Body

New research from Baylor College of Medicine scientists shows that a combination of deep brain stimulation (DBS) and exercise has potential benefits for treating ataxia, a rare genetic neurodegenerative disease characterized by progressive irreversible problems with movement.

Working with a mouse model of the human condition, researchers at Baylor and the Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital discovered that combining DBS targeted to the cerebellum, a major motor center in the brain, and exercise rescued limb coordination and stepping and that the benefits persisted without further stimulation. In addition, the study reports that stimulating mice with early-stage ataxia showed the most dramatic improvements. These and other findings, published in the journal Nature Communications, provide valuable new insights in designing future DBS strategies to treat the human condition.

"People with ataxia usually have progressive problems with movement, including impaired balance and coordination that affect the person's ability to walk, talk and use fine motor skills. There are limited treatment options for this condition, and patients typically survive 15 to 20 years after symptoms first appear," said first author Lauren Miterko, a graduate student in Dr. Roy Sillitoe's lab at Baylor.

DBS currently is used to relieve motor dysfunction in Parkinson's disease and other movement conditions, but its value in treating ataxia has not been extensively explored. In this study, the researchers worked with Car8, a mouse model of hereditary ataxia to investigate whether adjusting the parameters of DBS and the stimulation target location would help increase the treatment's efficacy for the condition.

Frequency matters

"We first targeted the cerebellum, because it's a primary motor center in the brain and this target location for DBS has seen encouraging success for treating motor problems that are associated with other conditions, such as a stroke," Miterko said. "We systematically targeted the cerebellum with different frequencies of DBS and determined whether there was an optimal frequency that would boost the efficacy of the treatment. When we used a particular frequency, 13 Hz, that was when motor function improved in our Car8 mice."

DBS plus exercise improved the outcomes

Neurostimulation with DBS improved muscle function and the general mobility of Car8 mice, but the researchers looked for additional ways to improve the condition.

"We know that exercise in general can benefit both muscle and neuronal health, and previous work in Parkinson's disease and stroke patients mentioned that neuromodulation techniques combined with physical stimulation showed benefits, so we decided to include exercise in our investigation," Miterko said. "We found that when the animals received DBS during exercise on a treadmill, there were improvements in motor coordination and stepping that we had not observed with DBS alone."

"In our ataxia model, improvements did not go away after one week of treatment, which has important practical implications for potential clinical applications," said co-author Dr. Meike E. van der Heijden, postdoctoral associate in the Sillitoe lab. "Also, all young mice with early stage ataxia responded, suggesting that it is possible that early treatment also might provide the biggest benefit for patients in the future."

The researchers also gained insights into the type of brain cells involved in the process of restoring movement in this ataxia mouse model. They found that Purkinje cell neurotransmission is needed for DBS to be effective. Purkinje cells are a type of neuron located in the cerebellar cortex of the brain. These cells are involved in the regulation of movement, balance and coordination among other functions.

"One of our goals is to further elucidate the role Purkinje cells play in recovering from ataxia," van der Heijden said.

"We are particularly excited about the results of this study because it may be possible to extrapolate our approach for treating not only other motor diseases, but perhaps also non-motor neuropsychiatric conditions," said corresponding author Dr. Roy Sillitoe, associate professor of pathology and immunology and neuroscience at Baylor College of Medicine, and director of the Neuropathology Core facility at the Jan and Dan Duncan Neurological Research Institute of Texas Children's Hospital.

Per- and polyfluoroalkyl substances (PFAS) are a class of man-made chemical compounds and a current, emerging concern to environmental health. PFAS substances have unique characteristics-resistance to heat, water, oil and stains-that make them useful in a variety of industrial applications and popular in consumer goods. Many PFAS are stable and long-lasting in the environment, acquiring the name "forever chemicals." Industrial use of some of these compounds has been halted; however, many derivatives are still in commerce and more are under development. PFAS are now found in many compartments of the environment.

In order to manage PFAs in the environment, a lot of research has been directed at understanding their sources, fate and transport in the environment, and their potential effects on humans and wildlife. Recently, Environmental Toxicology and Chemistry (ET&C) published a special issue dedicated to PFAS with 32 articles, providing a valuable summarization of risk assessment approaches for PFAS, which are needed for environmental managers and regulatory bodies to set appropriate drinking water standards and health advisory guidelines.

The published research illustrates that PFAS are ubiquitous and raise more questions than answers about their potential toxicity to humans and wildlife. The articles in the issue report that PFAS were found near defense bases, urban environments, treatment plants and waste disposal sites but also in remote, less inhabited areas. PFAS were detected in breeding kittiwakes in Svalbard, Norway, and ducks in Australian estuaries. They were found in hens' eggs, soil, tadpoles, zebrafish, house crickets; the list goes on. The breadth of the published research illustrates that PFAS have dispersed in every medium in the environment (soil, water and wildlife).

In some of the studies, the presence of PFAS was related to a nearby source while in others it was not determined. For example, the authors of the article that investigated PFAS in Australian ducks did find a correlation between local sources of PFAS and bioaccumulation in ducks and noted that "Human health risk assessment showed that only ducks inhabiting wetlands near local sources of PFAS were likely to pose a risk to consumers," and continued, "Management of food consumption from these locations is an effective measure to limit exposure." In another study published in this same issue, long-chain PFAS were found in eight fish species across ten European glacial lakes in the Alps region, and while correlated to urban areas, could not be attributed to a specific, nearby industry source.

The issue illustrates that there are a tremendous number of PFAS substances, and it is a challenge for environmental managers and regulatory bodies to devise an approach to identify, understand and manage them all. The series provided a great review of the state of the science of PFAs risk assessment and also identified data gaps and the work needed to fill them in order to devise an effective approach to manage PFAS.

On January 14, 2021, the Department of Health and Human Services (HHS) submitted notice to the Federal Register that it would issue practice guidelines that exempt physicians from the requirement to apply for a waiver to prescribe buprenorphine to treat opioid use disorder (OUD) in up to 30 patients at one time. This exemption has been placed on hold by the Biden administration and may require legislative change to implement. An exemption to the X-waiver has the potential to help reverse the morbidity and mortality associated with the opioid overdose epidemic, although without accompanying changes and attention it will not be enough.

The combination of the COVID-19 pandemic and the opioid overdose epidemic fueled by high-potency synthetic opioids have led to increased overdoses. However, national and state leadership, health professions schools, and health care systems in the US have not responded sufficiently. More than 83,000 drug overdose deaths occurred in the US in a 1-year period ending in June 2020, the highest number of overdose deaths ever recorded in a 12-month period, and an increase of more than 21% compared with the previous year.2 Nationally, 67% of opioid overdose deaths involved fentanyl in 2018 and drug overdoses increased most among non-Hispanic Black individuals. Despite these devastating losses, access to evidence-based care to prevent opioid overdose and treat OUD remains highly regulated, restricted, and very limited, particularly among Black individuals with OUD and in rural communities. It is estimated that only 18% of individuals with OUD in the US receive highly effective medications, such as buprenorphine or methadone, to treat OUD.3 For many, the COVID-19 pandemic has further limited access to medications for OUD (MOUD).

Unlike other medical conditions, treatment of OUD has substantial and unique restrictions imposed by US federal and state laws. Such restrictions do not facilitate access to care; on the contrary, they impede it. Methadone for OUD must be administered or dispensed by an accredited, registered, and certified opioid treatment program. The Drug Addiction Treatment Act of 2000 (DATA 2000) requires that prescribers of buprenorphine apply for a waiver (ie, X-waiver) to prescribe once certain educational and practice requirements have been met. However, this restriction has outlived any usefulness.

Although appropriate training is essential to care for any disease, federal law does not require such training or registration to prescribe for other diseases (and more specifically, not for prescribing opioids for other indications such as pain). However, health professions schools are mandated by entities such as the Association of American Medical Colleges (AAMC) and the Accreditation Council for Graduate Medical Education (ACGME) to provide training to treat most other diseases. As of 2018, only 1 of 191 medical schools provided training to their students that was sufficient to meet the DATA 2000 training requirement. Additionally, neither AAMC nor the ACGME require competency in OUD evaluation and treatment in medical education. Together, the absence of health professions school and graduate education; prescribing restrictions; stigma and misinformation among patients, families, and health care professionals; archaic payment structures and systems that emphasize acute care models over long-term treatment; care largely separate and uncoordinated from the rest of health care; and lack of support for patients' psychosocial needs have impeded the large expansion of MOUD treatment that is required to meet the need.

In an effort to address the vast need for MOUD treatment accessibility in the US, the HHS exemption proposed changes as follows. Physicians would need to place an "X" on the prescription, note that the prescription is to treat OUD, maintain separate records for such patients, prescribe to patients in the state in which they practice, and limit prescribing to no more than 30 patients at one time.1 Physicians who want to treat more than 30 individuals with OUD would need to seek additional training through the current 8-hour DATA 2000 mechanism. Notably, these guidelines do not apply to the large workforce of advanced practice clinicians who remain mandated to complete 24 hours of training to prescribe buprenorphine.

Relaxing restrictions on physician prescribing does have the potential to expand access to treatment and reduce opioid overdose deaths as it has in other countries. For example, in France, buprenorphine became available in 1995 and an estimated 3% of patients with OUD were treated that year with MOUD; by 2006, 67% of the 180?000 people with OUD were treated with methadone (n?=?26?000) or buprenorphine (n?=?95?000) in a setting with relaxed MOUD regulations.4 Rates of prescribing continue to be high, although over time, initiation of prescribing has shifted somewhat from primary care to specialized addiction treatment centers. While there are some cautionary tales from the rapid expansion of buprenorphine prescribing in France, such as subtherapeutic buprenorphine dosing, it has been estimated that a similar increase in prescribing in the US that occurred in France could have potentially led to an estimated 37?000 fewer deaths in 2018 alone if it were used appropriately, adherence was high, and the same conditions were being treated in the US as in France.4

Inaction is not an option when 40% of counties in the US do not have a single prescriber of MOUD.5 The proposed 2021 HHS guidelines represented progress toward MOUD expansion; however, they were far from enough to address the opioid overdose crisis. The US needs to normalize the treatment of OUD among health care professionals and individuals with OUD. Practicing health care professionals should be encouraged and incentivized to prescribe and obtain any needed training or support. OUD identification, evaluation, and treatment education should be integrated in all health care professions schools and should be implemented throughout all health care systems. It is also important to emphasize that medical management of OUD is effective, that buprenorphine alone at therapeutic doses can improve outcomes and prevent overdose,6 and that detoxification alone is insufficient to prevent overdose and treat OUD.

Buprenorphine prescribing by trained health care professionals can promote high-quality care and the new exemption could increase that prescribing. However, much more will need to be done. These additional steps include eliminating limits on the number of patients who could be treated by individual clinicians. One estimate suggests that by eliminating patient limits, the US could potentially treat nearly 800?000 additional individuals with OUD.7 Further needed actions include allowing prescribing by advanced practice clinicians; advocating for addiction training efforts at health professions schools, postgraduate programs, and as part of continuing education to make up for previously absent training; allowing office-based methadone treatment to ensure expansion to all types of MOUD; enforcing parity of benefits and insurance coverage for treatment; and addressing the stigma of addiction and addiction treatment. The effects of regulatory changes should be studied after implementation.

Recommendations to Help Ensure Access to High-Quality Medication Treatment for Opioid Use Disorder (OUD)

Pass federal legislation to ensure lasting changes on a national scale

Eliminate buprenorphine patient limits and Drug Enforcement Administration audits that discourage prescribing; include advanced practice clinician prescribers in any legislative change; and remove restrictions on methadone prescribing and dispensing outside opioid treatment programs

Improve and provide training for prescribers and health professional teams at all levels

Incentivize training and offset clinician training time; provide a menu of training options appropriate to the needs of the clinician; integrate substantial training into specialty-specific health professions schools, postgraduate programs, continuing education, and maintenance of certification; include patient perspectives in all training; and provide experiential learning, such as apprenticeship models (eg, with mentors), in practice

Expand access to all forms of OUD treatment shown to have efficacy

Increase access to strategies that reduce consequences of drug use ("harm reduction"); increase access to methadone treatment (eg, via primary care clinicians and pharmacies); and increase access to all treatment options (beyond specialty treatment programs) including medications

Address stigma and include patients receiving medications for OUD (MOUD) in educational campaigns

Enforce Parity (Mental Health Parity and Addiction Equity Act) to ensure equitable coverage and reimbursement for addiction and behavioral health treatments

Ensure equitable access to MOUD in all treatment settings

Study the effects of regulatory changes after implementation

Comprehensive treatment for OUD, including medical, psychiatric, and social services, can and should be provided by experienced clinicians and should be expanded, but MOUD urgently needs to be more accessible. The proposed HHS exemption would offer progress toward achieving that goal even though it was not, as written, a panacea. Improving access while ensuring high-quality care for individuals with OUD to sustain lasting reductions in opioid overdose deaths will require implementing these guidelines and additional strategies, many of which have been suggested for decades. As the new administration considers how to move forward, enacting an improved version of these guidelines and durable legislative changes to ensure access to high-quality MOUD offers a possibility to meaningfully address the overdose crisis.

Dr. Felix-Martin Werner, working at the Euro Academy Pößneck in Germany and Prof. Rafael Coveñas, working at the Institute of Neurosciences of Castilla and León, Salamanca in Spain, have been working on neurological and psychiatric disease for over ten years. In their most recent review, published in Current Pharmaceutical Design (Bentham Science Publishers) Werner and Coveñas cover information about the risk genes in schizophrenia and explain the importance of examining their single nucleotide polymorphisms (SNP's). In schizophrenia, 260 risk genes have been discovered, and an association between single SNPs and the clinical efficacy of a specific antipsychotic drug has been established. Among the risk genes in schizophrenia, the COMT, MAO A/B, GAD 67, DAOA, dysbindin-1 and neuregulin-1 genes are described, and their functions can be represented by an updated neural network model of the ventral tegmental area, hippocampus and prefrontal cortex. The COMT and MAO A/B genes encode a decreased dopamine degradation. As a consequence, dopamine hyperactivity via D2 receptors occurs in the hippocampus and ventral tegemental area. The GAD 67 gene encodes a GABA dysfunction. Consequently, GABAergic neurons weakly inhibit D2 dopaminergic neurons in the hippocampus and ventral tegmental area via GABAA receptors. The DAOA gene encodes a glutamatergic dysfunction. This leads to a weak presynaptic inhibition of 5-HT2A serotonergic neurons in the hippocampus and ventral tegmental area via NMDA receptors. Dysbindin-1 and neuregulin-1 genes encode as well a glutamatergic dysfunction. The most important SNPs, which show an association with a specific pharmacotherapy, are mentioned. The SNP rs169774 of the COMT gene and the SNP rs1801028 of the D2 receptor gene are linked with an increased efficacy of the antipsychotic drug risperidone. The SNP of the COMT and D2 receptor genes are related with a dopamine hyperactivity psychosis and treatment resistance. Patients suffering both hyperactivity and resistance could be treated with the antipsychotic drug clozapine in combination with the novel antipsychotic drug cariprazine. This drug combination improves the PANSS total score in treatment-resistant schizophrenic patients. "By examining in a cohort of schizophrenic patients the SNPs of the risk genes, it will be possible to differentiate patients with a good response to a specific antipsychotic drug from those with treatment resistance," notes Dr. Werner.

Memphis, Tenn. (February 25, 2021) - Early diagnosis of Alzheimer's disease has been shown to reduce cost and improve patient outcomes, but current diagnostic approaches can be invasive and costly. A recent study, published in the Journal of Alzheimer's Disease, has found a novel way to identify a high potential for developing Alzheimer's disease before symptoms occur.

Ray Romano, PhD, RN, completed the research as part of his PhD in the Nursing Science Program at the University of Tennessee Health Science Center College of Graduate Health Sciences. Dr. Romano conducted the research through the joint laboratory of Associate Professor Todd Monroe, PhD, RN, at The Ohio State University, who is also a graduate of the UTHSC Nursing Science PhD Program, and Ronald Cowan, MD, PhD, who is the chair of Psychiatry at UTHSC. The study is titled, "Could altered pain responsiveness be a phenotypic biomarker for Alzheimer's risk? A cross-sectional analysis of cognitively healthy adults."

Dr. Romano said, "There is a real need to find ways to diagnose Alzheimer's disease in the primary care setting, where most patients first present with concerns for their memory." Dr. Romano earned his PhD in Nursing Science at UTHSC in 2020.

The research found that cognitively healthy people at increased genetic risk of late-onset Alzheimer's disease showed significantly lower sensitivity to thermal pain, but felt greater unpleasantness related to that pain when compared to people at lower risk of the disease. These results suggest that altered pain perception could potentially be used as a biomarker of late-onset Alzheimer's disease before symptoms occur.

Previous research had identified a specific genetic allele, APOE4, as a marker associated with an increased incidence of developing late-onset Alzheimer's disease. In his groundbreaking study, Dr. Romano was able to identify individuals who were cognitively healthy but had the APOE4 allele. He was then able to determine whether people with the APOE4 allele responded differently to experimentally induced painful stimuli than did cognitively healthy individuals who did not have this allele.

Dr. Cowan noted, "This work also highlights the great strength of joint collaborations between nursing and psychiatry, which have been highly productive for our research programs."

The study included 49 cognitively healthy adults aged 30-89. Twelve of the subjects had the APOE4 allele, and 37 did not. They were assessed for group differences in pain thresholds and feelings of unpleasantness in response to experimentally induced thermal pain stimuli.

Use of this biomarker to identify people at risk of Alzheimer's disease before the onset of serious symptoms would be much less invasive than other methods of Alzheimer's diagnosis, which include lumbar punctures and positron emission topography (PET) scans. These are expensive tests that are not practical in primary care settings.

"In this exploratory study, Dr. Romano demonstrated that healthy adults with a specific gene for developing late-stage Alzheimer's disease experience pain differently than people without the genetic marker," Dr. Monroe said. "Next, we need to examine the brain's pain systems to determine why this may be occurring. If future studies confirm these results, findings may eventually translate into earlier screening in people at risk of developing Alzheimer's disease leading to more treatment options."

Although guidelines do not recommend use of opioids to manage pain for individuals with knee osteoarthritis, a recent study published early online in Arthritis Care & Research, an official journal of the American College of Rheumatology and the Association of Rheumatology Professionals, estimates that 858,000 Americans use opioids such as tramadol and oxycodone for their knee pain, equating to $14 billion in lifetime opioid-related societal costs, or nearly $0.5 billion annually.

A team led by Elena Losina, PhD, Robert W. Lovett Professor of Orthopedic Surgery, of Brigham and Women's Hospital, used a computer simulation to estimate the annual and lifetime contribution of opioids to knee osteoarthritis-related costs. The researchers show the direct medical cost of knee osteoarthritis treatment including opioids totals $7.45 billion or 53 percent of the total lifetime costs. The remaining 47 percent of lifetime costs to society is used to pay for lost productivity at work, criminal justice expenses due to opioid use disorders among patients with knee osteoarthritis and cost associated with diversion activities related to illicit use by others.

For an individual patient who used opioids to treat their knee osteoarthritis, the lifetime opioid-related cost was estimated at $13,770. "Given larger number of patients with knee osteoarthritis using opioids, our results provide additional evidence of the substantial economic burden of opioid use for knee osteoarthritis pain management and the potential savings from preventing opioid use," said Dr. Losina.

The results reveal a substantial economic burden of opioid use among patients with knee osteoarthritis, and they indicate that substantial savings can result from following current guidelines recommending against such use.

"The most important part of our study is that we estimated that almost half of the total societal cost of opioid use in persons with symptomatic knee osteoarthritis is used to pay for lost work productivity and criminal justice and other consequences of the diversion of prescribed opiates to unlawful use," concludes Dr. Losina. "These data offer new evidence of the magnitude of the societal burden generated by opioid use and misuse and could be used to educate health care providers and health policy decision makers on the best alternatives to opiate use."

Long-term use of a medication used to treat kidney transplant patients may not be necessary in individuals with low-to-moderate risk of organ rejection, according to the results of a study led by a University of Cincinnati transplant researcher.

The randomized clinical trial of 385 patients on immunosuppressive drugs tacrolimus and mycophenolate examined whether use of these medicines called corticosteroids could be eliminated at seven days after kidney transplantation. The study shows that 15 years after transplantation no difference in kidney transplant survival or patient survival rates were found between patients who received long-term corticosteroids versus those who had corticosteroid eliminated early, explains E. Steve Woodle, MD, the William A. Altemeier Endowed Chair and Professor of Surgery in the UC College of Medicine, and leader of the study.

"There are a lot of reasons to be off corticosteroids as soon as possible," says Woodle, also director of solid organ transplantation at UC Health. "Historically, the number one complaint that transplant patients express is the various side effects of corticosteroids. They really don't like the disfiguring effects of steroids, including changes in body shape with abnormal fat distribution."

"Corticosteroids make their face round, and they often also develop stretch marks in their skin," explains Woodle. "Acne is particularly problematic in young and teenage transplant patients. Beyond the cosmetic effects, corticosteroids cause bone disease and lead to loss of collagen in tissues causing skin to bruise easily. Diabetes, high blood pressure and high cholesterol increase cardiovascular complications, which in the long term reduces patient survival."

The study's findings were published online in JAMA Surgery.

The prospective trial was randomized and double-blinded, meaning doctors and patients didn't know if they were receiving the drug or a placebo and involved patients enrolled from 28 multiple kidney transplant sites. At the original five-year end of the study, there was no difference in death rates related to transplantation or other causes in the two groups, says Woodle.

Rates of moderate to severe short-term organ rejection also did not differ, but there was a higher rate of biopsy-confirmed (samples were taken from the transplanted kidney) signs of rejection in patients withdrawn from corticosteroids compared to those who continued with corticosteroid use. Biopsy-confirmed signs were 7% higher in patients not on corticosteroids but physicians were able to reverse that impact with limited use of corticosteroids, says Woodle.

Meanwhile, kidney function was similar between the groups on and off corticosteroids, but weight gain, serum triglyceride levels and insulin-requiring diabetes rates were lower in patients taken off corticosteroids.

"The current study extended follow-up in patients to over 15 years using data in the national UNOS transplant database," says Rita Alloway, PharmD, research professor in the UC Division of Nephrology, Kidney CARE and a study co-author. "Interestingly, an invited commentary on this 15-year report, suggested that physicians should no longer use corticosteroids unless there is a justifiable reason."

The study's result could have an impact on treatment for more than 22,000 people who received a kidney transplant in the U.S. last year. In the United States, more than 97,000 patients are on a waiting list for kidney transplantation. Woodle first tested the corticosteroid free regimen in 1995 and it remains the standard of care at UC today.

"This study is the culmination of 30 years of work in trying to eliminate the morbidity related to corticosteroid use in transplant patients," says Woodle. "It confirms that you do not pay a price in terms of how long a kidney lasts and how long the patient lives if you remove corticosteroids early."

What The Article Says: This JAMA Insights review from Centers for Disease Control and Prevention COVID-19 Response team members presents data on the number of long-term care facilities and the numbers of residents and staff of those facilities who received first-dose vaccination through mid-January under the agency's public-private partnership with CVS, Walgreens and Managed Health Care Associates.

Authors: Radhika Gharpure, D.V.M., M.P.H., of the COVID-19 Response at the CDC, is the corresponding author.

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

(doi:10.1001/jama.2021.2352)

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

The steadily increasing prevalence and high costs of treating chronic joint pain worldwide poses a challenge for healthcare systems and healthcare payers. New research published today in JAMA Network Open shows the effectiveness of a digital healthcare treatment with the potential to save insurance companies and their patients the costs and risks of joint surgeries - a finding that is especially promising as more patients turn to telemedicine as a safe treatment option amid the COVID-19 pandemic.

A new randomized controlled trial (RCT) conducted by the University of Nottingham using Joint Academy's clinical evidence-based digital treatment for chronic joint pain is the first to find clinically important improvements of treating knee osteoarthritis digitally compared to traditional treatment. Patients receiving digital treatment reduced their pain by 41 percent, while patients receiving traditional care only experienced a 6 percent decrease.

"We already knew that digital first-line treatment substantially improves symptoms of osteoarthritis at a significantly lower cost than face-to-face care. This study firmly establishes how effective digital treatment actually is in relation to traditional self-management care," says Leif Dahlberg, Chief Medical Officer at Joint Academy and Senior Professor in Orthopedics.

A total of 105 people, who were 45 years or older with a diagnosis of knee osteoarthritis, participated in the study. They were allocated at random to two groups. One was treated digitally and the other self-managed their symptoms according to guidelines. Patients in the digital treatment were connected with licensed physical therapists via a smartphone application where they received education and daily exercises. In the other group, patients continued their traditional self-management program and visited their general practitioner when needed.

"The results of the study really show how much can be gained by treating chronic knee pain digitally, and this will help reduce the burden on the healthcare system, especially when we are going through the COVID-19 pandemic where services are already stretched. We hope this study allows health policy-makers to consider the potential in digital alternatives when it comes to treating knee arthritis", says Sameer Akram Gohir, physical therapist and researcher at the University of Nottingham.

Osteoarthritis is one of the world's fastest growing and most costly chronic diseases. According to the Centers for Disease Control, more than 32 million U.S. adults are affected. It is also among the most expensive conditions to treat when joint replacement surgery is required. For the millions who suffer with the daily pain and stiffness of osteoarthritis, treatments to slow the progression of the disease are limited. The recommended first-line treatment, consisting of information, exercise and weight control when needed, is underutilized.

"The study shows the positive impact digital treatment has on the osteoarthritis burden for both patients and healthcare systems. Besides the beneficial outcomes in pain and physical function, the advantages of digital treatment include lower costs as well as making care more easily accessible for those living in rural areas far from the nearest physical therapist," Dahlberg concludes.

Joint Academy connects patients with licensed physical therapists through telemedicine, making it a safe treatment option during the COVID-19 pandemic. The treatment is now available under certain health plans in the United States and seeking to expand to become available to more providers and patients in 2021.

CLEVELAND, Ohio - Researchers at University Hospitals Rainbow Babies & Children's Hospital (UH Rainbow) published new findings today that wearing a face mask - either a cloth mask or a surgical mask - did not impair the ability of subjects to get air in and out of their bodies.

The study measured heart rate, transcutaneous carbon dioxide tension, and oxygen levels in 50 adult volunteers at the conclusion of six 10-minute phases: Sitting quietly and then walking briskly without a mask; sitting quietly and then walking briskly while wearing a cloth mask; and sitting quietly and then walking briskly while wearing a surgical mask. The median age of participation was 33 years and 32 percent of participants indicated they have a chronic health condition such as asthma.

In the study, not a single participant developed a low level of oxygen or high level of carbon dioxide in the blood while wearing a cloth or surgical mask either at rest or during exercise. According to the study's principal investigator, Steven L. Shein, MD, Division Chief of Pediatric Critical Care Medicine at UH Rainbow Babies & Children's Hospital, the risk to the general adult population of having significantly abnormal levels of oxygen or carbon dioxide when wearing a cloth or surgical mask is near-zero.

"We know face masks help to prevent the spread of COVID-19, but we also know people have concerns of discomfort or impaired breathing while wearing them," says Dr. Shein, who is also the Linsalata Chair in Pediatric Critical Care and Emergency Medicine, and Associate Professor of Pediatrics at Case Western Reserve University School of Medicine. "Our hope is these findings will reassure people that their body is able to adequately get oxygen in and carbon dioxide out while wearing a face covering."

A study aiming to develop a new therapeutic technique could bring a revolution in our approach to treating rare, fatal Sanfilippo syndrome, a disorder that affects children as young as 2 years old and leads to childhood dementia and premature death.

"We are using a combination of gene therapy, stem cells and small molecules to restore metabolic defects in the patient's brain cells" says Dr. Alexey Pshezhetsky, Professor at CHU Ste-Justine and lead GlycoNet Investigator on this project. "First results in the mouse models of the disease are very encouraging."

Sanfilippo syndrome belongs to a group of rare diseases known as lysosomal storage disorders.

The syndrome occurs in pediatric patients when the enzymes that the body needs to break down certain sugars are absent or defective. The sugars build up in the brain, causing severe damage.

"Children display symptoms like dementia," explains Pshezhetsky. "They experience behavioral problems and sleep disturbance, lose the ability to speak and most of them die before the age of 20."

Due to their individual rarity, lysosomal storage disorders have not traditionally been a focus for developing treatments. Only a few types have a treatment, and none of these has a cure.

Furthermore, the fact is that these "rare" diseases are not rare. Individually, they are considered rare, but collectively, they affect about 1 in 5,000 births. Moreover, some diseases are more frequent in specific populations such Tay-Sachs disease affecting Ashkenazi Jewish and French Canadians or Sandhoff disease with high prevalence in northern Saskatchewan.

A new treatment is needed

Lysosomal storage disorders that do not affect the brain are treated through enzyme replacement therapy, in which patients are injected weekly or monthly with the enzymes they lack. However, this treatment does not work well with Sanfilippo syndrome, as the injected enzymes cannot reach the brain--the place where they are needed.

"There is a physical barrier between the brain and the bloodstream that enzymes cannot pass through," says Pshezhetsky. "So, in cases where enzyme replacement therapy is ineffective, we are looking for new treatments that can potentially cure or ameliorate the disease."

In the method proposed by Pshezhetsky, he and his team are using a combination of gene therapy and transplantation of hematopoietic (blood-forming) stem cells. First, the patient's own stem cells are harvested and genetically corrected to eliminate enzyme defects. Then, these stem cells are injected back to the patient. Healthy blood cells that can secrete functional enzymes will proliferate and migrate to different tissues including the brain.

Unlike enzyme replacement therapy, this therapeutic technique will require only one-time treatment and would be in line with currently used clinical procedures. "It would be similar to a bone marrow replacement therapy. Once you get the treatment, you have a life-long supply of cells you need," says Pshezhetsky.

Based on the promising preliminary results of their mouse studies, Pshezhetsky and his colleagues are moving forward with plans to gather more data before testing the therapy in human patients.

Clinical applications to other types of rare disorders

Sanfilippo shares common pathology with other types of diseases in the same family of lysosomal storage disorders.

"About two-thirds of lysosomal storage disorders affect the brain. If we find out how to treat Sanfilippo syndrome, we can extend our knowledge to other similar diseases," says Pshezhetsky.

"I think it's important for people to know that recent discoveries lead to a paradigm shift for pediatric healthcare. Even if diseases are rare or ultra-rare we are not leaving patients behind but are developing customized ways to treat them," he adds.

There is a great potential for the novel treatment combining hemopoietic stem cells transplantation with gene therapies. This approach would be a new tool for clinicians to treat a range of rare genetic conditions that affect the brain.

DALLAS - Feb. 24, 2021 - Using machine learning tools to analyze hundreds of proteins, UT Southwestern researchers have identified a group of biomarkers in blood that could lead to an earlier diagnosis of children with autism spectrum disorder (ASD) and, in turn, more effective therapies sooner.

The identification of nine serum proteins that strongly predict ASD were reported in a study published today by PLOS ONE.

Earlier diagnosis, followed by prompt therapeutic support and intervention, could have a significant impact on the 1 in 59 children diagnosed with autism in the United States. Being able to identify children on the autism spectrum when they are toddlers could make a big difference, says Dwight German, Ph.D., professor of psychiatry at UT Southwestern and senior author of the study.

Currently, the average age of a child diagnosed with ASD in the U.S. is 4 years old. Diagnosis before the age of 4 means that a child is more likely to get effective, evidence-based treatment, such as therapies directed at core ASD symptoms, including inflexible behaviors and the lack of communication or social skills.

Many blood-based biomarker candidates have been investigated, including neurotransmitters, cytokines, and markers of mitochondrial dysfunction, oxidative stress, and impaired methylation. However, given the prevalence of ASD, the use of machine learning to incorporate demographic and clinical data into the analysis could more powerfully examine disease status and symptom severity.

For the study, serum samples from 76 boys with ASD and 78 from typically developing boys, all ages 18 months to 8 years, were examined.

All nine proteins in the biomarker panel were significantly different in boys with ASD compared with typically developing boys. Researchers found that each of the nine serum proteins correlated with symptom severity.

More than 1,100 proteins were examined using the SomaLogic protein analysis platform. A panel of nine proteins was identified as optimal for predicting ASD using three computational methods. The researchers then evaluated the biomarker panel for quality using machine learning methods. Future studies are needed to fully validate the present findings.

"The more significantly affected the child is, the higher or lower than normal the blood biomarker is," German says. "Ideally, there will be a day when a child is identified using blood biomarkers as being at risk for developing ASD and therapies can be started immediately. That would help the child develop skills to optimize their communication and learning."

The children in the study were recruited by Laura Hewitson, Ph.D., and Morgan Devlin at The Johnson Center for Child Health & Development, a multidisciplinary treatment center in Austin, Texas, that uses a unique combination of clinical care, research, and education to further the understanding of ASD and related developmental disorders. Hewitson noted that, "The earlier we can identify children with autism, the more understanding we can gain on ways to provide support and therapies that will improve their quality of life."

In a major advance in the treatment of multiple myeloma, a CAR T-cell therapy has generated deep, sustained remissions in patients who had relapsed from several previous therapies, an international clinical trial has found.

In a study posted online today by the New England Journal of Medicine, trial leaders report that almost 75% of the participants responded to the therapy, known as idecabtagene vicleucel (ide-cel), and one-third of them had a complete response, or disappearance of all signs of their cancer. These rates, and the duration of the responses, are significantly better than those produced by currently available therapies for patients with multiple relapses, according to investigators.

Based on these results, an application has been submitted to the Food and Drug Administration for approval of ide-cel as a standard therapy for patients with relapsed or treatment-resistant myeloma. A decision on the application is expected by the end of March 2021.

"Despite numerous advances in the treatment of multiple myeloma, relapses are common. Patients whose disease continues to worsen after receiving standard therapy have relatively few treatment options that provide high response rates," said Nikhil Munshi, MD, of Dana-Farber Cancer Institute, who led the trial. "The results of this trial represent a true turning point in the treatment of this disease. In my 30 years of treating myeloma, I have not seen any other therapy as effective in this group of patients."

Multiple myeloma is a cancer of plasma cells, which are white blood cells responsible for making antibodies against invasive germs. The disease is diagnosed in about 35,000 people in the United States each year, making it the second-most common blood cancer in adults. Among African Americans, it is the most common blood cancer.

Standard treatment for myeloma includes three main classes of therapy: immunomodulatory drugs, proteasome inhibitors (which block the action of protein-degrading structures in cells), and anti-CD38 antibodies. Patients who exhaust these approaches are in urgent need of better treatments.

Like all CAR T-cell therapies, ide-cel is made by collecting patient's immune system T cells and genetically modifying them to express a receptor for a protein on cancer cells. Infused back into the patient, the CAR T cells lock onto tumor cells and destroy them.

The target of ide-cel is a protein on myeloma cells called B-cell maturation antigen, or BCMA. BCMA has several advantages as a therapeutic target in myeloma, Munshi explained: It is expressed exclusively on plasma cells and in particularly large quantities on plasma-turned-myeloma cells; BCMA conducts signals important for myeloma cells' growth and survival; and it is expressed in virtually all patients with the disease.

In the trial, a phase 2 study dubbed KarMMa, 128 patients with active myeloma after receiving at least three previous therapies were treated with a single dose of ide-cel (different doses were tested in different patients). At a median follow-up of 13.3 months, 73% of the patients had a response - a measurable reduction in their cancer - and 33% had a complete response or better. Within this latter group, 79% had no detectable myeloma. The median progression-free survival - the length of time after treatment that the disease didn't worsen - was 8-9 months. Some of the patients have not relapsed more than two years after treatment.

These outcomes outshine those achieved by standard treatments for multiply-relapsed myeloma. Drugs such as selinexor, panobinostat, and isatuximab have a response rate of 25-30% and a progression-free survival of 3-4 months.

The most common side effects of treatment were low blood-cell counts and cytokine release syndrome, a frequent follow-on of CAR T-cell therapy in which the immune system generates an intensive inflammatory response. Clinicians have developed effective treatments for this condition.

The success of ide-cel in patients who had undergone several previous treatments has prompted investigators to launch trials of the therapy in patients in earlier stages of the disease.

BOSTON - Swelling of lymph nodes in the armpit area is a normal response to COVID-19 vaccinations, but when they are seen on mammograms, they can be mistaken for nodes that are swollen because of cancer. In some cases, the nodes are biopsied to confirm they are not cancer. To avoid confusion by patients and their providers, and to avoid delays in either vaccinations or recommended mammograms through the pandemic, radiologists at Massachusetts General Hospital (MGH) have published an approach to manage what is expected to be a fairly common occurrence as vaccination programs ramp up. The approach is described in the American Journal of Roentgenology.

"We had started to see more patients in our breast imaging clinic with enlarged lymph nodes on mammography, ultrasound, and magnetic resonance imaging. And we noticed they were coming to our clinic after a recent COVID-19 vaccination," explains lead author Constance Lehman, MD, PhD, director of Breast Imaging and co-director of the Avon Comprehensive Breast Evaluation Center at MGH. "We talked with our colleagues in primary care and in our breast cancer specialty clinics and realized we needed a clear plan for management."

The team's goals were to develop a program that supported patients to continue to engage in vaccination programs while also ensuring that patients continued to receive their routine health care needs, such as breast cancer screening. It was also important to reassure patients that swollen lymph nodes in the armpit is a normal and expected finding after vaccination.

The group's approach is based on three principles: 1) encouraging COVID-19 vaccination; 2) reducing and/or eliminating delays, cancellations, and rescheduling of breast imaging exams; and 3) reducing unnecessary additional imaging and/or biopsies of lymph nodes that have become swollen from recent vaccination.

"In addition to avoiding delays in vaccinations and breast cancer diagnoses, we hope that our model will reduce patient anxiety, health care provider burden, and costs of unnecessary evaluations of enlarged lymph nodes after vaccinations," says Lehman.

Lehman and her colleagues--including co-authors Leslie Lamb, MD, MSc, and Helen Anne D'Alessandro, MD--stress that no additional imaging tests are needed for swollen lymph nodes after recent vaccinations unless the swelling persists or if the patient has other health issues. This message should be communicated to both imaging staff and patients. Patient letters may read: "The lymph nodes in your armpit area that we see on your mammogram are larger on the side where you had your recent COVID-19 vaccine. Enlarged lymph nodes are common after the COVID-19 vaccine and are your body's normal reaction to the vaccine. However, if you feel a lump in your armpit that lasts for more than six weeks after your vaccination, you should let your health care provider know."

Lehman notes that drastic declines in screening mammography and breast cancer diagnoses are well documented across multiple health care institutions due to the COVID-19 pandemic. "This disruption of breast cancer screening is likely to result in a significant increase in cancers diagnosed at late stages and an increased demand for cancer screening procedures as delayed tests are rescheduled," she says. "We believe our model can avoid reducing or delaying vaccinations and avoid further reduced or delayed breast cancer diagnoses based on confusion amongst patients and/or their providers."

CLEVELAND, Ohio (Feb 24, 2021)--The aging population combined with increasing obesity rates has resulted in more women experiencing pelvic organ prolapse. Common treatment options include pelvic reconstructive surgery or the use of pessaries to prop up descending organs. A new study evaluated the long-term effectiveness of pessaries, as well as reasons why women discontinued their use. Study results are published online today in Menopause, the journal of The North American Menopause Society (NAMS).

Despite the fact that vaginal pessaries have existed in some form for thousands of years to help treat pelvic organ prolapse, few studies have been published regarding their long-term use and effectiveness. Pessaries are devices inserted into the vagina to support prolapsed pelvic structures. Vaginal pessaries offer nonsurgical alternatives to pelvic reconstructive surgery. Two types of pessaries are most commonly used in clinical practice: the ring pessary and the Gellhorn pessary (the second-line choice when the ring pessary fails). The ring pessary is the most popular because it can easily be inserted and removed.

This new study followed up with women with pelvic organ prolapse over a 5-year period to assess their overall satisfaction with pessaries, complication rates, and common reasons for discontinuing use. Of the 312 women originally assessed, 239 mostly postmenopausal women completed the 5-year study, and 180 women were successful.

On its completion, researchers concluded that vaginal pessaries represented a safe and effective treatment option for women with symptomatic pelvic organ prolapse. Specifically, three-fourths of study participants showed significant symptom improvements and continued pessary use at 5-year follow-up, with only minor complications reported. For those women who did not continue to use pessaries, most requested reconstructive surgery within 2 years.

The most common causes for discontinuing the use of pessaries included a shorter vaginal length (less than 7.5 cm), which resulted in discomfort as a result of inserting the pessaries; poor improvement in urinary symptoms; and an incapability of self-care (meaning that family members had to assist with the placement of the pessaries).

Results are published in the article "Vaginal pessary treatment in women with symptomatic pelvic organ prolapse: a long-term prospective study."

"This study highlights the efficacy and long-term acceptability of pessaries for women with symptomatic pelvic organ prolapse, positioning them as a simple and safe solution that may obviate the need for pelvic reconstructive surgery," says Dr. Stephanie Faubion, NAMS medical director.