Body

Sex differences in airway size are not innate, but likely develop because of hormonal changes around puberty, reports a new study by the University of Waterloo.

"Smaller airways can lead to the respiratory system limiting exercise performance in some people, and can have implications for the development and progression of lung diseases like chronic obstructive pulmonary disease and asthma," said Paolo Dominelli, a professor in Waterloo's Department of Kinesiology. "Having a smaller airway would be analogous to breathing through a straw - it takes more effort and is not as efficient."

The study used three-dimensional scans to assess the airways of 97 healthy females and 128 healthy males aged 1 to 17 years, and found no differences in airway size between the sexes in children under 12 years old.

However, males older than 14 years generally had larger airways than females, even when accounting for height. For example, the trachea was 25 per cent larger in males between the ages of 13 and 17.

Dominelli said this is the first study that assesses sex differences in airway size in healthy children and accounted for differences in height. Previously, other studies have used data from children with existing respiratory conditions. Another study had shown that in prepubescent children, females had faster swimming times, but at puberty, male swim times got faster than female times.

However, to prove causation, the next step would be to directly link the size of airways and the results of strenuous exercise in the same group of people.

"That would be the last point of this story, so to speak," Dominelli said. "It is important to emphasize, though, that even though male airways were, on average, larger in the older age groups, there is still considerable overlap and many females have larger airways than males, especially if they are tall."

Enlarged cerebral ventricles are found in 80% of individuals with schizophrenia, yet the mechanisms that lead to ventricular enlargement are mostly unknown. Scientists at St. Jude Children's Research Hospital have found that two microRNAs play a critical role in a mechanism that results in ventricular enlargement in a type of mouse model. The results were reported today in Nature Communications.

Deletion of a region on chromosome 22 (22q11.2-deletion syndrome) increases the risk of developing schizophrenia approximately 30-fold in humans. 22q11-deletion syndrome can be replicated in mice, creating a research model with scientific significance for studying schizophrenia. Researchers have previously observed ventricular enlargement in individuals with 22q11-deletion syndrome and in mouse models.

The researchers wanted to find out what drives ventricular enlargement in models of 22q11-deletion syndrome. They were interested in the motile cilia, structures that line the ventricle walls and help cerebral spinal fluid circulate.

"Schizophrenia itself is polygenic; there is no single gene that can explain all of the symptoms of this complex disease," said senior author Stanislav Zakharenko, M.D., Ph.D., of the St. Jude Department of Developmental Neurobiology. "But the 22q11-deletion syndrome model gives us an opportunity to identify the gene that contributes to ventricular enlargement."

The gene Dgcr8 is found within the region of DNA that is missing in 22q11-deletion syndrome. This gene plays a role in synthesizing microRNAs. The team found that deletion of Dgcr8 reduces the microRNAs miR-382-3p and miR-674-3p. When those microRNAs are reduced, a receptor on the surface of motile cilia lining the ventricle walls called Drd1 is increased.

Results show that when this mechanism is active, two changes occur in the ventricles: The motile cilia move more slowly, and the brain ventricles are enlarged.

"We found that this mechanism is necessary and sufficient for these two things, reduced motile cilia movement and ventricular enlargement," Zakharenko said. "In our model, we were able to remove the microRNAs and get this effect, and we were able to reintroduce these microRNAs and see that the ventricles and cilia return to normal."

The coronavirus probably has a stronger ability to spread than the World Health Organization has estimated so far. This according to a review of previous studies of the coronavirus' transmissibility performed not least by researchers at Umeå University in Sweden.

"Our review shows that the coronavirus is at least as transmissible as the SARS virus. And that says a great deal about the seriousness of the situation," says Joacim Rocklöv, professor of sustainable health at Umeå University and one of the authors of the study, published in the scientific Journal of Travel Medicine.

The World Health Organization estimates that the coronavirus has a transmissibility, expressed as a reproduction number, of between 1.4 and 2.5. A reproduction number is a measurement of how many people a contaminated person transmits the virus to in a previously healthy population. The higher the number, the more transferable the virus is and the higher the risk for rapid spread. When the reproduction number falls below 1.0, the epidemic is likely to die out.

Researchers in Umeå in Sweden, Heidelberg in Germany, and Zhangzhou in China have carried out a review of several scientific studies of the novel coronavirus, COVD-19. In total, the researchers found twelve studies of sufficiently high quality. The studies consisted of estimations of the growth rate based upon the cases observed in the Chinese population, and based upon statistical and mathematical methods.

The earliest studies of the coronavirus indicated a relatively low transmissibility. Thereafter, the transmissibility rose rapidly to stabilise between 2-3 in the most recent studies. The reproduction number in the studies summed up to a mean of 3.28, and a median of 2.79, which is significantly higher than the World Health Organization's estimation of 1.4-2.5.

"When looking at the development of the corona epidemic, reality seems to correspond well to or even exceed the highest epidemic growth in our calculations. Despite all intervention and control activities, the coronavirus has already spread to a significantly higher extent than SARS did," says Joacim Rocklöv.

BOSTON -- Scientists report promising activity of a novel drug that targets a key molecular driver of clear cell renal cell carcinoma (ccRCC) in patients with metastatic disease.

Researchers from Dana-Farber Cancer Institute report a response rate of 24 percent across all risk categories of patients given an oral first-in-class agent that targets hypoxia-inducible factor (HIF) 2-a, which promotes new blood vessel growth that fuels kidney tumors.

Results of treatment with the drug, known as MK-6482, are being presented in an abstract of a phase I/II study at the ASCO 2020 Genitourinary Cancers Symposium. Based on these findings, a phase III trial has been launched.

"A new drug as a single agent showing an overall response rate of 24 percent across all risk categories - poor, intermediate, and good and in a heavily refractory population - is quite promising," said Toni Choueiri, MD, first author of the abstract. Choueiri is director of the Lank Center for Genitourinary Oncology and the Jerome and Nancy Kohlberg Professor of Medicine at Harvard Medical School.

The drug targets a component of the body's mechanism for sensing oxygen levels and turning on genes that enable the body to adjust to hypoxia - a shortage of oxygen - by making more red blood cells and forming new blood vessels. Dana-Farber scientist and Choueiri's mentor and collaborator William G. Kaelin Jr., MD shared the 2019 Nobel Prize in Medicine with two other researchers for unraveling this complex mechanism, which can be hijacked by cancer to help tumors survive and grow.

In the vast majority of patients with clear cell renal carcinoma, a tumor suppressor protein known as Von Hippel-Lindau (VHL) is not functional. As a result, hypoxia inducible factor (HIF) proteins accumulate inside the tumor cell, wrongly signaling there is a shortage of oxygen, and activating the formation of blood vessels, fueling tumor growth. Understanding this abnormal process has paved the way for new cancer drugs - MK-6482 being one of them and is distinct in that it targets HIF-2a directly leading to blocking cancer cell growth, proliferation, and abnormal blood vessel formation.

The study of MK-6482 included 55 patients with advanced clear cell kidney cancer who had an average of 3 prior lines of therapies.

After a median follow-up period of 13 months, the overall response rate was 24 percent. Forty-one patients had stable disease with a disease control rate (complete response plus partial response plus stable disease) of 80 percent. There were partial responses in two of five favorable-risk patients; 10 of 40 intermediate-risk patients; and one of 10 poor-risk patients.

The median duration of response had not been reached: 81 percent of patients had an estimated response of more than six months, and 16 patients continued treatment beyond 12 months. The median progression-free response rate was 11 months.

The authors concluded that MK-6482 "is well-tolerated with a favorable safety profile and demonstrated promising single-agent activity in heavily pre-treated patients" with clear-cell kidney cancer across the various risk groups.

Bioengineers from Trinity College Dublin, Ireland, have developed a prototype patch that does the same job as crucial aspects of heart tissue.

Their patch withstands the mechanical demands and mimics the electrical signalling properties that allow our hearts to pump blood rhythmically round our bodies.

Their work essentially takes us one step closer to a functional design that could mend a broken heart.

One in six men and one in seven women in the EU will suffer a heart attack at some point in their lives. Worldwide, heart disease kills more women and men - regardless of race, than any other disease.

Cardiac patches lined with heart cells can be applied surgically to restore heart tissue in patients who have had damaged tissue removed after a heart attack and to repair congenital heart defects in infants and children. Ultimately, though, the goal is to create cell-free patches that can restore the synchronous beating of the heart cells, without impairing the heart muscle movement.

The bioengineers report their work, which takes us one step closer to such a reality, in the journal Advanced Functional Materials.

Michael Monaghan, ussher assistant professor in biomedical engineering at Trinity, and senior author on the paper, said:

"Despite some advances in the field, heart disease still places a huge burden on our healthcare systems and the life quality of patients worldwide. It affects all of us either directly or indirectly through family and friends. As a result, researchers are continuously looking to develop new treatments which can include stem cell treatments, biomaterial gel injections and assistive devices."

"Ours is one of few studies that looks at a traditional material, and through effective design allows us to mimic the direction-dependent mechanical movement of the heart, which can be sustained repeatably. This was achieved through a novel method called 'melt electrowriting' and through close collaboration with the suppliers located nationally we were able to customise the process to fit our design needs."

This work was performed in the Trinity Centre for Biomedical Engineering, based in the Trinity Biomedical Sciences Institute in collaboration with Spraybase®, a subsidiary of Avectas Ltd. It was funded by Enterprise Ireland through the Innovation Partnership Program (IPP).

Dr Gillian Hendy, director of Spraybase® is a co-author on the paper. Dr Hendy commended the team at Trinity on the work completed and advancements made on the Spraybase® Melt Electrowriting (MEW) System. The success achieved by the team highlights the potential applications of this novel technology in the cardiac field and succinctly captures the benefits of industry and academic collaboration, through platforms such as the IPP.

Engineering replacement materials for heart tissue is challenging since it is an organ that is constantly moving and contracting. The mechanical demands of heart muscle (myocardium) cannot be met using polyester-based thermoplastic polymers, which are predominantly the approved options for biomedical applications.

However, the functionality of thermoplastic polymers could be leveraged by its structural geometry. The bioengineers then set about making a patch that could control the expansion of a material in multiple directions and tune this using an engineering design approach.

The patches were manufactured via melt electrowriting - a core technology of Spraybase® - which is reproducible, accurate, and scalable. The patches were also coated with the electroconductive polymer polypyrrole to provide electrical conductivity while maintaining cell compatibility.

The patch withstood repeated stretching, which is a dominant concern for cardiac biomaterials, and showed good elasticity, to accurately mimic that key property of heart muscle.

Professor Monaghan added:

"Essentially, our material addresses a lot of requirements. The bulk material is currently approved for medical device use, the design accommodates the movement of the pumping heart, and has been functionalised to accommodate signaling between isolated contractile tissues."

"This study currently reports the development of our method and design, but we are now looking forward to furthering the next generation of designs and materials with the eventual aim of applying this patch as a therapy for a heart attack."

Dr Dinorath Olvera, Trinity, first author on the paper, added:

"Our electroconductive patches support electrical conduction between biological tissue in an ex vivo model. These results therefore represent a significant step towards generating a bioengineered patch capable of recapitulating aspects of heart tissue - namely its mechanical movement and electrical signalling."

Women who go on to develop type 2 diabetes after having gestational, or pregnancy-related, diabetes are more likely to have particular genetic profiles, suggests an analysis by researchers at the National Institutes of Health and other institutions. The findings provide insight into the genetic factors underlying the risk of type 2 diabetes and may inform strategies for reducing this risk among women who had gestational diabetes.

The study was conducted by Mengying Li, Ph.D., of the Division of Intramural Population Health Research at NIH's Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and colleagues. It appears in BMJ Open Diabetes Research & Care.

"Our study suggests that a healthful diet may reduce risk among women who have had gestational diabetes and are genetically susceptible to type 2 diabetes," said the study's senior author Cuilin Zhang, M.D., Ph.D., of NICHD's Division of Intramural Population Health Research. "However, larger studies are needed to validate these findings."

Gestational diabetes (high blood sugar that first occurs during pregnancy) increases the risk of complications for mothers and their infants. In most cases, the condition resolves soon after the baby is born, but nearly half of women with gestational diabetes go on to develop type 2 diabetes later in life. Type 2 diabetes increases the risk of heart disease, kidney disease and other health problems. However, little research has been done on the genetic factors influencing a woman's risk for progressing to type 2 diabetes after gestational diabetes.

In the current study, researchers analyzed data from 2,434 women with gestational diabetes who participated in the Diabetes & Women's Health Study. The study followed women before, during and after pregnancy and captured data on their health later in life. Of the original group, 601 women with gestational diabetes went on to develop type 2 diabetes.

Previous research has linked variations in certain genes (called single nucleotide polymorphisms) to a higher risk of type 2 diabetes. In the current study, researchers checked genetic scans of the 2,434 women for the presence of 59 gene variants thought to be more common in people who have type 2 diabetes. The researchers found that women who had the largest proportion of these gene variants were 19% more likely to develop type 2 diabetes, compared to those who had the lowest proportion of these variants.

The researchers also ranked the women's diets according to the proportion of healthy foods. Among women who adhered to a healthier diet, the risk associated with the gene variants was lower than that of the other women, but the differences between the two groups were not statistically significant.

The authors believe their study is among the largest to date that looks at genetic factors underlying development of type 2 diabetes among women with prior gestational diabetes. However, the number of women participating in the study may not be large enough to find a significant interaction between healthy diet and genetic susceptibility in relation to this risk, explained Dr. Zhang.

February 13, 2020, CLEVELAND: In a new Cleveland Clinic-led study published in JAMA Oncology, researchers show that a testosterone-related genetic variant - HSD3B1(1245C) - is associated with more aggressive disease and shorter survival in men with metastatic prostate cancer.

This study - the first clinical trial validation of the relationship between HSD3B1 status and clinical outcomes - suggests that genetic testing for HSD3B1(1245C) may help physicians identify patients most likely to benefit from additional and more aggressive treatment.

Nima Sharifi, M.D., of Cleveland Clinic's Lerner Research Institute, and colleagues retrospectively analyzed data from 475 participants enrolled in a large, multi-center national clinical trial testing the efficacy of androgen deprivation therapy (ADT) alone or in combination with docetaxel in prostate cancer. They compared clinical outcomes between men who carried the variant versus those who did not.

The researchers found that HSD3B1(1245C) inheritance is associated with faster progression to treatment resistance and shorter overall survival in men with low-volume metastatic prostate cancer regardless of the use of docetaxel. Interestingly, the genetic variant led to shortened survival despite the administration of any other therapies following the development of treatment resistance.

"These findings lay the groundwork for more personalized and effective treatments for prostate cancer," said Dr. Sharifi, senior author of the study. "If men carry this specific testosterone-related genetic abnormality we may be able to individualize their therapy."

In addition, HSD3B1(1245C) was not found to influence clinical outcomes in men with high-volume prostate cancer. Dr. Sharifi notes this is not surprising as previous studies have shown that disease progression and burden is vastly different between high- and low-volume prostate cancer.

Taken together, these findings suggest that the presence or absence of this genetic variant can be used to help identify men with low-volume metastatic prostate cancer most at risk for quick progression to treatment resistance and earlier death - a discovery with significant implications for clinical care and genetic counseling.

A limitation of the study was a lack of diversity due to the patient population enrolled in the original clinical trial and genetic variant frequencies. Validating this association with a more diverse population will be an important next line of investigation.

In 2013, Dr. Sharifi made the discovery that the HSD3B1(1245C) variant helps prostate cancer cells evade ADT, the first line of defense against the disease. ADT works by cutting off cells' supply of testicular androgens, hormones that fuel cancer cells to grow and spread. He showed that in men with the genetic change, cancer cells adapt to produce their own androgens, which leads to treatment-resistant prostate cancer. In 2017, he received the national Top Ten Clinical Achievement Award from the Clinical Research Forum for his discoveries linking HSD3B1(1245C) with poor prostate cancer outcomes.

"These findings represent a seven-year research story that started at the lab bench and has now reached the patient bedside," said Dr. Sharifi. "As the team has shown here, incorporating genetic testing in prostate cancer as part of routine care has significant potential to improve treatment success and quality and length of life for men with prostate cancer who carry the HSD3B1(1245C) variant. This work is another step in that direction."

The A143T variant of the GLA gene is associated with an increased risk of Fabry cardiomyopathy, according to a new study. The variant plays a role in lipid metabolism. According to the researchers, patients carrying the mutation and manifesting changes in the heart should initiate treatment to prevent the disease from progressing. The study, conducted at the University of Eastern Finland and Kuopio University Hospital, was published in the journal Heart.

However, not all carriers of the mutation develop Fabry cardiomyopathy, and the association of the A143T variant with the disease is not fully understood yet.

According to Professor Johanna Kuusisto from the University of Eastern Finland, the study was inspired by clinical work with patients.

"We had to consider the feasibility of initiating expensive enzyme replacement therapy when Cardiologist Kati Valtola discovered a cardiomyopathy in three members of the same family. Genetic testing revealed that they all carried the A143T variant, whose role in the pathogenesis of Fabry cardiomyopathy has been previously questioned," Professor Kuusisto says.

Fabry cardiomyopathy is a rare disease of the lipid metabolism where α-galactosidase A, i.e. the GLA enzyme, is missing or is functionally deficient due to a gene mutation. It leads to the accumulation of harmful lipids on blood vessel walls, the heart, the kidneys and the nervous system. More than 900 mutations of the GLA gene that are associated with Fabry cardiomyopathy are known to date. The symptoms caused by these mutations vary greatly in terms of their severity. In the classical and most severe form, GLA enzyme activity is fully or almost fully non-existent, and symptoms begin already in childhood. Patients are usually men and their symptoms are severe, including pain, sweating disorders and gastrointestinal problems. Typically, they develop a severe multisystem disease before reaching middle age. Women and men carrying a less severe mutation have some GLA enzyme activity, and they do not become symptomatic until adulthood. In this form of the disease, lipid usually accumulates only in the heart. The heart muscle thickens and starts to be replaced by connective tissue. Patients suffer from shortness of breath, chest pain and arrhythmia, and they may need a pacemaker due to conduction disorders. Cardiomyopathy may lead to heart failure, which is the most common cause of death in people with Fabry cardiomyopathy.

Ultrasound and magnetic imaging of the heart play a key diagnostic role. Fabry cardiomyopathy is confirmed by genetic testing and by analysing GLA enzyme activity from a blood sample. In unclear cases, heart and kidney biopsy is used to confirm lipid accumulation.

Asymptomatic carriers should be monitored, too

The progression of Fabry cardiomyopathy can be prevented by intravenous enzyme replacement therapy and, in carriers of some specific mutations, by orally administered drugs. Timely treatment can reduce the accumulation of harmful lipids. Untreated Fabry cardiomyopathy deteriorates the quality of life and predisposes to premature death. Even patients with minor symptoms can be at risk of a sudden death, as Fabry cardiomyopathy is associated with the risk of arrhythmia.

In Finland, more than 100 people so far have been diagnosed with Fabry cardiomyopathy or as asymptomatic carriers of the GLA mutation, and 19 of these individuals are from Kuopio University Hospital's catchment area.

"We are currently monitoring 13 patients of whom eight receive enzyme replacement therapy," Kuusisto says.

The newly published study analysed cardiomyopathy-associated gene mutations, including the variant A143T of the GLA gene, in altogether 11 members of the same family. The carriers of this variant were carefully examined using, e.g., laboratory tests and CMR and PET-CT imaging, and heart biopsies were taken from two patients with a history of heart symptoms.

Professor Kuusisto says that it wasn't clear in the beginning of the study whether the variant in question causes Fabry disease, or whether it is just a harmless mutation.

"Our study now shows that the A143T variant, a mutation of the GLA gene, is likely to cause late-onset Fabry cardiomyopathy. It is important to initiate enzyme replacement therapy in patients who are carriers of this mutation and who manifest changes in their heat. In addition, their family members who also are carriers of this mutation should be monitored for Fabry cardiomyopathy," Professor Kuusisto points out.

CHAPEL HILL, N.C. (Feb. 13, 2020) - Most clinical practice guidelines in the U.S. are created by medical specialty societies. While there is widespread awareness of the potential for intellectual and financial conflict of interest by individual panel members, there is little recognition of the potential for the processes used by guideline panels to create conflict of interest. This is particularly important for medical specialty societies, which have the dual obligation to advocate for patients served by the specialty and for the professional interest of their physician members.

A new study of the approval processes used by the 43 medical-specialty-society members of the Council of Medical Specialty Societies in the U.S. to create evidence-based guidelines finds that most use an approval procedure that has the potential to undermine editorial independence of the guideline development committee.

The review, published in PLOS ONE, was led by Jeffrey Sonis, MD, MPH, associate professor in the Department of Social Medicine and associate professor in the Department of Family Medicine in the University of North Carolina School of Medicine.

Sonis and Oliva M. Chen, MD, a UNC School of Medicine alumna now at the University of Michigan, independently evaluated guidelines and guideline development manuals that were publicly available on the specialty societies' web sites. They found that through May 2017, 36 of 43 specialty societies produced evidence-based practice guidelines. Of those 36 societies, 27 (75%) required approval by a committee representing the society as a whole, such as the Board of Directors or the Executive Committee. Importantly, none of the 27 specified the criteria used for approval decisions. Since an Executive Committee or Board of a medical specialty society has obligations to both the professional and economic interests of its members and to the patients served by those physicians, requiring them to approve an evidence-based clinical practice guideline introduces a potential conflict of interest.

Just six of the 27 specialty societies (17%) had in place procedures to maintain some editorial independence for the guideline development group, such as approval by a separate guideline committee or approval based on fidelity to pre-approved established guideline methodology, not content.

"This lack of editorial independence within each society may introduce conflict of interest into a process that is designed to produce recommendations based exclusively on evidence and patient preferences," Sonis said. "Medical specialty societies should adopt guideline approval processes that limit the possibility of conflict of interest. The processes used by the six specialty societies that maintain at least some editorial independence of the guideline development panel can serve as a useful model."

Lansoprazole, an over-the-counter acid reflux drug that is often taken by pregnant women, may be a promising therapy to reduce preterm birth, according to a computational drug repurposing study that also tested several of the drugs in mice.

The study also identified 12 other FDA-approved drugs that are deemed safe in pregnancy. While the drugs encompass a variety of modalities, the scientists said they all appear to act on biological pathways that affect the immune response, which is implicated in preterm birth.

"Inflammation clearly plays a role in initiating labor and preterm birth," said Marina Sirota, PhD, assistant professor of pediatrics, a member of the Bakar Computational Health Sciences Institute at UCSF, and the senior author of the study, published Feb. 13, 2020, in JCI Insight. "Immune pathways are very significantly dysregulated in women who end up delivering preterm, and they're also dysregulated in babies who are born early. However, we have seen from our previous work that there is an interaction between the maternal and fetal immune systems and a breakdown in maternal-fetal tolerance."

To identify candidate drugs that might be effective in preventing preterm birth, the scientists first looked at which genes were up- or down-regulated in the blood cells of women who experienced spontaneous preterm birth to identify a gene expression "signature." Then they looked for the opposite signature in cells that had been exposed to 1,309 different drugs, reasoning that if a drug could correct the effects that preterm birth had on the women's blood cells, the drugs might also prevent preterm birth itself.

The scientists identified 83 drug candidates, but when they excluded those found to have pregnancy risks in animal or human studies, they wound up with 13 drugs, ranked according to their "reversal score," a measure of the extent to which they were able to reverse the gene expression signature of preterm birth.

The other drugs identified by the computational screen included progesterone, which is already used to treat recurrent spontaneous preterm birth, folic acid, which is given to women during pregnancy to prevent birth defects, three antibiotics, an antifungal, an antidepressant, an anti-diabetic, and a blood pressure medication.

The fact that predictable drugs like progesterone came up in the screen gave the scientists confidence that the drugs they identified may turn out to be effective once they are tested in pregnant women. Three of the other drugs that came up in the screen--folic acid, clotrimazole and metformin--have also been shown in previous studies to be effective against preterm birth.

"Finding progesterone on the list was a promising validating step," said Brian Le, PhD, a postdoctoral scholar in the UCSF Department of Pediatrics and the Bakar Computational Health Sciences Institute, and the first author of the study. "Four of the drugs on our list have seen effectiveness in past studies that were either experimental or retrospective. This leads us to believe in the biology behind the identification of these drugs."

The scientists chose lansoprazole for further testing because, in addition to its high reversal score, it is available over the counter, and they know from their previous work that it affects a stress-response protein, heme oxygenase-1, that has been linked with pregnancy disorders. Lansoprazole, which is a proton-pump inhibitor marketed as Prevacid, had the second-highest reversal score of the 13 drugs identified as being safe and effective. Progesterone was further down the list.

The scientists tested lansoprazole in pregnant mice that had been given a bacterial component to induce inflammation, which causes some fetuses to die in utero, where they are reabsorbed. When these mice were given lansoprazole, they had more viable fetuses. Lansoprazole also worked better in these mice than progesterone.

Although it is a good measure of how inflammation affects pregnancy in mice, the scientists said the fetal resorption mouse model is not an adequate model of human preterm birth. They said more work, including studies in people, would need to be done before lansoprazole or any of the dozen other drugs they identified could be proven effective in pregnant women at risk for preterm birth. But the computational study provides leads for a condition that currently has few treatment options.

"This, basically, is a proof of concept that this drug has anti-inflammatory properties, which are not the properties the drug was designed for," said David K. Stevenson, MD, a professor of pediatrics at Stanford University and an author of the study. "This is a short way to get to new therapeutics for known diseases."

DUARTE, Calif. -- City of Hope scientists have identified an unlikely way to potentially prevent or slow the progression of aggressive breast cancer: target one's internal clock.

Often taken for granted, the circadian rhythm is gaining traction as a potential catalyst or brake for the onset of disease. For example, studies have shown that women who take frequent night shifts have disrupted internal clocks and increased risk of developing breast cancer. Now, City of Hope's David K. Ann, Ph.D., and his colleagues think they may have found a new role for the "clock gene": It is linked to triple-negative breast cancer, an aggressive form of the disease that often results in a poorer prognosis.

"We are the first to highlight the circadian protein BMAL1 as a tumor suppressor that interacts with the metabolism of prediabetic, obese people," said Ann, senior author of a new study and the Morgan & Helen Chu Dean's Chair of the Irell and Manella Graduate School of Biological Sciences at City of Hope. "Loss of BMAL1 in a prediabetic or obese environment gives breast cancer progression the competitive edge. This finding brings us one small step closer to the ability to provide more personalized breast cancer care based on an individual's genetics and lifestyle choices."

The retrospective study, to be published in the Feb. 21 issue of Cell Press' iScience, is a proof-of-concept investigation based on City of Hope's initial bioinformatics observations. Subsequent laboratory work used cell and mouse models to test the new hypothesis, which resulted in City of Hope scientists establishing a link among circadian rhythm, cell metabolism, breast cancer progression and nutritional health. Because obesity is a risk factor in many cancers, the City of Hope researchers next will look into how the clock gene may affect prediabetic, obese people with other major cancer types.

"The growing number of public databases in cancer genomics has afforded us the opportunity to generate hypotheses and validate discoveries for translational research," said Ching Ouyang, Ph.D., assistant research professor in the Center for Informatics and the Department of Computational and Quantitative Medicine at City of Hope, a world-renowned independent research and treatment center for cancer, diabetes and other life-threatening diseases. "City of Hope is a unique comprehensive cancer center that fosters collaboration. Physicians, researchers and data scientists find trends in clinical and laboratory data and work together to develop novel therapies."

In this study, the researchers found that obese, prediabetic mice without the BMAL1 protein derived from their clock gene experienced accelerated breast tumor growth compared to their lean animal model peers. Additionally, breast tumors spread to the lungs more quickly in obese mice, suggesting that BMAL1 is a novel target that can suppress tumor progression or metastasis in a prediabetic, obese environment.

Though more research is needed, Ann said that in the distant future, a doctor could determine an individual's BMAL1 levels, especially in tumors, as well as order blood work to understand the person's nutritional health. If BMAL1 levels are low and the individual is prediabetic or clinically obese, perhaps a not-yet-developed drug could be prescribed to increase BMAL1 levels. Additionally, the physician could advise the patient to reconsider her dietary habits.

"Although additional research is needed, something people can consider doing now is to eat smaller meals at more frequent intervals, decrease sugar intake, avoid high-fat foods and exercise more," Ann said.

A world-first clinical trial has called into question the effectiveness of using more than one antibiotic to treat the deadly 'super-bug', Methicillin-resistant staphylococcus aureus (MRSA) Bacteremia, commonly known as Golden Staph.

Researchers from The University of Queensland, in collaboration with global counterparts, have found using two antibiotics to treat MRSA infection provides no advantage over using a single antibiotic.

The three-year multi-centre study involved 352 patients at 27 hospitals in Australia, Singapore, Israel and New Zealand.

UQ Professor David Paterson said researchers tested whether adding a second antibiotic for seven days to a standard antibiotic treatment would lead to improved health outcomes after 90 days.

"We found no significant difference in mortality, bacteria in the blood, infection relapse or treatment failure," Professor Paterson said.

"Furthermore, patients who received two antibiotics had a higher rate of side effects related to kidney function than those who received just one antibiotic.

"For many years doctors have debated whether MRSA should be treated with two antibiotics or just one antibiotic.

"This trial now puts that debate to rest and will have a huge impact on how antibiotics are used for MRSA infections worldwide.

"These findings are hugely important on a number of levels - one of the most important implications of the research is how it can impact antibiotic use and the global issue of antibiotic resistance."

MRSA is a common and very serious cause of infection that affects more than 10,000 people in Australia every year, especially women aged 60 and over.

Treating the infection can take up to several months and requires lab testing for diagnosis.

The rise of fake news could be making disease outbreaks worse - according to new research from the University of East Anglia (UEA).

Researchers focused on influenza, monkeypox and norovirus across two studies - but they say their findings could also be useful for dealing with the COVID-19 Coronavirus outbreak.

The team say that efforts to stop people sharing fake news, misinformation and harmful advice on social media could save lives.

The worry that fake news might be used to distort political processes or manipulate financial markets is well established. But less studied is the possibility that misinformation spread could harm human health, especially during the outbreak of an infectious disease.

COVID-19 expert Prof Paul Hunter and Dr Julii Brainard, both from UEA's Norwich Medical School, set out to test the effect of sharing dangerously wrong information on human health during a disease outbreak.

Prof Hunter said: "Fake news is manufactured with no respect for accuracy, and is often based on conspiracy theories.

"Worryingly, research has shown that nearly 40 per cent of the British public believe at least one conspiracy theory, and even more in the US and other countries.

"When it comes to COVID-19, there has been a lot of speculation, misinformation and fake news circulating on the internet - about how the virus originated, what causes it and how it is spread.

"Misinformation means that bad advice can circulate very quickly - and it can change human behaviour to take greater risks.

"We have already seen how the rise of the anti-vax movement has created a surge in measles cases around the world.

"People in West Africa affected by the Ebola outbreak were more likely to practice unsafe burial practices if they believed misinformation. And here in the UK, 14 per cent of parents have reported sending their child to school with symptoms of contagious chickenpox - violating school policies and official quarantine advice.

"Examples of risky behaviour during infectious disease outbreaks include not washing hands, sharing food with ill people, not disinfecting potentially contaminated surfaces, and failing to self-isolate.

"Worryingly, people are more likely to share bad advice on social media, than good advice from trusted sources such as the NHS, Public Health England or the World Health Organisation."

The researchers created theoretical simulations which took into account studies of real behaviour, how different diseases are spread, incubation periods and recovery times, and the speed and frequency of social media posting and real-life information sharing.

They also took into account how a distrust in conventional authorities is closely linked to the tendency to believe in conspiracy theories, the phenomena that people interact within 'information bubbles' online, and the fact that people are more likely to share false stories than correct information online.

The researchers also investigated strategies to fight fake news - such as drowning bad information with good information and 'immunizing' people against bad information though better education.

Dr Julii Brainard said: "No previous studies have looked in such detail at how the spread of misinformation affects the spread of disease.

"We found that misinformation during epidemics of infectious disease could make those outbreaks more severe.

"We tested strategies to reduce misinformation. In our first study, focusing on the flu, monkeypox and norovirus, we found that reducing the amount of harmful advice being circulated by just 10 per cent - from 50 percent to 40 per cent - mitigated the influence of bad advice on the outcomes of a disease outbreak.

"Making 20 per cent of the population unable to share or believe harmful advice - or 'immunizing' them against fake news, had the same positive effect.

"Our second study, which focused on norovirus, showed that even if 90 per cent of the advice is good, some disease will still circulate.

"In our second study, we were also interested in the 'herd immunity' levels required to 'immunise' people against fake news. The modelling suggests that any 'immunity' against bad advice reduces outbreak impacts.

"But while we used very sophisticated simulation models, it is important to remember that this is not an observational study based on real behaviour," she added.

"The efficacy of implementing such strategies to fight fake news needs to be tested in real world settings, with costs and benefits ideally compared with real world disease reduction."

Novel blood-based biomarkers for dementia could identify disease at an early preclinical stage, serve as surrogate outcomes for clinical trials of investigational therapies and even identify future potential therapeutic targets. Unlike cerebrospinal fluid biomarkers that require a spinal tap, plasma biomarkers can be extracted from the blood, making their collection much less invasive and much more appealing for patients. In a study published in Annals of Clinical and Translational Neurology, a team led by investigators from Brigham and Women's Hospital describes the role of plasma ceramides in dementia and Alzheimer's disease (AD) and their potential as a blood-based biomarker.

"Our findings indicate that circulating ceramide ratios may be useful predictors of future dementia risk and may have a role in predicting dementia at an early, preclinical stage, when the greatest opportunity for disease modification exists," said Emer McGrath, MD, PhD, associate neurologist in the Department of Neurology at the Brigham. "However, these results will require replication in other cohorts."

Altered lipid metabolism is believed to play an important role in the development of dementia and Alzheimer's disease. Ceramides are a type of lipid belonging to the sphingolipid family and are thought to play an important role in lipid aggregation, inflammation, endothelial dysfunction and neuronal cell death. Recently, attention has focused on the possibility that the adverse effects of ceramides may be related to the relative proportions of circulating very-long-chain to long-chain fatty acyl chains, rather than simply due to elevated total ceramide levels. Very-long-chain fatty acyl ceramides are important for myelin function and may have a protective effect against dementia, while long-chain ceramide species are linked with deleterious pro-inflammatory and apoptotic effects.

In their study, McGrath and colleagues compared levels of very-long chain and long-chain ceramides in blood samples from approximately 1,900 participants in the Framingham Heart Study Offspring cohort. They analyzed the risk of dementia, MRI structural measures of vascular brain injury and β-amyloid burden on brain PET, AD's gold-standard imaging marker. The team found that an elevated ratio of very-long-chain to long-chain ceramides was associated with a 27 percent reduction in the risk of dementia and AD dementia as well as a lower burden of white matter injury on MRI of the brain.

In an exploratory analysis of 48 individuals with available amyloid-PET data, an elevated ratio of ceramide 24:0 (very-long chain ceramide) to ceramide 16:0 (long-chain ceramide) was associated with a reduced burden of ß-amyloid. Ceramides have previously been shown to stimulate ß-amyloid formation and inhibition of ceramide synthesis results in reduced production of ß-amyloid. It is possible that pharmacological inhibition of long-chain ceramide synthesis could slow down or even prevent the progression of AD dementia through prevention of ß-amyloid accumulation. Modification of ceramides could represent an attractive therapeutic option for prevention of vascular contributions to dementia, although this remains to be tested.

A new study published in Maternal and Child Health Journal, led by Anna M. Scolese, Master of Public Health student at George Mason University, found that 23.3% of women who experienced intimate partner violence (IPV) reported their child's school attendance was disrupted due to IPV. The study used baseline data from a sub-sample of 659 women in Mexico City who recently experienced IPV and reported having a child under age 18. Researchers identified four distinct classes of IPV experiences: Low Physical and Sexual Violence; Low Physical and High Sexual Violence, High Physical and Low Sexual Violence and Injuries; and High Physical and Sexual Violence and Injuries.

The study found that women in both the High Physical and Sexual Violence and Injuries class and the High Physical and Low Sexual Violence and Injuries class were at greater risk of IPV disrupting children's school attendance than the women in the Low Physical and Sexual Violence class.

"Our analysis (LCA) allows us to identify patterns of IPV experience, such as those who experience more physical violence and injuries, and determine how these different patterns of IPV affect disruptions in school attendance," says Scolese. "Our results show that children of women who experience High Physical Violence and Injuries - with or without Sexual Violence- are at greater risk of school disruption. In short, if a mother experiences high physical violence and injuries from intimate partner violence, this is more likely to affect a child's school attendance."

Other study authors are from Warrant Alpert School of Medicine at Brown University, International Rescue Committee, Harvard TH Chan School of Public Health, and National Autonomous University of Mexico, Mexico City, Mexico.