Body

DES PLAINES, IL -- A multicenter randomized controlled clinical trial confirms that both chemical-first and electrical-first approaches are effective strategies for acute atrial fibrillation; however, an electrical-first strategy results in a significantly shorter emergency department (ED) length of stay. The study findings are published in the September 2019 issue of Academic Emergency Medicine (AEM), a journal of the Society for Academic Emergency Medicine (SAEM).

The lead author of the study is Frank X. Scheuermeyer, MD, MHSc, program head, clinical associate professor, and director of research in the Department of Emergency Medicine at St. Paul's Hospital and the University of British Columbia, Vancouver.

The trial results showed that in uncomplicated ED atrial fibrillation patients of less than 48 hours, a significantly greater proportion of ED patients were discharged from the ED within four hours when managed with an electrical-first cardioversion strategy, compared to a chemical?first cardioversion strategy. In addition, the median LOS was shorter by 1.2 hours for the electrical?first group.

The findings add to the literature by comparing two accepted treatments, measuring important outcomes--including patient-reported results--and demonstrating that these patients, irrespective of initial management strategy, are safe; have minimal discomfort after their ED visit; and have an acceptable QoL at 3 and 30 days.

The study may assist clinicians by demonstrating that the electrical-first strategy may restore sinus rhythm more quickly. The results should encourage clinicians to initially consider an electrical-first approach for such patients.

Commenting on the study is Editor-in-Chief of the Canadian Journal of Emergency Medicine, Ian G. Stiell, MD, MSc, a distinguished professor and senior scientist in the Department of Emergency Medicine, Ottawa Hospital Research Institute, University of Ottawa:

"This study confirms that both chemical-first and electrical-first approaches are effective strategies for acute atrial fibrillation. Immediate rhythm control by ED physicians allows rapid discharge of patients and early return to normal activities. Whether drug first or shock first should be determined by patient or physician preference."

PHILADELPHIA -- CAR T-cell therapy, a rapidly emerging form of immunotherapy using patients' own cells to treat certain types of cancers, may be a viable treatment option for another life-threatening condition: heart disease. In a first-of-its-kind study, published today in Nature, researchers at Penn Medicine used genetically modified T cells to target and remove activated fibroblasts that contribute to the development of cardiac fibrosis--a scarring process found in most forms of heart disease that results in heart stiffness and decreased function of the heart. The team found the approach significantly reduced cardiac fibrosis and restored heart function in mice with heart disease caused by high blood pressure.

"The ability to harness patients' own cells to fight cancer has been one of the most promising research breakthroughs of the past decade, and we are excited to find ways to leverage this same type of technology to address other common illnesses," said the study's corresponding author Jonathan A. Epstein, MD, executive vice dean, chief scientific officer and the William Wikoff Smith Professor of Cardiovascular Research. "While much more research is needed before we can introduce this approach into the clinical setting, this marks a significant step forward in our efforts to treat - and potentially reverse - a condition that accelerates the progression of heart failure."

Heart disease is the leading cause of death in the United States, and excessive cardiac fibrosis is an important factor in the progression of many forms of heart disease. It develops after chronic inflammation or cardiac injury, when cardiac fibroblasts - cells that play an important role in the structure of the myocardium, the muscular middle layer of the heart's wall - become activated and begin to remodel the myocardium via extracellular matrix deposition. Research has shown that the removal of activated cardiac fibroblasts can reduce heart stiffness, making it easier for the ventricles to relax. However, there are no therapies that directly target excessive fibrosis, and very few interventions have shown the ability to improve heart function and outcomes among patients with impaired cardiac compliance.

CAR T-cell therapy, which involves genetically modifying a patient's own T cells to fight disease, is primarily used to treat blood cancers, including types of lymphoma and leukemia. Penn Medicine's Abramson Cancer Center developed what became the world's first approved CAR T-cell therapy, Kymriah. Driven by the recent breakthroughs in the treatment of cancers, researchers sought to determine the viability of using the CAR T-cell approach to target and attack the activated cardiac fibroblasts that contribute to fibrosis.

As a first step, researchers launched a genetic proof-of-concept experiment using mice that can express an artificial antigen (OVA) on cardiac fibroblasts. The mice were treated with agents to model hypertensive heart disease, a condition associated with left ventricular hypertrophy (enlargement or thickening of the heart walls), systolic and diastolic dysfunction (pumping of blood in and out of the heart), and widespread cardiac fibrosis. To selectively target the OVA proteins expressing cardiac fibroblasts, the team treated one cohort of mice with engineered CD8+ T cells that express a cognate T-cell receptor against the OVA peptide. At the four-week mark, the mice who were treated with the reengineered cells had significantly less cardiac fibrosis, whereas the mice in the control groups still had widespread fibrosis.

After establishing the feasibility of this approach, researchers sought to identify a protein specifically expressed by activated fibroblasts that they could program the genetically modified T cells to recognize and attack. Using an RNA sequence database, the team analyzed gene expression data of patients with heart disease and identified the target: fibroblast activation protein (FAP), a cell surface glycoprotein. Researchers then transferred engineered FAP CAR T-cells into mice at the one and two week marks, aiming to target and deplete FAP-expressing cardiac fibroblasts. Within a month, researchers saw a significant reduction of cardiac fibrosis in the mice that were treated with the engineered cells, as well as improvements in diastolic and systolic function.

Researchers note additional studies are needed to confirm FAP as the optimal target and to ensure safety risks are minimized.

"We've seen enormous progress in the treatment of certain cancers via the use of engineered T cells. Our findings suggest that this approach may extend beyond cancer and serve as an effective treatment for heart disease," said first author Haig Aghajanian, PhD, a member in Epstein's lab.

Bottom Line: Gender identity conversion efforts to try to change a person's gender identity to match their sex assigned at birth were associated with increased likelihood of adverse mental health outcomes, including suicide attempts, in this study of nearly 28,000 transgender adults from across the United States. Professional organizations, including the American Psychiatric Association, have called conversion therapy for gender identity unethical and ineffective, and some states have outlawed the practice. This observational study is based on the results of a survey distributed through community outreach to transgender adults in all 50 states, the District of Columbia, some territories and overseas U.S. military bases. Of 27,715 transgender adults who responded, 19,741 (71.3%) reported having spoken to a secular or religious professional about their gender identity and of these 3,869 (19.6%) reported exposure to gender identity conversion efforts. That exposure was associated with severe psychological distress during the previous month and prior suicide attempts during their lifetime compared with transgender adults who reported talking about their gender identity with a professional but weren't exposed to conversion efforts. Reported exposure to conversion efforts before the age of 10 also was associated with greater lifetime odds of suicide attempts. Limitations of the study include its inability to determine causation; it didn't capture conversion efforts by others such as family members; and it's possible that some adults with worse mental health might have sought conversion therapy. The study findings support that gender identity conversion efforts should be avoided in children and adults.

Authors: Jack L. Turban, M.D., M.H.S., of the Massachusetts General Hospital, Boston, and coauthors

(doi:10.1001/jamapsychiatry.2019.2285)

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

Bottom Line: How often the U.S. Food and Drug Administration (FDA) has approved drugs and devices based on nonrandomized clinical trials (non-RCTs) and whether those approvals are associated with the sizes of treatment effects were the focus of this study. Applications for 606 drugs from 2012 to August 2018 and for 71 medical devices from 1996 to August 2017 were assessed, and approved applications based on non-RCTs were included in this study called a systematic review and meta-analysis. Of the 677 applications, 68 (10%) were approved by the FDA based on non-RCTs. A meta-analysis was conducted to examine differences between applications that required further testing with RCTs and those that didn't. The authors report estimated treatment effects were higher for treatments or devices approved based on non-RCTs than for treatments or devices for which further testing in RCTs was required. There was no clear threshold of treatment effect above which no RCTs were requested. A limitation of the study was the small sample size.

Authors: Benjamin Djulbegovic, M.D., Ph.D., City of Hope, Duarte, California, and coauthors

(doi:10.1001/jamanetworkopen.2019.11111)

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

What The Study Did: This observational study examined among liver transplant candidates whether the association of frailty and increased risk of death while on the waiting list for a transplant varied by body mass index.

Authors: Jennifer C. Lai, M.D., M.B.A., of the University of California San Francisco, is the corresponding author.

(doi:10.1001/jamasurg.2019.2845)

Editor's Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Multiple cancer drug candidates in clinical trials kill tumor cells through off-target effects instead of by interacting with their intended molecular targets, according to a new study. The unexpected findings demonstrate that the targets of these drugs are not essential for the survival of cancer cells - contradicting over 180 previous reports about their importance - and may help explain why seemingly effective cancer drugs often fail to be translated to the clinic. Most cancer drugs that are tested in preclinical and clinical studies never receive FDA approval, largely because the drugs turn out to be too toxic or ineffective in humans. However, it is unclear why so many candidates run into these issues. Ann Lin and colleagues previously discovered that the small molecule OTS167 killed cancer cells by inhibiting proteins other than its designated target. In this study, the authors used CRISPR gene editing techniques to examine the mechanisms of ten other cancer drugs that target one of six proteins, which have been reported as important for the survival of cancer cells in over 180 publications. The drugs studied have been used in at least 29 different clinical trials involving a total of over 1,000 patients, and include prominent candidates such as citarinostat and ricolinostat, which are being tested against multiple myeloma. Contrary to the previous reports based on RNA silencing, the drugs did not actually kill cancer cells by inhibiting their target proteins: they still worked when given to cells deficient in their target. Rather, the drugs induced cell death through off-target mechanisms; for example, the authors found the true target of the drug candidate OTS964 (designed to target the PBK enzyme) was another enzyme named CDK11. Lin et al. argue that it will be necessary to adopt more rigorous genetic approaches in preclinical trials to verify that future drug candidates work as intended.

September 11, 2019 -Attention to menstruation and its relationship to girls' schooling is gaining ground, yet many challenges remain. Interventions have often focused on developing WASH --water, sanitation and hygiene -- infrastructure and menstrual hygiene products which may not be sufficient. New research conducted by Columbia Mailman School of Public Health and colleagues at the University of Edmonton and Real Medicine Foundation Pakistan looks at the root causes of poorly maintained WASH infrastructure in Pakistan where there has been little evidence to date. The study is among the first to identify the social and institutional structures and processes that lead to poorly maintained WASH infrastructure in schools in Pakistan. The results are online in the Journal of Adolescence.

"We found that deeply embedded socio-cultural values and beliefs around menstrual hygiene management still need to be addressed in order to provide truly supportive school environments for menstruating girls," said Marni Sommer, DrPH, RN, associate professor of Sociomedical Sciences. "To be truly effective, we must strategize to identify the root causes of poor WASH infrastructure and ensure facility design is sensitive to the needs of girls."

To conduct the study, data were collected in six rural and urban sites in three provinces in Pakistan between February 2015 and March 2017. The researchers used participatory activities with 312 girls aged 16-19 years of age both in-school and out-of-school. They also interviewed 42 key informants with school administrators and teachers, health care providers, mothers and local religious elders, and observed seven school WASH facilities.

Three key themes emerged from the data: a poorly maintained, girls-unfriendly School WASH infrastructure was a result of gender-insensitive design, a cultural devaluation of toilet cleaners and inadequate governing practices; the design of WASH facilities did not align with traditionally-determined modes of disposal of the most common used absorbents; and traditional menstrual management practices situate girls in an 'alternate space' characterized by withdrawal from many daily routines.

"These three socio-culturally determined practices interacted in a complex manner, often leading to interrupted class engagement and attendance," noted Sommer. "Schools were not the most hospitable space for menstruating girls, and further analysis of our data suggested the most logical step, as reported by the girls and teachers, was to stay at home for the first 2-3 days of menses."

"Findings from our study identify additional gaps in the research, but can also lead to policy and practice recommendations that will make school environments more enabling and improve girls' engagement during menstruation."

BOSTON - The KRAS gene is one of the commonly mutated genes in cancer. More than 40 percent of colorectal cancers have a mutated KRAS gene, or oncogene, that is at least partially responsible for cancer development. Mutated KRAS genes are commonly found in other cancers as well, including pancreatic, lung, myeloma and endometrial, and not all KRAS mutations in the same organ tissue cause the same disease severity, according to three new studies from researchers at the Cancer Center at Beth Israel Deaconess Medical Center (BIDMC). Using mouse models of cancer, the research shows for the first time that cancer disease incidence and severity are influenced by both the specific type of KRAS mutation as well as by the tissue in which the mutation is located. These findings were recently published in Cancer Discovery, Cell Reports, and Cell Systems.

"The unifying theme of these three papers is that the way we practice precision medicine today is not precise enough," said principal investigator and author Kevin Haigis, PhD, Director, Cancer Genetics Program at the Cancer Research Institute at the Cancer Center at BIDMC. "Basket trials, in which patients with a particular genetic mutation like KRAS are grouped into the same basket and given a drug against that mutation, are not sufficient. Our work shows for the first time that every single mutant form of KRAS differs in terms of cancer-causing ability and downstream signaling of relevant molecular pathways."

Mutation Subtypes influence Disease Severity

Although KRAS is generally the most commonly mutated oncogene, it comes in many different forms, or alleles. In the past, various mutant forms were considered redundant. "This conventional assumption informs the way clinical trials are done today, with people grouped as either KRAS mutant or KRAS wild-type with no mutation," explained Haigis, who is also Associate Professor of Medicine at Harvard Medical School. "Our new research shows that you simply cannot place all KRAS mutant cancers in the same basket - each allele is actually quite distinct from one another. Clinicians need to know exactly which mutation a patient has and create a mutation-specific basket for a clinical trial."

While circumstantial evidence points to various KRAS alleles activating different biological pathways, Haigis's group is the first to genetically engineer a mouse model in which groups of mice possess different KRAS alleles. In this way, they were able to study various mutant KRAS alleles in several cancer types in an experimentally controlled system.

In the group's Cancer Discovery study published in April, the team looked at colorectal cancer caused by rare or common KRAS mutations. Homing in on a KRAS mutation associated with a region of the gene known as codon 146, their mouse model showed that animals with the 146 mutation live longer than animals with another type of KRAS mutation, called G12D. "In colon cancer, the 146 mutation does cause colon cancer, but those colon cancers are much weaker and the mice survive longer," Haigis explained. They also saw that the proteome, or the signaling pathways, is dramatically different between the two types. "That's why we think cancers with different mutations will respond differently to drugs."

In a similar paper published in Cell Reports, Haigis' team, with colleagues from Northeastern University, compared the molecular signaling produced by different KRAS alleles. They found that the codon 12 KRAS allele produced strong signaling - not surprising given that the codon 12 mutation is the most common KRAS mutation in all cancer patients, regardless of organ type. They also tested the codon 13 KRAS allele in colon cancer, which accounts for about 10 percent of all KRAS mutations in colon cancer and produces a very weak oncogenic signal, similar to the 146 signal in the Cancer Discovery paper.

These observations are important because treatment guidelines for the most commonly used FDA therapy for colon cancer (a therapy against epidermal growth factor receptor, or EGFR) recommend its use only in colon cancer patients without KRAS mutations. This is based on the fact that when the drug was in development, researchers saw that patients with KRAS mutations did not appear to respond well to it. "But some clinical trials show that patients with the codon 13 KRAS mutation do respond to EGFR therapy," said Haigis. "When you begin to separate the mutations from one another, there may be therapies that are available on the market that will help some patients. Even if those mutations are rare, those patients exist."

Mutations Have Tissue Specificity

In a paper published in Cell Systems, Haigis and colleagues kept the KRAS mutation constant and altered either the organ in which it was located or other elements of the mouse's genetic background. Although pancreatic and colon cancers both commonly have KRAS mutations, the other genes that are mutated in those cancers are quite different. For example, more than 85 percent of colon cancers have adenomatous polyposis coli (APC) mutations, which are never seen in pancreatic cancer. Instead, pancreatic tumors commonly have p53 mutations. The team genetically engineered mice so that they have mutant KRAS either in the colon or the pancreas. They then engineered them further to have other mutated genes, either APC or p53. "What we showed was that the signaling properties of KRAS are different depending on what organ you are in and what other genes are mutated," said Haigis. "KRAS, like any oncogene, has to tap into the intrinsic signaling network of the tissue to produce cancer and the permissive network only exists in certain tissues."

Looking Ahead: the future of precision medicine

In combination with other researchers, Haigis recently received an award from the Cancer Research UK Grand Challenge to further study this concept. "The concept that no single factor can predict whether a cancer responds to a particular therapy will be key to the future of precision medicine," he said. "Clinicians and scientists need to know which tissue the cancer comes from, which oncogene is mutated and which allele is created, and the other genes that are mutated; all of that determines if and how well a cancer will respond to a given drug. That is precision medicine and that's the level we have to get to."

On Oct. 15, 2017, actress Alyssa Milano sparked a firestorm on social media when she asked her Twitter followers to reply "me too" if they had ever been sexually harassed or assaulted. (Social justice activist Tarana Burke founded the "Me Too" movement more than 10 years ago as a way to help sexual assault survivors heal.) What followed were 1.5 million responses -- many from sexual assault survivors sharing their experiences, others from people showing support and some from critics -- all using the hashtag #MeToo.

Meanwhile, San Francisco State University Assistant Professor of Economics Sepideh Modrek watched the movement unfold online from her home. Her Twitter feed filled up with friends and acquaintances disclosing details of their own abuse, she says, and something compelled her to start archiving the tweets. One night she stayed up until 2 a.m. taking screenshots of #MeToo tweets, ultimately compiling 400 pages of shots. She didn't know it at the time, but this would be the foundation for her latest research project.

"I was floored that people were sharing details. They were writing things like, 'When I was 15, this happened,'" she said. "I was seeing pretty intimate details being shared in a public forum in a way I'd never thought people would do. I was impressed and captivated."

Her research, published Sept. 3 in the Journal of Medical Internet Research, is a snapshot of the online movement during that first week when it reached critical mass. With the help of machine learning, Modrek and her research assistant Bozhidar Chakalov studied more than 12,000 #MeToo tweets posted between Oct. 15 and 21. After applying and gaining access to Twitter's application programming interface, or API, they were able to count every undeleted #MeToo tweet. They then downloaded a representative subset, which helped them describe magnitude of the movement in terms of size, demographics and the personal narratives shared.

They found that 11% of all novel tweets (meaning tweets that weren't retweets, replies to other replies or messages with pictures or links) included a revelation of sexual assault or abuse. Nearly 6% of those incidents occurred early in life (any time before the age 22).

The majority of people sharing were white women between the ages of 25 and 50. What's striking is that women were reporting these events 20 to 30 years after they happened, Modrek says. "They still remember it. There's clear enduring trauma associated with each disclosure," she said.

Modrek's analysis also showed that voices were systematically missing. For example, African American women were less likely to disclose details on Twitter, but other data shows that they are equally or more likely to have experienced sexual abuse or assault.

To be included in their data pool the #MeToo tweets had to meet certain criteria. They had to be novel, in English and geotagged in the U.S. This shrank their data set from 1.5 million to just over 12,000 tweets. Part of the reason for the parameters was so they could hone in on tweets that contained personal disclosures of sexual abuse.

It's been nearly two years since the start of the #MeToo movement, the largest public discourse on sexual violence in history. A lot has changed in that time, says Modrek, including some people's perceptions of the movement. But she hopes her research will remind people of the movement's significance and the possibility that (as she wrote in her research) it helped bring about a "deeper understanding of the prevalence, early life experience and enduring trauma of sexual assault and abuse."

"A lot of people spoke up and publicly shared these experiences," she said, "and it completely changed our dialogue. I wanted to capture and honor their courage."

The "worm wars" debate has been raging for over 10 years. On one side, there are established global advocacy organizations continuing to raise funds to implement these programmes, distributing free deworming medicines to whole continents in pursuit of this goal, with development economists and parasitologists underpinning the argument. On the other, some academics have raised questions about the evidence base for these policies, originating from Cochrane and the first edition of a review in 2000. Cochrane reviews are independent rigorous summaries and appraisals of all the relevant research evidence around a topic, and there is a new edition out this week.

What is in this new edition? The review authors have consolidated the results, performing analyses that the critics have said hides true effects; they have added six new trials and responded to a 50-page published criticism of the review. The final result? The substantive findings are little changed from 2015. With now a total of over 50 trials including 84,336 participants, plus the additional trial of one million children: the team found no benefit for haemoglobin, cognition, school performance, and mortality. While weight studies carried out over 20 years ago showed large effects on weight, this has not been seen in the more recent, much larger studies.

LSTM's Professor Paul Garner, who is an author on the review, said: "All the new trials are well conducted, and show little or no effect; studies conducted in isolated populations over 20 years ago should not be selected out to support current policies. Treat worms through health services - yes, but these data suggest donors and countries should re-assess policies for mass treatment".

University of Liverpool's Professor David Taylor-Robinson(link is external) is an author on the review. He said: "People developing global guidelines should be clear on what basis deworming programmes are being promoted. Current evidence does not support large public health programmes of deworming in low- and middle-income settings, particularly in terms of wider, societal and educational benefit. Policymakers should consider the findings of our review and make their own minds up."

Dr. Thomas Grünewald studies the genetics and molecular pathology of Ewing sarcoma, a malignant bone cancer that is found primarily in children, adolescents and young adults. Most cases of Ewing sarcoma are associated with a single dominant driver mutation which, however, may not be fully sufficient to trigger tumorigenesis. Grünewald leads a Max-Eder Junior Research Group in Pediatric Sarcoma Biology at LMU's Institute of Pathology. In a paper published in Nature Genetics in 2015, he and his colleagues demonstrated that Ewing sarcoma tumorigenesis is driven by the interplay of an acquired somatic mutation that occurs spontaneously in the tissue concerned and an inherited germline variant that is present in all the patient's cells.

In a new study, which appears in the online journal Nature Communications, Grünewald's team shows how such genetic interplay determines the course of the disease in individual patients. "The clinical course of the disease is very heterogeneous," says Grünewald, "and this variation cannot be attributed to the acquired somatic driver mutation, since this mutation is common to all patients. We therefore took a closer look at the somatic mutation in the context of the individual genome. The acquired mutation occurs in a variety of genetic backgrounds, and it turns out that inherited variations in regulatory elements have a marked effect on how the driver mutation acts in different individuals.

All patients with Ewing sarcoma share the same somatic mutation in the affected tissue, but they differ from one another in terms of the genetic variability they have inherited. The driver mutation results in the fusion of two genes, and leads to the production of a hybrid transcription factor, which binds to, and activates other genes. The new study demonstrates that inherited variation in the regulatory sequences of several of these target genes defines their affinity for the hybrid protein. This factor in turn determines the level of their expression - and the rate of growth of the tumor. This interplay is what accounts for the differences in the severity of the disease from patient to patient. "Up to now, personalized cancer therapy has focused mostly on the acquired somatic mutations. Our study shows that the genetic context is a crucial determinant of disease progression, and that it can inform therapeutic decisions," says Grünewald. Julian Musa, lead author of the new paper, explains why this is the case: "Depending on their levels of activation, genes that are regulated by such a genetic interplay can be targeted to different degrees by particular drugs. This interplay can at least in part explain why one and the same drug can effectively inhibit the growth of one patient's tumor, but maybe not that of the patient in the next bed." The LMU team now plans to investigate this phenomenon in greater detail.

Grünewald and his colleagues also want to explore whether the growth of other tumors is also subject to this sort of dual control. "Our work on Ewing sarcoma is one of the first studies to document the impact of the interplay between germline genetic variations and somatic mutations on the progression of malignant disease in individual patients. We assume that this principle also applies to other types of cancer."

Against a backdrop of disappointing Alzheimer's disease clinical trial outcomes, two researchers are proposing a new approach for future study of the disease.

Caleb Finch of the USC Leonard Davis School of Gerontology and Alexander Kulminski of the Social Science Research Institute at Duke University have outlined a framework called the "Alzheimer's Disease Exposome" to address major gaps in understanding how environmental factors interact with genetic factors to increase or reduce risk for the disease. The theoretical article appears today in Alzheimer's & Dementia: The Journal of the Alzheimer's Association.

"We propose a new approach to comprehensively assess the multiple brain-body interactions that contribute to Alzheimer's disease," Finch said. "The importance of environmental factors in gene-environment interactions is suggested by wide individual differences in cognitive loss, particularly among people who carry genes that increase the risk of Alzheimer's disease."

How environmental and genetic risk factors interact

Increasing age is the most important known risk factor for Alzheimer's disease, but many other risk factors -- including environmental exposures -- are poorly understood. Previous studies of Swedish twins by USC's Margaret Gatz suggested that half of individual differences in Alzheimer's disease risk may be environmental.

The two classes of Alzheimer's disease genes are considered in the exposome model. One class called familial Alzheimer's genes are dominant, meaning someone who inherits those genes will ultimately develop Alzheimer's. The other class include gene variants like apolipoprotein E4 (APOE4), where risk increases along with more copies of the genes. Among carriers of APOE4, a few people reach age 100 and older without ever developing the disease -- demonstrating environmental risk is contributing to that variability.

Cited in their article is a study that showed the onset of dementia was a decade earlier for carriers of a dominant Alzheimer's gene living in cities and who came from lower socioeconomic backgrounds or less education.

"Environmental factors, including exposure to air pollution and low socioeconomic status, shifted the onset curve by ten years," explained Finch. "It's in the research literature but until now, no one has paid sufficient attention to it."

More recent examples come from Finch's research on the gene-environment interactions between parasitic infections and the Alzheimer's risk gene APOE4. Among a pre-industrial tribe of Bolivian people called the Tsimane, the presence of the gene, along with chronic parasitic infections, seemed to lead to better, not worse, cognition.

Finch says the startling results provide an example of how the exposome concept could lead to enhanced understanding of risks for dementia.

"Those are just some of the environmental interactions we have brought up in building a larger framework called the exposome, which lists the different types of environmental factors that are known to interact with Alzheimer's, but haven't been studied broadly for how they impact the Alzheimer's-linked genes," Finch said. "This is the story of the gene-environment interaction."

Exposome originally used to understand cancer risk

The exposome concept was first proposed by cancer epidemiologist Christopher Paul Wild in 2005 to draw attention to the need for more data on lifetime exposure to environmental carcinogens. The exposome is now a mainstream model, eclipsing previous characterizations of environmental factors as affecting risk "one by one."

"Epidemiologists have been using the exposome to have a broader outlook on whatever they're studying, whether it's lead toxicity or head trauma," Finch said. "It's our point that a number of things need to be considered for interaction and many effects are additive."

The authors say the exposome concept extends and leverages the National Institute on Aging/ Alzheimer's Association Research Framework -- a consortium that follows clinical cohorts by brain imaging for biomarkers to assess neurodegeneration -- to include gene-environment interactions across individual age and duration of exposure.

Endogenous and exogenous factors

The proposed AD exposome includes macrolevel external factors such as living in rural versus urban areas, exposure to pollution and socioeconomic status, along with individual external factors such as diet, cigarette smoking, exercise and infections. This external or exogenous domain overlaps and interacts with internal or endogenous factors including individual biomes, fat deposits, hormones and traumatic brain injury, which has been observed in professional boxers who develop Alzheimer's.

"Analysis of endogenous and exogenous environmental factors requires consideration of these interactions over time," Finch said.

The researchers assume that some interactions can change factors of the exposome; describing, for example, a "lung-brain axis" for inhaled neurotoxicants of air pollution and cigarette smoke and a "renal-cardiovascular disease-brain axis" for renal aging driven by diet and hypertension. Each of these axes may have different gene-environment interactions for each risk gene.

The future of Alzheimer's research

Many studies are looking at conditions such as heart disease, stroke, high blood pressure, obesity and diabetes with the goal of understanding of how reducing risk factors for these conditions could reduce the risk of Alzheimer's disease. Additional research--including studies where Finch is the co-principal investigator--examines how urban air pollution contribute to accelerated brain aging and dementia risk.

The authors note that large-scale initiatives such as UK Biobank and "All of Us" in the United States are generating mega-cohorts; these massive data will make possible new methods to examine interactions of multiple factors in the exposome. In addition, new computational approaches to these multilevel complexities may identify interventions for individual brain aging.

To further develop an Alzheimer's disease "roadmap" of modifiable factors in brain aging and dementia, the authors suggest several research targets for funding agencies and policymakers for large-scale, multinational collaborative initiatives. They recommend integrating environmental data from service agencies and industry with existing data and expanding exposure data to air pollution, cigarette smoke, and household toxins using personal monitors for multiple toxic chemicals and gases.

Another suggestion is expanding studies of other age-related disorders and aging to include cognitive aging and dementia, with the authors pointing out that multi-generational cohorts with extensive information are available for the Framingham Heart Study and the Long-Life Family Study.

University Park, Pa.--Small gestures of kindness by employers can have big impacts on employees' health and work performance, according to an international team of researchers. The team specifically examined the effects of employers enhancing the lunches of bus drivers in China with fresh fruit and found that it reduced depression among the drivers and increased their confidence in their own work performance.

"An ultimate solution to improve worker performance and health could be big pay raises or reduced workloads, but when those solutions aren't feasible, we found that even small offerings can make a big difference," said Bu Zhong, associate professor of journalism at Penn State.

According to Zhong, bus drivers are vulnerable to specific health problems due in large part to their stressful working environment, which often includes irregular shift schedules, unpredictable traffic conditions and random meal times. In addition, the sedentary nature of driving and continuous whole-body vibration contributes to fatigue, musculoskeletal problems such as lower-back pain, cardiovascular diseases and gastrointestinal issues.

Zhong and his colleagues conducted an experiment with 86 Shenzen bus drivers. During the experiment, on-duty bus drivers were given, in addition to their typical box lunch which includes no fruit, a serving of fresh fruit--either an apple or a banana--for three weeks. The cost of the fruit was 73 cents per meal.

The team distributed surveys to the bus drivers at three time intervals--one week before the experiment began, once in the middle of the three-week-long experiment and one week following the end of the experiment. The findings appear today in the International Journal of Occupational Safety and Ergonomics.

The researchers assessed depression with a personal health questionnaire that is recommended by the U.S. Centers for Disease Control and Prevention. The scale consisted of eight items, asking the participants to rate, for example, how often during the past two weeks they felt down, depressed or hopeless, and had trouble falling or staying asleep.

"Bus drivers reported significantly decreased depression levels one week after the experiments ended compared to one week before it began," said Zhong.

The team measured self-efficacy--perceived confidence and ability to implement the necessary actions and tasks so as to achieve specific goals--using the 10-item General Self-Efficacy Scale. Items on this scale included, "I can always manage to solve difficult problems if I try hard enough" and "I can usually handle whatever comes my way."

"We found that self-efficacy was significantly higher in the middle of the experiment week than in the week after the experiment ended," said Zhong.

Zhong concluded that while eating an extra apple at lunchtime may seem trivial, its impact can be large.

"This research suggests that employees can be sensitive to any improvement at the workplace," he said. "Before an ultimate solution is possible, some small steps can make a difference--one apple at a time."

Bottom Line: HPV vaccination has been recommended for U.S. females since 2006 and since 2011 for males to prevent anogenital HPV infections and associated cancers. Prevention of oral HPV infections and associated cancers of the mouth and throat is not a vaccine indication due to lack of clinical trials.  Therefore, study investigators generated nationally representative data on oral HPV infections in the U.S. from 2009-2016 to look for evidence of herd protection in unvaccinated men and women ages 18 to 59. Vaccination rates increased among men and women during the study period. Study authors report the prevalence of vaccine-type oral HPV infections (e.g. those included in the vaccine) declined from 2.7% to 1.6% in unvaccinated men, with no change in nonvaccine-type HPV infections. Oral HPV infections in unvaccinated women remained unchanged for both vaccine- and nonvaccine-types. The findings suggest herd protection among men against oral HPV infections, which the authors say is likely due to the increased level of HPV vaccination in women. The apparent lack of herd protection among unvaccinated women may be because of low statistical power in the study due to a low prevalence of oral HPV infections in women. A limitation of the study is the use of self-reported information on HPV vaccination.

Authors: Maura L. Gillison, M.D., Ph.D., MD Anderson Cancer Center, Houston, and coauthors at the National Cancer Institute

(doi:10.1001/jama.2019.10508)

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

Methotrexate and the more expensive mycophenolate mofetil performed similarly in a head-to-head clinical trial that compared the two drugs for treating noninfectious uveitis, an eye disease that accounts for up to 15% of blindness in the U. S. In cases of more severe disease, posterior uveitis and panuveitis, the international trial showed that methotrexate was more effective in controlling inflammation. Investigators published results from the trial today in the Journal of the American Medical Association. The National Eye Institute, part of the National Institutes of Health, funded the trial.

"This study gives doctors and their patients with uveitis a starting point when considering treatment beyond corticosteroids," said lead study author Nisha Acharya, M.D., M.S., University of California, San Francisco.

Uveitis is inflammation of the eye's blood vessel-rich middle layer of tissue called the uvea. The condition can affect the iris (anterior uveitis), ciliary body (intermediate uveitis), and choroid (posterior uveitis) parts of the eye and is often chronic. Panuveitis affects multiple areas of the uvea. Clinicians often first treat intermediate and posterior or panuveitis with oral corticosteroids like prednisone to control inflammation, but seek to quickly taper patients to a low dose and switch them to steroid-sparing drugs such as methotrexate and mycophenolate mofetil. Long-term, high-dose corticosteroid use risks serious side effects including osteoporosis, diabetes, and weight gain, and other eye problems including glaucoma and cataract. Other steroid alternatives such as biologics like adalimumab also carry serious side effects.

The First-line Antimetabolites for Steroid-sparing Treatment (FAST) Uveitis Trial enrolled and randomly assigned 216 patients with intermediate or posterior/panuveitis from India, the United States, Australia, Saudi Arabia and Mexico to methotrexate (107 participants) or mycophenolate (109 participants) treatment groups. Over six months, participants tapered to a maximum dose of 7.5 milligrams prednisone daily, while receiving either three grams oral mycophenolate daily or 25 milligrams methotrexate weekly. Participants reduced their dose, if necessary, to control adverse side effects such as nausea.

To assess control of inflammation, the research team performed clinical exams and ocular imaging in the front and back parts of the eye. They also checked visual acuity.

At six months, 67% of participants in the methotrexate group and 57% of participants in the mycophenolate group had controlled their inflammation and successfully tapered steroids. The remainder had the option to switch treatments. Differences in success rates between treatment groups were not statistically significant at six months. At 12 months, 69% of participants who had switched from mycophenolate to methotrexate achieved treatment success, whereas only 35% of those participants who switched from methotrexate to mycophenolate achieved treatment success. Of the participants who continued with their original treatments, 80% on methotrexate and 74% on mycophenolate maintained inflammatory control at 12 months.

In patients with posterior or panuveitis, the most severe forms, 74% in the methotrexate group achieved control at six months, versus 55% in the mycophenolate group, indicating that methotrexate was significantly more effective at controlling inflammation for this subtype of uveitis.

Both methotrexate and mycophenolate mofetil, which are systemic and affect multiple cell types in the body, can cause side effects such as fatigue, nausea and headaches, but serious side effects are rare. Because participants were allowed to reduce dosage to control these side-effects, few of them dropped out of the FAST study due to their inability to tolerate the medication. Total rates of adverse events were similar between the two drugs.

"Based on this head-to-head clinical trial, methotrexate is as good as or better than mycophenolate for treating uveitis. That's important because the prior literature and a survey on treatment preferences suggests most clinicians believe the opposite. Now we have a randomized trial to provide guidance on treatment." said Acharya. "Additionally, there's a cost difference in the U.S. where mycophenolate to control uveitis is over five times more expensive."