Body

Here the research team tested a safe and well-established microbe-based immune adjuvant to restore immune homeostasis and counteract inflammation-associated obesity in animal models.

Taken together, they concluded that oral vaccination with cholera toxin B helps stimulate health-protective immune responses that counteract age-associated obesity.

Dr. Susan E. Erdman from the Division of Comparative Medicine, at the Massachusetts Institute of Technology in Cambridge, MA, United States said, "The global burden of chronic inflammatory diseases is increasing at alarming rates."

The continuous rise of obesity, cardiovascular and chronic respiratory diseases, diabetes, infertility, allergy and autoimmunity, cancer, and central nervous system dysfunctions, including anxiety and autism, appears to link with modernized lifestyle but remains inexplicable.

Figure 1: Early-life intervention with ctB rescues mice from age-associated obesity and inflammation. Shown are data collected from C57BL/6 mice of both genders at the age of 9 months. (a) At gross examination of whole body morphology, both female and male mice that consumed low doses of ctB eight months earlier have leaner physiques by comparison with untreated controls. (b) Treated mice also have less crown-like structures (CLS, arrow-heads), caused by adipocyte death-related inflammation, in their abdominal fat; (c) less myeloperoxidase-positive (MPO) granulocytes in their spleens; and (d) more anti-inflammatory Foxp3-positive regulatory T cells in their mesenteric lymph nodes compared to control mice. (e) Body weight and histomorphometrical analyses shows that the long-lasting effects of ctB are statistically significant. (a) Hematoxylin and Eosin. Scale bars: 250 μm. IHC; Diaminobenzidine chromogen, Hematoxylin counterstain. Scale bars: 25 μm. (b) Numbers on the y-axis of bar graphs correspond to the mean±SEM of the parameter assessed; *p<0.05, **p<0.01, ***p<0.001.

Underlying systemic immune imbalances linked with bacteria residing in the gut have been proposed as a probable cause of obesity.

In this context, obesity is one of many chronic inflammatory diseases associated with modern living.

Important effects of gut microbiota in mammalian physiology, including metabolism and CNS functions, place gut microbe-immune cell interactions in the hypothetical center of chronic inflammatory disorders such as obesity.

In this regard, postbiotic gut bacterial fractions used for oral immunizations have been found to stabilize the immune system and counteract destructive inflammatory responses later in life in both humans and animals.

Immune adjuvant properties of cholera-toxin, make it an attractive tool for induction of tolerance that stabilizes the immune system.

The Erdman research team concluded, "Indeed, systemic immune imbalances related to failure of tolerance have been proposed as a cause of extra-intestinal cancer linked with bacteria residing in the gut.

It remains to be seen whether this gut immune-centric strategy broadly translates to successes in the clinic; however, the versatility of ct B to manipulate immune responses make this protein a promising adjuvant for vaccine development to combat a growing Westernized public health crisis."

Journal

Oncotarget

DOI

10.18632/oncotarget.27137

DARIEN, IL – Patients and medical providers should be aware that chronic opioid use can interfere with sleep by reducing sleep efficiency and increasing the risk of sleep-disordered breathing, according to a position statement from the American Academy of Sleep Medicine.

Opioid use has boomed in the last decade, with nearly 92 million Americans using prescription opioids and 11.5 million people misusing them. In addition to understanding the risks of opioid addiction and abuse, it is important for health care providers to be aware that chronic opioid use is associated with changes in sleep architecture and an increased risk of respiratory depression during sleep.

“This statement increases awareness among health care providers of the important adverse events that can occur in patients on chronic opioid therapy,” said co-author Dr. R. Nisha Aurora, Associate Professor of Medicine at Rutgers Robert Wood Johnson Medical School in New Jersey. “The paper also highlights the need for providers to recognize and diagnose sleep-related breathing disorders that are frequently seen with chronic opioid use.”

The position statement was developed by the AASM board of directors and is published in the Nov. 15 issue of the Journal of Clinical Sleep Medicine.

Patients who have chronic pain often experience fatigue and disturbed sleep. Studies have shown that chronic opioid therapy has the potential to further disrupt sleep by reducing sleep efficiency, slow wave sleep, and rapid eye movement sleep. Another adverse effect of opioid use is respiratory depression, which can increase the risk of sleep-related breathing disorders such as sleep-related hypoventilation, central sleep apnea and obstructive sleep apnea.

If left untreated, sleep-related breathing disorders can be harmful to a patient’s health. However, they can be diagnosed by a medical provider following an overnight sleep study in a sleep center. Effective treatments also are available, including several modalities of positive airway pressure therapy. Medical providers who care for patients on chronic opioid therapy need to be aware of the signs of disrupted sleep, such as snoring and excessive daytime sleepiness, in order to provide their patients with high quality care.

“Because of the complex relationship between pain, sleep, daytime functioning, and opioid therapy, a strong collaboration between pain specialists, sleep physicians, and primary care providers is needed to optimize patient benefit and minimize complications when opioids are part of chronic therapy,” said Dr. Aurora.

While opioid therapy can contribute to sleep disruption and sleep disorders, it can be an effective treatment for patients with restless legs syndrome (RLS), a sleep disorder associated with disturbed sleep. Some patients with severe, refractory RLS, who are unresponsive or intolerant to other therapies, may find relief by using opioid medications at much lower doses than those used to treat chronic pain.

Dr. Aurora is currently collaborating with the Brain Health Institute at Rutgers to study sleep in those seeking therapy for opioid addiction.

Survivors of sepsis--a life-threatening response to an infection--have expressed a need for advocacy and follow-up support, according to a study authored by professors at the University of Tennessee, Knoxville, and the University of Tennessee Health Science Center in Memphis, and published in Dimensions of Critical Care Nursing.

"Sepsisis a devastating and life-threatening illness with serious long-term consequences," said Reba Umberger, lead author of the study and an assistant professor in UTHSC's Acute and Tertiary Care Department.

Umberger was previously an assistant professor at UT Knoxville, where the study was conducted.

Sepsis can lead to conditions such as septic shock, acute kidney injury, altered mental status, or organ failure. It is a medical emergency that requires prompt recognition and treatment.

"Sepsis mortality rates in hospitals have decreased over the past decade, increasing the number of survivors who may experience long-term consequences," she said. "Our study aims to identify how participants perceive their illness and its aftermath."

Researchers conducted interviews with survivors nearly two years after their admission to an intensive care unit with sepsis. UT Knoxville's Transdisciplinary Phenomenology Research Group, led by Sandra Thomas, a professor of nursing, assisted in analyzing interview transcripts to identify common themes.

The study identified five major themes among survivors: how they survived, blurring of time and counting time by events, helpful versus unhelpful assistance, feeling powerless and striving for control, and survival without full recovery.

"Participants were younger than expected, possibly indicating that those we could not reach were too ill to respond. We knew that survivors can develop post-intensive care syndrome (PICS) as well as increased risk for new infections," said Umberger. "Recovery after sepsisis very individual, and our method of interviewing participants allowed them to direct what stood out as important, so we did not probe about symptoms unless they shared them."

Many participants did report some psychological, physical, and cognitive symptoms associated with PICS, and interviews reflected chronic illness. Most participants were interviewed nearly two years after sepsis,and the majority still expressed the need for a caregiver. Only one participant had returned to work.

"Because of the unique qualitative nature of the in-depth interviews, this study revealed the meaning of the sepsis experience to the participants, which was previously not well understood," said Umberger. "Our recent analysis of the 2015 Nationwide Readmission Database shows that about 18 percent of patients admitted with sepsis experienced at least one readmission with sepsis within three months.

"Care during this period is fragmented, without systematic support for patients after their ICU discharge. My team's next study will target this high-risk period to better understand physical, psychological, cognitive, and immune function recovery, and how peer support may benefit survivors of sepsis and their caregivers," Umberger said.

Integrating behavioral health services into pediatric primary care in three Boston-area community health centers increased primary care visits by children with mental health diagnoses without raising Medicaid costs.

In mid-2016, the Dimock Center in Roxbury, Codman Square Health Center in Dorchester, and the Lowell Community Health Center began working with Boston University (BU) and Boston Medical Center (BMC) to implement the Transforming and Expanding Access to Mental Health Care in Urban Pediatrics (TEAM UP) model of fully-integrated pediatric behavioral health within primary care, with support from the Richard and Susan Smith Family Foundation.

Now, a new study published in Health Services Research and led by a Boston University School of Public Health (BUSPH) researcher finds that, in the first year and a half of the program, children with mental health diagnoses who were served by the TEAM UP sites went for more primary care visits than similar children served by nearby non-participating community health centers.

Despite this increase in visits, children who were part of TEAM UP did not see a change in avoidable health care utilization (such as emergency department visits or hospitalizations) or in healthcare costs.

"Notwithstanding the direct investment of implementing the intervention, integrating behavioral health into the pediatric medical home for low-income children has measurable value in as little as one and a half years, without further increasing patient spending," says lead study author Dr. Megan Cole, assistant professor of health law, policy & management at BUSPH. "If increased engagement in primary care leads to earlier and improved treatment for children with mental health conditions, longer-term cost savings could result."

An estimated one in five children in the US has a behavioral health issue, but there are major unmet needs and systemic barriers to access care. Progress to integrate behavioral health into pediatric primary care has been slow, especially at centers serving low-income families who already face the greatest barriers. Read more about TEAM UP here.

Podcast permanent link:

English: https://soundcloud.com/cmajpodcasts/190395-guide

French: https://soundcloud.com/cmajpodcasts/190395-guide-fre

A new guideline from the Canadian Task Force on Preventive Health Care recommends against routine screening for thyroid dysfunction in nonpregnant adults without symptoms or risk factors. This guideline, which is based on a rigorous systematic review of the latest evidence, is published in CMAJ (Canadian Medical Association Journal) http://www.cmaj.ca/lookup/doi/10.1503/cmaj.190395

Routine testing for thyroid dysfunction is commonly ordered, by checking the "thyroid stimulating hormone (TSH)" box on a blood test requisition form, although practice varies by primary care practitioner. An abnormal TSH level may indicate an underactive (hypothyroidism) or overactive thyroid gland (hyperthyroidism).

"If you are a clinician who orders TSH tests as part of preventive health visits, we would like you to reconsider this practice. The evidence isn't there to suggest a health benefit for this type of screening as a routine part of care," says Dr. Richard Birtwhistle, Emeritus professor of Family Medicine and Public Health Sciences at Queen's University and Chair of the Task Force Thyroid Dysfunction working group.

The task force identified no screening trials in their evidence review but looked at 22 studies on the effectiveness of treatment for abnormal TSH findings in asymptomatic adults and found no evidence of benefits from screening and treatment in people without symptoms.

Harms of unnecessary testing include the need to take medication unnecessarily and have regular medical visits and follow-up blood tests to check TSH levels.

"Patients who are unusually tired; sensitive to cold or heat; or experience hair loss, heartbeat irregularities, unexpected weight loss or gain should visit their primary care practitioner," says Dr. Donna Reynolds, a family doctor and specialist in public health and preventive medicine and a member of the task force working group. "This recommendation does not apply to people with symptoms that may indicate an over- or under-active thyroid gland, or who have risk factors for thyroid disease, such as previous head or neck radiation, exposure to certain medications, and pituitary or hypothalamic diseases."

Alignment with other guidelines

The British Columbia Ministry of Health and Toward Optimized Practice from Alberta recommend against testing for TSH in asymptomatic patients.

The College of Family Physicians of Canada, Nurse Practitioner Association of Canada and the Canadian Society of Endocrinology and Metabolism have endorsed the guideline.

"Given the lack of clinical effectiveness and the burden on patients, including financial costs, screening patients without symptoms consumes resources that could be better used elsewhere," says Dr. Birtwhistle.

For the full guideline, infographic overview and clinician FAQs, visit the http://canadiantaskforce.ca/guidelines/published-guidelines/asymptomatic-thyroid-dysfunction/ at http://www.canadiantaskforce.ca.

In a related commentary http://www.cmaj.ca/lookup/doi/10.1503/cmaj.191437 Drs. Omar El Kawkgi and Juan Brito, Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, Minnesota, write that "by issuing a strong recommendation against population screening for thyroid dysfunction, the task force may help physicians to stop uncovering a large reservoir of people with mild thyroid dysfunction who are unlikely to benefit from identification or treatment, thereby preventing the overdiagnosis and overtreatment of otherwise healthy people."

They note that the task force's recommendation diverges from some other medical societies that recommend screening, especially in older people.

Trento, 15 November 2019 – (a.s.) New drugs can be developed from old ones. This revolutionary pharmacological approach that has been gaining ground recently was confirmed by a study conducted by two major research centres of the University of Trento and published today in Nature Communications. The study, which investigated the relationship between diseases and pharmacological effects at molecular level, was jointly carried out by two research teams within the University: one at Cosbi (Fondazione The Microsoft Research - University of Trento Centre for Computational and Systems Biology), which is specialized in computer science application to big data, and one at Cibio Department, which is focused on biology and genomics.

Everything starts from an analysis of big data: the existing drugs and, in particular, their molecular properties, were analyzed with a new algorithm designed by Cosbi, to see whether they could be used to treat other conditions, to bring benefits to patients with conditions that are difficult or impossible to treat. This technique, known as ‘drug repositioning’, has been already used in the past, but it has become even more effective today thanks to new technologies, which facilitate the quick and systematic analysis of a vast amount of data. We have achieved promising results, explained Enrico Domenici, president of Cosbi: "We have tested the new algorithm to search for new therapies to treat metabolic syndrome, a condition that increases the risk of heart disease and type 2 diabetes and which is characterized by obesity, elevated levels of cholesterol and/or triglycerides, high blood pressure and diabetes. We identified the mutated genes that are responsible for these alterations and then searched pharmaceutical databases for already approved molecules that could interact with the networks that these genes form in the adipose tissue, liver and muscles. To carry out such a complex study we adopted a new computational approach that measures the "distance" between the proteins targeted by the drug and those found in the networks affected by the disease. That is how we found a new application for an already existing drug: Ibrutinib, which was originally developed to treat completely different conditions, and specifically B-cell tumors like mantle cell lymphoma, chronic lymphocytic leukemia, and Waldenström macroglobulinemia. Other studies on this drug are under way to determine if it could be used to treat autoimmune diseases".

The results of the computational analysis were validated at Cibio on zebrafish larvae to confirm the response to the drug. The head of the research team at Cibio department, Maria Caterina Mione, explained how it worked: "By testing this drug in the laboratory we saw that the it is possible to limit the detrimental impact of obesity induced by a high-fat diet. The drug succeeded in limiting the inflammatory condition associated with lipid accumulation. Testing the effectiveness of a drug that is already on the market makes it possible to skip a number of long and complex stages of the approval process for new medical products, because their tolerance and safety have already been demonstrated. Our data are just a start and more in-depth studies and clinical tests are required, but they demonstrate that combining experience in big data analysis and the ability to develop models for biological validation can boost drug repurposing research".

Finding out that a market approved drug can potentially be used to treat metabolic syndrome is great news. The incidence of the disease and seriousness of its consequences on health (cardiovascular diseases and diabetes complications) have made metabolic syndrome a social problem in recent decades, especially in wealthy societies, where many people have a diet rich in sugars and fats and a sedentary lifestyle. In particular, the disease affects people over 50 years of age, about 30% of the male population and 35-40% of women. The metabolic syndrome becomes more common in women after menopause.

The study has enabled researchers to shorten the drug discovery process, but the findings would need to be validated in a clinical context to be able to use the drug for a disease different from the original indication. More research will be needed in the coming years to translate the experimental finding into a clinical application.

About the article:

About the article:

A network-based approach to identify deregulated pathways and drug effects in metabolic syndrome

Karla Misselbeck1,2, Silvia Parolo 1*, Francesca Lorenzini3, Valeria Savoca3, Lorena Leonardelli1, Pranami Bora1, Melissa J. Morine1, Maria Caterina Mione 3, Enrico Domenici 1,3* & Corrado Priami 1,4*

1 Fondazione The Microsoft Research-University of Trento Centre for Computational and Systems Biology (COSBI), Rovereto (TN), Italy. 2 Department of Mathematics, University of Trento, Trento, Italy. 3 Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, Italy. 4 Department of Computer Science, University of Pisa, Pisa, Italy.

*email: parolo@cosbi.eu; enrico.domenici@unitn.it; priami@cosbi.eu

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Journal

Nature Communications

DOI

10.1038/s41467-019-13208-z

Living implies change. This is what happens to the cells of our bodies as we grow older: they accumulate genetic alterations, most of which are harmless. However, in some specific cases, these mutations can affect certain genes and can lead to the development of cancer. The source of these alterations can be exogenous (e.g., solar radiation, tobacco smoke or some toxic substance) or endogenous (e.g., errors in DNA processing).

Scientists led by ICREA researcher Núria López-Bigas, head of the Biomedical Genomics Laboratory at the Institute for Research in Biomedicine (IRB Barcelona) and Assistant Professor at the Pompeu Fabra University, have characterised for the first time the genetic alterations caused by six therapies widely used for the treatment of cancer (five based on drugs used as chemotherapies, and radiotherapy). The results have been published today in the journal Nature Genetics.

Chemotherapies have revolutionized the treatment of cancer, allowing the survival of large numbers of patients. Some of these therapies kill cancer cells by damaging their DNA. However, these drugs can also harm the healthy cells of the patient, thereby explaining their side effects.

"It is important to remember that chemotherapies are highly efficient for the treatment of cancer," says Oriol Pich, a PhD student at IRB Barcelona and first author of the study. "But long-term side effects have also been reported in some patients. Studying the DNA mutations that occur in cells as a result of chemotherapies is the first step towards understanding the relationship between these mutations and the long-term side effects of these treatments".

To carry out the study, the Hartwig Medical Foundation in the Netherlands provided the scientists with the sequences of the metastatic tumours of around 3,500 patients and information about the treatments that they received. Using bioinformatics techniques, López-Bigas' group has been able to identify a specific pattern of mutations in the metastatic tumours of the patients for each of the most widely used therapies--their "mutational footprint".

"Once this 'footprint' has been identified, we can quantify the DNA mutations that have been caused by each kind of chemotherapy, as well as those caused by treatment combinations," explains López-Bigas. "We have compared these numbers with the genetic alterations caused by natural endogenous processes. We have calculated that, during treatment, some of these chemotherapies cause DNA mutations at a rate that is between 100 and 1000 times faster than what normally occurs in a cell."

This knowledge will allow the optimization of cancer treatments. "The aim is to maximize the beneficial effects of chemotherapies by destroying tumour cells while minimizing the number of mutations caused in the healthy cells of the patients. This would be achieved through a careful combination of dose and treatment duration," says López-Bigas.

ANN ARBOR--University of Michigan scientists and their colleagues used glowing fluorescent gel to test the potential effectiveness of vaccines to control rabies and other diseases in wild bats.

The study, led by researchers at U-M and the University of Glasgow and scheduled for publication Nov. 18 in the journal Nature Ecology & Evolution, found that a low-effort vaccination program could substantially reduce rabies transmission in wild vampire bats, thereby reducing the risk of lethal infections in humans and livestock.

The gel, which contained a fluorescent tracer dye called Rhodamine B, was applied to wild vampire bats at three colonies in Peru, where it simulated the bat-to-bat spread of an orotopical rabies vaccine. Such vaccines--which are applied orally or topically and are then spread between bats through oral contact during grooming--have already been shown to protect multiple bats against rabies for every individual vaccinated in the laboratory, but their levels of spread in wild bats was unknown until now.

When the gel was ingested by bats that groomed each other, it led to fluorescence in the bats' hair follicles, which was then monitored by fluorescent microscopic analysis of hair samples collected by the scientists.

The study demonstrated that because of bat-to-bat transfer, orotopical rabies vaccines would protect 2.6 bats for every bat that's vaccinated, compared to a single bat protected by conventional nonspreadable vaccines.

"We provide the first evidence that vaccinating bats could lead to meaningful reductions in human and livestock rabies," said the study's lead author, U-M's Kevin Bakker.

The researchers used mathematical models to show that observed levels of vaccine transfer would reduce the probability, size and duration of rabies outbreaks, even at low but realistically achievable levels of vaccine deployment.

The models further showed that a spreadable vaccine would control rabies more effectively than the current policy of killing the bats with a poisonous gel that spreads by the same route of contact and grooming.

"We demonstrate why over 40 years of culling vampire bats has failed to contain the disease in Latin America," said Bakker, a postdoctoral researcher in the U-M Department of Statistics.

"Our mathematical models reveal that bats would have to be effectively eliminated to reduce rabies more efficiently than vaccines, and our field studies imply that this level of culling effort is not practically attainable in real-world campaigns."

Vampire bat rabies is a lethal viral disease found throughout Latin America. In places where vampire bats routinely feed on human blood, rabies is estimated to cause up to 960 deaths per 100,000 people, while losses from livestock mortality exceed $50 million annually, disproportionately affecting impoverished rural communities.

Existing management strategies have been unable to mitigate the burden of rabies, with uptake of protective vaccines for humans and livestock limited by high costs and inaccessibility to remote areas. Another strategy, poisoning the bats to reduce their populations, is controversial and has had mixed results for rabies control.

"Vampire bat rabies still has severe medical and agricultural impacts across North, Central and South America despite decades of efforts to mitigate its burden. Our findings demonstrated that bat-to-bat transfer of oral rabies vaccines could increase population-level immunity up to 2.6 times beyond the same effort using conventional, non-spreadable vaccines," said Daniel Streicker, senior author of the paper and a senior research fellow at the University of Glasgow's Institute of Biodiversity, Animal Health & Comparative Medicine and the MRC-University of Glasgow Centre for Virus Research.

"Until recently, controlling diseases in reclusive animals like wild bats seemed unimaginable. Our findings reveal the exciting potential for using a new generation of spreadable vaccine technologies to protect human and animal health by fighting diseases within their wildlife hosts."

Because rabies relies on vampire bat movement between colonies, a strategic switch from poisoning to vaccination would increase immunity and may lead to a dramatic reduction in rabies across Latin America, said Bakker, who earned a doctorate from the U-M Department of Ecology and Evolutionary Biology in 2017, then completed an eight-month postdoctoral fellowship at the University of Glasgow. He is now a National Institutes of Health Research Fellow in the U-M Department of Statistics.

"Hopefully, this is just the first step in evaluating spreadable vaccines to control disease transmission across a multitude of pathogens and hosts," Bakker said.

What The Study Did: A 12-month randomized clinical trial used internet recruitment of men who have sex with men to evaluate the effects of providing self-tests for HIV to increase HIV testing and diagnosis among the men and people in their social networks.

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

Authors: Robin J. MacGowan, M.P.H., of the Centers for Disease Control and Prevention in Atlanta, is the corresponding author.

(doi:10.1001/jamainternmed.2019.5222)

Editor's Note: The article contains 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.

LA JOLLA, CALIF. - Nov. 18, 2019 - Scientists at Sanford Burnham Prebys Medical Discovery Institute have identified a combination of two anti-cancer compounds that shrank pancreatic tumors in mice--supporting the immediate evaluation of the drugs in a clinical trial. U.S. Food and Drug Administration (FDA)-approved versions of the compounds are used today to treat certain leukemias and solid tumors, including melanoma. The study was published in Nature Cell Biology.

"The sad reality is that at present, pancreatic cancer therapy is lagging since there is no effective treatment for these tumors," says Ze'ev Ronai, Ph.D., professor in Sanford Burnham Prebys' Tumor Initiation and Maintenance Program and senior author of the study. "Our study identifies a potential treatment combination that can immediately be tested against these aggressive tumors. We are already meeting with oncologists at Oregon Health & Science University to discuss how to advance this discovery into clinical evaluation."

Pancreatic cancer is one of the deadliest cancers. It is often difficult to diagnose because symptoms--such as pain in the abdomen, yellow skin and eyes, and weight loss--don't typically occur until the disease is advanced. Less than 10 percent of people with pancreatic cancer remain alive five years later. More than 56,000 Americans are expected to receive a pancreatic cancer diagnosis in 2019, according to the American Cancer Society.

In the study, the scientists used a drug called L-asparaginase to starve pancreatic tumors of a key nutrient, asparagine--an amino acid required for protein synthesis. Instead of dying, they found that the tumor turned on a stress response pathway that allowed the cancer cells to produce asparagine themselves. The scientists then treated mice with a second drug that blocked the stress response pathway and shrank the pancreatic tumor. L-asparaginase is FDA approved to treat certain leukemias; and the second drug, a MEK inhibitor, is approved for the treatment of solid tumors, including melanoma, a type of skin cancer.

"This research lays the basis for the inhibition of pancreatic tumor growth by a combined synergistic attack based on asparagine restriction and MAPK signaling inhibition," says Eytan Ruppin, M.D., Ph.D., a study author and chief of the Cancer Data Science Library at the National Cancer Institute, part of the National Institutes of Health (NIH). "Our lab was able to further support these findings through a computational analysis of patient data."

Adds Rosalie C. Sears, Ph.D., a professor at Oregon Health & Science University, "It's clear we're not going to find a single magic bullet that cures cancer but will instead need several drugs that target multiple vulnerabilities. This study identifies a promising dual treatment for pancreatic cancer--one of the deadliest cancers--and I look forward to seeing these drugs tested in patients."

In the same study, the scientists showed that the two treatments also shrank melanoma tumors in mice. Due to the large unmet clinical need in pancreatic cancer, the scientists have decided to focus on this cancer first.

What The Study Did: This study explored how health is associated with legislative activity by examining whether outbreaks of vaccine-preventable diseases, such as measles, mumps, whooping cough and chickenpox, were associated with the introduction of legislation in states to change vaccine exemption laws.

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

Author: Neal D. Goldstein, Ph.D., M.B.I., of the Dornsife School of Public Health at Drexel University in Philadelphia, is the corresponding author.

(doi:10.1001/jamapediatrics.2019.4365)

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

Nov. 18, 2019-- The American Thoracic Society, Centers for Disease Control and Prevention, European Respiratory Society and the Infectious Diseases Society of America have published an official clinical guideline on the treatment of drug-resistant tuberculosis (DR-TB) in the Nov. 15 American Journal of Respiratory and Critical Care Medicine.

The guideline makes new recommendations for the choice and number of drugs, as well as the duration of treatment for DR-TB. These recommendations prioritize the use of medications that can be administered orally.

The guideline makes clear that treatment should be tailored based on drug-susceptibility testing, and that individuals should not receive medicines to which the Mycobacterium tuberculosis strain is resistant.

The guideline includes two other new recommendations. It recommends treatment with a later-generation fluoroquinolone of all infected contacts of multidrug-resistant tuberculosis (MDR-TB) patients, rather than watchful observation, and it provides evidence-based guidance for the treatment of pregnant women with MDR-TB for the first time.

Treatment for MDR- and extensively drug-resistant (XDR)-TB is long and difficult. The availability of potent new and repurposed medicines allows practitioners, for the first time, to choose alternatives to injectable drugs, which have long been considered an essential component of treatment regimens for DR-TB. These injectable drugs have well-known toxicities, including irreversible hearing loss.

By prioritizing the use of orally administered medicines, the guideline writing committee believes clinicians can spare patients some of the most debilitating effects of TB treatment, make treatment more tolerable and improve outcomes.

The guideline committee included specialists in pulmonary medicine, infectious diseases, pediatrics, primary care, public health, epidemiology, economics, pharmacokinetics, microbiology, systematic review methodology and advocacy.

"Having the participation of committee members from multiple medical societies and the CDC, as well as patient advocate perspectives, was absolutely critical to discussing the balance between desirable and undesirable health effects of interventions, making certain they were favorable for MDR-TB patients, including for children and pregnant women," said Payam Nahid, MD, MPH, chair of the guideline committee and a professor of medicine at the University of California, San Francisco.

This guideline is generally consistent with the World Health Organization's recommendations but includes some different recommendations that are specifically tailored to low-incidence, higher-resource countries of North America and Europe.

In making its recommendations, the committee reviewed findings from 50 studies, conducted in 25 countries involving more than 12,000 patients with DR-TB.

The committee grouped questions to be answered by the guideline into six topics: 1) number of effective drugs in a regimen for DR-TB, duration of intensive and continuation phases of treatment for DR-TB; 2) review of drug and drug classes for the treatment of DR-TB; 3) the use of a standardized, shorter-course regimen of

The committee used the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) framework to indicate the strength of the evidence supporting the 25 recommendations included in the clinical guidance.

"The individual patient data level analyses conducted by investigators at McGill University were essential to the development of our recommendations, representing a substantial analytic advance over prior approaches that relied on aggregate data," said Barbara Seaworth, MD, guideline committee co-chair and medical director of the Heartland National TB Center, at the University of Texas Health Science Center at Tyler. "However, the certainty in the evidence for observational studies is lower than for clinical trials, and much greater investment is urgently needed to allow the TB research community to conduct high-quality randomized, interventional TB clinical trials that will define safe and effective all-oral regimens for treatment of all patients with DR-TB."

The guideline is available online.

Stigma and safety fears have made daily dose tapering of opioid prescriptions more common. New research from UC Davis Health physicians, however, shows tapering can occur at rates as much as six times higher than recommended, putting patients at risk of withdrawal, uncontrolled pain or mental health crises.

The study -- "Trends and Rapidity of Dose Tapering Among Patients Prescribed Long-term Opioid Therapy, 2008-2017" -- is published in JAMA Network Open. The results also will be presented at the Nov. 16-19 North American Primary Care Research Group meeting in Toronto.

"Tapering plans should be based on the needs and histories of each patient and adjusted as needed to avoid adverse outcomes," said study author Alicia Agnoli, assistant professor of family and community medicine. "Unfortunately, a lot of tapering occurs due to policy pressures and a rush to get doses below a specific and sometimes arbitrary threshold. That approach can be detrimental in the long run."

In 2016, the U.S. Centers for Disease Control and Prevention (CDC) recommended dose tapering, or a slow reduction in prescription opioid doses over time, if the risks of continuing opioids outweigh the benefits. That point in time is usually when a patient is taking 90 morphine milligram equivalents -- or MMEs -- each day, and that dose is no longer reducing pain or improving daily functions. The CDC advises a slow decrease of 10% MMEs per month.

The study team set out to examine trends in opioid dose tapering and if tapering rates were consistent with CDC recommendations.

"We wanted to understand how often opioid dose tapering happens, how rapidly patients' doses were being reduced when tapering, and which patients were more likely to have doses tapered," said lead author Joshua Fenton, professor of family and community medicine.

Tapering faster than recommended

Fenton and Agnoli evaluated medical and pharmacy claims and enrollment records for more than 100,000 commercial insurance and Medicare Advantage enrollees, representing a diverse mixture of ages, races, ethnicities and locations across the U.S. They focused on individuals whose opioid doses were stable for at least a year and identified tapering patients as those with a 15% or more reduction in daily MMEs during a seven-month follow-up period.

They found that dose tapering became more common throughout the study period of 2008-2017, with the biggest jump following the CDC's 2016 prescribing guidelines. Tapering increased from 10.5% to 13.7% from 2008 to 2015, and from 16.2% to 22.4% from 2016 to 2017. Tapering was much more common in patients prescribed higher opioid dosages.

They also found that the rate of dose reduction often was well beyond the CDC's recommendation of 10% per month. The average reduction overall was 27.6% per month. Nearly 20% of patients tapered at a rate of 40% per month, and 5% tapered at a rate faster than 60% per month.

The 2016 policy could have been misinterpreted, leading many prescribers and health systems to insist on faster-than-recommended tapering, according to Agnoli.

"There is definitely a lot of pressure to reduce opioid use among patients, but there also is a need for more training and guidance for prescribers on how to help them safely do so," Agnoli said.

Women and tapering

Fenton and Agnoli also identified patient variables associated with tapering and uncovered an interesting difference in tapering rates based on sex.

While men have much higher rates of opioid use disorder and adverse outcomes related to opioids, women were more likely than men to have their opioid doses tapered.

"We think this has a lot to do with the gender dynamics of pain management and the physician-patient relationship," Agnoli said. "How women experience pain and discuss pain with their physicians is perhaps very different than men. There also could be some sex bias in terms of the patients that physicians choose to initiate conversations with about dose reduction."

Minimizing tapering risks

The researchers hope to build on this work to inform best practices for safe decision-making around dose reduction for all patients prescribed opioids.

"Ultimately, we want to clarify the effects of tapering on patients and how to help them taper to maximize benefits and minimize risks," Fenton said. "We expect this line of research will have important implications for how physicians manage and monitor patients who are undergoing opioid tapering."

Lisbon, Portugal: Survival for patients with the most common forms of advanced breast cancer could be substantially improved if both younger and older patients had access to a group of anti-cancer drugs called CDK4/6 inhibitors, according to experts at the Advanced Breast Cancer Fifth International Consensus Conference (ABC5) in Lisbon today (Saturday). [1]

In a session agreeing new guidelines for treating advanced breast cancer, they said there was now enough evidence that this class of medicines helps patients live longer and with the same or better quality of life. However, they said the medicines were not being offered to the majority of patients who could benefit.

The experts also highlighted that difficulties with access to opioid pain relief around the world, including a lack of supply in poorer countries and a backlash against opioid addiction in the USA, are leading to breast cancer patients suffering unnecessarily and dying in pain.

A key aim of the Advanced Breast Cancer Conferences and the ABC Global Alliance [2] is to double survival among patients with the disease by 2025. Chair of the ABC5 Conference, Professor Fatima Cardoso, Director of the Breast Unit of the Champalimaud Cancer Centre in Lisbon, Portugal, said: "We now have a family of drugs, CDK4/6 inhibitors, that can substantially prolong life in the most common subtype of breast cancer.

"These drugs bring us much closer to our aim of doubling the time patients with advanced breast cancer live without their disease progressing, but we can only achieve that if they are available to everyone who needs them."

Around 70% of advanced breast cancers are oestrogen receptor positive (ER+) and HER2 negative - also called hormone dependent cancers. ER+ cancers are driven by the hormone oestrogen.

"For these cancers, CDK4/6 inhibitors should be the standard of care, both for younger, pre-menopausal and older, menopausal women, as well as men with advanced breast cancer," said Prof Cardoso. "However, the major problem is the cost of these medicines and, at present, only a small proportion of patients around the world are being treated with them. The same occurs with anti-HER2 therapies, which can prolong survival substantially for another subtype of advanced breast cancer - HER2 positive breast cancer.

"There is unequal access to these medicines not only between countries, but within countries as well, and between pre- and post-menopausal women. Our panel of world experts on the treatment of breast cancer agrees that CDK4/6 inhibitors should be make available to every patient who could benefit from them, not just a small percentage."

The experts also called on policy-makers worldwide to ensure that fears about the abuse of opioids should not limit cancer patients' access to adequate pain control.

In the new guidelines, they state: "The advanced breast cancer (ABC) community is aware of limitations that are being imposed worldwide, as a consequence of the perceived abuse of opioids in certain areas of the world. The ABC community is united in insisting that cancer patients should not have restrictions placed that will limit their access to adequate pain control."

Professor Eric Winer, Director of the Breast Cancer Program at Dana-Farber and the Dana-Farber/Harvard Cancer Center, Boston, USA, and co-chair of the conference, said: "Patients with advanced breast cancer can suffer pain and other symptoms, particularly towards the end of their lives. We need to ensure that appropriate pain medications and other symptom interventions are available to them.

"We acknowledge that the misuse of opioids is a big problem, particularly in the United States, but we need to make sure that in trying to deal with this problem we do not interfere with pain management in cancer patients. In addition, in some low- and middle-income countries, such as some in Africa, there are problems with patients being able to access any form of pain relief, and this needs to be addressed urgently."

The panel of experts also called for further research into the use of cannabis for managing symptoms and pain in patients with advanced breast cancer. However, they stressed that it should never replace existing medicines that have been proven to work, such as morphine.

"The panel encourages research on the potential role of cannabis to assist in pain and symptom control but strongly stresses that it cannot replace proven medicines, such as morphine, for adequate pain control," say the experts in their new guidelines.

These issues were among several addressed by 1,500 experts and patients from approximately 90 countries around the world at the conference as they agreed new and modified guidelines for the treatment and management of all types of advanced breast cancer. The new guidelines will be published in Breast and Annals of Oncology in 2020.

There are no reliable figures for the numbers of women (and men) living with advanced breast cancer. However, there are over two million new cases of breast cancer a year in the world and 0.6 million deaths. About 5-10% of cases are either locally advanced or have spread to other parts of the body (metastasised) at diagnosis, and these figures reach almost 80% in developing countries. About a third of all early breast cancer cases will become metastatic even with the best care, and the average overall survival for these patients is around three years.

Dr Tony Shien-Ping Feng of the Department of Mechanical Engineering at the University of Hong Kong (HKU) and his team invented a Direct Thermal Charging Cell (DTCC) which can effectively convert heat to electricity, creating a huge potential to reduce greenhouse effects by capturing exhaust heat and cutting down primary energy wastage.

The new invention is recently published in the prestigious journal Nature Communications (http://www.i-nanoeng.com/upload/2019/09/20190918160051.pdf), and the research has been featured in the Nature Communications Editors' Highlights webpage. HKU's Technology Transfer Office has filed for the invention's US provisional patent and PCT (Patent Cooperation Treaty) patent.

Low grade heat is abundantly available in industrial processes (80 to 150°C), as well as in the environment, living things, solar-thermal (50 to 60°C) and geothermal energy. Over 60% of the world's primary energy input, whether it is in the industrial process or domestic energy consumption, is wasted as heat. A majority of this loss as waste heat is regarded as low-grade heat.

The newly designed DTCC is a game-changing electrochemical technology which can open new horizons for applications to convert low-grade heat to electricity efficiently. It is a simple system with the basic unit sized only 1.5 sq.cm and thickness 1 to 1.5 mm. The cell is bendable, stackable and low cost.

DTCC can be used in HVAC (heating, ventilation, and air conditioning) system to recycle low-grade heat from the compressor and condenser into electricity for use in electrical devices. It can be integrated with the window frame to harvest solar thermal energy to power electrochromic windows, or used as portable devices to power iphones or life-saving equipment in the wilderness. With the increasing popularity of wearable technology, this system may one day harness body heat to power wearable electronic devices or medical devices for monitoring body health conditions like blood sugar levels and blood pressure.

Dr Feng said: "Efficient low-grade heat recovery can help to reduce greenhouse gas emission but current technologies to convert this heat to electricity is still far from optimum. DTCC yields a conversion efficiency of over 3.5%, surpassing all existing thermo-electrochemical and thermo-electric systems, which is either too costly or complicated, or too low in efficiency for everyday applications. DTCC is a revolutionary design with great potentials in smart and sustainable energy devices."

The new thermal charging cell uses asymmetric electrodes: a graphene oxide/platinum (GO/Pt) cathode and a polyaniline (PANI) anode in Fe2+/Fe3+ redox electrolyte via isothermal heating operation without building thermal gradient or thermal cycle. When heated, the cell generates voltage via a thermo-pseudocapacitive effect of GO and then discharges continuously by oxidizing the PANI anode and reducing Fe3+ to Fe2+ under isothermal heating on cathode side till Fe3+ depletion. The energy conversion works continuously under isothermal heating during the entire charge and discharge process. The system can be self-regenerated when cooled down. This synergistic chemical regeneration mechanism allows the device cyclability.

The team is selected as one of the 16 finalists out of 300 applications and one of the only two finalists in Hong Kong competing in the Hello Tomorrow Regional Summit 2019, a competition for start-ups to adapt their research for real-world commercial uses, which will take place in Singapore this Thursday (November 7).

The invention has won the Championship in the HKU 2018 DreamCatchers 100K Entrepreneurship Competition. The team has established a start-up company, High Performance Solution, which is aided by the Technology Start-up Support Scheme for Universities (TSSSU). The company also joined the Incu-Tech 3-year programme at the Hong Kong Science Park and received its first revenue from the prototypes. The team has participated in the first X-plan roadshow of Talent Development Forum in Great Bay Area held by the Hong Kong X Foundation. It has also taken part at the Entrepreneurship Forum in Bahrain, Middle East.