Body

SINGAPORE, 24 March 2020 - "'Persistent cough in underweight patients with diabetes warrants screening for active tuberculosis." This is the message in the editorial of the December 2019 issue of the International Journal of Tuberculosis and Lung Disease, based on findings from a Singapore-based study that have reported that patients with diabetes and who were also underweight had an eight-fold increase in their risk of contracting active TB, compared to obese individuals without diabetes.

Health experts have established that diabetes is a risk factor for active TB disease. Epidemiologic studies have also shown that individuals with low body mass index (BMI), especially those in the lean or underweight range, have a higher risk of active TB compared to their heavier counterparts. However, since increased BMI is a risk factor for diabetes, most patients with diabetes tend to have high BMI in Western populations. In contrast, in Asian populations, and also in Singapore, a large proportion of patients with diabetes are not overweight, but are lean or even underweight. Hence, it is of public health importance to study the joint effect of diabetes and BMI in modulating the risk of TB in Asian populations, where diabetes develops at lower BMI.

Researchers in Singapore, led by Koh Woon Puay, who is Professor at Duke-NUS Medical School and the National University of Singapore's Saw Swee Hock School of Public Health, used data from the population-based study, the Singapore Chinese Health Study, to examine the combined association of diabetes and BMI with risk of active TB disease.

Professor Koh, the Principal Investigator of the Singapore Chinese Health Study, explained, "The key finding in this study is that diabetes and low BMI are independent risk factors for active TB disease. Hence, patients with diabetes and who are also lean or underweight have a substantially increased risk from the effects of both factors."

Dr Cynthia Chee, a co-author of the study, commented, "Singapore's TB incidence rate of 35 to 40 per 100,000 population is 5-10 times that of the US, Australia and the UK. Diabetes is a major problem in Singapore, affecting one in nine persons aged 18 to 69. In order to bring down our TB rate, it is important for all physicians to have a heightened awareness of the link between diabetes and TB, so as to facilitate the early diagnosis of active TB in this important risk group."

"The National Tuberculosis Programme - also known as the Singapore Tuberculosis Elimination Programme, or STEP - welcomes the publication of this landmark study and is proud to have played a part," said Adjunct Associate Professor Jeffery Cutter, Acting Director, National Tuberculosis Programme, National Centre for Infectious Diseases.

Based on this study, Professor Anthony Harries, who is a renowned researcher in TB from the International Union Against Tuberculosis and Lung Disease, called for physicians in diabetes clinics to practice targeted screening with a focus on underweight individuals, and for the conduct of trials to study the value of targeted TB preventive therapy among underweight patients with diabetes.

With the significant part of the global population forced to work from home, the occurrence of lower back pain may increase. Lithuanian scientists have devised a spinal stabilisation exercise programme for managing lower back pain for people who perform a sedentary job. After testing the programme with 70 volunteers, the researchers have found that the exercises are not only efficient in diminishing the non-specific lower back pain, but their effect lasts 3 times longer than that of a usual muscle strengthening exercise programme.

According to the World Health Organisation, lower back pain is among the top 10 diseases and injuries that are decreasing the quality of life across the global population. It is estimated that non-specific low back pain is experienced by 60% to 70% of people in industrialised societies. Moreover, it is the leading cause of activity limitation and work absence throughout much of the world. For example, in the United Kingdom, low back pain causes more than 100 million workdays lost per year, in the United States - an estimated 149 million.

Chronic lower back pain, which starts from long-term irritation or nerve injury affects the emotions of the afflicted. Anxiety, bad mood and even depression, also the malfunctioning of the other bodily systems - nausea, tachycardia, elevated arterial blood pressure - are among the conditions, which may be caused by lower back pain.

During the coronavirus disease (COVID-19) outbreak, with a significant part of the global population working from home and not always having a properly designed office space, the occurrence of lower back pain may increase.

"Lower back pain is reaching epidemic proportions. Although it is usually clear what is causing the pain and its chronic nature, people tend to ignore these circumstances and are not willing to change their lifestyle. Lower back pain usually comes away itself, however, the chances of the recurring pain are very high", says Dr Irina Kliziene, a researcher at Kaunas University of Technology (KTU) Faculty of Social Sciences, Humanities and Arts.

Dr Kliziene, together with colleagues from KTU and from Lithuanian Sports University has designed a set of stabilisation exercises aimed at strengthening the muscles which support the spine at the lower back, i.e. lumbar area. The exercise programme is based on Pilates methodology.

According to Dr Kliziene, the stability of lumbar segments is an essential element of body biomechanics. Previous research evidence shows that in order to avoid the lower back pain it is crucial to strengthen the deep muscles, which are stabilising the lumbar area of the spine. One of these muscles is multifidus muscle.

"Human central nervous system is using several strategies, such as preparing for keeping the posture, preliminary adjustment to the posture, correcting the mistakes of the posture, which need to be rectified by specific stabilising exercises. Our aim was to design a set of exercises for this purpose", explains Dr Kliziene.

The programme, designed by Dr Kliziene and her colleagues is comprised of static and dynamic exercises, which train the muscle strength and endurance. The static positions are to be held from 6 to 20 seconds; each exercise to be repeated 8 to 16 times.

In order to check the efficiency of the programme, 70 female volunteers were randomly enrolled either to the lumbar stabilisation exercise programme or to a usual muscle strengthening exercise programme. Both groups were exercising twice a week for 45 minutes for 20 weeks. During the experiment, ultrasound scanning of the muscles was carried out.

As soon as 4 weeks in lumbar stabilisation programme, it was observed that the cross-section area of the multifidus muscle of the subjects of the stabilisation group has increased; after completing the programme, this increase was statistically significant (p

"There are only a handful of studies, which have directly compared the efficiency of stabilisation exercises against other exercises in eliminating lower back pain", says Dr Kliziene, "however, there are studies proving that after a year, lower back pain returned only to 30% of people who have completed a stabilisation exercise programme, and to 84% of people who haven't taken these exercises. After three years these proportions are 35% and 75%."

According to her, research demonstrates that the spine stabilisation exercise programme is more efficient than medical intervention or usual physical activities in curing the lower back pain and aiming to avoid the recurrence of the symptoms in the future.

What The Study Did: Researchers combined the results of 42 studies in this analysis to examine associations between the quantity, quality and onset of screen use by children and language skills.

Author: Sheri Madigan, Ph.D., of the University of Calgary in Canada, is the corresponding author.

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

(doi:10.1001/jamapediatrics.2020.0327)

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

What The Study Did: This observational study compared changes in opioid-related emergency department visits and hospitalizations before and after the 2014 Affordable Care Act (ACA) Medicaid expansion in states that implemented expansions with states that didn't. Medicaid expansions improve access to outpatient treatment and have the potential to reduce opioid-related hospital use.

Authors: Aparna Soni, Ph.D., of American University in Washington, D.C., is the corresponding author.

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

(doi:10.1001/jamainternmed.2020.0473)

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

The Wasan Laboratory in the Faculty of Pharmaceutical Sciences at the University of British Columbia in partnership with iCo Therapeutics Inc. (Vancouver BC, Canada) have developed a novel oral formulation of Amphotericin B to treat systemic fungal and parasitic infections. Amphotericin B is a polyene macrolide antibiotic used in the treatment of blood borne fungal infections such as candidiasis and aspergillosis and parasitic infections such as visceral leishmaniasis. However, its effectiveness has been limited by dose-dependent nephrotoxicity, drug formulation costs, patient medication adherence and parenteral administration, which is not always accessible, costly and has additional toxicities associated with this route of administration. The rationale for the development of an oral amphotericin B formulation was that it could help overcome the aforementioned limitations by being less nephrotoxic, cost-effective, improve patient drug adherance and eliminate parenteral administration-associated costs and toxicities. The Wasan lab conducted in vitro cell culture studies and various animal studies to identify a lead formulation for clinical development. This lead formulation has recently successfully completed phase 1b human clinical trials and will start on phase 2 human clinical trials in comparing Oral Amp B to fluconazole in a head-to-head study in vulvovaginal candidiasis later in 2020. As noted in iCo Therapeutics recent press release Dr. Kishor Wasan, co-inventor of the Oral Amp B technology and Amphotericin B expert, noted that "traditionally Amphotericin B has been limited by an intravenous (IV) route of administration and limited therapeutic window. The impressive safety profile of Oral Amp B addresses one of two such limitations. I look forward to the initiation of a Phase 2 study in the near future which will investigate the efficacy of an oral version of Amphotericin B versus current standard of care, potentially addressing the second limitation of the current generic IV version of the drug."

All print, broadcast and online journalists who receive the Obesity embargo alert agree to abide by the embargo and may not publish, post, broadcast or distribute embargoed news releases or details of the embargoed studies before the embargo date and time.

When writing about these studies, journalists are asked to attribute the source as the journal Obesity and to include the online link to the Obesity articles as provided below. Links become active when articles post at 3:00 a.m. (EST) on March 23, 2020, unless indicated differently below.

Editors' Choice 1 -How Does Mental Health Influence Surgery Selection and Outcomes?, Michael D. Morledge and Walter J. Pories, poriesw@ecu.edu
(http://onlinelibrary.wiley.com/doi/10.1002/oby.22752)

Editors' Choice 2 - Highly Selective SGLT2 Inhibitor in Patients with Obesity, T2DM, Steven B. Heymsfield, Annaswamy Raji, Silvina Gallo, Jie Liu, Annpey Pong, Hakima Hannachi, and Steven G. Terra, steven.g.terra@pfizer.com
(http://onlinelibrary.wiley.com/doi/10.1002/oby.22748)

Editors' Choice 3 -New Meta-Analysis on Antibiotics During Pregnancy and Infancy, Shengrong Wan, Man Guo, Ting Zhang, Qing Chen, Maoyan Wu, Fangyuan Teng, Yang Long, Zongzhe Jiang, Jiangzongzhe555@126.com, and Yong Xu, xywyll@aliyun.com (http://onlinelibrary.wiley.com/doi/10.1002/oby.22747) - already online

Editors' Choice 4 -Biobehavioral Regulation and Childhood Growth Trajectories, Lori A. Francis, laf169@psu.edu, Brandi Y. Rollins, Crystal I. Bryce, and Douglas A. Granger
(http://onlinelibrary.wiley.com/doi/10.1002/oby.22762)

ADDITIONAL EMBARGOED RESEARCH

Incidence of Depression and First-line Antidepressant Therapy in People with Obesity and Depression in Primary Care, Freya Tyrer, fct2@le.ac.uk, Francesco Zaccardi, Kamlesh Khunti, and Richard Moriss - embargo lifts April 8 at 3:00 a.m. (EST)

Scroll down to find abstracts for each of the above papers. To request the full text of any of these studies and agree to the embargo policy, or to arrange an interview with a study's author or an obesity expert, please contact communications@obesity.org.

Editors’ Choice Abstracts

Editors’ Choice 1 – Mental Health in Bariatric Surgery: Selection, Access, and Outcomes

Severe obesity has many psychiatric consequences that can be influenced by bariatric surgery. The goal of this article is to review these challenges, including the mental health status of patients with severe obesity, the evaluation of surgical candidates, and the early and late effects of the operations, and to offer some recommendations to manage these challenges. The failure of the insurance-mandated preoperative psychosocial evaluation is also discussed.

Editors’ Choice 2 – Efficacy and Safety of Ertugliflozin in Patients with Overweight and Obesity with Type 2 Diabetes Mellitus

Objective: This study aimed to evaluate ertugliflozin in patients with overweight and obesity with type 2 diabetes mellitus.

Methods: Data from three placebo-controlled, randomized, Phase 3 studies were pooled. Patients with baseline BMI ≥ 25 (1,377/1,544; 89%) were assessed with a stratification by BMI subgroup.

Results: At week 26, reductions from baseline in glycated hemoglobin A1c (HbA1c), fasting plasma glucose, body weight (BW), and systolic blood pressure (SBP) were greater with ertugliflozin versus placebo. For placebo, ertugliflozin 5 mg, and ertugliflozin 15 mg, respectively, least squares mean change was 0.1%, −0.8%, and −0.9% for HbA1c and −1.2 kg, −3.1 kg, and −3.2 kg for BW. HbA1c reductions were consistent across BMI subgroups. For ertugliflozin 5 mg and 15 mg, least squares mean change (placebo adjusted) in absolute BW was −1.4 kg and −1.2 kg for BMI 25 to Conclusions: Meaningful reductions in HbA1c, fasting plasma glucose, BW, and SBP were observed with ertugliflozin in patients with overweight and obesity with type 2 diabetes mellitus. Ertugliflozin improved HbA1c and SBP and reduced BW across BMI subgroups. Ertugliflozin was generally well tolerated.

Editors’ Choice 3 – Impact of Exposure to Antibiotics During Pregnancy and Infancy on Childhood Obesity: A Systematic Review and Meta-Analysis

Objective: This study aimed to investigate whether antibiotic exposure during pregnancy and infancy was associated with childhood overweight or obesity.

Methods: PubMed, Embase, and Cochrane Library databases were searched from the inception date to April 18, 2019, to identify observational studies that investigated the association between antibiotic exposure during pregnancy and infancy and childhood overweight or obesity. After study selection and data extraction, the meta-analysis was conducted using Stata software version 12.0 (StataCorp LP, College Station, Texas). The evaluation of the methodological quality was carried out by AMSTAR 2 (Bruyère Research Institute, Ottawa, Ontario, Canada).

Results: A total of 23 observational studies involving 1,253,035 participants were included. The meta-analysis showed that prenatal exposure to antibiotics was not significantly associated with childhood overweight or obesity, whereas an increased risk of overweight or obesity was seen in subgroup analysis of the second trimester (risk ratio = 1.13; 95% CI: 1.06-1.22; P = 0.001). In contrast, antibiotic exposure during infancy could increase the risk of childhood overweight or obesity (risk ratio = 1.14; 95% CI: 1.06-1.23; P = 0.001).

Conclusions: This meta-analysis found that antibiotic exposure during the second trimester and infancy could increase the risk of childhood overweight or obesity.

Editors’ Choice 4 – Biobehavioral Dysregulation and its Association with Obesity and Severe Obesity Trajectories from 2 to 15 Years of Age: A Longitudinal Study

Objective: This study aimed to identify obesity trajectories from childhood to adolescence (2-15 years of age) and investigate differences in behavioral, eating, and adrenocortical regulation by trajectory membership.

Methods: A total of 1,077 households from the National Institute of Child Health and Human Development Study of Early Child Care and Youth Development were included. Anthropometrics were measured 11 times between ages 15 months and 15 years. Behavioral self-regulation was assessed at ages 3 and 4 years. Disordered eating behaviors and awakening cortisol were assessed at age 15 years.

Results: Latent growth curve modeling identified four BMI trajectories: two nonoverweight trajectories based on average BMI at the 40th and 70th percentiles and overweight/obesity and severe obesity trajectories. Youth in the severe obesity trajectory exhibited lower behavioral self-regulation in early childhood and lower awakening cortisol at age 15 years compared with youth in the nonoverweight trajectories. Youth in the overweight/obesity and severe obesity trajectories showed higher levels of disordered eating behaviors at age 15 years.

Conclusions: Obesity trajectories were associated with biobehavioral markers of dysregulation in early childhood and adolescence. Dysregulation across biobehavioral domains was particularly apparent among youth who developed severe obesity. Further work is needed to better understand resilience factors that distinguish youth who develop obesity and severe obesity from those who do not.

ADDITIONAL EMBARGOED RESEARCH

Incidence of Depression and First‐line Antidepressant Therapy in People with Obesity and Depression in Primary Care

Objective: The aim of this study was to describe age‐ and gender‐specific incidence of depression, the dose‐response relationship between BMI and risk of depression (Cox proportional hazards), and antidepressant drug prescribing in adults who have overweight or obesity.

Methods: A retrospective electronic health record study using the Clinical Practice Research Datalink was conducted to identify adults with overweight and obesity (≥ 18 years) with incident depression (no prior depression diagnosis in their records), followed up from 2000 to 2019.

Results: Among 519,513 adults, incidence of depression was 9.2 per 1,000 person‐years and was higher in women and in 40‐ to 59‐year‐old men who had severe obesity. Compared with having overweight, the hazard of depression increased with each BMI category as follows: 1.13 (30‐34 kg/m2; 95% CI: 1.10‐1.16), 1.34 (35‐39 kg/m2; 1.29‐1.40), 1.51 (40‐44 kg/m2; 1.41‐1.61), and 1.67 (45‐49 kg/m2; 1.48‐1.87), attenuating at BMI 50+ kg/m2 (1.54; 2.91‐1.84). Antidepressants were prescribed as first‐line therapy in two‐thirds (66.3%) of cases. Prescriptions for fluoxetine reduced over time (20.4% [2000]; 8.8% [2018]), and prescriptions for sertraline increased (4.3% [2000]; 38.9% [2018]).

Conclusions: We recommend guidance on antidepressant drug prescribing and specific services for people with obesity and depression that address both symptoms and behaviors.

Journal

Obesity

Below please find link(s) to new coronavirus-related content published today in Annals of Internal Medicine. All coronavirus-related content published in Annals of Internal Medicine is free to the public. A complete collection is available at https://annals.org/aim/pages/coronavirus-content.

Supporting Clinicians During the COVID-19 Pandemic
Charlene Dewey, MD, Med; Susan Hingle, MD; Elizabeth Goelz, MD; Mark Linzer, MD
Ideas & Opinions
Abstract: http://annals.org/aim/article/doi/10.7326/M20-1033

Media contact: To speak with lead author, Charlene Dewey, MD, Med, please contact Wayne Wood at wayne.wood@vumc.org.

New Rochelle, NY, March 20, 2020--Key factors must be taken into account in determining the need for and allocation of scarce ventilators during a severe pandemic, especially one causing respiratory illness. Strategies to help state and local planners in allocating stockpiled ventilators to healthcare facilities, including pre-pandemic actions and actions to be taken during the pandemic, are detailed in a timely article published in Health Security, a peer-reviewed journal from by Mary Ann Liebert, Inc., publishers. Click here to read the full-text article free on the Health Security website.

Lisa Koonin, Health Preparedness Partners, and colleagues from the Centers for Disease Control and Prevention (Atlanta, GA), coauthored the article entitled "Strategies to Inform Allocation of Stockpiled Ventilators to Healthcare Facilities During a Pandemic." Prior to a pandemic, planners should determine existing inventories and facilities' ability to make use of additional ventilators in the event of a public health emergency. This information needs to be updated at the time of a pandemic. Determining where to allocate stockpiled ventilators should be based on an assessment of need, the consideration of ethical principles discussed in the article, the ability of facilities to absorb additional ventilators, and the ability to ensure access to ventilators for vulnerable or high-risk populations.

"Ventilators will be pivotal to saving countless lives in this COVID pandemic. Understanding CDC's plans and recommendations for state and local planners around ventilator management in this kind of crisis will be key for helping them make decisions under very difficult conditions," says Editor-in-Chief Thomas V. Inglesby, MD, Director, Johns Hopkins Center for Health Security, Baltimore, MD.

Oncotarget Volume 11, Issue 11 reported that at clinical progression, 64 EGFR T790M plasma positive patients were subjected to second line-treatment with osimertinib and strictly monitored during the first month of therapy.

Plasma analysis by the EGFR Cobas test showed in 57 cases a substantial decrease in the levels of the sensitizing EGFR mutant allele, down to a not detectable value.

The research team's data indicate that plasma monitoring by a simple RT-PCR-based EGFR mutation test in the first month of treatment may be useful for a rapid identification of patients to be subjected to further characterization by MPS.

Dr. Antonio Marchetti from the Laboratory of Diagnostic Molecular Oncology, Center for Advanced Studies and Technology (CAST) and The Department of Medical and Oral Sciences and Biotechnologies at the University of Chieti as well as The Department of Pathology, SS Annunziata Clinical Hospital said, "In Non-Small-Cell Lung Cancer (NSCLC) patients treated with Tyrosine Kinase-Inhibitors (TKIs) therapy, the emergence of acquired resistance can be investigated by plasma monitoring of circulating tumor DNA (ctDNA)"

"In Non-Small-Cell Lung Cancer (NSCLC) patients treated with Tyrosine Kinase-Inhibitors (TKIs) therapy, the emergence of acquired resistance can be investigated by plasma monitoring of circulating tumor DNA (ctDNA)"

- Dr. Antonio Marchetti, Laboratory of Diagnostic Molecular Oncology, Center for Advanced Studies and Technology (CAST), The Department of Medical and Oral Sciences and Biotechnologies at the University of Chieti, & The Department of Pathology, SS Annunziata Clinical Hospital

Several studies have shown a high concordance between the presence of EGFR mutations in tissue and plasma, especially in patients with diffuse metastatic disease.

In a previous study, the authors have shown for the first time that NSCLC patients carrying EGFR mutations in tumor tissue and subjected to first-line treatment with EGFR TKIs, can be strictly monitored in the first days of treatment by repeated blood draws to quantify EGFR mutant alleles in plasma.

These results strongly suggest that the amount of EGFR sensitizing mutations in plasma reflects the tumor burden and that the fluctuations in the levels of EGFR sensitizing mutations in plasma are closely related to tumor load variations.

However, after a medium period of about 12 months, even patients subjected to second-line treatment with osimertinib, develop resistance with various mechanisms, including EGFR SNV, MET, and HER2 amplification, genetic fusions, etc. Recently, a series of clinical trials led to the approval of first-line treatment of EGFR-positive NSCLC patients with osimertinib.

The Marchetti Research Team concluded in their Oncotarget Research paper, "our results indicate that a subset of NSCLC patients subjected to second-line treatment with osimertinib are resistant to treatment due to the presence of different types of mutations. Plasma monitoring by a simple RT-PCR-based EGFR mutation test in the first month of treatment may be useful to rapidly identify these cases and subject them to MPS analysis for further characterization and treatment."

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DOI - https://doi.org/10.18632/oncotarget.27517

Full text - http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=27517&path[]=90092

Correspondence to - Antonio Marchetti - amarchetti@unich.it

Keywords -
epidermal growth factor receptor (EGFR),
tyrosine-kinase Inhibitors,
circulating tumor-DNA (ct-DNA),
massive parallel sequencing (MPS),
resistance-inducing mutation

About Oncotarget

Oncotarget is a weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology.

To learn more about Oncotarget, please visit http://www.oncotarget.com or connect with:

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Media Contact
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Journal

Oncotarget

DOI

10.18632/oncotarget.27517

Cambridge, MA--In a visible sign of data sharing leadership, Vivli, the Center for Clinical Research Da,ta has committed to serving the open science community through the launch of a COVID-19 portal for sharing of completed interventional treatment trial data. All member and user fees would be waived for sharing and access.

"Today, we are announcing this initiative as it is so important for the entire data sharing community to come together and do everything we can to share the data from these completed clinical trials," said Rebecca Li, Vivli Executive Director. "Sharing data transparently and openly is the best way to honor the decisions made by participants in these trials and bring us closer to safe and effective treatments and vaccines."

Vivli co-founder, UCSF professor and lead author of a Science article published today that advocates for more open data sharing by the NIH echoed these concerns.

"Vivli has been at the forefront of data sharing and I am delighted to see us do all that we can to advance the knowledge around the COVID-19 pandemic," Sim said. "Vivli was created to make data sharing practical and easy to do. COVID-19 trials should be made open to all researchers so that no stone is left unturned in reviewing and analyzing the data."

The new article, published in the Policy Forum section of Science by Vivli and key data transparency leaders advocates for additional changes and enhancements to strengthen the current draft NIH Data Sharing Policy. In the piece the authors recommend, "Specific, practical, and implementable NIH policies can help transform academic culture and practice toward routine data sharing."

Researchers at the University of East Anglia have discovered why some prostate cancers are more aggressive, spread to different parts of the body, and ultimately cause death.

It is hoped that the discovery, published today, could transform patient treatment.

The findings come after the same team developed a test that distinguishes between aggressive and less harmful forms of prostate cancer, helping to avoid sometimes-damaging unnecessary treatment.

The new study shows how the number of 'aggressive' cells in a tumour sample defines how quickly the disease will progress and spread.

The findings also reveal three new subtypes of prostate cancer that could be used to stratify patients for different treatments.

Lead researcher Prof Colin Cooper, from UEA's Norwich Medical School, said: "Prostate cancer is the most common cancer in men in the UK. It usually develops slowly and the majority of cancers will not require treatment in a man's lifetime. However, doctors struggle to predict which tumours will become aggressive, making it hard to decide on treatment for many men.

"This means that many thousands of men are treated unnecessarily, increasing the risk of damaging side effects, including impotence from surgery."

The team developed a test to distinguish aggressive prostate cancers from less threatening forms of the disease, by applying some complex maths known as Latent Process Decomposition.

Collaborator Prof Vincent Moulton, from UEA's School of Computing Sciences, said: "By applying the Latent Process Decomposition process and analysing global prostate cancer datasets, we discovered an aggressive form of prostate cancer known as DESNT - which has the worst clinical outcomes for patients."

In the latest study, published today, the team studied gene expression levels in 1,785 tumour samples. They found that the amount of DESNT subtype cells in a sample is linked with the likelihood of disease progression - the more DESNT cells, the quicker the patient is likely to progress.

Co-lead researcher Dr Daniel Brewer said: "If you have a tumour that is majority DESNT you are more likely to get metastatic disease, in other words it is more likely to spread to other parts of your body. This is a much better indication of aggressive disease.

"We also identified three more molecular subtypes of prostate cancer that could help doctors decide on different treatment options for patients.

"This research highlights the importance of using more complex approaches for the analysis of genomic data," he added.

One of the last arrows in the quiver in the fight against dangerous bacteria is the reserve antibiotic daptomycin. It is used primarily when conventional drugs fail due to resistant bacteria. Although the antibiotic was developed around 30 years ago, its exact mode of action was previously unclear. Scientists at the University of Bonn have now deciphered the puzzle: Daptomycin blocks the integration of important building blocks into the cell wall of the pathogens, thereby killing the bacteria. The results have now been published in the journal Nature Communications.

When it comes to bacterial infections, antibiotics are the medical weapons of choice - but they are becoming increasingly blunt. The number of resistances is increasing, which is why many antibiotics are no longer effective against the dangerous pathogens. Some of these active substances are intended for particularly severe infections with resistant bacteria. One example is daptomycin, which was launched in the USA in 2003 and in Germany in 2006. It is used for the treatment of infections with methicillin-resistant Staphylococcus aureus (MRSA) and resistant enterococci.

"Although daptomycin was discovered around 30 years ago, the exact mode of action remained elusive until now," explains Prof. Dr. Tanja Schneider from the Institute of Pharmaceutical Microbiology at the University of Bonn and the German Center for Infection Research (DZIF). There were different theories on how this antibiotic attacks and kills bacteria. One of them was that daptomycin perforates the bacterial envelope and leads to a potassium efflux that ends with the death of the bacterium. "Nobody understood how daptomycin actually works," says Dr. Anna Müller, one of the lead authors from Prof. Schneider's research group.

Interdisciplinary research team

The interdisciplinary team from the fields of medicine, pharmacology and physical chemistry used a wide variety of scientific methods to discover the antibiotic's mode of action. The researchers first labelled daptomycin with a fluorescent dye that glows green. This enabled them to follow exactly where the antibiotic docks to the staphylococcal cells under the high-resolution microscope. "Daptomycin binds to the bacteria in regions where the new cell wall is just being synthesized," said Dr. Fabian Grein, another lead author and colleague of Prof. Schneider.

Like in a construction kit, the bacterial cell wall is assembled from numerous building blocks. Further analyses carried out by the researchers on staphylococci and synthetically produced bacterial walls showed that two of these building blocks in particular are hugely important for the effect of daptomycin: the central cell wall building block "lipid II" and the membrane lipid phosphatidylglycerol (PG). "The combination of lipid II and PG together is the Achilles' heel of the bacteria," says Schneider. This is exactly where daptomycin comes into play: The antibiotic captures these important building blocks and blocks the further construction of the cell wall. As a result, the bacterial cell wall becomes unstable resulting in the outflow of various ions, including potassium. "The outflow of ions is not the actual killing mechanism of daptomycin, as originally thought, but a consequence of bacterial cell death," concludes Schneider.

"We were able to show how daptomycin really works and to which molecular target structures it docks," comments Prof. Dr. Ulrich Kubitscheck from the Department of Biophysical Chemistry at the University of Bonn. This is an important prerequisite for the further optimization of daptomycin. Since new active substances cannot be developed to the desired extent to fight antibiotic resistance, researchers are focusing on combination therapies using different active substances. "The strategy is to target already resistant bacteria with differently acting weapons," says Prof. Schneider. However, this would only work if the mode of action and targets of the antibiotics are known.

The study was conducted in the Transregional Collaborative Research Center TRR261 "Antibiotic CellMap - Cellular Mechanisms of Antibiotic Action and Production" located at the Universities of Bonn and Tübingen and funded by the German Research Foundation (DFG). The German Center for Infection Research is also involved. "It was only through this transdisciplinary cooperation that we were able to take the decisive step forward and solve a puzzle that science has been mulling over for 30 years," says Schneider.

Bottom Line: Using standard-of-care computed tomography (CT) scans in patients with advanced non-small cell lung cancer (NSCLC), researchers utilized artificial intelligence (AI) to train algorithms to predict tumor sensitivity to three systemic cancer therapies.

Journal in Which the Study was Published: Clinical Cancer Research, a journal of the American Association for Cancer Research

Author: Laurent Dercle, MD, PhD, associate research scientist in the Department of Radiology at the Columbia University Irving Medical Center

Background: "Radiologists' interpretation of CT scans of cancer patients treated with systemic therapies is inherently subjective," said Dercle. "The purpose of this study was to train cutting-edge AI technologies to predict patients' responses to treatment, allowing radiologists to deliver more accurate and reproducible predictions of treatment efficacy at an early stage of the disease."

To determine if patients with NSCLC are responding to systemic therapy, radiologists currently quantify changes in tumor size and the appearance of new tumor lesions, Dercle explained. However, this type of evaluation can be limited, especially in patients treated with immunotherapy, who can display atypical patterns of response and progression, he noted. "Newer systemic therapies prompt the need for alternative metrics for response assessment, which can shape therapeutic decision-making," Dercle said.

How the Study was Conducted and Results: Dercle and colleagues utilized data from multiple phase II/phase III clinical trials that evaluated systemic treatment in patients with NSCLC. These patients were treated with one of three agents: the immunotherapeutic agent nivolumab (Opdivo), the chemotherapeutic agent docetaxel (Taxotere), or the targeted therapeutic gefitinib (Iressa). The researchers retrospectively analyzed standard-of-care CT images from 92 patients receiving nivolumab in two trials; 50 patients receiving docetaxel in one trial; and 46 patients receiving gefitinib in one trial.

To develop the model, the researchers used the CT images taken at baseline and on first-treatment assessment (three weeks for patients treated with gefitinib; eight weeks for patients treated with either nivolumab or docetaxel). Tumors were classified as treatment-sensitive or treatment-insensitive based on the reference standard of each trial (median progression-free survival in the nivolumab and docetaxel cohorts; analysis of surgical specimen following gefitinib treatment). Among all three cohorts, patients were randomized into training or validation groups.

The researchers used machine learning to develop a multivariable model to predict treatment sensitivity in the training cohort. Each model could predict a score ranging from zero (highest treatment sensitivity) to one (highest treatment insensitivity) based on the change of the largest measurable lung lesion identified at baseline.

Because the gefitinib cohort had a limited number of patients, the researchers built and validated a model using a cohort of metastatic colorectal cancer patients (302 individuals) treated with anti-EGFR therapies. The radiologic features to predict treatment sensitivity identified in the colorectal cancer cohort were then used to build a model in the training cohort of patients with NSCLC treated with gefitinib.

Across all cohorts, a total of eight radiologic features were used to build the three prediction models. These features included changes in tumor volume, heterogeneity, shape, and margin. Both the nivolumab and gefitinib models used four radiologic features, and the docetaxel model used one.

The performance of each signature was evaluated by calculating the area under the curve (AUC), a measure of the model's accuracy, where a score of 1 corresponds to perfect prediction. The nivolumab, docetaxel, and gefitinib prediction models achieved an AUC of 0.77, 0.67, and 0.82 in the validation cohorts, respectively.

Author's Comments: "We observed that similar radiomics features predicted three different drug responses in patients with NSCLC," Dercle said. "Further, we found that the same four features that identified EGFR treatment sensitivity for patients with metastatic colorectal cancer could be utilized to predict treatment sensitivity for patients with metastatic NSCLC."

Dercle noted that radiomic signatures offer the potential to enhance clinical decision-making. "With AI, cancer imaging can move from an inherently subjective tool to a quantitative and objective asset for precision medicine approaches," he said.

Study Limitations: Limitations of the study include the small sample size. "Because AI can continuously learn from real-world data, using AI on larger patient datasets will help us to identify new patterns to build more accurate prediction models," noted Dercle.

Philadelphia, March 19, 2020 - In the United States today, healthcare providers seem appropriately confused about present and future issues concerning coronavirus disease 2019 (COVID-19). In a commentary in The American Journal of Medicine, published by Elsevier, internationally recognized public health experts say that the current, incomplete totality of evidence provides cause for serious concerns, but more importantly it creates an urgent need for public health leadership that can direct the country's response with neither reassurance nor alarm.

"Based on the existing incomplete totality of evidence, it appears that coronavirus is comparable in communicability to influenza but with perhaps a 10 fold higher case fatality rate," said lead author Charles H. Hennekens, MD, DrPH, First Sir Richard Doll Professor & Senior Academic Advisor to the Dean at Florida Atlantic University, Charles E. Schmidt College of Medicine, Boca Raton, FL, USA.

In the flu season from 2018 to 2019, about 42.9 million Americans were clinical cases, of which 647,000 were hospitalized and about 61,200 died. If the epidemic continues to propagate in the US in a similar fashion, there may be 612,000 deaths and perhaps millions of hospitalizations. This staggering estimate of number of hospitalizations could paralyze the US healthcare delivery system.

Professor Dennis Maki, MD, Professor of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA, and senior author stated further, "Public health considerations should govern everything we do during this pandemic, not political expediency."

From influenza to smallpox, the authors write, the systematic collection, consolidation, and dissemination of data to all who need to know, along with robust surveillance systems, were critical factors in the control of pandemics. They cite the example of the collaboration between Alexander D. Langmuir, MD, who directed epidemiologic programs at the Centers for Disease Control and Prevention (CDC), and Donald A. Henderson, who was the chief of Virus Disease Control at CDC. Over just slightly more than a decade, and during the tenures of four Presidents - Kennedy, Johnson, Nixon, and Ford - these public health experts led both American and worldwide efforts that resulted in smallpox being the first human disease ever eradicated from earth. Both Dr. Hennekens and Dr. Maki trained under Dr. Langmuir and Dr. Henderson as Lieutenant Commanders in the United States Public Health Service Commissioned Corps (USPHS) serving as Epidemic Intelligence Service (EIS) Officers with the CDC.

The authors emphasized that collegial and collaborative multifactorial preventive and therapeutic measures in the US and throughout the world are warranted to control the COVID-19 pandemic. As to who should lead this effort, the authors have a recommendation. "We believe Anthony S. Fauci, MD, Director of the United States National Institute of Allergy and Disease, is the Babe Ruth of virology in general and influenza in particular. His proven capacity and capability for collaborative expert leadership to guide the US and the world through this pandemic and to ensure our preparedness for the challenges ahead would be beneficial to all."

A new study has provided the most comprehensive analysis of human genetic diversity to date, after the sequencing of 929 human genomes by scientists at the Wellcome Sanger Institute, the University of Cambridge and their collaborators. The study uncovers a large amount of previously undescribed genetic variation and provides new insights into our evolutionary past, highlighting the complexity of the process through which our ancestors diversified, migrated and mixed throughout the world.

The resource, published in Science (20 March), is the most detailed representation of the genetic diversity of worldwide populations to date. It is freely available to all researchers to study human genetic diversity, including studies of genetic susceptibility to disease in different parts of the world.

The consensus view* of human history tells us that the ancestors of present-day humans diverged from the ancestors of extinct Neanderthal and Denisovan groups around 500,000-700,000 years ago, before the emergence of 'modern' humans in Africa in the last few hundred thousand years.

Around 50,000-70,000 years ago, some humans expanded out of Africa and soon after mixed with archaic Eurasian groups. After that, populations grew rapidly, with extensive migration and mixture as many groups transitioned from hunter-gatherers to food producers over the last 10,000 years.

This study is the first to apply the latest high-quality sequencing technology to such a large and diverse set of humans, covering 929 genomes from 54 geographically, linguistically and culturally diverse populations from across the globe. The sequencing and analysis of these genomes, which are part of the Human Genome Diversity Project (HGDP)-CEPH panel**, now provides unprecedented detail of our genetic history.

The team found millions of previously unknown DNA variations that are exclusive to one continental or major geographical region. Though most of these were rare, they included common variations in certain African and Oceanian populations that had not been identified by previous studies.

Variations such as these may influence the susceptibility of different populations to disease. However, medical genetics studies have so far predominantly been conducted in populations of European ancestry, meaning that any medical implications that these variants might have are not known. Identifying these novel variants represents a first step towards fully expanding the study of genomics to underrepresented populations.

However, no single DNA variation was found to be present in 100 per cent of genomes from any major geographical region while being absent from all other regions. This finding underlines that the majority of common genetic variation is found across the globe.

Dr Anders Bergström, of the Francis Crick Institute and an alumnus of the Wellcome Sanger Institute, said: "The detail provided by this study allows us to look deeper into human history, particularly inside Africa where less is currently known about the timescale of human evolution. We find that the ancestors of present-day populations diversified through a gradual and complex process mostly during the last 250,000 years, with large amounts of gene flow between these early lineages. But we also see evidence that small parts of human ancestries trace back to groups that diversified much earlier than this."

Hélène Blanché, Head of the Biological Resource Centre at the Centre d'Etude du Polymorphisme Humain (CEPH) in Paris, France, said: "The Human Genome Diversity Project resource has facilitated many new discoveries about human history in the past two decades. It is exciting to see that with the latest genomic sequencing technology, these genomes will continue to help us understand our species and how we have evolved."

The study also provides evidence that the Neanderthal ancestry of modern humans can be explained by just one major 'mixing event', most likely involving several Neanderthal individuals coming into contact with modern humans shortly after the latter had expanded out of Africa. In contrast, several different sets of DNA segments inherited from Denisovans were identified in people from Oceania and East Asia, suggesting at least two distinct mixing events.

The discovery of small amounts of Neanderthal DNA in west African people, most likely reflecting later genetic backflow into Africa from Eurasia, further highlights how human genetic history is characterised by multiple layers of complexity. Until recently, it was thought that only people outside sub-Saharan Africa had Neanderthal DNA.

Dr Chris Tyler-Smith, recently retired from the Wellcome Sanger Institute, said: "Though this resource is just the beginning of many avenues of research, already we can glimpse several tantalising insights into human history. It will be particularly important for better understanding human evolution in Africa, as well as facilitating medical research for the full diversity of human ancestries."