Body

Volume 11, Issue 23 of @Oncotarget reported that tissue microarrays of 132 patients were stained for survivin using immunohistochemistry and correlated with outcomes.

Using a genomic database, the authors then correlated survivin mRNA expression with the radiosensitivity index in 52 samples of Neuroendocrine tumors. Finally, they studied the effect of radiation on survivin expression in human cell lines and the impact of knock-down of BIRC5 on cell proliferation and radiation sensitivity.

The authors found that survivin positivity by IHC correlated with shorter survival.

Radiation exposure increased BIRC5 gene expression in a human carcinoid cell line.

Survivin expression in Neuroendocrine tumors correlates with an inferior survival and survivin expression in human carcinoid cell lines increases after exposure to ionizing radiation.

Dr. Renuka Iyer from The Department of Medicine at Roswell Park Comprehensive Cancer Center in Buffalo, New York said, "Neuroendocrine tumors (NET) are a heterogeneous group of neoplasms that arise from neuroendocrine cells or their precursors."

NET can occur throughout the body but is mostly associated with the digestive or bronchopulmonary systems.

Classification of NET ranges from well-differentiated neuroendocrine tumors to poorly differentiated neuroendocrine carcinomas based on their morphology and histological grade assessed by the Ki-67 proliferation index or a number of mitoses per 10 high-powered fields.

Tumors that progress on first-line therapies has limited systemic options that include cytotoxic chemotherapy, molecularly targeted therapy, interferon- and more recently, peptide receptor radioligand therapy.

To test the potential of survivin as a prognostic marker and therapeutic target the authors evaluated survivin expression in NET and correlated it with clinical outcomes using annotated tumor tissue microarrays from patients with NETs. To better understand the role if any survivin in NETs of lung origin, using a genomic database the authors correlated the survivin mRNA expression with sensitivity to radiation using the validated radio-sensitivity index.

Finally, to determine if survivin targeting may increase response to radiation, the authors assessed change in survivin expression in a pulmonary carcinoid cell line in response to radiation and effects of survivin knockdown using si RNA on cell proliferation and radiation sensitivity.

The Iyer Research Team concluded in their Oncotarget Research Paper that these observations led to attempts at creating a vaccine that can trigger a stronger immune response against survivin.

Several vaccine approaches targeting survivin have been evaluated in clinical or pre-clinical studies, including dendritic cell vaccines, DNA vaccines, and peptide vaccines, with variable responses.

More recently, researchers at Roswell Park developed a survivin long peptide-mimic vaccine, Sur Vax M, that was shown to generate survivin-specific immunological response through activation of CD8+ CTL as well as CD4+ helper T cells.

Based on the safety and efficacy signal of this vaccine in malignant gliomas that are survivin positive by IHC and our finding of survivin being a prognostic marker and present in NETs, the authors find survivin to be a potential target in NET and have begun a pilot trial of Sur Vax M in survivin expressing NETs. Its association with RSI makes it an attractive candidate to be targeted using combination strategies using PRRT upon completion of further preclinical studies testing Sur Vax M, survivin antibodies and CAR T-cell approaches to guide optimal therapy and sequencing schedule.

"The authors find survivin to be a potential target in NET and have begun a pilot trial of Sur Vax M in survivin expressing NETs"

Using electronic health record (EHR) data to simulate drug trials for pregnant patients could one day offer a solution to the current practice of delivering babies pre-term if an expectant mother contracts COVID-19, according to a position paper published in Nature Medicine.

Pregnant patients have typically been excluded from drug trials out of concern for fetal safety. And when human health is on the line, drug studies assessing fetal safety in animal models may be viewed as far from definitive. Due to sheer lack of data concerning implications for fetal and maternal safety, clinicians are often unsure about prescribing drugs to pregnant patients.

A position paper led by first author Anup Challa and senior author David Aronoff, MD, director, Division of Infectious Diseases at Vanderbilt University Medical Center (VUMC), outlines how these deficits can lead to undertreatment of chronic and acute illness in pregnant patients, while also posing additional risk of adverse drug reactions.

"Pregnant patients are an especially vulnerable population, since exposure to many common drugs could harm their unborn children," said Challa, principal investigator of Modeling Adverse Drug Reactions in Embryos (MADRE), a team of drug safety researchers across Vanderbilt, Northwestern, Harvard, and the National Institutes of Health. "Further complicating this problem is the fact that pregnant patients are not allowed to enroll in clinical trials, given the ethical issues that a harmful drug reaction in their fetuses could pose.

"These factors have significantly reduced quality of care for pregnant patients with COVID-19, as the current guidance to OB/GYNs is to deliver pregnant patients if they contract COVID-19, even if the patients are pre-term. This could significantly harm their fetuses, and recent case reports have shown that COVID-19 transmission occurs in utero if not treated in the mother," he added.

Challa and Aronoff propose that using EHR data to emulate randomized, controlled trials could offer an alternative to delivering all pregnant patients with COVID-19.

Used to compare treatments, these trials involve enrollment of subjects who undergo interventions carried out in real time. In contrast, target trials are a type of observational study that simulates the trial through retrospective analysis of existing clinical data.

"We could identify therapeutics that are safe for use in these patients by using high-powered algorithms like machine learning to learn from cases in which pregnant patients have been exposed to current therapeutic candidates and understand how much risk they pose to a fetus," Aronoff said.

VUMC has EHRs for more than 2 million patients, which allows investigators to design and conduct "trials" that simulate not only a real trial's treatment strategies (drug vs. no drug) and outcomes, but also eligibility criteria and random assignment to treatment at baseline.

Such trials are arguably "the only ethical way to gather human drug exposure data for pregnant people on a significant scale and across all classes of drugs," the authors said.

"If expanded, the Vanderbilt platform of target trials may offer an alternative to delivering all pregnant patients with COVID-19 by identifying therapeutics that are safe," Challa said. "Without a good understanding of safety for these drugs, we might be missing opportunities to treat COVID-19 in pregnant patients."

The COVID-19 pandemic is having a significant impact on people with obesity as they struggle to manage their weight and mental health during shelter-in-place orders, according to research led by The University of Texas Health Science Center at Houston (UTHealth) and UT Southwestern.

The study, published today in the journal Clinical Obesity, surveyed 123 weight management patients at the UT Southwestern Weight Wellness Program and a community bariatric surgery practice.

"Everyone was told to stay home to protect themselves from infection and this was especially important for people with severe obesity, who are more likely to have serious complications and higher risk of death with the coronavirus," said Sarah Messiah, PhD, MPH, the study's senior author and professor of epidemiology, human genetics, and environmental sciences at UTHealth School of Public Health in Dallas. "But these are also patients who often have comorbidities such as heart disease and diabetes that need consistent care. This was the first assessment of this patient population to see the effects of the upheaval of their daily lives on their health behavior and well-being."

The study revealed that nearly 73% of patient experience increased anxiety and close to 84% had increased depression. Nearly 70% reported more difficulty in achieving weight loss goals, while 48% had less exercise time, and 56% had less intensity in exercise. Stockpiling of food increased in nearly half of patients and stress eating was reported in 61%.

Two of the patients tested positive for SARS-CoV-2, but nearly 15% reported symptoms of the virus. Almost 10% lost their jobs and 20% said they could not afford a balanced meal.

"You don't have to contract the virus to be adversely affected by it. The major strength of this study is that it is one of the first data-driven snapshots into how the COVID-19 pandemic has influenced health behaviors for patients with obesity," said Jaime Almandoz, MD, MBA, first author and an endocrinologist and assistant professor of internal medicine at UT Southwestern. Almandoz is also medical director for the UT Southwestern Weight Wellness Program, a multidisciplinary weight management and post-bariatric care clinic.

According to the Centers for Disease Control and Prevention, more than 42% of American adults are obese. Obesity-related health conditions include heart disease, stroke, Type 2 diabetes, and certain types of cancer that are some of the leading causes of preventable, premature death.

Almandoz pointed out that many patients with obesity already struggle with access to appropriate fresh, healthy foods. Some reside in food deserts lacking grocery stores, where the only options are fast food and processed foods from convenience stores.

"Unchecked diabetes, hypertension, and other obesity-related comorbidities will create a huge backlog of needs that will come back to haunt us. When you throw in disruptions like social isolation, coupled with losing your job and insurance coverage, a potential disaster is waiting to unfold," Almandoz said.

With clinics across the country reporting a decrease in patient visits, Messiah said that people with obesity are potentially missing medical appointments, surgeries, and medications due to the pandemic. People who lost their jobs, and thus their health insurance benefits, may now experience less access to care.

"We don't yet know how many additional lives will be lost to heart disease and diabetes simply because people did not receive care during COVID-19," said Messiah, who is the director of the Center for Pediatric Population Health. "Unfortunately, many of these are ethnic minorities who are already hit hard with disease burdens."

The researchers believe their work can inform clinicians and other health professionals on effective strategies to minimize the physical and psychosocial health impacts from COVID-19 among adults with obesity.

"Those with obesity and severe obesity are already at the highest risk of death from COVID-19. We're concerned that they can be severely affected if a second wave hits in the fall," Messiah said.

The study data came from an online questionnaire conducted April 15 through May 31, 2020. The study population was racially and ethnically diverse, had a mean age of 51, and 87% were women. The mean body mass index for these patients was 40.

New Rochelle, NY, June 10, 2020--Managing women with breast cancer who are breastfeeding is a complex issue. The Academy of Breastfeeding Medicine presents new recommendations in the peer-reviewed journal Breastfeeding Medicine. Click here to read the article now.

"The aim of this new protocol is to guide clinicians in the delivery of optimal care of breastfeeding women as it relates to breast cancer, from screening to diagnosis, treatment, and survivorship," state coauthors Helen Johnson, MD and Katrina Mitchell, MD.

It addresses the spectrum of care, including oncologic breast surgery, chemotherapy, and adjuvant and endocrine therapy. A section on breastfeeding women who have a previous history of breast cancer is included.

Arthur I. Eidelman, MD, Editor-in-Chief of Breastfeeding Medicine, states: "This protocol is a guide for mothers who are undergoing diagnosis and treatment for breast cancer. It emphasizes that they do not have to categorically give up on their nurturing role as breastfeeding moms."

Breast cancer is the most common malignancy in women worldwide. One in 20 women will develop breast cancer in their lifetime.

Researchers in Japan have replicated cancer cells from diseased bladder tissue in dogs, minimizing the use of costly stem cell products. The synthesized tumor cells allow scientists to diagnose cancer and optimize treatment without putting the patient through tiresome rigors of chemotherapy trial and error.

The research team led by Senior Assistant Professor Tatsuya Usui from the Laboratory of Veterinary Pharmacology at the Tokyo University of Agriculture and Technology published their findings in the journal Scientific Reports on June 10th, 2020.

Organoids are a niche within the booming field of 3D bioprinting, which includes a growing stable of chemical and biological processes that generate living tissue for use in research and medical procedures. Presently, clinically viable 3D bioprinting is limited to simple structures like a small patch of skin, fat, or cartilage. Ultimately the medical community hopes to generate viable replacement organs, eliminating the need for transplant donors.

Professor Usui's team set out to create a type of organoids without the use of cell-stimulating supplements and Matrigel, a costly product derived from stem cells harvested from genetically engineered rodents. The scarcity of 3D bioprinting products makes them a poor choice for research on a scale that would yield timely cancer diagnoses and new treatments.

To study this new cell culture approach, the researchers focused on bladder cancer in dogs, a disease which occurs at a rate similar to humans. They captured diseased cells voided in the dogs' urine and replicated them using a new process that generates bodies mimicing key characteristics of the original tumor cells closely enough that they can effectively be used to diagnose disease and identify possible treatments. The team created the organoids by culturing the captured diseased cells in a protein-rich medium.

"Interestingly, we were able to grow organoid cells using techniques just shy of the traditional, complete 3D bioprinting process - a sort of 2.5D process - while producing most of the 3D organoid features. This means that we could potentially produce cheaper biomaterials for testing and research without jeopardizing much for the accuracy." Professor Usui said.

Once the team succeeded in creating organoids from the dogs' diseased cells, they tested their response to three common anti-cancer drugs as well as several antibodies. They later applied a preservative to the study samples, essentially halting the treatment processes to analyze the results. They also reversed the process, generating 3D organoid cells using traditional bioprinting, then planted them into mice. The cells became tumors as anticipated, giving the team further evidence that 2.5D organoids may be an accurate and effective research medium.

"We are confident that our method will make a breakthrough in bladder cancer diagnosis and treatment in both animals and humans, as it efficiently reduces the culture time, handling, gel, and media supplement costs, and therefore it can be an important platform for the development of new bladder cancer therapy," Usui said.

Researchers funded by the National Institutes of Health have launched an effort to evaluate drugs prescribed to treat COVID-19 in infants, children and adolescents across the country. The study leverages an existing clinical trial that examines drugs that are prescribed off-label to children for a variety of medical conditions. Because many drugs have not been tested specifically for use in children, physicians will often prescribe drugs off-label to children because they lack an alternative, approved treatment.

"As we search for safe and effective therapies for COVID-19, we want to make sure that we do not overlook the needs of our youngest patients who may respond differently to these drugs, compared to adults," said Diana W. Bianchi, M.D., director of NIH's Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), which oversees the project.

Researchers will investigate several drugs currently given to children diagnosed with COVID-19, including antiviral and anti-inflammatory drugs. Products will be added or removed from the list as researchers learn more about the treatment needs of patients with COVID-19. The study is not a clinical trial with a control group. Rather, healthcare providers who are already treating patients with drugs on the list may enroll patients whose parents or guardians have given their consent. The study is called Pharmacokinetics of Understudied Drugs Administered to Children Per Standard of Care.

Researchers will analyze blood samples collected from routine medical procedures to understand how drugs move through the bodies of children, from newborns to adolescents under 21 years of age. They will also collect information on potential side effects and patient outcomes, such as the duration and type of respiratory support that may be needed and length of hospital stay. The study is designed to gather information to refine dosing and improve safety for infants, children and adolescents; it is not designed to evaluate which drug is the best treatment for COVID-19.

The study is being conducted in approximately 40 sites of the NICHD-funded Pediatric Trials Network. Importantly, many study sites are located near diverse communities, given reports that COVID-19 disproportionately affects racial and ethnic minorities across all ages. The study also aims to analyze drug dosage and safety for special populations, including premature infants, critically ill children, children with Down syndrome and obese children.

The study is part of NICHD's Best Pharmaceuticals for Children Act (BPCA) research program, which investigates drugs and therapies commonly prescribed to infants and children but not sufficiently tested in them. Data from BPCA studies are available to researchers through NICHD's Data and Specimen Hub (DASH).

Philadelphia, June 9, 2020 - As the COVID-19 pandemic sent entire communities into lockdown, doctors quickly adopted telehealth strategies without knowing whether they would be effective or feasible. Now, a new study from the Division of Neurology at Children's Hospital of Philadelphia (CHOP) shows that for pediatric neurology care, the transition was very successful even in a short period of time and may provide guidance on the future of pediatric care after the pandemic subsides. The findings were published today in the journal Neurology.

The response to the pandemic required a rapid and unprecedented conversion of outpatient clinical care from in-person to remote telehealth services. In the field of neurology prior to this pandemic, telemedicine had been used to deliver care for adult stroke patients and had been piloted in rural health systems and specific populations such as those experiencing epilepsy and headaches. Until now, pediatric neurology telemedicine studies have not been performed systematically.

The Division of Neurology wanted to assess whether newly implemented audio-video telemedicine visits are an effective way of delivering care during these unprecedented times. Specifically, they wanted to perform a quality improvement study to determine the effectiveness of these visits, the utility of telemedicine for future care, the need for short-term, in-person follow-up after these appointments, and whether both patients and caregivers were satisfied.

In the course of a week, all in-person visits were changed to audio-video telemedicine visits. Established patients who lacked access to a smartphone or computer application were offered dedicated telephone visits. Providers were surveyed at the end of each encounter regarding their satisfaction with the visit, technical barriers, and the need for in-person assessment. Patients and caregivers were also asked about their propensity for using telehealth in the future. In order to comprehensively review the data, the study team utilized Arcus, an informatics platform developed by the CHOP Research Institute that links biological, clinical, research, and environmental data to securely access and analyze data generated over the course of a patient's clinical encounters and research study visits throughout childhood and adolescence.

"With our robust pediatric neurology care network, our team was uniquely suited to serve as the first center to examine this new and important aspect of healthcare," said Ingo Helbig, MD, a pediatric neurologist at CHOP, director of the genomic and data science core of CHOP's Epilepsy Neurogenetics Initiative (ENGIN) and senior author on this study. "Our healthcare analytics approach allowed us to mine all of the electronic medical records of our patients essentially in real time during this transition."

A total of 2,589 telehealth visits were analyzed for the study, with included 2,093 telemedicine visits and 496 telephone appointments. Of the surveys that were completed after these appointments, the clinical team considered telemedicine satisfactory in 93% (1200/1286) of them and suggested telemedicine as a component for follow-up care in 89% (1144/1286) of cases. According to the survey, 40% (519/1314) experienced some sort of technical challenge. An in-person assessment was considered following approximately 5% (65/1285) of the appointments. Patients and caregivers indicated that they would be interested in using telemedicine for future care 86% of the time (187/217).

The study team believes that the high rate of satisfaction despite the technical issues may have been influenced by the lack of alternate methods for these visits to occur during the COVID-19 pandemic. To address those technical issues going forward, the authors recommend software updates and increased bandwith across the hospital's networks to better handle telemedicine visits.

Additionally, telemedicine may address previously existing barriers to clinical care. Expanding telemedicine may be ideal for underserved patients whose caregivers cannot afford to miss work or travel to the clinic for in-person appointments, who live far from a hospital or other facility where the visits normally take place, or who have complex transportation needs.

The authors also observed that racial and ethnic minority groups were more likely to have to do a telephone appointment instead of a audio-video telemedicine visit for reasons such as a lack of access to a computer, suggesting that the inequity between groups needs to be properly addressed moving forward.

"While there is a need to make technical improvements as well as make certain that every patient receives the same level of care, our findings demonstrate that telemedicine is safe, timely, patient-centered and efficient, and both patients and clinicians found this transition to be an effective one during these unprecedented circumstances," said Donna Stephenson, MD, Medical Director of Operations and Outreach and an attending physician in the Division of Neurology at CHOP who was one of the senior authors of the study. "We hope that the appropriate resources are allocated to allow telemedicine to continue to serve the needs of patients well beyond what current circumstances dictate."

"This is the largest telemedicine study that has ever been done in pediatric neurology and was made possible based on the growth of our network, the adaptability of our clinical team in order to provide the best patient care under these circumstances, and our excellent relationship with our patients and caregivers, without whom this transition could not have come together as quickly as it did," said Brenda Branwell, MD, Chief of the Division of Neurology at CHOP and holder of the Grace R. Loeb Endowed Chair in Neurosciences. "Safe and effective care is always at the top of our minds every single day, and this study has shown that going forward, telemedicine may have a sustained role in making sure every patient receives the attention they deserve."

ANN ARBOR, Mich. - In a new commentary piece, published in JAMA Health Forum, two health researchers describe the decrease in emergency department use during the COVID-19 pandemic.

"While data are still being collected and reviewed, we know there was a dramatic drop in patients seeking care in emergency departments during March and April 2020," says Keith Kocher, M.D., MPH, an associate professor of emergency medicine and learning health sciences at Michigan Medicine and a member of the University of Michigan Institute for Healthcare Policy and Innovation.

Kocher, along with Michelle Macy, M.D., M.S., of Ann & Robert H. Lurie Children's Hospital of Chicago, highlight in the commentary major reasons for the decline and their implications, including emergency department demand being related to patients' physical and social environments.

"Social distancing, frequent hand washing and wearing masks in public, all help lower the transmission of viruses and infectious illnesses, which are often reasons why patients, especially children, seek emergency care," Macy says.

In addition, Kocher and Macy say the epidemiology of injuries changed during the pandemic, such as fewer motor vehicle accidents occurring due to less travel, and health care administration and policy decisions affected patients' ability to obtain care. For example, cancellations of scheduled procedures and expansion of telehealth appointments kept patients from physically going to a hospital for care.

They also note that the pandemic altered when and how quickly patients turn to the emergency department for urgent care needs.

"This is truly tragic because if someone is experiencing concerning symptoms, we want them to come in as quickly as possible for care," Kocher says. "Our emergency department is safe and ready to care for you."

(LOS ANGELES) -- Mesenchymal stem cells (MSCs) are multipotent in that they naturally replenish the cell types that build our bone, cartilage and adipose tissues. However, their much broader regenerative potential, based on their capacity to migrate and engraft in injured tissues and secrete factors that enhance the formation of new blood vessels, suppress inflammation and cell death, and promote healing, makes them exquisite candidates for cell-based therapies for diseases as varied as cardiovascular, liver, bone and cartilage diseases, lung and spinal cord injuries, autoimmune diseases and even cancer and skin lesions.

MSCs provoke no or negligible adverse reactions in patients that receive them from healthy donors, and can be easily isolated from human tissues, expanded to clinical scales, biopreserved, and stored for point-of-care delivery. This efficiency in preparing medical grade MSCs contrasts with the relative inefficiency with which they currently can be delivered to target tissues in patients. Clinicians often need to administer massive numbers of MSCs with high precision to reach sufficient numbers of cells that successfully engraft and remain functional over time.

To overcome this bottleneck, researchers have developed materials-based approaches in which MSCs are embedded in biomaterial scaffolds that then can be implanted as "patches" in minimally invasive procedures into damaged tissues. However, those cells are often limited in their ability to migrate, overcome tissue barriers, and successfully engraft in tissue microenvironments where their action is needed most. In principle, injection approaches can introduce MSCs into tissues via hypodermic needles in a more targeted manner, but any direct injection to the tissue is invasive and can cause inadvertent tissue damage and side effects like the formation of scar tissue.

Now, a new study reported in Advanced Functional Materials by a team at the Terasaki Institute for Biomedical Innovation in Los Angeles and the University of California, Los Angeles (UCLA) has developed a minimally invasive approach, which deploys "microneedles" that provide a bioactive depot of MSCs. By embedding comparatively low numbers of MSCs in a gel-like material that prolongs their viability and functionality, and targeting damaged tissues with high spatial precision, the researchers showed their approach to accelerate wound healing in a mouse model with excised skin segments.

"Microneedles have been successfully used in the past to painlessly deliver drugs to target tissues such as skin, blood vessels and eyes. We demonstrate here with 'Detachable Microneedle Depots' that an analogous approach can deploy therapeutic cells at target sites," said co-corresponding author Ali Khademhosseini, the Director and CEO of the Terasaki Institute who was previously Director of the UCLA Center for Minimally Invasive Therapeutics. "To achieve this, we developed an entirely new microneedle patch that supports stem cells' viability, responsiveness to wound stimuli, and ability to accelerate wound healing."

At the beginning of their study, Khademhosseini and his co-workers hypothesized that embedding MSCs in a biocompatible and biodegradable biomaterial matrix could help create a hydrated environment with the mechanical properties that stem cells need in order to remain alive and functioning over a longer time. The researchers started by engineering a matrix of gelatin fibers that are cross-linked to each other into a network that could accommodate MSCs. The biomaterial mimicked the normal extracellular environment of tissues that MSCs normally reside in, and it helped to remodel the specific matrix environment in a way that allowed MSCs to take up nutrients and communicate with damaged tissue via soluble factors that they normally receive and dispatch.

The other part of the challenge was to introduce the literal "needle" quality into the cell-delivering device that would enable it to gently penetrate tissues in order to reach their target sites. To this aim, the researcher encased the softer MSC-containing gelatin matrix with a second, much harder biomaterial known as poly(lactic-co-glycolic)acid, in short PLGA. Once the needles were brought into place in a wound bed, the "PLGA shell", which also is biocompatible and biodegradable, slowly degraded, but during the process kept the MSC-containing gelatin matrix in place, allowing MSCs to release their therapeutic factors through emerging gaps in the shell into the damaged tissue. The team showed that in the composite microneedle 90% of MSCs were kept viable for 24 hours, and that, importantly the cells did not lose their potential as stem cells ("stemness"), which was critical for their healing properties.

Finally, the team set out to investigate their microneedle concept in a mouse skin wound model in which a defined excision is made in the epidermal tissue layers. To be able to strategically place individual microneedles within the wound bed, a simple and effective deployment mechanism was devised by attaching an array of microneedles on a small strip of scotch tape with their pointy ends facing away from the tape. Precisely positioning the tape with its patterned microneedle surface on the wound, allowed the individual microneedles to penetrate into the wound bed. Then, the tape was peeled off, causing the microneedles to detach and remain embedded in the wound tissue. Khademhosseini and his co-workers summarized the device's salient features by naming it: "Detachable Hybrid Microneedle Depot" (d-HMND).

In the mouse model, the MSC-loaded d-HMND device indeed stimulated a number of critical parameters associated with wound healing. Compared to an equal number of MSCs injected directly into wounded skin, and a version of the d-HMND device that did not contain any MSCs (cell-free), the MSC-containing d-HMND accelerated the contraction of the wound and re-growth of the epidermal skin layers (re-epithelialization). The researchers used a panel of histological and molecular markers to confirm over a period of 14 days that the device suppressed inflammation, and stimulated tissue remodeling, the formation of new blood vessels, and re-growth of hair - all vital signs of a robust wound healing response.

"In future scenarios, d-HMNDs could be rapidly fabricated in clinical laboratories shortly before use, applied to treat skin injuries, and explored more broadly as treatments for a variety of other disorders, including melanoma and other dermatological disorders that could benefit from the power of MSC cells," said Khademhosseini. "The concept would even be compatible with using patient-derived cells in more personalized device approaches." Khademhosseini and his colleagues are exploring further uses of this technology as part of the Terasaki Institute's research program.

Bottom Line: The U.S. Preventive Services Task Force (USPSTF) recommends screening for unhealthy drug use in adults 18 or older by asking questions about such use when services for diagnosis, treatment, and care can be offered or referred. Unhealthy drug use includes using illegal drugs or using a prescription drug in ways that are not recommended by a doctor. The USPSTF routinely makes recommendations about the effectiveness of preventive care services and this is a new recommendation, replacing the 2008 statement that found insufficient evidence at the time. Evidence continues to be insufficient regarding screening for unhealthy drug use in adolescents. Drug use is one of the most common causes of preventable death, injuries and disability. In 2017, unhealthy drug use caused more than 70,000 fatal overdoses.

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

(doi:10.1001/jama.2020.8020)

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

Note: More information about the U.S. Preventive Services Task Force, its process, and its recommendations can be found on the newsroom page of its website.

According to a new study, people with small airways relative
to the size of their lungs may have a lower breathing capacity and, consequently, an increased risk for COPD--even if they don't smoke or have any other risk factors. The study, funded in part by the National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health, will publish in the June 9 issue of JAMA.

Chronic obstructive pulmonary disease (COPD), a debilitating lung condition, often develops as a result of smoking, but researchers have long puzzled over why nearly a third of cases occur in people who never smoked. Now they may finally have an answer--and it may be linked to how lungs develop in certain people.

Lung development may explain why some non-smokers get COPD and some heavy smokers do not

According to a new study, people with small airways relative to the size of their lungs may have a lower breathing capacity and, consequently, an increased risk for COPD--even if they don't smoke or have any other risk factors. The study, funded in part by the National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health, will publish in the June 9 issue of JAMA.

Chronic obstructive pulmonary disease (COPD), a debilitating lung condition, often develops as a result of smoking, but researchers have long puzzled over why nearly a third of cases occur in people who never smoked. Now they may finally have an answer--and it may be linked to how lungs develop in certain people.

"This work, stemming from the careful analysis of lung images of COPD patients, shows that an abnormal lung development may account for a large proportion of COPD risk among older adults," said James Kiley, Ph.D., director of NHLBI's Division of Lung Diseases. "More research is needed to understand what drives this occurrence and to devise possible interventions."

COPD, the fourth leading cause of death in the United States, causes airflow blockage and breathing-related problems that can severely limit a person's day-to-day activities. Smoking, asthma, or air pollution account for many COPD cases, but up to 30% of cases occur in people who never smoked, and only a minority of heavy smokers develop the disease, suggesting that there are other risk factors at play.

Previous research offered a clue about a possible cause, finding that about half of older adults with COPD appeared to have low lung function early in life. Benjamin Smith, M.D., a pulmonary physician in the Department of Medicine at Columbia University Irving Medical Center, New York City, who was involved in the new study, explained the phenomenon.

When people breathe, they move air through their airways, beginning with the windpipe or trachea, which branches out to smaller airways called bronchi and bronchioles. As people grow, their airways are thought to develop in proportion to their lungs, but in some people, the airways grow smaller or larger than expected--a condition called dysanapsis-- for reasons that are not clear.

To find out if small airways might be the culprit for COPD in people who did not smoke or have other risk factors, a team led by Smith looked at records for more than 6,500 older adults participating in three studies that included smokers and nonsmokers with and without COPD. Each study--the Multi-Ethnic Study of Atherosclerosis (MESA) Lung Study, the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS), and the Canadian Cohort of Obstructive Lung Disease (CanCOLD) study--assessed dysanapsis using computed tomography (CT) scans of the lungs.

The MESA Lung study, based in six U.S. cities, included white, African American, Hispanic, and Chinese American people who were age 69 on average. The participants from the CanCOLD study were age 67 on average and came from nine Canadian cities. SPIROMICS, based at 12 U.S. medical centers, included people who were age 63 on average and reported 20 or more pack-years of smoking.

In the MESA Lung and CanCOLD studies, participants with smaller airways relative to lung size were much more likely to develop COPD compared with those with the larger airways relative to lung size. The association remained after considering standard COPD risk factors, including smoking, pollutants, and asthma.

The researchers then focused on participants from the CanCOLD study who never smoked and heavy smokers from the SPIROMICS study. Never smokers with COPD had much smaller airways relative to lung size, whereas the heavy smokers who did not have COPD had larger than normal airways.

"These results show that small airways relative to lung size are a very strong risk factor for COPD," said Smith, the lead study author. "This helps us to understand why 30% of COPD can occur in people who never smoked." With normal aging, lung function declines, so people who already have low lung function to begin with may develop COPD later in life, even if they don't smoke, he explained.

Smith added that the findings may also help explain why some lifelong heavy smokers do not develop COPD. People with larger airways relative to lung size may be able to withstand lung damage from smoking and still have enough breathing reserve to prevent them from developing COPD. Still, given the multiple health problems caused by tobacco, Smith emphasized that smokers should do their best to quit.

The percentage of children and young people who have severe kidney disease and require renal replacement therapy (RRT) is relatively low at approximately 2% [2]. The disease is life-changing for those affected, however. If transplantation is not available as an option, the children are dependent on dialysis treatment, which is generally carried out three times a week for 4 hours. A 'normal' childhood is barely possible in that case. The children are ill, but it is not only their quality of life that suffers, but also their prognosis: Children requiring dialysis have an approximately 55-fold mortality risk compared to the healthy population of the same age [3]. Duration of dialysis and the age at the start of dialysis are generally considered to be risk factors, but these are factors that cannot be influenced.

It is highly important, therefore, to identify what other causes are behind the mortality rates and which risk factors can be influenced in order to improve the outcomes of young patients.

A study published yesterday in NDT, the official journal of the ERA-EDTA, investigated the risk factors. The authors analyzed a cohort of 363 patients under the age of 30 who had started dialysis therapy in childhood (at less than 19 years of age). 105 variables relating to demographics, HD treatment and laboratory measurements were evaluated for their significance as predictors of 5-year mortality. A flexible machine learning approach (random forest) was used for this purpose.

The results showed that low albumin and elevated lactate dehydrogenase were the two important risk factors. However, many other factors also had an impact, including a reduced red blood cell count, hemoglobin, albumin/globulin ratio, ultra-filtration rate, z-score weight for age, or inadequate dialysis dose (spKt/V below target).

"The variety of retained risk factors probably highlights the importance of multimodal intervention strategies in addition to adequate HD treatment", explains corresponding author, Verena Gotta, Basel, Switzerland.

NDT editor-in-chief, Professor Denis Fouque, Lyon, France, also draws attention to the utmost importance of providing comprehensive care to pediatric patients: "Nephrological care must not be confined to good dialysis treatment, but must also include factors such as nutrition, exercise, and the prevention of inflammation, anemia and cardiovascular disease. Only by applying a multimodal approach can we reduce the intolerably high mortality risk among pediatric and adolescent dialysis patients. The study is important because it provides arguments vis-à-vis health authorities for more intensive care of these patients."

An algorithm that analyses MRI images and automatically detects small changes in knee joints over time could be used in the development of new treatments for arthritis.

A team of engineers, radiologists and physicians, led by the University of Cambridge, developed the algorithm, which builds a three-dimensional model of an individual's knee joint in order to map where arthritis is affecting the knee. It then automatically creates 'change maps' which not only tell researchers whether there have been significant changes during the study but allow them to locate exactly where these are.

There are few effective treatments for arthritis, and the technique could be a considerable boost to efforts to develop and monitor new therapies for the condition. The results are reported in the Journal of Magnetic Resonance Imaging.

Osteoarthritis is the most common form of arthritis in the UK. It develops when the articular cartilage that coats the ends of bones and allows them to glide smoothly over each other at joints, is worn down, resulting in painful, immobile joints. Currently there is no recognised cure and the only definitive treatment is surgery for artificial joint replacement.

Osteoarthritis is normally identified on an X-ray by a narrowing of the space between the bones of the joint due to a loss of cartilage. However, X-rays do not have enough sensitivity to detect subtle changes in the joint over time.

"We don't have a good way of detecting these tiny changes in the joint over time in order to see if treatments are having any effect," said Dr James MacKay from Cambridge's Department of Radiology, and the study's lead author. "In addition, if we're able to detect the early signs of cartilage breakdown in joints, it will help us understand the disease better, which could lead to new treatments for this painful condition."

The current study builds on earlier work from the same team, who developed an algorithm to monitor subtle changes in arthritic joints in CT scans. Now, they are using similar techniques for MRI, which provides more complete information about the composition of tissue - not just information about the thickness of cartilage or bone.

MRI is already widely used to diagnose joint problems, including arthritis, but manually labelling each image is time-consuming, and may be less accurate than automated or semi-automated techniques when detecting small changes over a period of months or years.

"Thanks to the engineering expertise of our team, we now have a better way of looking at the joint," said MacKay.

The technique MacKay and his colleagues from Cambridge's Department of Engineering developed, called 3D cartilage surface mapping (3D-CaSM), was able to pick up changes over a period of six months that weren't detected using standard X-ray or MRI techniques.

The researchers tested their algorithm on knee joints from bodies that had been donated for medical research, and a further study with human participants between 40 and 60 years old. All of the participants suffered from knee pain, but were considered too young for a knee replacement. Their joints were then compared with people of a similar age with no joint pain.

"There's a certain degree of deterioration of the joint that happens as a normal part of aging, but we wanted to make sure that the changes we were detecting were caused by arthritis," said MacKay. "The increased sensitivity that 3D-CaSM provides allows us to make this distinction, which we hope will make it a valuable tool for testing the effectiveness of new therapies."

The software is freely available to download and can be added to existing systems. MacKay says that the algorithm can easily be added to existing workflows and that the training process for radiologists is short and straightforward.

As part of a separate study funded by the European Union, the researchers will also be using the algorithm to test whether it can predict which patients will need a knee replacement, by detecting early signs of arthritis.

Most of the registered clinical trials of potential treatments for COVID-19 underway as of late March were designed in ways that will greatly limit their value in understanding potential treatments, according to a study from researchers at Johns Hopkins Bloomberg School of Public Health.

The researchers, whose findings appear June 9 in the journal BMJ Open, analyzed the 201 clinical trials for drugs or plasma that, as of March 26, had been registered in the U.S. under ClinicalTrials.gov and in the international clinical trials registry maintained by the World Health Organization (WHO). Of the trials analyzed in this early snapshot, 100 (49.8 percent) were registered in China and 78 (37.8 percent) in the U.S. The majority of trials in the U.S. clinical trials registry were registered from international researchers. Among the 201 trials analyzed, 126 were recruiting participants from China, 31 from Europe, 14 from the U.S.

The researchers found that many of the trials lacked key features needed to optimize their scientific value such as the use of control groups and patient and clinician blinding.

The analysis found that one-third of trials lacked clinical endpoints to clearly define success or failure. Nearly one-half were designed to enroll fewer than 100 patients, limiting their usefulness to assess modestly-sized treatment benefits. Two-thirds were "open label," meaning that patients and doctors were aware who did and didn't receive the treatment--in principle, allowing their unconscious expectations to influence the results.

"Because of these weaknesses, many of these studies are likely to yield only preliminary evidence," says study first author Hemalkumar Mehta, PhD, an assistant professor in the Department of Epidemiology at the Bloomberg School. "Given the urgency of identifying definitive evidence on potential COVID-19 treatments, this is an instance where we wish we did not have to say 'further research is needed' because of basic trial design shortcomings and small trials."

The rapid initiation of so many clinical trials reflects the lack of any effective treatment for acute COVID-19 disease, whose global toll exceeds 400,857 deaths worldwide as of June 8, 2020, according to the World Health Organization's situation report. Of the 201 trials the researchers analyzed in their paper, the vast majority involved treatments already used for other diseases--treatments that could potentially be repurposed for COVID-19 relatively quickly because they have existing safety profiles and have already been evaluated by the U.S. Food and Drug Administration or other regulators around the globe.

U.S. doctors generally have wide discretion to prescribe FDA-approved drugs for other, "off-label" conditions. The authors note that off-label use can carry risks, and it is essential that therapies, including those used off-label, are studied for safety and effectiveness for COVID-19.

In all, the 201 trials involved 92 distinct drugs as well as antibody-containing blood plasma.

Mehta and colleagues found that most of these trials demonstrated design weaknesses. For example, about a third had no defined clinical endpoint, such as hospital discharge or survival, by which success could be measured. About a quarter lacked the standard random assignment of patients to a candidate treatment or control/comparator drug. Of the 152 trials that did randomize patients to a treatment or comparator, only 55 involved the usual practice of 'blinding'--a bias-reducing strategy in which patients as well as doctors and others who direct care and assess outcomes are kept from knowing who received the treatment or placebo.

"We understand the urgency of clinical research on COVID-19, but this is a time when we need rigorous science to inform policy and clinical decision-making," says study senior author G. Caleb Alexander, MD, professor in the Department of Epidemiology at the Bloomberg School. "Any treatment that is ultimately deemed safe and effective via robust trials could potentially be used by millions of people."

The researchers noted that the number of U.S.- or WHO-registered clinical trials of potential COVID-19 treatments tripled from the beginning of March to March 26 when they did their snapshot survey, and since March 26 has risen to more than 2,000 registered trials as of June 8, 2020, as new trials are registered on a daily basis.

"As the safety and effectiveness of new treatments are evaluated, it's vital that we use the best science to do so," Mehta says. "It's especially important at this juncture with many lives in the balance."

PULLMAN, Wash. - People suffering from post-traumatic distress disorder report that cannabis reduces the severity of their symptoms by more than half, at least in the short term, according to a recent study led by Carrie Cuttler, a Washington State University assistant professor of psychology.

Cuttler and her colleagues analyzed data of more than 400 people who tracked changes in their PTSD symptoms before and after cannabis use with Strainprint, an app developed to help users learn what types of medical cannabis work best for their symptoms. The group collectively used the app more than 11,000 times over a 31-month period.

The study, recently published in Journal of Affective Disorders, shows cannabis reduced the severity of intrusions, returning thoughts of a traumatic event, by about 62%; flashbacks by 51%, irritability by 67%, and anxiety by 57%. The symptom reductions were not permanent, however.

"The study suggests that cannabis does reduce symptoms of PTSD acutely, but it might not have longer term beneficial effects on the underlying condition," said Cuttler. "Working with this model, it seems that cannabis will temporarily mask symptoms, acting as a bit of a band aid, but once the period of intoxication wears off, the symptoms can return."

PTSD is a disorder affecting people recovering from traumatic events and impacts women at about twice the rate as men with a 9.7% to 3.6% lifetime prevalence, respectively. While therapy is recommended as the primary treatment, Cuttler said there is growing evidence that many people with PTSD are self-medicating with cannabis.

"A lot of people with PTSD do seem to turn to cannabis, but the literature on its efficacy for managing symptoms is a little sparse," Cuttler said.

This study provides some insight into the effectiveness of cannabis on PTSD symptoms, but as the authors note, it is limited by reliance on a self-selected sample of people who self-identify as having PTSD. Also, it is not possible to compare the symptom reductions experienced by cannabis users to a control group using a placebo.

While some placebo-controlled clinical trials have been done with nabilone, a synthetic form of THC, few have examined the effects of the whole cannabis plant on PTSD.

In this study, Cuttler and her colleagues looked at a variety of variables but found no difference in the effect of cannabis with differing levels of tetrahydrocannabinol (THC) and cannabidiol (CBD), two of the most studied constituents of cannabis. The results imply that it is some combination of THC, CBD and perhaps some of the many other parts of the cannabis plant that create the therapeutic effect. Cannabis has many molecules that can create a biological effect, including up to 120 cannabinoids, 250 terpenes and around 50 flavonoids.

"We need more studies that look at whole plant cannabis because this is what people are using much more than the synthetic cannabinoids," said Cuttler. "It is difficult to do good placebo-controlled trials with whole plant cannabis, but they're still really needed."