Body

Tuberculosis (TB), an ancient disease, is the leading infectious cause of death globally, yet the world's only licensed TB vaccine, Bacille Calmette-Guerin (BCG), was developed a century ago. Given to infants via a needle placed just under the skin, BCG protects babies from a form of the disease called disseminated TB but is far less effective at preventing pulmonary TB, the major cause of illness and deaths, in teens or adults.

Now, researchers from NIH's National Institute of Allergy and Infectious Diseases (NIAID) and their colleagues have shown that simply changing the dose and route of administration from intradermal (ID) to intravenous (IV) greatly increases the vaccine's ability to protect rhesus macaques from infection following exposure to Mycobacterium tuberculosis (Mtb), the bacterium that causes TB. The findings provide a new understanding of the mechanisms of BCG-elicited protection against tuberculosis infection and disease. In addition, the findings support investigation of IV BCG administration in clinical trials to determine whether this route improves its effectiveness in teens and adults.

Study investigators at the NIAID Vaccine Research Center were led by Robert A. Seder, M.D., and Mario Roederer, Ph.D. Their collaborators included JoAnne L. Flynn, Ph.D., of University of Pittsburgh School of Medicine.

To control Mtb infection and prevent clinical disease, a TB vaccine must elicit strong, sustained responses from the immune system's T cells, specifically those in the lungs. However, the standard, ID, route of BCG administration may not generate enough of these critical cells in the lungs. The NIAID researchers and their colleagues hypothesized that administration of BCG by IV or aerosol (AE) routes would overcome this hurdle and thus confer substantially better protection from infection and/or disease in rhesus macaques following challenge with virulent Mtb.

In their study, groups of animals received the BGC vaccine by ID, AE or IV routes. The scientists assessed immune responses in blood and in fluid drawn from the lungs for a 24-week period following vaccination. IV BCG vaccination resulted in the highest durable levels of T cells in the blood and lungs.

Six months after vaccination, the researchers exposed groups of vaccinated rhesus macaques (immunized via ID, AE or IV routes) and a group of unvaccinated macaques to a virulent strain of Mtb by introducing the bacteria directly into the animals' lungs. They then tracked the infection and disease development over three months. Nine out of 10 animals vaccinated with IV BCG were highly protected; six showed no detectable infection in any tissue tested and three had only very low counts of Mtb bacteria in lung tissue. All unvaccinated animals and those immunized via ID or AE routes showed signs of significantly greater infection.

The investigators concluded that IV BCG conferred an unprecedented degree of protection in an animal model of severe TB and "represents a major step forward in the field of TB vaccine research."

PITTSBURGH, Jan. 1, 2020 - Worldwide, more people die from tuberculosis (TB) than any other infectious disease, even though the vast majority were vaccinated. The vaccine just isn't that reliable. But a new Nature study finds that simply changing the way the vaccine is administered could dramatically boost its protective power.

Researchers at the University of Pittsburgh School of Medicine and the National Institute of Allergy and Infectious Diseases (NIAID) discovered that intravenous TB vaccination is highly protective against the infection in monkeys, compared to the standard injection directly into the skin, which offers minimal protection.

"The effects are amazing," said senior author JoAnne Flynn, Ph.D., professor of microbiology and molecular genetics at the Pitt Center for Vaccine Research. "When we compared the lungs of animals given the vaccine intravenously versus the standard route, we saw a 100,000-fold reduction in bacterial burden. Nine out of 10 animals showed no inflammation in their lungs."

Flynn's team tested several routes and doses of the only commercially available human TB vaccine, Bacille Calmette-Guérin (BCG), which is made of a live, weakened form of TB bacteria found in cattle.

The BCG vaccine has been around for 100 years and is among the most widely used vaccines in the world, but its efficacy varies widely.

The idea for an intravenous TB vaccination came from earlier experiments by the other senior author on the study, Robert Seder, M.D., at the NIAID's Vaccine Research Center. Seder showed in both animals and humans that the malaria vaccine is more effective when delivered intravenously.

To test whether the method of administration matters for TB, Flynn and colleagues separated their colony of monkeys into six groups: unvaccinated, standard human injection, stronger dose but same injection route, mist, injection plus mist, and finally, the stronger dose of BCG delivered as a single shot directly into the vein.

Six months later, the researchers exposed the animals to TB and monitored them for signs of infection.

Monkeys are extremely susceptible to TB. All of the animals who received the standard human dose had persistent lung inflammation, and the average amount of TB bacteria in their lungs was only slightly less than in the monkeys who received no vaccine at all. The other injected and inhaled vaccines offered similarly modest TB protection.

The intravenous vaccine, on the other hand, offered nearly full protection. There was virtually no TB bacteria in the lungs of these animals, and only one monkey in this group developed lung inflammation.

"The reason the intravenous route is so effective," Flynn explained, "is that the vaccine travels quickly through the bloodstream to the lungs, the lymph nodes and the spleen, and it primes the T cells before it gets killed."

Flynn's team found BCG and activated T cells in the lungs of all the intravenously vaccinated animals. Among the other groups, BCG was undetectable in the lung tissue and T cell responses were relatively meagre.

Next, the researchers plan to test whether lower doses of intravenous BCG could offer the same level of protection without the side effects, which mostly consist of temporary inflammation in the lungs.

But before this method can be translated to humans, researchers need to know that it's not only safe, but also practical. An intravenous vaccine requires more skill to administer and carries a higher risk of infection.

"We're a long way from realizing the translational potential of this work," Flynn said. "But eventually we do hope to test in humans."

A preventive treatment for dementia may proceed to clinical trials after successful animal testing.

The US-led research is looking to develop effective immunotherapy via a new vaccine to remove 'brain plaque' and tau protein aggregates linked to Alzheimer's disease.

Recent success in bigenic mice models supports progression to human trials in years to come, the researchers say.

A new paper in the journal Alzheimer's Research & Therapy paves the way for more work in 2020, with medical researchers at the Institute for Molecular Medicine and University of California, Irvine (UCI) working with a successful vaccine formulated on adjuvant developed by Flinders University Professor Nikolai Petrovsky in South Australia.

The latest research aims to come up with a new treatment to remove accumulated beta-amyloid (Aβ) plaques and neurofibrillary tangles composed of hyperphosphorylated tau, which together lead to neurodegeneration and cognitive decline in Alzheimer's disease.

Alzheimer's disease (AD) is the leading cause of age-related dementia, affecting about 5.7 million people in the US. Major challenges in AD include the lack of effective treatments, reliable biomarkers, or preventive strategies.

Professor of the Institute for Molecular Medicine Anahit Ghochikyan and colleagues, Associate Professors Hvat Davtyan and Mathew Blurton-Jones from UCI, and other co-authors tested the universal MultiTEP platform-based vaccines formulated in the adjuvant developed at Professor Petrovsky's Australian lab.

The possible new therapies were tested in bigenic mice with mix Aβ and tau pathologies.

"Taken together, these findings warrant further development of this dual vaccination strategy based on the MultiTEP technology for ultimate testing in human Alzheimer's disease," the lead authors Professor Ghochikyan and Blurton-Jones conclude.

Professor Petrovsky says the Advax adjuvant method is a pivotal system to help take the combination MultiTEP-based Aβ/tau vaccines therapy, as well as separate vaccines targeting these pathological molecules, to clinical trials - perhaps within two years.

"Our approach is looking to cover all bases and get past previous roadblocks in finding a therapy to slow the accumulation of Aβ/tau molecules and delay AD progression in a the rising number of people around the world," says Professor Petrovsky, who will work in the US for the next three months.

Several promising drug candidates have failed in clinical trials so the search for new preventions or therapies continues.

A recent report on human monoclonal antibody, aducanumab, showed that high dose of this antibody reduced clinical decline in patients with early AD as measured by primary and secondary endpoints.

However, it is obvious that it could not be used as a preventive measure in healthy subjects due to the need for frequent (monthly) administration of high concentrations of immunotherapeutic.

Professor Ghochikyan says there is a pressing need to keep searching for new preventive vaccine to delay AD and slow down progression of this devastating disease.

The new combined vaccination approach could potentially be used to induce strong immune responses to both of the hallmark pathologies of AD in a broad population base of vaccinated subjects with high MHC (major histocompatibility complex) class II gene polymorphisms, the new paper concludes.

1. MIV-711 not associated with pain reduction, but may reduce disease progression in osteoarthritis

Abstract: http://annals.org/aim/article/doi/10.7326/M19-0675

Editorial: http://annals.org/aim/article/doi/10.7326/M19-3809

URLs go live when the embargo lifts

MIV-711, a novel selective cathepsin K inhibitor, was not more effective than placebo for reducing pain related to knee osteoarthritis. However, MIV-711 significantly reduced bone and cartilage progression. Findings from a randomized, placebo-controlled study are published in Annals of Internal Medicine.

Osteoarthritis of the knee is a painful, disabling condition affecting more than 14 million people in the United States and hundreds of millions worldwide. The pain of knee OA arises from a series of pathologic processes involving articular cartilage, subchondral bone, synovium, meniscus, and other joint structures, ultimately leading to joint failure and pain-related functional limitations. Researchers sought to test the hypothesis that cathepsin K inhibitor could alleviate osteoarthritis symptoms by reducing degeneration of bone and cartilage.

In a multicenter study led by the University of Leeds, 244 patients with primary knee osteoarthritis were randomly assigned to receive either 100 or 200 mg daily of MIV-711 or matched placebo for 26 weeks to evaluate the efficacy, safety, and tolerability of MIV-711. The primary endpoint of the study was change in pain score, but changes in disease progression were also assessed using quantitative MRI outcomes. The researchers found that compared with placebo, MIV-711 was associated with less bone remodeling, less cartilage volume loss, and lower levels of bone resorption and collagen loss. However, it showed no beneficial effects on osteoarthritic knee pain. According to the authors, further evaluation is needed to confirm the structural benefits of MIV-711 and to determine whether these translate to more tangible benefits on disease symptoms.

The authors of an accompanying editorial from Brigham and Women's Hospital say that while the work is promising, they agree that more research is needed to determine the longer term benefits of MIV-711. They point out the study findings do not contradict that there is a foundational link between modification of structure and improvement in osteoarthritis pain, but rather clarify that changes in structure do not beget immediate changes in symptoms.

Media contacts: For embargoed PDFs please contact Lauren Evans at Laevans@acponline.org. To speak with the lead author, Philip G. Conaghan, PhD, please contact him at p.conaghan@leeds.ac.uk.

2. Fewer than half of California pharmacies provide correct drug disposal information

Abstract: http://annals.org/aim/article/doi/10.7326/M19-2409

URLs go live when the embargo lifts

Fewer than half of California pharmacies provided correct prescription drug disposal details to "secret shoppers" inquiring about unwanted medications. Only one tenth reported take-back programs at their location. That percentage dropped if participants called on a weekend. Findings from a brief research report are published in Annals of Internal Medicine.

Retail pharmacists are in an ideal position to provide drug disposal information, but evidence is limited regarding the accuracy of the information they provide. Researchers from the University of California, San Francisco identified licensed pharmacies located in urban and rural settings in California, a state that accounts for 10 percent of all U.S. pharmacies. They wrote a script that guided 4 male and 2 female "secret shoppers" to call and ask about how to dispose of leftover antibiotics (sulfamethoxazole-trimethoprim tablets) and a liquid opioid-based painkiller (hydrocodone-acetaminophen). From late-February to late-April 2018, the participants called 898 pharmacies and found that fewer than half provided correct disposal details, a percentage that dropped sharply if the callers made their call on a weekend. Asked specifically about drug take-back programs, just 11 percent said their pharmacy had one that could be used to dispose of antibiotics or opioids.

According to the researchers, these findings suggest that patients and pharmacy employees lack knowledge about proper medication disposal. Strengthening education of patients and those advising patients as well as expanding disposal programs could help to improve disposal practices.

Media contacts: For an embargoed PDF, please contact Lauren Evans at laevans@acponline.org.

To reach the lead author, Hillary Copp, MD, MS, please contact Laura Kurtzman at Laura.Kurtzman@ucsf.edu

Also new in this issue:

Eliminating Medical School Debt: A Dean and Geriatrician's View From Opposite Ends of the Training Pipeline

Mark S. Lachs, MD, MPH, and Augustine M.K. Choi, MD

Ideas & Opinions

Abstract: http://annals.org/aim/article/doi/10.7326/M19-2897

PHILADELPHIA - Direct-to-consumer hormone-based "fertility testing" for women is viewed by consumers as both an alternative, empowering tool for family planning, and a confusing and misleading one, according to the results of a new study from Penn Medicine. Findings from the small, first-of-its-kind ethnographic study reinforce the need for consumer education around the purpose and accuracy of the tests, which have seen increasing interest in recent years due to the low cost and widespread availability. The study was published in the journal of Social Science and Medicine.

Many DTC companies in the "FemTech" space offer a test for anti-Mullerian hormone (AMH), a marker that estimates the size of a woman's egg supply or "ovarian reserve," which have also been called the 'egg timer' or 'biological clock test.' Fertility products and testing is frequently marketed as an accessible, low-cost option for investigating fertility status, yet the tests are not predictive of natural conception. In fact, a 2019 policy statement by the American College of Obstetricians and Gynecologists discouraged testing in otherwise healthy women without a history of infertility.

Measuring AMH levels has primarily been used as a clinical diagnostic tool prior to ovarian stimulation for in vitro fertilization (IVF) in women with infertility, or before oocyte cryopreservation (i.e. egg freezing), in order to guide medication selection and anticipate success rates. However, recently more women have been engaging with DTC testing, due, in part, to barriers to care like strict guidelines for diagnosis of infertility, insurance coverage limitations, high costs, and rising concern about age-related fertility decline.

"Consumers continue to desire these tests, and they're attractive, but they don't deliver on their promise," said Moira Kyweluk, PhD, MPH, a fellow in the department of Medical Ethics and Health Policy in the Perelman School of Medicine at the University of Pennsylvania, and the author of the paper. "I view DTC testing as an entry point into what I term the 'new (in)fertility pipeline' for women today. Because it is low cost and widely available, it's reaching a larger demographic, people of diverse identities and backgrounds, and raising awareness of more advanced procedures and technologies like egg freezing."

To better understand the decisions and experiences around DTC fertility testing, Kyweluk closely followed 21 participants pursuing fertility testing recruited in Chicago in 2018. The participants represented different ethnicities, socioeconomic statuses, sexual orientations, gender identifies, and ages. Through an online company, the women visited an accredited laboratory to have their blood drawn for analyses; however, many companies offer at-home kits for women to collect a sample of their own blood, which is sent in for hormone analysis.

Four major themes emerged from participant interviews, surveys, and observation of follow up consultations with a nurse practitioner from the selected DTC fertility testing company including: knowledge, empowerment, DTC fertility services as a viable alternative for family planning, and finally, participant feelings of varying degrees of uncertainty.

This last theme, Kyweluk says, is the most important, and reinforces the need for better education to consumers around the true purpose for these tests.

"Though there may be some benefits to consumers using DTC fertility testing, across the board participants were left with incorrect assumptions about the power of hormone testing to predict fertility," Kyweluk said. "No test or medical procedure guarantees future fertility--including egg freezing--and these startups directly target women who are concerned about their reproductive futures."

Overall, the findings suggest that DTC fertility testing may allow for a larger population of women to be exposed to a range of assisted reproductive technologies and other information around fertility to inform family planning at any age. Kyweluk calls for future, similar research to better understand consumer experiences and outcomes with these products, as the infertility care industry and DTC fertility market are expected to expand.

"This study offers one model that social scientists can use to investigate the impact of new medical technologies and online delivery systems as they emerge...and create a better understanding of the ethical, legal, and social impacts of these options," she wrote.

A systematic review and meta-analysis led by St. Michael's Hospital of Unity Health Toronto found children who drank whole milk had 40 per cent lower odds of being overweight or obese compared with children who consumed reduced-fat milk.

The research, published in The American Journal of Clinical Nutrition, analyzed 28 studies from seven countries that explored the relationship between children drinking cow's milk and the risk of being overweight or obese. None of the studies - which involved a total almost 21,000 children between the ages of one and 18 years old - showed that kids who drank reduced-fat milk had a lower risk of being overweight or obese. Eighteen of the 28 studies suggested children who drank whole milk were less likely to be overweight or obese.

The findings challenge Canadian and international guidelines that recommend children consume reduced-fat cow milk instead of whole milk starting at age two to reduce the risk of obesity.

"The majority of children in Canada and the United States consume cow's milk on a daily basis and it is a major contributor of dietary fat for many children," said Dr. Jonathon Maguire, lead author of the review and a pediatrician at St. Michael's Hospital.

"In our review, children following the current recommendation of switching to reduced-fat milk at age two were not leaner than those consuming whole milk."

Dr. Maguire, who is also a scientist at the MAP Centre for Urban Health Solutions, next hopes to establish the cause and effect of whole milk and lower risk of obesity in a randomized controlled trial.

"All of the studies we examined were observational studies, meaning that we cannot be sure if whole milk caused the lower risk of overweight or obesity. Whole milk may have been related to other factors which lowered the risk of overweight or obesity," Dr. Maguire said.

"A randomized controlled trial would help to establish cause and effect but none were found in the literature."

WASHINGTON -- Adding a medication used to treat epilepsy, bipolar disorder and migraines to a blood pressure medicine reversed some aspects of breast cancer in the offspring of mice at high risk of the disease because of the high fat diet fed to their mothers during pregnancy. Conversely, this treatment combination increased breast cancer development in the offspring whose mothers had not been fed a high fat diet during pregnancy. The study by Georgetown Lombardi Comprehensive Cancer Center researchers appeared December 30, 2019, in Scientific Reports.

The key drug in the study regimen was valproic acid which, among several targets, inhibits histone deacetylase (HDAC), an important epigenetic silencer of genes. In contrast to mutations that permanently disrupt the normal functions of genes, epigenetic modifications are reversible. Valproic acid was combined with the blood pressure medication hydralazine that inhibits another critical epigenetic regulator, DNA methyltransferase (DNMT). Early treatment studies in people have shown that these two drugs can work in tandem to disrupt tumor growth.

"We believe that our research is the first to show that we can reverse some aspects of increased breast cancer risk found in offspring of mouse mothers fed a high fat diet during pregnancy," said Leena A. Hilakivi-Clarke, PhD, a professor of oncology at Georgetown Lombardi. "This finding may have important implications in people because exposures in the womb to certain chemicals, or a mother's high fat diet, or being obese, can subsequently increase a daughter's breast cancer risk."

These research findings demonstrate how impactful an epigenetic methyl group addition or subtraction from DNA can be. Compounds that reduce methylation of tumor suppressor genes that are excessively methylated (hypermethylated) can be beneficial. However, these drugs can have the opposite effect if tumor suppressor genes are not hypermethylated; they may remove methyl groups from cancer-causing genes, making these genes more active and potentially leading to more aggressive cancers.

The other key aspect of this finding involves the potential impact of diet on cancer risk. Many fruits and vegetables have compounds (such as flavones) that chemically react in the same ways as the HDAC- and DNMT-inhibiting drugs in this study. Some compounds in these foods, especially folic acid, have opposite effects. This research suggests that exposure to a high fat diet or endocrine disrupting chemicals in the womb might be reversed by the consumption of foods high in DNMT and HDAC inhibitors, while those who have not had such exposures might also gain a cancer protective benefit from consuming foods high in folic acid. The scientists note, however, that their findings, particularly as they relate to diet, need to be studied in people.

"Our next step will be to try to identify biomarkers in humans that indicate an exposure in the womb to diets or endocrine disrupting chemicals that could increase breast cancer risk later in life," said Hilakivi-Clarke. "If we can identify such biomarkers, we'll look to see if specific foods consumed by women can reverse epigenetic changes to their DNA that might lead to increased breast cancer risk."

Children born prematurely, i.e. before week 37, are more likely to be placed outside the home as a supportive child welfare measure than their full-term counterparts, according to a population study conducted by the Finnish Institute for Health and Welfare (THL). The more premature a child is born, the greater the probability that the child will be placed outside the home.

In terms of the entire Finnish population, approximately three out of one hundred children are placed outside the home at some stage of their childhood. The present study indicates that children born preterm are at least one and a half times more likely to be placed outside the home than others.

The likelihood is slightly higher also for children born close to term, i.e. born at 37-38 weeks of gestation. The risk is highest during early childhood (aged 0-5 years), as this is a very straining time for family life. The study found no difference between children born at different weeks of gestation in cases where a child was placed outside the home at the age of over five.

The increased probability of being placed outside the home is not explained by factors sometimes related to prematurity, such as the socioeconomic status of the parents, age of the parents, or the number or age difference of siblings. Moreover, prenatal disorders in the mother or chronic illnesses in the born child have no effect, either.

"Based on this study, prematurity in itself seems to be an independent risk factor for adversity in early childhood," says Professor Eero Kajantie, who is in charge of the study.

For the first time, the impact of premature birth on the risk of being placed outside the home is studied in a way that considers all levels of prematurity, ranging from moderate to extreme preterm, as well as the child's age during the first placement.

Timely and accessible support can prevent problems in families

The study does not give a direct explanation for why children born preterm and close to term are placed outside the home more likely and at a younger age than others.

"When a child is born preterm, the parents can, for example, feel that their resources, hopes and expectations do not match the challenges of early childhood caused by preterm birth. During the first year, caring for even a moderately preterm infant is substantially different than caring for a full-term child," says Researcher Suvi Alenius.

Families are not necessarily aware of the available support and services, or these measures may be found shattered and difficult to access. Getting support often requires justifications and an active approach from the parents, for which many may not have the time or resources in their stressful situation.

"It would be important for the social welfare and health care services and, for example, the day care services to better acknowledge that premature birth is a risk factor for abnormal events in early childhood. Timely and easily accessible support can avert problems from occurring in families and, for example, prevent the need for child welfare measures," says Alenius.

The results are based on the "Finnish 1987-90 Birth Cohort" study. This sub-study included all Finnish families who had a live infant following a single pregnancy during 1987-1990. The study included 193,033 children, their parents and the possible siblings. Of the children, 8,356 were born prematurely and 32,989 at 37-38 weeks of gestation. The study combined the Medical Birth Register, Child Welfare Register, Register of Congenital malformations and Care Register for Health Care, all maintained by the Finnish Institute for Health and Welfare, with the information contained in the population register and the register information of Statistics Finland.

What The Study Did: Researchers looked at whether certain patterns of connectivity between specific regions of the brain in children at age 7 (measured by magnetic resonance imaging) were associated with later development of symptoms related to attention-deficit/hyperactivity disorder and major depressive disorder.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

Authors: Susan Whitfield-Gabrieli, Ph.D., of the University of California at Berkeley, is the corresponding author.

(doi:10.1001/jamapsychiatry.2019.4208)

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.

A pooled analysis of nine prospective studies involving more than 750,000 adults finds that recommended amounts of leisure-time physical activity were linked to a lower risk for seven cancers, with several cancer types having a 'dose/response' relationship. The study was led by investigators at the National Cancer Institute, the American Cancer Society, and the Harvard T.H. Chan School of Public Health and appears in the Journal of Clinical Oncology.

While it's long been known that physical activity is associated with a lower risk of several cancers, less clear has been the shape of the relationship and whether recommended amounts of physical activity are associated with lower risk. Updated guidelines for activity now state that people should aim for 2.5 to 5 hours/week of moderate-intensity activity or 1.25 to 2.5 hours/week of vigorous activity. Moderate-intensity activities are those that get you moving fast enough or strenuously enough to burn off three to six times as much energy per minute as sitting quietly (3 to 6 METs). Vigorous-intensity activities burn more than 6 METs.

For the current analysis, investigators pooled data from nine prospective cohorts with self-reported leisure-time physical activity and follow-up for cancer incidence, looking at the relationship between physical activity with incidence of 15 types of cancer.

They found engaging in recommended amounts of activity (7.5 to 15 MET hours/week) was associated with a statistically significant lower risk of seven of the 15 cancer types studied, with the reduction increasing with more MET hours. Physical activity was associated with a lower risk of colon cancer in men (8% for 7.5 MET hours/week; 14% for 15 MET hours/week), female breast cancer (6%-10%), endometrial cancer (10%-18%), kidney cancer (11%-17%), myeloma (14%-19%), liver cancer (18%-27%), and non-Hodgkin lymphoma (11%-18% in women). The dose response was linear in shape for half of the associations and nonlinear for the others.

The analysis had some limitations: Even with 750,000 participants, patient numbers were limited for some cancers; participants were primarily white; there was a limited number of cohorts with detailed physical activity measures; and the authors relied on self-reported physical activity.

The authors conclude: "These findings provide direct quantitative support for the levels of activity recommended for cancer prevention and provide actionable evidence for ongoing and future cancer prevention efforts."

"Physical activity guidelines have largely been based on their impact on chronic diseases like cardiovascular disease and diabetes," said Alpa Patel, Ph.D., senior scientific director of epidemiology research at the American Cancer Society. "These data provide strong support that these recommended levels are important to cancer prevention, as well."

Above average or high BMI - often linked to cancers, diabetes, cardiovascular and other diseases - may in some cases improve the chance of survival among certain cancers, new research from Flinders University indicates.

Focusing on clinical trials of atezolizumab, a common immunotherapy treatment for non-small-cell lung cancer (NSCLC), the Australian cancer researchers found improved responsiveness to the drug in those with a high body mass index (BMI).

The surprising result - published today in JAMA Oncology - contrast with regular warnings about the health risks of patients who are overweight and obese.

"This is an interesting outcome and it raises the potential to investigate further with other cancers and other anti-cancer drugs," says lead investigator Dr Ganessan Kichenadasse, a medical oncology researcher at the Flinders Centre for Innovation in Cancer.

"We need to do further studies into the possible link between BMI and related inflammation, which might help to understand the mechanisms behind paradoxical response to this form of cancer treatment."

"Previous studies have explored a concept called as 'obesity paradox' where obesity is associated with increased risks for developing certain cancers and, counter-intuitively, may protect and give greater survival benefits in certain individuals.

"Our study provides new evidence to support the hypothesis that high BMI and obesity may be associated with response to immunotherapy," says Dr Kichenadasse.

The Flinders researchers found NSCLC patients with high BMI (BMI ? 25 kg/m2) in four clinical trials had a significant reduction in mortality with atezolizumab, apparently benefiting from immune checkpoint inhibitor (ICI) therapy.

Treatment options for this form of lung cancer are rapidly evolving and includes ICIs, molecular targeted drugs and chemotherapies.

"While our study only looked at baseline and during treatment, we believe it warrants more studies into the potentially protective role of high BMI in other cancer treatments."

The WHO estimates at least 2.8 million people die each year as a result of being overweight or obese. Overweight and obesity leads to adverse metabolic effects on blood pressure, cholesterol, triglycerides and insulin resistance. Risks of coronary heart disease, ischemic stroke and type 2 diabetes mellitus increase steadily with increasing body mass index (BMI), a measure of weight relative to height.

Of the 1434 participants studied in the Australian research, 49% were normal weight, 34% were overweight and 7% were obese.

PHILADELPHIA - Proton therapy leads to significantly lower risk of side effects severe enough to lead to unplanned hospitalizations for cancer patients when compared with traditional radiation, while cure rates between the two groups are almost identical. The findings come from an expanded analysis of the largest review of its kind, performed by researchers in the Perelman School of Medicine at the University of Pennsylvania, to evaluate whether or not patients undergoing radiation therapy at the same time as chemotherapy experienced serious adverse events within 90 days. Researchers found proton therapy reduces the relative risk of these side effects by two-thirds. JAMA Oncology published the findings today.

"This is exciting because it shows that proton therapy offers a way for us to reduce the serious side effects of chemo-radiation and improve patient health and wellbeing without sacrificing the effectiveness of the therapy," said the study's lead author Brian Baumann, MD, an adjunct assistant professor of Radiation Oncology at Penn and an assistant professor of Radiation Oncology at Washington University School of Medicine in St. Louis.

Proton therapy has a few key differences from traditional photon radiation. Photon radiation typically uses multiple x-ray beams to deliver radiation to the tumor target but unavoidably deposits radiation in the normal tissues beyond the target, potentially damaging those tissues as the beam exits the body. Proton therapy is an FDA-approved alternative radiation treatment that directs positively charged protons at the tumor. They deposit the bulk of the radiation dose to the target with almost no residual radiation delivered beyond the target, reducing damage to surrounding healthy tissue and potentially reducing side effects.

For this study, researchers evaluated side effects including pain or difficulty swallowing, difficulty breathing, nausea, or diarrhea, among others. Researchers focused on grade-three effects or higher, defined as side effects severe enough for patients to be hospitalized. They evaluated data on 1,483 cancer patients receiving radiation and chemotherapy at the same time. Of these, 391 patients received proton therapy, while 1,092 underwent photon treatment. All patients had non-metastatic cancer and were undergoing treatment intended to be curative. Patients with brain cancer, head and neck cancer, lung cancer, gastrointestinal cancer, and gynecologic cancer treated with concurrent chemo-radiation were included.

The primary outcome was whether or not patients experienced adverse side effects that were grade-three or higher within 90 days of treatment. In the proton group, only 11.5 percent of patients (45) did, compared to 27.6 percent of patients (301) in the photon group. A weighted analysis of both patient groups, which controlled for other factors that may have led to differences between the patient groups, found that the relative risk of a severe toxicity was two-thirds lower for proton patients compared to photon patients.

"We know from our clinical experience that proton therapy can have this benefit, but even we did not expect the effect to be this sizeable," said senior author James Metz, MD, chair of Radiation Oncology, leader of the Roberts Proton Therapy Center at Penn, and a member of Penn's Abramson Cancer Center.

Importantly, overall survival and disease-free survival were similar between the two groups, suggesting that the reduction in toxicity seen with proton therapy did not come at the cost of reduced effectiveness. Researchers say these results hint at the promise of proton therapy as a way to deliver intensified systemic therapy and/or higher dose radiation therapy more safely, which could improve survival outcomes. In fact, data showed that while older patients with more comorbidities were more likely to receive proton therapy, they experienced fewer side effects.

"This tells us proton therapy may allow older patients to receive the most effective combined treatments, and that older, sicker patients can more safely be included in clinical trials that use proton therapy," Baumann said.

While researchers say further research is needed, they point out that this study is the best information we have so far as randomized controlled trials continue to prove difficult to complete.

Natalia Khorkina https://www.hse.ru/en/org/persons/65017 and Marina Lopatina, researchers with the HSE University Department of Applied Economics, examined how the level of physical activity among working Russians changed from 2011 to 2017. They analyzed the results of a survey of Russian men ages 25-60 and women ages 25-55 -- who were either employees, self-employed or ran their own businesses -- conducted by the Levada Center at the request of HSE University.

In 2011, approximately 20% of both women and men reported doing some form of physical exercise at least once a week. By 2017, that figure had grown only slightly among women -- to 25% -- but more substantially among men -- to 31%.

The trend is positive, researchers noted, but the proportion of physically active working Russians remains below the European average.

The physical activity of Russia's working population does not meet World Health Organization standards

To improve health, WHO experts recommend that adults devote at least 150 minutes per week to moderate-intensity physical exercise (e.g., standard push-ups, squats, slow running, brisk walking and relaxed cycling) or at least 75 minutes to high-intensity exercise (e.g., running, swimming, fast cycling, aerobics and team sports).

Almost 60% of physically active working Russian men engage in exercise or sport at least three times a week but for only a relatively brief 15-30 minutes. Most women in this category work out less frequently, but longer -- from 30 to 60 minutes at a time.

A lack of time and money, as well as laziness, prevent people from exercising more

Thirty-two per cent of women and 29% of men blamed a lack of free time for not exercising more. Next came laziness and insufficient funds to buy sporting equipment or gym memberships as justification. These were followed by a lack of interest or self-confidence, the belief that 'I don't need that' and the habits of smoking and drinking as constraints to exercise. Only men cited the last two as factors preventing an active lifestyle.

The desire to be in shape does not depend on the state of health

Approximately 80% of the respondents who described their health as 'poor' do no physical exercise. That figure is not much better -- 60% -- among those who described their health as 'good' or 'very good.'

Sports infrastructure is adequate, but people are in no hurry to use it

Almost 100% of respondents are certain that Russia has plenty of fitness centres, playing fields and gyms, including at their places of work and study. Far from everyone makes use of them, however: approximately 60% of respondents said they prefer working out at home. Women least preferred workplace or university gyms and men cited swimming pools as their least favourite place to exercise.

[chart]

Where Russians engage in physical activity and sport
(2017, % of all working men and women)

Home
In a park or public square
At an outdoor sports facility
At a workplace or university gym
At a swimming pool
At an indoor sports facility

Men / Women

More than 80% of working Russians spend no money on fitness or sport

Russians who go to fitness centres or play sports pay 1,000 rubles - 3,000 rubles per month on average for those activities. However, many avoid that cost by working out at home. As a result, the overwhelming majority of Russians do not consider physical exercise a strain on the family budget, and more than 80% say such activity costs them nothing at all.

The size of the average per capita income influences the likelihood of engaging in fitness and sports

The greater a person's income, the more likely he or she is to be physically active. This is especially true of men. The survey found that in families earning 25,000 rubles ($400) per month or more per family member, 34% of the men and 30% of the women were involved in fitness and sports.

Children affect the physical activity of parents in different ways

The more children a family has, the less time fathers devote to physical activity and sports, whereas the opposite is true of mothers, who devote the most time to these activities if they have three or more children.

Involvement in fitness and sport does not depend on the length of the workweek

Almost one in three respondents cited a lack of free time as a barrier to physical activity. But is that the case? The study found that work does not interfere: the number of physically active men and women -- approximately 32% and 23% respectively -- was the same whether they worked more or less than 40 hours per week.

City dwellers are more likely to engage in fitness and sports and account for most of Russia's physical culture indicators

City dwellers are more physically active than villagers: 1.3 times more among men and 1.1 times more among women. Those who live in large cities have greater access to developed sports infrastructure, workout groups and classes, athletic competitions, etc. At the same time, according to the researchers, 'the size of a city has practically no bearing on the proportion of physically active residents.' That is, the proportion of physically active residents is not a function of scale -- whether a city has more than a million residents or is simply a regional centre -- but of whether the person lives in a city or a non-urban setting.

Parkinson's disease is a neurodegenerative disorder that manifests through symptoms such as tremor, slow movements, limb rigidity and gait and balance problems. As such, nearly all diagnostic testing revolves around how a patient moves and requires the patient to walk for extensive distances and amounts of time. The discomfort caused to patients by this kind of testing is unacceptable, according to an international team of researchers based in Saudi Arabia and Sweden.

They proposed a new kind of computational analysis based on less physically-demanding testing in IEEE/CAA Journal of Automatica Sinica, a joint publication of the Institute of Electrical and Electronics Engineers (IEEE) and the Chinese Association of Automation (CAA).

"Apart from gait and balance data, the measurement of computer keystroke time series that contain information of the hold time occurring between pressing and releasing a key has been proposed for detecting early stages of Parkinson's disease," said Tuan D. Pham, paper author and professor of biomedical engineering in the Center for Medical Image Science and Visualization at Linköping University in Sweden.

"Being similar to the motivation for determining the minimum number of strides for the analysis of gait dynamics, our study was interested in answering the question if there are methods that can process very short time series and achieve good results for differentiating healthy controls from subjects with early Parkinson's disease."

The disease itself is not fatal, but complications from Parkinson's disease can be serious. It affects about 10 million people across the globe, and it can take years for the disease to progress to a symptomatic state--making early detection a top priority for researchers.

In this experiment, subjects press one or two buttons on a device such as an iPhone as fast as possible for a short period of time. Pham and the team took these data and analyzed them through fuzzy recurrence plots, which take multiple short-time series data points and translate them into a two-dimensional grey-scale images of texture. In the image, related points appear as a dense grey, with more disparate data points becoming fuzzier. The algorithm used for the fuzzy recurrence plots learns how the data points connect and can help provide difference and similarities in subject groups such as people with early Parkinson's disease and those without.

"While having a very short length, the time series is augmented with a relatively large number of feature dimensions," Pham said. "The results obtained from the fuzzy recurrence plots are encouraging for the collection of practical data recorded from participants and their usage for the classification task."

The team plans to further study the use of fuzzy recurrence plots and improve the algorithm to better determine a subject's disease state. They also plan to extend the research to study gait dynamics of patients with Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis, also known as Lou Gehrig's disease.

For most patients, ultrasound is a relatively painless procedure. Conventional ultrasound is safe, low-cost, non-ionizing, and one of the most commonly used imaging modalities worldwide. In a typical exam, a clinician presses an ultrasound probe with gel on the skin surface to generate an image at the desired location. The probe emits sound waves into the tissue and various features such as muscle, fat, blood vessels, and bones reflect sound back to the probe, which records the reflected signals and produces an ultrasound image. Since the probe must make contact with the skin surface to transmit and detect ultrasound, the probe's orientation on and compression of the skin surface creates contact sensitive images. This contact sensitivity causes unaccounted image variations that restricts ultrasound performance. Clinicians imaging the same region at two different times will typically produce two different images, rendering quantitative tracking of tissue change over time impossible. Furthermore, skin contact may be limiting in situations where patients don't tolerate probe contact well, such as neonates, trauma/burn victims, or surgical patients.

In a new paper published in Light Science & Application, Xiang (Shawn) Zhang and Brian Anthony from the Mechanical Engineering Department at Massachusetts Institute of Technology, in Cambridge, United States, developed an alternative approach to conventional ultrasound that does not require direct contact with the skin surface. The new laser ultrasound technique uses eye- and skin-safe lasers to remotely generate and detect ultrasound on the skin surface. The transmit laser sends a light pulse which is rapidly absorbed on the skin and converted into sound waves via the photoacoustic effect - the generation of sound by light. The generated sound waves interact with tissue identical to conventional ultrasound and the reflected signals are detected by a laser interferometer on the skin surface. The lasers are moved across the skin surface to produce an image. The system was successfully tested on human subjects and showed that laser ultrasound is sensitive to tissue features presently detected using conventional ultrasound. The new technique can image at centimeter depths which is significantly deeper than other optical ultrasound techniques and is comparable to imaging depths of modern clinical ultrasound,

These first laser ultrasound image results are very encouraging. "We're at the beginning of what we could do with laser ultrasound. Imagine we get to a point where we can do everything ultrasound can do, now at a distance. This gives you a whole new way of seeing internal structures, without making contact with the patient." The researchers hope to improve upon the current technology and push laser ultrasound toward future clinical use. "As related technological fields advance, one can imagine designing a laser scanning system that can remotely and volumetrically image a patient without ever disturbing or making contact."