhibition of RICTOR or the mTORC2 pathway could be used as a distinctive therapeutic opportunity with chemotherapy for treating colon cancer.

"Identification of biological targets to enhance sensitivity to chemotherapy is becoming a priority for effectively treating cancers to reduce toxicities caused by chemotherapy or to overcome resistance," explained corresponding author Sam Thiagalingam, PhD, associate professor of biomedical genetics, medicine and pathology & laboratory medicine and pharmacology & experimental therapeutics at Boston University School of Medicine (BUSM).

Previous studies by Thiagalingam and his colleagues found that SMAD4 gene mutations correlate to an advanced stage of colon cancer and SMAD4 acts as a metastasis suppressor by interacting to block the functionality of transcription factors that promote metastatic cancer progression. Furthermore, clinical data and studies performed using cell culture systems by Thiagalingam and others found that loss of or low SMAD4 expression is associated with poor response to 5-fluorouracil, the backbone of almost all chemotherapy combinations used in the treatment of metastatic colon cancer.

The researchers hypothesized that SMAD4 could elicit the metastatic suppressor function not only by blocking functionality of transcription factors but also by disabling metastasis promoting signaling pathways. "We found for the first time that SMAD4 interacts with RICTOR to suppress mTORC2 functionality and therefore the loss of SMAD4 function results in oncogenic activation of the mTORC2 pathway, leading to enhancement in metastatic colon cancer progression and resistance to chemotherapeutic agents," said Thiagalingam.

According to the researchers, this study suggests that effectiveness of cancer therapies involving chemotherapeutic agents such as irinotecan for colon, pancreatic or other cancers eliciting defect in SMAD4 functionality would be highly effective when combined with targeted inhibition of RICTOR/mTORC2 pathway.

In addition to colon cancer, poor prognosis has been associated with mutations, deletions and low levels of SMAD4 in gliomas and pancreatic, prostate and lung cancers.

Autistic mothers are more likely to report post-natal depression compared to non-autistic mothers, according to a new study of mothers of autistic children carried out by researchers at the University of Cambridge. A better understanding of the experiences of autistic mothers during pregnancy and the post-natal period is critical to improving wellbeing. The results are published in Molecular Autism.

The team recruited an advisory panel of autistic mothers with whom they co-developed an anonymous, online survey. After matching, this was completed by 355 autistic and 132 non-autistic mothers, each of whom had at least one autistic child.

Sixty percent of autistic mothers in the study reported they had experienced post-natal depression. By comparison, only 12% of women in the general population experience post-natal depression. In addition, autistic mothers had more difficulties in multi-tasking, coping with domestic responsibilities, and creating social opportunities for their child.

The study also found that when autistic mothers disclosed their autism diagnosis to a professional, they were not believed the majority of the time. Autistic women felt misunderstood by professionals more frequently during pre- and post-natal appointments and found motherhood an isolating experience. Despite these challenges, autistic mothers reported they were able to act in the best interest of their child, putting their child's needs first and seeking opportunities to boost their child's self-confidence.

Dr Alexa Pohl, who led the study, said: "Autistic mothers face unique challenges during the perinatal period and parenthood. Despite these challenges, an overwhelming majority of autistic mothers reported that parenting overall was a rewarding experience. This research highlights the need for increased awareness of the experiences of motherhood for autistic women and the need for more tailored support."

Professor Simon Baron-Cohen, Director of the Autism Research Centre at Cambridge, and part of the team, said: "This worryingly high number of autistic mothers who experience post-natal depression means we are failing them and their infants at a critical point in their lives. We now need more research into why the rates are so much higher, whether they are seeking help and not getting it, or if they are not seeking help and for what reasons. A new research priority is to develop autism-relevant screening tools and interventions for post-natal depression in these mothers."

Monique Blakemore, an autistic advocate and member of the team, said: "This vital study was initiated by the autistic community, who collaborated as equal partners with researchers in the design, dissemination and interpretation of the survey. This is an excellent example of what can be achieved through such partnership."

Every year in the United States, more than 35,000 people die and 2.8 million get sick from antibiotic-resistant infections. Now, a team led by Hebrew University of Jerusalem (HU)'s Professor Nathalie Balaban and Shaarei Zedek Medical Center's Dr. Maskit Bar-Meir has shown that resilient bacteria may be treatable with currently-available therapies. In a study published in Science magazine, the researchers show that aggressive bacteria can be controlled - but only if doctors administer treatment within a short window of opportunity.

Like all living organisms, germs like bacteria develop defenses against hostile elements in their environment. One common tactic is "tolerance", that is, lying dormant during antibiotic treatment. In this way, bacteria evade antibiotic treatment because antibiotics can only spot and kill growing targets. However, this intermediary stage called "antibiotic tolerance" lasts only a few days and cannot be detected in standard medical labs. Therefore, doctors miss the tolerance window and with it the opportunity to treat a serious infection before it becomes altogether resistant. This short window does not affect most healthy adults but for those patients fighting off a blood infection with a weakened immune system, this window is critical and could mean the difference between life and death.

In a previous study, Balaban and PhD student Irit Levin-Reisman studied lab-controlled bacteria. They developed a mathematical model that successfully described, measured and predicted when bacteria would develop tolerance to a particular antibiotic. Further, they observed that when bacteria developed tolerance to one antibiotic, they were more likely to develop tolerance to other antibiotics in the cocktail. "We observed that bacteria acquired tolerance within a few days. These tolerance mutations then acted as a stepping stone to acquire resistance and, ultimately, treatment failure," described Balaban.

Now, as published in the latest edition of Science, HU's Balaban lab and Dr. Jiafeng Liu teamed up with Bar-Meir and repeated their study and tolerance test technique. Only this time, they analyzed daily bacterial samples from hospitalized patients with life-threatening, persistent MRSA (methicillin-resistant Staphylococcus aureus) infections. The pattern that they found was strikingly similar to their lab findings: First, the patients' bacteria developed tolerance, then resistance, and ultimately antibiotic treatment failed.

Looking ahead, Balaban believes that the same evolutionary processes involved in the development of antibiotic tolerance and resistance are likely at play in cancer and might be used to inform treatment. For example, tumor cells might first become tolerant of chemotherapy, develop resistance to it, and then develop resistance to other cancer drugs, as well.

In the short term, Balaban and Bar-Meir would like to give new hope for patients with life-threatening infections by encouraging medical centers to adopt the laboratory test they developed which gauges antibiotic tolerance. This readout would enable doctors to quickly and easily detect whether a patient's bacteria are tolerant of a planned antibiotic treatment before it's administered. Further, based on the patient's bacteria profile, doctors could handpick antibiotics with a greater chance of success that, as is currently done, blindly choose antibiotics for which the patient may have already developed a tolerance. "Using the right combination of available antibiotic drugs at the outset could dramatically increase a patients' survival rate before their infection becomes tolerant to all the antibiotics in our arsenal," Balaban concluded.

(Boston)-- Half of women undergoing mammography have dense breasts. Mandatory dense breast notification and educational materials have been shown to confuse women rather than empower them. Now, researchers from Boston University School of Medicine (BUSM) are developing a smartphone App that acts as an interactive health counselor to improve a womans' knowledge about breast density.

"Many women receive letters after they have a mammogram telling them they have dense breasts, but these letters are hard to understand. Interactive, smartphone-based education can add to these letters making medical information easier to understand. The public should know about the different evidence-based materials that may be offered to help them understand complex health issues, like breast density," explained corresponding author Christine Gunn, PhD, assistant professor of medicine at BUSM.

In an effort to educate women about breast density, researchers from BUSM, in partnership with the Pink & Black Education and Support Network, a Boston-based breast cancer advocacy group, designed and tested an interactive, animated health counselor to provide women with information about their breast density.

Focus groups and a survey given before and after watching a demo of the program were conducted with 44 women. Participants were very satisfied with the prototype and knowledge about breast density increased for six of twelve items.

The researchers hope that this prototype is the start of developing a comprehensive suite of
mammography education tools that can help women understand key information throughout the
entire breast cancer screening process. "There's a lot of complex information, and the medical
system doesn't always do the best job of explaining things or can't answer questions quickly if
you aren't in a doctor's office. We hope tools like our virtual health counselor can support
women, no matter where they are, understand their own health and empower them to get the
right care when they need it," added Gunn.

These finding appear online in the Journal of General Internal Medicine.

INFORMS Journal Information Systems Research New Study Key Takeaways:

Online restaurant reviews in addition to periodic health inspections is key to continuous good hygiene at restaurants.

Roughly 30% of all restaurants in New York City deteriorate in terms of their hygiene within 90 days of certification from the health departments.

More frequent health inspections are not feasible given the growing number of establishments.

CATONSVILLE, MD, January 13, 2020 - Eating out, ordering in or carrying out? Most Americans indulge in some form of restaurant eating. Consumers believe that cleanliness at these establishments is a key factor in determining where they satisfy their cravings.

While the local health department may make sure inspections are kept up to date, with so many new and existing restaurants, it can be hard to stay on top of them all. In New York City alone, there are 20,000 restaurants. New research in the INFORMS journal Information Systems Research says using online reviews from the average person can help keep things in check.

The study, "A for Effort? Using the Crowd to Identify Moral Hazard in New York City Restaurant Hygiene Inspections," looks at hygiene inspections at New York City restaurants from 2010-2016 alongside the associated set of online reviews for the same set of restaurants from Yelp.

Health inspection programs are designed to protect consumers. They typically occur at long intervals of time, allowing restaurant hygiene to remain unmonitored in the interim. This research finds online reviews may be effective to gauge restaurant hygiene during these periods.

"Online reviews of restaurants can effectively identify cases of hygiene violations even after the restaurants have been inspected and certified, thereby identifying moral hazard," said Shawn Mankad, one of the study authors, from Cornell University.

Online reviews of restaurants can provide city regulators with information that can help identify restaurants that are likely to be at risk for important hygiene violations even after receiving high hygiene grades. They can also pinpoint restaurants that are consistently diligent about their hygiene practices.

Mankad, along with Jorge Mejia of Indiana University and Anand Gopal of the University of Maryland, develop a social-media-based dictionary that captures the observed counts of hygiene-related words within online reviews of restaurants.

"Based on the dictionary word counts, we find that roughly 30% of all restaurants in New York City deteriorate in terms of their hygiene within 90 days of certification from the health department," continued Mankad.

"Augmenting the hygiene inspection regime with information from online reviews would enhance the effectiveness of these inspections long term."

Inspecting restaurants is costly and time-consuming and real-time changes in hygiene quality are difficult to observe through infrequent inspections. Continuous monitoring is not possible.

"Traditional techniques to detect and prevent moral hazard, such as rigorous inspections and a strong set of incentives, contribute toward decreasing these inefficiencies in the market," said Mankad. "However, we believe that techniques of text analysis within the domain of machine learning, alongside access to crowd-sourced data from online review platforms such as Yelp, can further enhance the efficacy of hygiene inspections."

LEBANON, NH - Obesity, a global epidemic, is a known contributor to several cancers, including breast, colon, and pancreatic. Stopping the obesity epidemic could be a critical aid in preventing and treating numerous cancers. Researchers with the laboratory of Craig Tomlinson, PhD, at Dartmouth's and Dartmouth-Hitchcock's Norris Cotton Cancer Center have found a critical target in this cause. The team discovered that a receptor found in almost all cells, called AHR, and known primarily to combat exposures to environmental chemicals, also plays a big role in the body's metabolism. Blocking AHR not only prevented, but reversed obesity in study mice. The team's findings, "Reversal of obesity and liver steatosis in mice via inhibition of aryl hydrocarbon receptor and altered gene expression of CYP1B1, PPARα, SCD1, and osteopontin," are newly published in the International Journal of Obesity.

"We carried out experiments showing that when a drug named NF and known to block the AHR, was added to a high-fat diet, mice did not become any fatter than mice on a low-fat control diet," says Tomlinson. "Mice on the high-fat diet with no NF became very obese within the same time span. No ill effects were observed from the drug."

The team then asked whether blocking the AHR with NF could not only prevent obesity but reverse it. "In these experiments, we allowed the mice to become obese on a high-fat diet, and then half the mice were switched to the high-fat diet containing the AHR blocker NF. Over the next few weeks, the mice switched to the high-fat diet containing NF dropped to the same body weight as those mice on the low-fat diet. The remaining mice on the high-fat diet became obese. Again, no ill effects were observed," explains Tomlinson.

Finally, Tomlinson's team investigated the mechanisms behind how the AHR, when blocked by NF, prevented and reversed obesity. Using previous knowledge that the AHR regulates key genes in fat metabolism, the team discovered that in liver cells and in fat cells, the AHR, when blocked by NF, fails to induce several key genes required for fat storage and synthesis. They concluded that the prevention and reversal of obesity from blocking the activity of the AHR is due to key genes regulated by the AHR that are involved in fat metabolism. "Few to no studies have shown that obesity can be reversed by a drug treatment; it is even rarer to know the underlying cellular mechanism," notes Tomlinson.

Tomlinson's team has begun investigating several key questions, including those around the dietary compounds in the food we eat that activate the AHR to cause obesity, and the role that gut bacterial play regarding the AHR and obesity. Most importantly, they have initiated a clinical trial to determine whether the AHR may serve as a therapeutic target to reduce obesity in humans. "We are beginning to understand how the blockage of the AHR prevents and reverses obesity, which may lead to a therapeutic treatment of obesity in humans," says Tomlinson.

Companies, universities, and other institutions that conduct clinical trials are required to record the results of most of them in a federal database, so that doctors and patients can see whether new treatments are safe and effective. But a Science investigation has found that many persist in not reporting those results, and FDA and NIH are doing little to nothing to enforce the reporting requirement despite recent promises to the contrary. While many pharma companies have improved their reporting of trial results over the last few years, a large number of universities and academic medical centers continue to have bad records. Ironically, NIH itself is part of the problem--its top institutes for clinical trials have a poor record of reporting results of those trials for which they are responsible. Science checked all 4,768 trials whose results have come due under legal requirements finalized by NIH and FDA three years ago. Overall, sponsors violated the reporting law more than 55% of the time. Yet FDA has never fined a trial sponsor for non-compliance and NIH has never publicly named or withdrawn a grant from violators, although such actions were vowed in 2016 when ClinicalTrials.gov's requirements were clarified.