Body

An anticancer drug of fungal origin could be the way.

Scientists at Waseda University succeeded in developing a method for a total synthesis of cotylenin A, a plant growth regulator which has attracted considerable attention from the scientific community due to its promising bioactivity as an anti-cancer agent. This method was reported in the Journal of the American Chemical Society on March 16, 2020.

"Our method will be able to provide steady supply of cotylenin A, which could possibly lead to the development of an effective anticancer drug," says Masahisa Nakada, a professor of synthetic chemistry at Waseda University in Tokyo, Japan and corresponding author of this study.

Nakada believes that this is the world's first total synthesis of cotylenin A to ever be reported.

Previous biological studies have revealed that cotylenin A combined in treatment can program cell death for a wide range of human cancer cell lines and suppress tumor growth. In addition, cotylenin A was found to induce the differentiation of myeloid leukemia cells when combined with a specific pharmaceutical drug.

Despite its potential, producing cotylenin A from natural resources is not possible because the fungus which produces cotylenin A loses all its ability to proliferate during preservation, which would create a dearth of supply. Also, cotylenin A has a complex structure where two carbocyclic five-membered rings are fused with a formidable carbocyclic eight-membered ring with a uniquely-structured, glucose-based sugar attached. Chemically synthesizing a carbocyclic eight-membered ring is known to be difficult, and because the carbocyclic ring system includes a number of functional groups such as moieties, these features have made it challenging for scientists in the field to artificially synthesize cotylenin A.

"What we did in our method was to separate the structure of cotylenin A into three fragments," Nakada explains. "Each fragment was then prepared with commercially-available chemical compounds using different reactions, such as a catalytic asymmetric intramolecular cyclopropanation (CAIMCP) developed by us. Afterwards, we assembled the two fragments back together using a coupling reaction, followed by a cyclization of the carbocyclic eight-membered ring which was mediated by the chemical element palladium and a coupling with the sugar-part fragment which was catalyzed by the chemical element rhodium." He adds, "The total synthesis took about 25 steps, and our synthesized product is identical to those of naturally occurring cotylenin A."

Nakada says that his team has now succeeded in achieving this synthesis in only 20 steps, and by further reducing the number of steps, producing an adequate amount of cotylenin A will become possible. He hopes that the method they developed will contribute to further biological studies of cotylenin A and to the discovery of an anticancer drug that exhibits stronger anticancer activity and causes no side effects by modifying cotylenin A, as well as to the application for a total artificial synthesis of various compounds in the future.

For normal gut and body function, the diet should contain sufficient amounts of (at least 25 - 35 grams of) various (a variety of )dietary fibres. Fibres are a type of carbohydrates forming a big group of molecules of very different structures and sizes that have different functions in our body.

In their recent study, the Center of Food and Fermentation Technologies in cooperation with the National Institute for Health Development and scientists of the Microbiomics Research Group from TalTech Department of Chemistry and Biotechnology analyzed the links between the dietary fibres in common Estonian diet, the body mass index, the content of blood lipids and the faecal microbiota.

The head of the research carried out by the Center of Food and Fermentation Technologies, Senior Researcher of TalTech Division of Food Technology, Kaarel Adamberg says, "The volunteers participating in the study filled out a food frequency questionnaire and completed dietary records in the days prior to the analysis. The blood and fecal samples collected at the beginning and end of the two months study. The goal was to map Estonians' eating habits in more detail, with a focus on fibre intake."

A significant innovation compared to the previous dietary studies was that the fibres were divided into seven categories to differentiate the variety of fibre profiles consumed. The categories were based on the chemical composition of fibres that require similar enzymes for degradation. The categories were as follows: the fructans, pectins, arabinoxylans, beta-glucan, lignin, cellulose, and others. In addition, the content of other nutrients in the daily diets was analyzed on the basis of the dietary records.

Kaarel Adamberg says, "Our findings confirmed the results of a previous survey conducted by the National Institute for Health Development indicating that Estonians eat less fibre than recommended in the dietary guidelines (a daily intake of dietary fibre of 25-35 g, i. e. at least 13 grams per 1000kcal). Categorizing of the fibres helped us to determine the fibres and the related foods that are most often absent or underrepresented in the common diets."

Based on the total fibre intake, the study subjects were divided into high and low fibre intake groups, with intakes of above 30 grams and below 19 grams per day (normalized for a 2000 kcal diet) respectively. Several differences were seen between these groups, in particular the fact that the average body mass index (BMI) of the high fibre intake group was lower than that of the subjects of the low fibre intake.

In high fibre diets the main sources of fibres were arabinoxylan rich cereals (such as rye and whole wheat), fruit (especially apples), β-glucan rich oats and pectin and cellulose rich vegetables (carrots, cabbages). Bacteria from the groups of Roseburia, Bacteroides xylanisolvens and Oxalobacter formigenes were found in the gut microbiota of people eating high fibre foods. In the low fibre intake group, however, the consumption of refined cereals (white bread), meat and confectionery products was considerably higher. The low-fibre diet contained proportionally more fructans, which is implied also by the characteristic composition of their gut bacteria dominated by Collinsella, Coprococcus and Dorea. These bacteria have been associated with overweight also in other studies and it is assumed that may be involved in the the activation of inflammatory processes in the gut.

"The study indicates that our eating habits are closely related to the composition of our faecal microbiota and health indicators and that a proper diet (e.g. high-fibre diet that provides the necessary dietary fibres) couldsupport health by improving the intestinal microbiota," Kaarel Adamberg says.

Machine learning and AI are highly unstable in medical image reconstruction, and may lead to false positives and false negatives, a new study suggests.

A team of researchers, led by the University of Cambridge and Simon Fraser University, designed a series of tests for medical image reconstruction algorithms based on AI and deep learning, and found that these techniques result in myriad artefacts, or unwanted alterations in the data, among other major errors in the final images. The effects were typically not present in non-AI based imaging techniques.

The phenomenon was widespread across different types of artificial neural networks, suggesting that the problem will not be easily remedied. The researchers caution that relying on AI-based image reconstruction techniques to make diagnoses and determine treatment could ultimately do harm to patients. Their results are reported in the Proceedings of the National Academy of Sciences.

"There's been a lot of enthusiasm about AI in medical imaging, and it may well have the potential to revolutionise modern medicine: however, there are potential pitfalls that must not be ignored," said Dr Anders Hansen from Cambridge's Department of Applied Mathematics and Theoretical Physics, who led the research with Dr Ben Adcock from Simon Fraser University. "We've found that AI techniques are highly unstable in medical imaging, so that small changes in the input may result in big changes in the output."

A typical MRI scan can take anywhere between 15 minutes and two hours, depending on the size of the area being scanned and the number of images being taken. The longer the patient spends inside the machine, the higher resolution the final image will be. However, limiting the amount of time patients spend inside the machine is desired, both to reduce the risk to individual patients and to increase the overall number of scans that can be performed.

Using AI techniques to improve the quality of images from MRI scans or other types of medical imaging is an attractive possibility for solving the problem of getting the highest quality image in the smallest amount of time: in theory, AI could take a low-resolution image and make it into a high-resolution version. AI algorithms 'learn' to reconstruct images based on training from previous data, and through this training procedure aim to optimise the quality of the reconstruction. This represents a radical change compared to classical reconstruction techniques that are solely based on mathematical theory without dependency on previous data. In particular, classical techniques do not learn.

Any AI algorithm needs two things to be reliable: accuracy and stability. An AI will usually classify an image of a cat as a cat, but tiny, almost invisible changes in the image might cause the algorithm to instead classify the cat as a truck or a table, for instance. In this example of image classification, the one thing that can go wrong is that the image is incorrectly classified. However, when it comes to image reconstruction, such as that used in medical imaging, there are several things that can go wrong. For example, details like a tumour may get lost or may falsely be added. Details can be obscured and unwanted artefacts may occur in the image.

"When it comes to critical decisions around human health, we can't afford to have algorithms making mistakes," said Hansen. "We found that the tiniest corruption, such as may be caused by a patient moving, can give a very different result if you're using AI and deep learning to reconstruct medical images - meaning that these algorithms lack the stability they need."

Hansen and his colleagues from Norway, Portugal, Canada and the UK designed a series of tests to find the flaws in AI-based medical imaging systems, including MRI, CT and NMR. They considered three crucial issues: instabilities associated with tiny perturbations, or movements; instabilities with respect to small structural changes, such as a brain image with or without a small tumour; and instabilities with respect to changes in the number of samples.

They found that certain tiny movements led to myriad artefacts in the final images, details were blurred or completely removed, and that the quality of image reconstruction would deteriorate with repeated subsampling. These errors were widespread across the different types of neural networks.

According to the researchers, the most worrying errors are the ones that radiologists might interpret as medical issues, as opposed to those that can easily be dismissed due to a technical error.

"We developed the test to verify our thesis that deep learning techniques would be universally unstable in medical imaging," said Hansen. "The reasoning for our prediction was that there is a limit to how good a reconstruction can be given restricted scan time. In some sense, modern AI techniques break this barrier, and as a result become unstable. We've shown mathematically that there is a price to pay for these instabilities, or to put it simply: there is still no such thing as a free lunch."

The researchers are now focusing on providing the fundamental limits to what can be done with AI techniques. Only when these limits are known will we be able to understand which problems can be solved. "Trial and error-based research would never discover that the alchemists could not make gold: we are in a similar situation with modern AI," said Hansen. "These techniques will never discover their own limitations. Such limitations can only be shown mathematically."

COLUMBUS, Ohio - Fatty food may feel like a friend during these troubled times, but new research suggests that eating just one meal high in saturated fat can hinder our ability to concentrate - not great news for people whose diets have gone south while they're working at home during the COVID-19 pandemic.

The study compared how 51 women performed on a test of their attention after they ate either a meal high in saturated fat or the same meal made with sunflower oil, which is high in unsaturated fat.

Their performance on the test was worse after eating the high-saturated-fat meal than after they ate the meal containing a healthier fat, signaling a link between that fatty food and the brain.

Researchers were also looking at whether a condition called leaky gut, which allows intestinal bacteria to enter the bloodstream, had any effect on concentration. Participants with leakier guts performed worse on the attention assessment no matter which meal they had eaten.

The loss of focus after a single meal was eye-opening for the researchers.

"Most prior work looking at the causative effect of the diet has looked over a period of time. And this was just one meal - it's pretty remarkable that we saw a difference," said Annelise Madison, lead author of the study and a graduate student in clinical psychology at The Ohio State University.

Madison also noted that the meal made with sunflower oil, while low in saturated fat, still contained a lot of dietary fat.

"Because both meals were high-fat and potentially problematic, the high-saturated-fat meal's cognitive effect could be even greater if it were compared to a lower-fat meal," she said.

The study is published in the American Journal of Clinical Nutrition.

Madison works in the lab of Janice Kiecolt-Glaser, professor of psychiatry and psychology and director of the Institute for Behavioral Medicine Research at Ohio State. For this work, Madison conducted a secondary analysis of data from Kiecolt-Glaser's study assessing whether high-fat meals increased fatigue and inflammation among cancer survivors.

Women in the study completed a baseline assessment of their attention during a morning visit to the lab. The tool, called a continuous performance test, is a measure of sustained attention, concentration and reaction time based on 10 minutes of computer-based activities.

The high-fat meal followed: eggs, biscuits, turkey sausage and gravy containing 60 grams of fat, either a palmitic acid-based oil high in saturated fat or the lower-saturated-fat sunflower oil. Both meals totaled 930 calories and were designed to mimic the contents of various fast-food meals such as a Burger King double whopper with cheese or a McDonald's Big Mac and medium fries.

Five hours later, the women took the continuous performance test again. Between one and four weeks later, they repeated these steps, eating the opposite meal of what they had eaten on the first visit.

Researchers also analyzed participants' fasting baseline blood samples to determine whether they contained an inflammatory molecule that signals the presence of endotoxemia - the toxin that escapes from the intestines and enters the bloodstream when the gut barrier is compromised.

After eating the meal high in saturated fat, all of the participating women were, on average, 11 percent less able to detect target stimuli in the attention assessment. Concentration lapses were also apparent in the women with signs of leaky gut: Their response times were more erratic and they were less able to sustain their attention during the 10-minute test.

"If the women had high levels of endotoxemia, it also wiped out the between-meal differences. They were performing poorly no matter what type of fat they ate," Madison said.

Though the study didn't determine what was going on in the brain, Madison said previous research has suggested that food high in saturated fat can drive up inflammation throughout the body, and possibly the brain. Fatty acids also can cross the blood-brain barrier.

"It could be that fatty acids are interacting with the brain directly. What it does show is the power of gut-related dysregulation," she said.

The statistical analysis accounted for other potential influences on cognition, including depressive symptoms and the participants' average dietary saturated fat consumption. The women in the study ate three standardized meals and fasted for 12 hours before each lab visit to reduce diet variations that could affect their physiological response to the high-fat meals.

The findings suggest concentration could be even more impaired in people stressed by the pandemic who are turning to fatty foods for comfort, Kiecolt-Glaser said.

"What we know is that when people are more anxious, a good subset of us will find high-saturated-fat food more enticing than broccoli," she said. "We know from other research that depression and anxiety can interfere with concentration and attention as well. When we add that on top of the high-fat meal, we could expect the real-world effects to be even larger."

A recent study from Turkey found that women's sexual desire and frequency of intercourse increased during the COVID-19 pandemic, but their quality of sexual life decreased. The findings are published in the International Journal of Gynecology & Obstetrics.

In the study of 58 women, women participated in sexual intercourse on average 2.4 times per week during the pandemic, compared with 1.9 times in the 6-12 months prior to the pandemic. Before the pandemic 32.7% of participants desired to become pregnant, compared with 5.1% during the pandemic; however, use of contraception decreased during the pandemic.

Menstrual disorders were more common during the pandemic than before (27.6% versus 12.1%), and participants generated worse scores on a questionnaire based on sexual function during the pandemic compared with scores before the pandemic.

What We Can Learn From Singapore's COVID-19 Containment Response in Primary Care

Singapore, a global hub for international travel and business, was among the first countries affected by the COVID-19 pandemic. With its first confirmed COVID-19 case on January 23, 2020, the country mounted aggressive public health and containment measures. The country's network of primary care clinics were at the front lines of these measures. In this new report, those physicians share their triage, containment and infection control measures--including protocols they put in place to ensure the safety of health care workers. At the time of writing the report, zero health care workers within their primary care network were infected with COVID-19. The authors describe the framework for how their primary care clinics responded to this pandemic in the hope others may find solutions to their unique needs."

COVID-19: Notes From the Front Line, Singapore's Primary Health Care Perspective
Wei Han Lim, MBBS, et al
Raffles Medical Group, Department of Primary Care, Singapore
http://www.annfammed.org/content/18/3/259

Opportunities for Human Connectedness in "Physically Distant" Care

Relationships between patients and clinicians matter, even in telehealth visits. A new article explores how clinicians can invest in relationships during a variety of visit types, from short-term telehealth, urgent care, and emergency department visits to ongoing visits for well care and chronic disease management. In a telehealth visit, for example, clinicians can invest in the relationship by giving "full attention to [the] patient via the screen, or allowing no visual if that's what the patient wants." In a more in-depth chronic disease management visit, clinicians can consider the illness context and the patient's life story in order to help the patient identify personal and community resources for managing their condition.

As patients are more often treated by health care teams, and with the emergence of telemedicine, virtual visits are becoming more common--often with health care providers who do not know the patient or their health history. Investing in relationships in all types of visits can personalize the experience for both patients and providers and may also result in more efficient, less costly care.

The authors conclude, "what we need in a pandemic is not social distancing, but physical distancing with social connectedness."

Physical Distancing With Social Connectedness
Kurt C. Stange, MD, PhD, et al
School of Medicine, Case Western Reserve University, Cleveland, Ohio
http://www.annfammed.org/content/18/3/272

Lung Cancer Screenings Study Shows Low Complication Rates With the Support of a Coordinated Multidisciplinary Care Team

The benefits of routine lung cancer screenings have been hotly debated in the medical community. After reviewing a national trial published in 2011, the US Preventive Services Task Force introduced a recommendation for systematic low-dose CT lung cancer screenings for people at high risk. At the time, some leaders in the primary care community were not convinced that there was strong enough evidence in the initial trial to support routine screening. A new lung cancer screening cohort study conducted at a large integrated health system suggests that lung cancer screening in primary care is feasible. The study demonstrated low adverse event rates, and 70 percent of diagnosed lung cancer cases were detected at early stages in their development.

"Screening can be highly beneficial but can also create an illusion of benefits even when causing a net harm," notes Mayo Clinic clinical epidemiologist Chyke A. Doubeni and colleagues, in an editorial response to the Handy et al study. The "window of net benefit" depends on a number of factors in the screening and treatment process, including "quality of CT images and quality of interpretation, disease prevalence in the population, patient health status, and the timeliness, safety, and effectiveness of treatment for abnormal screening results."

Still, the authors write, "Family medicine is critical for increasing the reach of lung cancer screenings," and primary care is an "ideal setting to improve access to screenings, particularly for underserved populations." Therefore, family physicians should be engaged and equipped with guidance on best practices in lung cancer screenings and referrals.

Results of Lung Cancer Screening in the Community
John R. Handy, Jr, MD, HonD, et al
Providence Cancer Institute, Portland, Oregon
http://www.annfammed.org/content/18/3/243

Lung Cancer Screening Guidelines Implementation in Primary Care: A Call to Action
Chyke A. Doubeni, MD, MPH, et al
Mayo Clinic College of Medicine and Science, Rochester, Minnesota
http://www.annfammed.org/content/18/3/196

A Hidden History of Artificial Intelligence in Primary Care

Artificial intelligence methods are being utilized in radiology, cardiology and other medical specialty fields to quickly and accurately process large quantities of health data to improve the diagnostic and treatment power of health care teams. Compared to other medical specialty fields, primary care physicians deal with a very broad spectrum of illnesses, taking a person-centric approach to care, with fewer diagnostic instruments or tests available. The nature of primary care may pose unique challenges to the meaningful application of AI.

A comprehensive review of 405 studies led by researchers at Western University in Ontario shows that work on AI for primary care is at an early stage of maturity. The scoping review summarizes major trends in primary care AI.

"For the field to mature," the authors note, "value must be placed both on developing rigorous [AI] and on identifying potential impacts...on care delivery and longer-term health outcomes."

"Changing primary care is difficult when only one out of every seven of these papers includes a primary care author," says Winston Liaw, MD MPH and Ioannis A. Kakadiaris, PhD, in an accompanying editorial. "Without input from primary care, these teams may fail to grasp the context of primary care data collection, its role within the health system, and the forces shaping its evolution." Liaw and Kakadiaris lay out seven challenges that primary care AI teams must address in order to move AI forward.

Artificial Intelligence and Primary Care Research: A Scoping Review
Jacqueline K. Kueper, MSc, et al
Western University, Schulich School of Medicine & Dentistry, London, Ontario, Canada
http://www.annfammed.org/content/18/3/250

Primary Care Artificial Intelligence: A Branch Hiding in Plain Sight
Winston Liaw, MD, MPH, et al
University of Houston College of Medicine, Department of Health Systems and Population Health Sciences, Houston, Texas
http://www.annfammed.org/content/18/3/194

#ThisIsOurLane: How Physicians Can Take Action to Reduce Gun Violence

As strategies to curb gun violence at the federal level have stalled, leaders in primary care and health policy have identified the role doctors can play in national gun safety efforts and the prevention of firearm suicide. In this pair of recommendation papers, clinicians place themselves at the front lines of this public health issue and offer a call to action for the medical community. Both papers lay out a grassroots course of action to help physicians engage with their patients and policy makers.

Thomas M. Wickizer and colleagues at the Ohio State University focus on the issue of firearm suicide and how improvements in primary care health screening could enhance physicians' ability to identify patients most at risk. Adding firearm safety questions to mental health screening could make firearm safety a more routine part of primary care. The authors also call on collective advocacy for policy change, recognizing the role that physician organizations have historically played in bringing about state-level drunk driving laws and regulation of tobacco advertising. In the wake of gun violence tragedies, physicians have mobilized on social media, using #ThisIsOurLane. The authors believe the medical community can harness the momentum of their online conversations to collectively influence the political discourse on firearms.

Amy Lynn McGuire and colleagues at the Baylor College of Medicine and the Center for Medical Ethics and Health Policy, identify barriers that doctors face in addressing the issue of gun safety and violence with patients. State-level legislation has attempted to prohibit physicians from inquiring about a patient's firearm ownership, resulting in long lasting fears of a "gag order" heightening physicians' concerns over potential liability. Additionally, physicians may be concerned that discussing firearm safety could break the trust they establish in the doctor-patient relationship. The authors advocate that discussions about gun safety and violence become a standard component of routine clinical care to step up the effort to protect public safety and improve public health.

The Firearm Suicide Crisis: Physicians Can Make a Difference
Thomas M. Wickizer, PhD, MPH, et al
The Ohio State University, College of Public Health, Columbus, Ohio
http://www.annfammed.org/content/18/3/265

Physician Involvement in Promoting Gun Safety
Amy Lynn McGuire, JD, PhD, et al
Baylor College of Medicine, Center for Medical Ethics and Health Policy, Houston, Texas
http://www.annfammed.org/content/18/3/262

Trouble Getting a Doctor's Appointment May Drive Medicaid Enrollees to Opt for the ER

The expansion of Medi-Cal, California's Medicaid program, gave millions of low-income Californians access to health insurance, but this study conducted in Northern California found that new patients may have to wait up up to a month for an appointment with a participating primary care provider, depending on their county of residence. It is not uncommon for Medi-Cal enrollees to visit emergency rooms if they require more immediate care.

This study looks at the variation between contiguous counties in the availability of new patient primary care appointments for Medi-Cal enrollees and at the correlation between primary care access and rates of Medi-Cal patients' emergency room usage. Researchers found that counties where it was more difficult to schedule new patient primary care appointments had higher rates of emergency room usage by Medi-Cal patients. This places a greater strain on already overburdened emergency departments and drives up health care costs overall.

How California's challenges compare with those faced by other states that have expanded Medicaid eligibility under the Affordable Care Act is unclear, though the data suggest that "adequate access to primary care will begin to improve health outcomes and control costs among beneficiaries of Medicaid expansion."

Primary Care Access to New Patient Appointments for California Medicaid Enrollees: A Simulated Patient Study
Joy Melnikow, MD, MPH, et al
University of California, Davis, Center for Healthcare for Policy and Research, Sacramento, California
http://www.annfammed.org/content/18/3/210

Arthritis Clinical Trial Shows Support for Dextrose Injection to Alleviate Knee Pain

A randomized controlled trial conducted by a research team at a primary care clinic at the Chinese University of Hong Kong indicates that intra-articular-only injection therapy with hypertonic dextrose is safe and effective for alleviating symptoms of knee osteoarthritis.

Over 52 weeks of treatment, the study followed 76 patients who were between 45 and 75 years old who had been diagnosed with knee osteoarthritis and who suffered moderate to severe chronic knee pain for at least three months. One group of 38 patients received the hypertonic dextrose injection therapy, while the other had the same therapy only using normal saline. While both groups reported some improvement, the hypertonic dextrose group reported more significant reductions in pain by the conclusion of the study. The researchers note that longer-term follow-up, direct comparison with other injection therapies, and cost-effective analysis are all needed.

Efficacy of Intra-Articular Hypertonic Dextrose (Prolotherapy) for Knee Osteoarthritis: A Randomized Controlled Trial
Regina Wing Shan Sit, MBBS, et al
The Chinese University of Hong Kong, Jockey Club School of Public Health and Primary Care, Hong Kong
http://www.annfammed.org/content/18/3/235

After Cancer: The Role of Primary Care in Cancer Survivorship Care

Primary care physicians are treating an increasing number of cancer survivors, yet they have no clear guidance on how best to care for such patients. This study considers how primary care physicians perceive their role in delivering care to cancer survivors. The researchers conducted interviews with 38 primary care clinicians and collected data on the 14 practices in which they worked. While most felt cancer survivor care was within their purview, their approaches toward treating cancer survivors varied widely. More broadly, this study brings into question the role of primary care in addressing the complex needs of cancer survivors. Researchers recommend coordinating care between primary care physicians and oncologists as patients transition to long-term survivorship.

Cancer Survivorship Care Roles for Primary Care Physicians
Jenna Howard, PhD, et al
Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey
http://www.annfammed.org/content/18/3/202

My Patient Wants to Kill Me

When trying to ease patients off of prescription opioids, primary care physicians may meet with resistance, anger--or worse--from those they seek to help. Dr David Bittleman shares his experience of dealing with a death threat from one such patient under his care at a Veterans Affairsclinic. The VA's existing protocols for responding to volatile situations could protect him while at work, but he felt vulnerable to a possible attack in the world outside the clinic. He ultimately sought a civil restraining order against his patient. While Dr Bittleman's experience did not result in any physical harm, he continues to feel concerned about the dangers that he and other medical practitioners face when treating patients who are prone to anger and violence. He feels that "violence is an important problem in health care, both underreported and understudied." One way to diffuse potential problems before they become dangerous, he suggests, is by allowing patients to express their feelings, including their grievances about their treatment plans, in honest, open conversations with their care teams.

My Patient Wants to Kill Me
David Bittleman, MD
Veterans Affairs San Diego Health Care System, San Diego, California
http://www.annfammed.org/content/18/3/269

Primary Care Practice Transformation Introduces Different Staff Types

The Comprehensive Primary Care initiative was launched in 2012 by the CMS Innovation Center as a four-year multi-payer initiative designed to strengthen primary care. This study examines shifts in staffing patterns, from 2012 to 2016, at 461 primary care practices participating in the CPC transformation initiative with those at 358 non-CPC practices.

Over the four years of the study, CPC practices moved away from a traditional staffing model of physicians with medical assistants as they added a variety of new staff, most commonly care managers or coordinators and behavioral health staff, to support patients with comprehensive, team-based care. Non-CPC practices, by comparison, did not increase their team size or diversity as much as CPC practices did. For example, in 2016, 84% of CPC practices had care managers or care coordinators, but only 36% of comparison practices had them.

The authors suggest that future studies should examine the effect of team-based care and staff composition on health care cost, service utilization, patient experience and the overall sustainability of new staffing models. In addition, future work should also address how practices make decisions about augmenting staff in response to patients' medical and social needs.

Primary Care Practice Transformation Introduces Different Staff Types
Kaylyn E. Swankoski, MA, et al
Mathematica Policy Research, Princeton, New Jersey
http://www.annfammed.org/content/18/3/227

Primary Care Case Management Among Frequent Users With Chronic Conditions

Case management is an effective, collaborative, and cost-effective way to help frequent users of health care services integrate all aspects of their care. The research team behind this study developed a program theory to investigate how, and in what circumstances, case management in primary care works to improve outcomes among frequent users who have chronic conditions.

The researchers note that their study only looks at case management in primary care for frequent users of health care, rather than case management use more generally. They also note that further research is still required to examine if the care setting or the professional role of case managers, such as nurses and social workers, may have an influence on the development of the patient-case manager relationship.

Case Management in Primary Care for Frequent Users of Health Care Services: A Realist Synthesis
Catherine Hudon MD, PhD, et al
University of Sherbrooke, Department of Family and Emergency Medicine, Sherbrooke, Quebec, Canada
http://www.annfammed.org/content/18/3/218

Innovations in Primary Care

Innovations in Primary Care are brief one-page articles that describe novel innovations from health care's front lines. In this issue:

Electronic Medical Record-Based Referrals to Community Nutritional Assistance for Food-Insecure Patients - More than 2,500 food-insecure households from two outpatient clinics were successfully referred to community food resources using the combination of a brief, standardized screening tool and an integrated referral mechanism in the Hennepin County Medical Center's electronic medical record system.
http://www.annfammed.org/content/18/3/278

Singapore, a global hub for international travel and business, was among the first countries affected by the COVID-19 pandemic. With its first confirmed COVID-19 case on January 23, 2020, the country mounted aggressive public health and containment measures. The country's network of primary care clinics were at the front lines of these measures. In this new report, those physicians share their triage, containment and infection control measures--including protocols they put in place to ensure the safety of health care workers. At the time of writing the report, zero health care workers within their primary care network were infected with COVID-19. The authors describe the framework for how their primary care clinics responded to this pandemic in the hope others may find solutions to their unique needs."

What The Study Did: In this study, a risk score based on characteristics of patients with COVID-19 at the time of hospital admission was developed that may help predict a patient's risk of developing critical illness.

Authors: Jianxing He, M.D., Ph.D.,  and Nan-Shan Zhong, M.D., of the The First Affiliated Hospital of Guangzhou Medical University, are the corresponding authors.

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

(doi:10.1001/jamainternmed.2020.2033)

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

The benefits of routine lung cancer screenings have been hotly debated in the medical community. After reviewing a national trial published in 2011, the US Preventive Services Task Force introduced a recommendation for systematic low-dose CT lung cancer screenings for people at high risk. At the time, some leaders in the primary care community were not convinced that there was strong enough evidence in the initial trial to support routine screening. A new lung cancer screening cohort study conducted at a large integrated health system suggests that lung cancer screening in primary care is feasible. The study demonstrated low adverse event rates, and 70 percent of diagnosed lung cancer cases were detected at early stages in their development.

"Screening can be highly beneficial but can also create an illusion of benefits even when causing a net harm," notes Mayo Clinic clinical epidemiologist Chyke A. Doubeni and colleagues, in an editorial response to the Handy et al study. The "window of net benefit" depends on a number of factors in the screening and treatment process, including "quality of CT images and quality of interpretation, disease prevalence in the population, patient health status, and the timeliness, safety, and effectiveness of treatment for abnormal screening results."

Still, the authors write, "Family medicine is critical for increasing the reach of lung cancer screenings," and primary care is an "ideal setting to improve access to screenings, particularly for underserved populations." Therefore, family physicians should be engaged and equipped with guidance on best practices in lung cancer screenings and referrals.

A new study published Monday in the Journal of the American Medical Association (JAMA) by researchers from the David B. Falk College of Sport and Human Dynamics at Syracuse University shows that an increase in repetitive head impacts for NFL players leads to an increased risk of premature death.

Recent national attention has focused on the long-term effects of concussions on NFL players, including chronic traumatic encephalopathy (CTE). But repetitive head impacts that do not result in concussions can also lead to CTE and premature death, the study shows.

Led by Brittany Kmush, Ph.D., an assistant professor of public health at Syracuse University, the research team studied nearly 14,000 NFL players from 1969-2017 and created a cumulative head impact index determined by combining padded practice time and games played as reported in Pro Football Reference.

"We wanted to see if there was an association between repetitive head impacts and mortality among professional football players," Kmush said. "We found that increasing head impacts, not just concussions, increased the risk for mortality among NFL players."

The article "Association of Professional Football Cumulative Head Impact Index Scores With All-Cause Mortality Among National Football League Players" was published today as part of the JAMA Network Open, a monthly open access medical journal covering all aspects of the biomedical sciences.

To account for a player's position, the researchers used a player position risk adjustment based on helmet accelerometer studies developed by Boston University's Alzheimer's Disease and CTE Center at the Boston University School of Medicine. The study adjusted for birth year, body mass index and height, and it did not include special teams' players because there was no data for that group of players.

The research suggests that the continued application of rule and equipment changes that minimize repetitive head impacts will lower the mortality risk.

"NFL players are a highly selected group of people; we need future studies to focus on the effects of head impacts on youth, high school, and college football players as well as expand this research into other sports and activities," Kmush said. "Our goal is to make sports safer."

Artificial intelligence methods are being utilized in radiology, cardiology and other medical specialty fields to quickly and accurately process large quantities of health data to improve the diagnostic and treatment power of health care teams. Compared to other medical specialty fields, primary care physicians deal with a very broad spectrum of illnesses, taking a person-centric approach to care, with fewer diagnostic instruments or tests available. The nature of primary care may pose unique challenges to the meaningful application of AI.

A comprehensive review of 405 studies led by researchers at Western University in Ontario shows that work on AI for primary care is at an early stage of maturity. The scoping review summarizes major trends in primary care AI.

"For the field to mature," the authors note, "value must be placed both on developing rigorous [AI] and on identifying potential impacts...on care delivery and longer-term health outcomes."

"Changing primary care is difficult when only one out of every seven of these papers includes a primary care author," says Winston Liaw, MD MPH and Ioannis A. Kakadiaris, PhD, in an accompanying editorial. "Without input from primary care, these teams may fail to grasp the context of primary care data collection, its role within the health system, and the forces shaping its evolution." Liaw and Kakadiaris lay out seven challenges that primary care AI teams must address in order to move AI forward.

Amsterdam, NL, May 12, 2020 - Parkinson's disease (PD) is expected to reach over 14 million cases worldwide by 2040. As longevity increases, so does the number of persons living with PD. Writing in the Journal of Parkinson's Disease (JPD), scientists discuss several avenues through which the COVID-19 pandemic might contribute to the expected exponential growth of PD in the coming years, compounding the economic and societal impacts of the disease.

The potential long-term neurological manifestations of COVID-19 infection are unknown. However, clinical symptoms like the loss of smell and taste and encephalitis suggest that the SARS-CoV-2 virus might have the ability to invade the central nervous system.

"The interesting aspect of the olfactory pathway hypothesis for SARS-CoV-2 neuroinvasion is the potential presence of the virus in the brainstem, which contains the respiratory nuclei responsible for breathing rhythm," explains senior author Carla Alessandra Scorza, PhD, Discipline of Neuroscience, Department of Neurology and Neurosurgery, Federal University of São Paulo/Paulista Medical School, São Paulo, Brazil. She cites studies that found patients with the severe form of COVID-19 infection were more likely to develop acute cerebrovascular disease, as well as studies that found evidence of encephalopathy and intracerebral hemorrhage on brain scans of patients with the infection.

Early evidence of a potential link between viruses and PD stems from an epidemic of encephalitis lethargica following the 1918 influenza outbreak. Dr. Scorza notes that while the evidence linking that influenza outbreak to PD pathogenesis was correlational, it led to further investigations. Some of the primary motor symptoms and histological features of PD have been associated with the H1N1 influenza virus and other viruses such as Coxsackie virus, West Nile virus, Japanese encephalitis B, and HIV.

While the authors acknowledge that further research is needed to understand the role of viruses in the pathogenesis of PD, they believe the findings suggest that both neurotropic and non-neurotropic viruses may contribute to the initiation of PD, either directly by the physical presence of the virus in the central nervous system, or indirectly, by inducing a long-lasting inflammatory process in the brain.

Given that studies have found SARS-CoV-2 may induce the severe immune reaction known as a cytokine storm and hyperinflammation in patients with severe COVID-19 infection, is it possible, the authors hypothesize, that the infection could be a triggering event of the neurodegenerative cascade underlying PD? In addition, previous in vitro studies found that other human coronaviruses may remain latent in blood cells and thus, could induce central nervous system infections later. While clinical signs of Parkinsonism and PD have not been associated with previous coronavirus outbreaks, coronavirus antibodies have been detected in cerebrospinal fluid samples in persons with PD.

The scientists also speculate whether COVID-19 survivors may represent a disproportionately large fraction of the future PD patient population, leading to greater societal impacts. Although the evidence is still inconclusive, persons who were born or were young at the time of the 1918 influenza outbreak had a two- to three-fold higher risk of developing PD than those born prior to1888 or after 1924.

JPD Co-Editor-in-Chief Patrik Brundin, MD, PhD, of the Van Andel Institute, Grand Rapids, MI, comments, "Although it is obviously too early to know what the long term consequences of COVID-19 will be on the brain, the clinical psychiatry and neurology research communities definitely need to be vigilant in monitoring how those who recover from moderate and severe COVID-19 fare in the future. Depressive disorders are undoubtedly associated with inflammation, and for PD there is mounting evidence that both inflammation and infections are associated with elevated risk for PD later in life. Furthermore, published studies on experimental animals indicate that other RNA viruses are linked to marked elevations in alpha-synuclein in the brain, adding further concern regarding what the long term effects of SARS-CoV-2 might be on the brain."

Noting that PD is already the fastest growing neurological disorder, sustained by a continuously aging population, Daniella Balduino Victorino, the lead author of the commentary warns: "As other global pandemics in the past, the COVID-19 pandemic will likely last for a limited amount of time. Yet, it is about time we recognize that the pandemic of PD is not going away anytime soon. All the cutting-edge science seeking viable vaccines and therapies against SARS-CoV-2/COVID-19 infection has only been made possible thanks to a tremendous amount of early scientific endeavors. Last year, while the NIH allocated more than U$6 billion on infectious diseases research, less than US$300 million was spent on PD research. PD breakthroughs heavily depend on devoting more resources to advancing this field of research."

The goal of a vaccine is to trigger a response that safely protects against an infection and/or the burden of disease. While this is true for all vaccines, the steps leading to a safe and effective product can be different for each infection. In the case of COVID-19, caused by the virus SARS-CoV-2, researchers at Baylor College of Medicine and Texas Children's Hospital have found that vaccine design can face specific challenges and that vaccine development approaches require an understanding of how the immune system naturally responds to a specific infection as well as how vaccines might trigger specific protective responses.

The National School of Tropical Medicine at Baylor and the Center for Vaccine Development at Texas Children's, co-led by Dr. Maria Elena Bottazzi and Dr. Peter Hotez, currently are developing coronavirus vaccines. The researchers are applying their years of experience developing vaccines for neglected tropical and emerging infectious diseases such as SARS and MERS to develop a safe and effective COVID-19 vaccine.

"As we proceed with the designing and testing of vaccine candidates, we felt the need to collaborate with a clinical immunologist, who also is engaged in basic and translational research, so that together we can inform our vaccine development efforts and ensure we evaluate both the protective mechanisms and avoid inducing any undesirable immunological responses that have been associated with some respiratory viruses," said Bottazzi, professor of pediatrics and of molecular virology and microbiology and associate dean of the National School of Tropical Medicine at Baylor.

Bottazzi and Hotez approached Baylor's pulmonologist Dr. David Corry, professor of immunology, allergy and rheumatology and Fulbright Endowed Chair in Pathology in the Department of Pathology & Immunology. He also is a member of the Dan L Duncan Comprehensive Cancer Center.

One of the outcomes of their collaboration is the recent publication of two papers, one in Microbes and Infection and the other in Nature Reviews Immunology.

"These publications are the result of an in-depth literature search and analysis that has informed our vaccine development strategy. We highlight experimental and clinical evidence showing some of the challenges toward the development of COVID-19 vaccines -- what we know and what we don't know -- and the critical points we should pay close attention to as we advance and evaluate our vaccine candidates," Bottazzi said.

What does a protective response against COVID-19 look like?

COVID-19 is a new disease and while most of the evidence points to natural infection with the virus generating protective immunity, important gaps still remain.
Researchers know, for instance, that the mechanism of protection most likely will need to rely on a robust antibody response with neutralizing capacity, coupled with a balanced cellular response and cytokines or immune proteins. In recent studies, rhesus macaques infected with SARS-CoV-2 have shown to develop protective antibodies and resistance to reinfection. Previous studies from SARS-CoV in 2003 also showed that persistent antibody responses against the virus spike protein -- the protein the virus uses to bind and invade a cell -- and specifically against a part of the spike protein known as the receptor binding domain, supported immunity.

"We are encouraged by the evidence supporting the likelihood that immunizing against the spike protein's receptor binding domain represents a realistic and viable vaccination strategy. However, many questions remain." said Hotez, who serves as dean of the National School of Tropical Medicine at Baylor, as well as the Texas Children's Hospital Endowed Chair in Tropical Pediatrics.

"Studying the immunological responses triggered in people infected by the virus is one way researchers can select what viral components or antigens are promising candidates to use when designing the vaccine," Bottazzi said. "That, coupled with studies using laboratory models of disease, is how scientists attempt to predict what are the ideal mechanisms of protection triggered by vaccines."

On that basis, the Baylor and Texas Children's teams, in collaboration with the New York Blood Center, developed a vaccine strategy based on this fragment of the viral protein, the receptor binding domain.

How to design a vaccine that safely protects against COVID-19

Experimental and preclinical observations made during prior attempts to develop vaccines against respiratory viruses suggest that some vaccine formulations may trigger undesirable responses. Some of these responses may be cell mediated while others may be triggered by antibodies.

Cell-mediated responses

Preclinical testing of some experimental vaccines followed by viral infection in animal models showed tissue damage caused by cellular infiltrates after the induction of an immune response.

"Some experimental animals developed an inflammatory response in the lung or liver characterized by significant infiltration of immune cells -- lymphocytes, monocytes and eosinophils," Corry said. "Our literature search suggests that this cellular infiltration can be associated with IL-6, a cytokine or immune protein that is strongly increased in patients with COVID-19 who experience a cytokine storm, an excessive production of cytokines that can be life-threatening."

"We also found studies that show that type Th17 immune responses likely could account for the cellular infiltrates, including eosinophils, observed in animal models," said Hotez.

This immune infiltration was observed with experimental viral-vectored vaccines. Viral-vectored vaccines use a chemically weakened and different virus to transport components or antigens of the COVID-19 virus into the body to stimulate an immune response.

Although more research is needed to understand the mechanisms of cell-mediated responses and their relevance to clinical outcomes, the potential of significant immune cell infiltration has important implications for COVID-19 vaccine development.

Research also has suggested that the selection of adjuvants -- agents traditionally added to vaccines to boost a positive immune response -- may impact the type of immune response triggered. For instance, in SARS vaccines, using alum reduces cellular infiltration, indicating that this adjuvant could minimize these undesirable responses.

"Based on prior evidence, we also opted to evaluate and use alum in our COVID-19 vaccine formulation since our goal is to ensure we reduce the possibility of inducing an undesirable immune response," Bottazzi said.

Antibody-mediated responses

Called antibody-dependent enhancement, this response has been previously observed in dengue and other viral infections.

"Antibody-dependent enhancement in dengue occurs when antibodies bind to the virus and shuttle it inside infection-fighting cells called macrophages. Once the virus coated with an antibody is inside macrophages, it doesn't die. It replicates," Corry said. "The macrophages end up spreading the infection inside the organism as macrophages move around."

Whether this phenomenon is relevant to human coronavirus infection is unclear. In laboratory experiments, antibody-dependent enhancement seems to occur with both non-neutralizing and neutralizing antibodies.

"For this reason, we selected the receptor binding domain of the virus. It excludes the epitopes or sections of viral proteins that might potentially induce antibody-dependent enhancement," Hotez said.

"We have not found any evidence that our vaccine triggers antibody-dependent enhancement in laboratory pre-clinical experiments. Experimental evidence suggests that our vaccine against the receptor binding domain leads to the neutralization of the virus," Bottazzi said. "Preclinical studies performed with our partners at the University of Texas Medical Branch, show that the receptor binding domain on alum is indeed a promising vaccine candidate. It can trigger an immune response that is protective and does not induce undesirable cellular immune responses. We are working to advance this approach into the clinic for phase 1 studies."

"There are many challenges to overcome but like never before, scientists around the world are working together to develop effective and affordable vaccines," Corry said. "We'll get there, it will just take time to do it right."

"We believe that we need to have many vaccine candidates, platforms and trials, so we can evaluate as many vaccine options as possible to select the ones that are the most appropriate and prove to be the most effective and safe," said Hotez.

"We invested almost a decade of research to maximize immune protection and minimize or prevent immune enhancement. Ultimately our goal is that these vaccines are made for the global population, accessible and affordable to all."

A new tool using cutting-edge technology is able to distinguish different types of blood clots based on what caused them, according to a study published in eLife.

The tool could help physicians diagnose what caused a blood clot and help them select a treatment that targets cause to break it up. For example, it could help them determine if aspirin or another kind of anti-clotting drug would be the best choice for a person who has just had a heart attack or stroke.

Blood clots occur when small sticky blood cells called platelets cluster together. This can help stop bleeding after a cut, but it can also be harmful in causing a stroke or a heart attack by blocking a blood vessel. "Different types of blood clots are caused by different molecules, but they all look very similar," explains lead author Yuqi Zhou, a PhD student at the Department of Chemistry, University of Tokyo, Japan. "What's more, they are nearly impossible to tell apart using existing tools such as microscopes."

To develop a more effective approach to identifying different types of blood clots, Zhou and her colleagues took blood samples from a healthy individual and then exposed them to different clotting agents. The team captured thousands of images of the different types of clots using a technique called high-throughput imaging flow cytometry.

They next used a type of machine-learning technology called a convolutional neural network to train a computer to identify subtle differences in the shape of different types of clots caused by different molecules. They tested this tool on 25,000 clot images that the computer had never seen before and found it was also able to distinguish most of the clot types in the images.

Finally, they tested whether this new tool, which they named the intelligent platelet aggregate classifier (iPAC), can diagnose different clot types in human blood samples. They took blood samples from four healthy people, exposed them to different clotting agents, and showed that iPAC could tell the different types of clots apart.

"We showed that iPAC is a powerful tool for studying the underlying mechanism of clot formation," Zhou says. She adds that, given recent reports that COVID-19 causes blood clots, the technology could one day be used to better understand the mechanism behind these clots too, although much about the virus currently remains unknown.

"Using this new tool may uncover the characteristics of different types of clots that were previously unrecognised by humans, and enable the diagnosis of clots caused by combinations of clotting agents," says senior author Keisuke Goda, Professor at the Department of Chemistry, University of Tokyo. "Information about the causes of clots can help researchers and medical doctors evaluate the effectiveness of anti-clotting drugs and choose the right treatment, or combination of treatments, for a particular patient."

Elevated blood levels of toxic chemicals found in pesticides, nonstick cookware, and fire retardants have been tied to an increased risk for celiac disease in young people, new research shows.

According to NYU Grossman School of Medicine researchers who led the study, people with the immune disorder have severe gut reactions, including diarrhea and bloating, to foods containing gluten, a protein found in wheat, rye and barley. The only treatment is a gluten-free diet, with no bread, pasta, or cake, says lead investigator and doctoral student Abigail Gaylord, MPH.

Reporting in the journal Environmental Research online May 12, the NYU Langone team found that children and young adults with high blood levels of pesticides -- and with high levels of pesticide-related chemicals called dichlorodiphenyldichlorethylenes (DDEs) -- were twice as likely to be newly diagnosed with celiac disease as those without high levels.

The study also found that gender differences existed for celiac disease related to toxic exposures. For females, who make up the majority of celiac cases, higher-than-normal pesticide exposure meant they were at least eight times more likely to become gluten intolerant. Young females with elevated levels of nonstick chemicals, known as perflouoroalkyls, or PFAs, including products like Teflon, were five to nine times more likely to have celiac disease.

Young males, on the other hand, were twice as likely to be diagnosed with the disease if they had elevated blood levels of fire-retardant chemicals, polybrominated diphenyl ethers, or PBDEs.

Study co-investigator and health epidemiologist Leonardo Trasande, MD, MPP, the Jim G. Hendrick, MD Professor at NYU Langone, says further studies are needed to demonstrate that these toxic chemicals are a direct cause of celiac disease. But he noted that all are known to disrupt animal and human hormone levels, which are key to controlling both sexual development and immune defenses against infection.

Previous research has suggested that the origins of celiac disease, which afflicts one in 100 adults worldwide, were largely genetic and passed down from parents to offspring. Trasande, who also serves as chief of environmental pediatrics in the Department of Pediatrics at NYU Langone, and his colleagues wanted to investigate whether a link existed between environmental exposure to toxins and risk for a particular immune disorder directly affected by hormone levels, such as celiac disease.

"Our study establishes the first measureable tie-in between environmental exposure to toxic chemicals and celiac disease," says senior study investigator and pediatric gastroenterologist Jeremiah Levine, MD. "These results also raise the question of whether there are potential links between these chemicals and other autoimmune bowel diseases, which all warrant close monitoring and further study," says Levine, a professor in the Department of Pediatrics at NYU Langone.

Trasande says that if further studies show similar connections, such results could serve as evidence that the basis or underlying cause for many of these autoimmune disorders may not just be genetic, but also environmental.

For the study, researchers analyzed levels of toxic chemicals in the blood of 30 children and young adults, ages 3 to 21, who were newly diagnosed with celiac disease at NYU Langone Hassenfeld Children's Hospital. Test results were compared with those from 60 other young people of similar age, gender, and race. People with genes HLA-DQ2 and HLA-DQ8 are known to be at greater risk of being diagnosed with celiac disease. Other symptoms of celiac disease include diarrhea, fatigue, and anemia.