Chemical compound promotes healthy aging: study

 A recently discovered chemical compound helped elderly mice with obesity lose fat and weight, add muscle and strength, reduce age-related inflammation and increase physical activity, a new study shows.

The study, published in the Journal of Cachexia, Sarcopenia and Muscle, provides the first evidence that BAM15, a mitochondrial uncoupler, prevents sarcopenic obesity, or age-related muscle loss accompanied by an increase in fat tissue.

"Loss of muscle mass is typically not a concern in younger adults with obesity. However, as people age, that changes. Older adults with sarcopenic obesity suffer accelerated muscle loss. They become less active. As a result, they are at high risk for falls, stroke, heart disease, poorer quality of life and premature death," said Christopher Axelrod, MS, Director of Pennington Biomedical Research Center's Integrated Physiology and Molecular Medicine Laboratory.

The weakness and frailty common to sarcopenic obesity are offset in older mice -- the equivalent of aged 60-65 in human years -- given BAM15. The mice, all of whom had obesity, were fed high-fat diets. Despite that, the mice given BAM15 lost weight and got stronger and more active.

"Typically, when you lose weight, you also lose muscle, and in some circumstances, you can lose a lot of it," Axelrod said. "In this study, the aged mice increased their muscle mass by an average of 8 percent, their strength by 40 percent, while they lost more than 20 percent of their fat."

BAM15 works by making the mitochondria, the power plants of the cell, less efficient. The result is that the mitochondria burn more energy. The researchers are reluctant to describe BAM15 as a miracle drug. More research will be needed to determine its effectiveness for people.

However, the findings about BAM15 have important implications for improving the quality of life for older adults, especially for the rapidly growing number of people with obesity. Preventing, delaying, or reversing the causes and consequences of sarcopenic obesity may allow people to live longer and healthier lives.

"These data highlight that mitochondrial uncouplers may play an important role in improving health span -- the time a person enjoys good health -- in advanced age," said Pennington Biomedical Executive Director John Kirwan, Ph.D.

BAM15 improves many of the key determinants of health and aging, including:

• Removing damaged mitochondria
• Making more healthy mitochondria, and
• Reducing "inflammaging," or age-related inflammation, linked to muscle loss

"Extending health span is even more important than extending lifespan," Kirwan said. "Suppose you could add 20 or 30 years to a person's life. What would be the point if their quality of life was awful?"

Axelrod and Kirwan are the study's corresponding authors. Wagner Dantas, Ph.D., a Postdoctoral Researcher in Kirwan's Integrated Physiology and Molecular Medicine Laboratory, is the lead author.

This work used core facilities that are supported in part by Pennington Biomedical's Center for Biomedical Research Excellence through National Institutes of Health awards 5P30GM118430 and 1P20GM135002 and Nutrition Obesity Research Center through National Institutes of Health award P30DK072476. This research was supported in part by the National Institutes of Health award U54GM104940. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Story Source:

Materials provided by Pennington Biomedical Research Center. Note: Content may be edited for style and length.

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Journal Reference:

1. Wagner S. Dantas, Elizabeth R.M. Zunica, Elizabeth C. Heintz, Bolormaa Vandanmagsar, Z. Elizabeth Floyd, Yongmei Yu, Hisashi Fujioka, Charles L. Hoppel, Kathryn P. Belmont, Christopher L. Axelrod, John P. Kirwan. Mitochondrial uncoupling attenuates sarcopenic obesity by enhancing skeletal muscle mitophagy and quality control. Journal of Cachexia, Sarcopenia and Muscle, 2022; DOI: 10.1002/jcsm.12982

https://www.sciencedaily.com/releases/2022/04/220407101053.htm

COVID-19 alters levels of fertility-related proteins in men: study

 Many people who recover from COVID-19 experience long-term symptoms, such as brain fog or heart problems. Increasing evidence suggests that the virus can also impair fertility. Now, researchers reporting in ACS Omega have analyzed protein levels in semen of men who have recovered from COVID-19. The pilot study suggests that even mild or moderate illness could change the levels of proteins related to male reproductive function, the researchers say.

Although SARS-CoV-2 mainly affects the respiratory system, the virus -- and the body's response to it -- also damages other tissues. Recent evidence indicates that COVID-19 infection can reduce male fertility, and the virus has been detected in male reproductive organs. Firuza Parikh and Rajesh Parikh at Jaslok Hospital, Sanjeeva Srivastava at the Indian Institute of Technology and colleagues wondered if COVID-19 infection could have long-term impacts on the male reproductive system. To find out, they decided to compare levels of proteins in the semen of healthy men and those who previously had mild or moderate cases of COVID-19.

The researchers analyzed semen samples from 10 healthy men and 17 men who had recently recovered from COVID-19. None of the men, who ranged in age from 20 to 45, had a prior history of infertility. The team found that the recovered men had significantly reduced sperm count and motility, and fewer normally shaped sperm, than men who hadn't had COVID-19. When the researchers analyzed semen proteins using liquid chromatography-tandem mass spectrometry, they found 27 proteins at higher levels and 21 proteins at lower levels in COVID-19-recovered men compared with the control group. Many of the proteins were involved in reproductive function. Two of the fertility-related proteins, semenogelin 1 and prosaposin, were present at less than half their levels in the semen of the COVID-19-recovered group than in the semen of controls. These findings suggest that SARS-CoV-2 has direct or indirect effects on male reproductive health that linger after recovery, the researchers say. The work might also reveal insights into the pathophysiology of human reproduction in recovered men, they add. However, they note that larger studies should be done to confirm these findings, and a control group of men who recently recovered from other flu-like illnesses should be included to ensure that the findings are specific for COVID-19.

The authors acknowledge funding from Jaslok Hospital.

Story Source:

Materials provided by American Chemical Society. Note: Content may be edited for style and length.

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Journal Reference:

1. Susmita Ghosh, Swapneil Parikh, Mehar Un Nissa, Arup Acharjee, Avinash Singh, Dhruv Patwa, Prashant Makwana, Arundhati Athalye, Abhilash Barpanda, Malini Laloraya, Sanjeeva Srivastava, Firuza Parikh. Semen Proteomics of COVID-19 Convalescent Men Reveals Disruption of Key Biological Pathways Relevant to Male Reproductive Function. ACS Omega, 2022; 7 (10): 8601 DOI: 10.1021/acsomega.1c06551

https://www.sciencedaily.com/releases/2022/04/220407141845.htm

IO Biotech: Data from MM1636 Phase 1/2 Clinical Trial Presented at 2022 AACR

 IO Biotech announced updated efficacy data and subgroup analyses from the MM1636 Phase 1/2 clinical trial evaluating IO102-IO103 as investigational agents in metastatic melanoma in an e-poster presentation at the American Association of Cancer Research conference (AACR), being held April 8-13, 2022 in New Orleans, Louisiana. Data highlights from the e-poster titled, “High clinical efficacy in poor prognosis patients with metastatic melanoma treated with an IDO/PD-L1 peptide vaccine in combination with nivolumab” are outlined below: All 30 patients were evaluated after completing the IDO-PD-L1 vaccination schedule in combination with nivolumab as of the December 1, 2021 data cut-off and after a median follow up of 2.7 years; the three-year OS probability was 73%; the median progression free survival (mPFS) was 25.3 months. Confirmed overall response rate was 73% with 46.7% of patients obtaining complete responses in poor prognosis patients; a response rate of 81.8% (mPFS: 30.9 months) was seen in patients with elevated baseline LDH-levels; in patients classified as M1c at baseline response rate was 88.2%, (mPFS: 25.6 months); In a subgroup analysis, a response rate of 94.1% was observed in PD-L1+ patients (mPFS: 30.9 months) and 61.5% in PD-L1(-) patients (mPFS: 7.2 months); Immune-related adverse events were comparable to those in patients receiving nivolumab monotherapy. No additional toxicity was observed in poor prognosis patients.

https://www.marketscreener.com/quote/stock/IO-BIOTECH-INC-129052295/news/IO-Biotech-Announces-Presentation-of-New-Data-from-MM1636-Phase-1-2-Clinical-Trial-Presented-at-2022-40008336/

2Seventy Bio: New Preclinical Data on Investigational Dual-Targeting Gene-Edited CAR T Cell Therapy At AACR

 2seventy bio, Inc. will present preclinical data on bbT369, an investigational novel CD79a/CD20 dual-targeting CBLB gene edited CAR T cell therapy at the American Association for Cancer Research (AACR) Annual Meeting 2022 in New Orleans, LA. These data will be presented in a poster session (poster #581) on April 10, 1:30-5:30 PM CT. bbT369 is an innovative therapeutic approach designed to address known limitations of anti-CD19 CAR T cell therapy: Emerging data suggests several failure modes for anti-CD19 CAR T cell therapies, including loss or down-regulation of CD19 antigen, loss of co-stimulatory ligands on tumor cells, exhaustion of CAR T cells, and immunosuppressive microenvironments. bbT369 was purposely designed with three layers of innovation to address the potential mechanisms of anti-CD19 CAR T cell therapy failure: First, bbT369 targets a novel combination of antigens highly expressed in B cell lymphomas, CD79a and CD20. CD79a, a novel target, is a critical signaling component of the B cell receptor and CD20 is a known clinical target for lymphoma. The dual targeting of bbT369 may limit antigen escape as a mechanism of lymphoma relapse. Second, bbT369 is designed with a combination of a traditional 2nd generation CAR and an investigative “chimeric co-stimulatory” architecture (CCR-CAR), a split co-stimulation signaling technology intended to drive more robust T cell activation in response to either antigen compared with dual CAR designs. Third, cells are gene-edited with megaTAL™ technology to remove the function of CBLB, a known negative regulator of T cells. Removal of CBLB function may enable robust antigen-dependent CAR T cell expansion and allow cells to resist anergy and maintain activity in sub-optimal conditions for T cell activation. bbT369 demonstrates increased anti-lymphoma activity and duration of response in preclinical models: Increased tumor control was seen with bbT369’s CCR-CAR design compared to dual CAR designs, and cell killing was observed when bbT369 encountered either antigen. Compared with non-gene edited cells in different in vitro model systems, bbT369 demonstrated a lower threshold for stimulation, retained activity in the presence of the immunosuppressive factor TGFß, reduced reliance on tumor cell co-stimulation, and exhibited increased capacity for multiple rounds of tumor cell killing. bbT369 resulted in three-fold increased cell expansion and prevention of late relapses in B-NHL mouse models compared with a non-gene edited control. bbT369 outperformed CD19 CAR T cells in cell-based and mouse models, with increased IL-2 secretion and prolonged duration of tumor remission, suggesting bbT369 may have enhanced functionality compared with the other constructs. Infusion of first patients in Phase 1/2 study of bbT369 in B-NHL is anticipated in 2022: CRC-403 (NCT05169489), an open-label, multi-site Phase 1/2 dose-escalation study, is currently enrolling patients, and will assess the safety and potential efficacy of bbT369 in patients with relapsed and/or refractory B-NHL, including patients who relapsed after CD19 CAR T cell therapy as well as patients who are CAR-naïve. Initial assessment of feasibility of bbT369 drug product manufacturing and patient safety is expected in 2H 2022. The study will also serve as a proof-of-concept assessment of 2seventy bio’s proprietary megaTAL™ gene editing platform, dual-targeting strategies and split co-stimulation signaling technology.

https://www.marketscreener.com/quote/stock/2SEVENTY-BIO-INC-128358117/news/2Seventy-Bio-Inc-to-Present-New-Preclinical-Data-on-bbT369-an-Investigational-Dual-Targeting-Gene-40008335/

Surprisingly, physician burnout could lead to slightly better outcomes

 

• Despite concerns about widespread provider burnout as the pandemic stretches into its third year, a new study found no evidence that burnout negatively impacts the quality of patient care. Counterintuitively, physicians who report burnout could be contributing to slightly better outcomes instead.
• The study, which tied data from more than 1,000 family physicians to Medicare claims, found no statistically significant relationship between seven categories of self-reported burnout and measures of ambulatory care, ER visits, readmissions or costs. Instead, reported burnout seemed to be mildly correlated with slightly better outcomes, compared to doctors who are never burned out.
• But this doesn't indicate that physician burnout is beneficial or should be tolerated, researchers said, stressing that the relationship between burnout and outcomes is complex and needs further investigation.

Concerns about burnout have been growing even before COVID-19, with research showing high levels of stress and exhaustion contribute to medical errors, job dissatisfaction and poor patient experiences. But there is little research about the extent to which burnout affects the actual cost or quality of care being delivered, even as the pandemic contributes to drive record burnout and turnover in the field.

In the study published in Health Affairs on Monday, researchers from the Weill Cornell Medical College and University of Kentucky hypothesized that patients of family doctors who report frequent burnout would have higher annual Medicare costs and higher rates of ambulatory care-sensitive admissions (defined as hospital admissions that could have been prevented by good outpatient care), along with preventable ED visits and 30-day readmissions.

Doctors who are burned out may give less time or effort, resulting in worse outcomes — especially for dual-eligible patients, researchers theorized.

But the study didn't find any consistent relationship between burnout and outcomes.

"Surprisingly, we found that physicians who reported at least some frequency, or even a high frequency, of burnout had generally lower rates of undesirable outcomes," researchers said, though they noted few of the results were statistically significant, so extrapolating this conclusion may be specious or premature pending further research.

"It may be that physicians who report at least some burnout are highly conscientious and give extra effort to providing good care to their patients," researchers continued. "This effort, and their concern about their patients, may be stressful and produce a feeling of burnout, particularly when physicians experience time pressure or other obstacles to providing care."

The study also analyzed physician callousness toward patients, and found patients of the 2.4% of doctors who reported daily callousness did have worse outcomes.

That implies burnout could be associated with concern for patients (and subsequent better outcomes) as opposed to physicians who report callousness, who may lack this concern, the study said.

Previous research does suggest burnout may have a relationship to self-reported medical errors, and physicians who report more burnout also report making more errors. The study noted there's uncertainty about the accuracy of self-reported errors, as burned-out doctors may be more likely to report perceived errors, or perceived errors may make doctors feel more burned out.

The study stressed that the results in no way mean it's good for doctors to feel burned out, as the phenomenon could contribute to worse care experiences, distress and turnover.

https://www.healthcaredive.com/news/physician-burnout-could-better-outcomes-health-affairs/621418/

Nearly 80% of patients with infection following cardiac implant not treated appropriately

 

• Nearly 80% of patients that have an infection from a cardiac implant are not treated according to clinical practice guidelines, increasing their chances of death from infection, according to data presented at the American College of Cardiology's annual meeting.
• The study, which was presented Sunday at ACC's conference, examined data from over 1 million Medicare patients from 2006 to 2019. According to the data, 78.9% of patients did not have devices extracted following a diagnosis of an infection, while 13% of patients had devices extracted within six days of diagnosis and 5.1% between seven to 30 days. The data showed that removing devices within six days of infection was associated with a lower mortality risk.
• When patients with implantable cardiac devices have an infection, current practice guidelines state that "removal is recommended for all patients with definite [cardiovascular implantable electronic devices] system infection," according to documents from the Heart Rhythm Society that were shared by Philips. "This is an important message about a persistent gap in care: These devices should be removed when an infection occurs, and their removal saves lives," Sean Pokorney, lead author of the study, said in a press release from Duke University's health center.

The study examined data from about 1 million patients with implanted cardiac devices, such as a pacemaker or cardioverter-defibrillator, and with infection more than 12 months after implantation. The patients were all from the Medicare population and were all age 65 or older.

Patients that had a device removed within six days of infection had a 36% lower risk of death compared to no removal. According to data in the Duke press release, the one-year mortality was 32.4% for patients without extraction within 30 days, compared to 18.5% among patients who had extractions within six days and 23.2% for patients who had extractions on days seven to 30.

The study did not just show that the majority of patients overall were not receiving device removal following infection, but that Black patients and female patients were less likely to have a device removed than others.

Jonathan Piccini, a lead investigator on the study and the director of cardiac electrophysiology section at the Duke Heart Center, said in a press release from Philips that ensuring patients have access to guideline-recommended care can be life-saving.

"This study highlights the life-threatening nature of device infections and the significant opportunities to improve care in these complex patients. The findings also emphasize the importance of timely diagnosis and complete treatment," Piccini said.

Philips said that the study was done independently by Duke University with support from a company research grant, adding that, "Philips had no role in the design or conduct of the analysis." The medtech does have products used for device removal following cardiovascular implantable electronic device (CIED) infection, however, and they were mentioned in the press release.

About 1 million CIEDs are implanted globally every year, and about one out of 20 of these patients will experience an infection within three years, according to the Philips release. While patients with CIED infections are treated with antibiotics, there is a high chance that infections will relapse, requiring device removal.

Of the patients examined for the study across 14 years, roughly 11,600 (or 1.1%) contracted a CIED infection. Annually, about 16,000 patients globally contract a CIED infection and "are at risk each year due to improper treatment," according to Philips.

"Any extraction was associated with lower mortality when compared to no extraction, but the highest benefit was to those who had devices removed within six days of an infection," said Pokorney, who is also an electrophysiologist and cardiologist in the Department of Medicine at Duke. "This speaks to the importance of putting systems in place to identify these patients and get them quickly and appropriately treated, because delays in care result in higher mortality."

https://www.healthcaredive.com/news/patients-infection-cardiac-implant-not-treated-guidance-acc/621628/

Surprise billing compliance termed 'very daunting'

 Even for an industry rife with complex regulations, complying with the ban on surprise billing may prove especially "daunting" for healthcare providers, experts say.

The No Surprises Act passed by Congress went into effect earlier this year, tackling one of the most vexing problems in healthcare: unexpected medical bills that leave patients stuck in the middle between payers and providers.

It has been a persistent issue for American consumers receiving care from hospitals or doctors outside of their insurance networks.

The bill is best known for its signature achievement that protects patients from out-of-network bills in emergencies. It also shields them if they go to an in-network facility for a procedure but are unknowingly treated by an out-of-network clinician.

Complying with the law, which now bans most forms of surprise billing, certainly won't be a cakewalk for healthcare systems, according to experts.

Implementation will be "very daunting," said Manatt professional services firm partner Harvey Rochman, who has likened the legislation to a "small ACA," the landmark healthcare bill from 2010 that reshaped the industry.

That's because there are lesser-known requirements of the bill that may come as a shock to some practices and are onerous to put in place, compliance experts said.

Strict rules, deadlines for providing good-faith estimates

"If you had to single out one thing that is really the most complex and difficult ... it's the good-faith estimate," said Rochman, who is working directly with provider clients on compliance.

The bill goes beyond outlawing balance bills from fly-by out-of-network doctors, air ambulances and emergency rooms.

A much broader range of providers are required to hand over a "good-faith estimate," or a cost estimate for a procedure, for uninsured and self-pay patients when they ask. Practices are also required to alert patients they're entitled to such an estimate.

It's this requirement that may catch some practices off guard, according to compliance experts.

A dermatology practice is a good example, according to Varsha Gadani, an attorney at law firm McGuireWoods, who is working directly with provider clients on compliance.

Dermatology practice leaders may think they're not subject to the No Surprises Act because they don't provide emergency services at hospitals, Gadani said. While they may not be subject to that particular aspect of the law, they would be subject to providing good-faith estimates.

"The No Surprises Act is a lot more convoluted than you initially realize," Gadani said.

On the face of it, providing cost estimates to patients may seem like a small hurdle to clear, but there are additional wrinkles that make it more complex and harder to put into practice.

Providers are under strict time constraints and must hand over an estimate within one business day after the procedure is scheduled in some situations. In situations where the procedure is 10 days or more after scheduling, providers may have three days to draw up an estimate.

In addition, providers soon will be responsible for anticipating other services a patient may need as part of the procedure and will have to collect cost estimates from other providers to include in the overall estimate. Regulators decided to delay enforcement of this provision in 2022 because it's so complicated, Rochman said.

The "convening provider" will be responsible for assembling an overall estimate, but experts say it's not always clear who should play the role of convening provider. It can be the provider who schedules the procedure — but is that the surgeon or the hospital?

"So this is a very complex obligation, and it all has to be done in an extremely short amount of time — days at best," Rochman said.

In a letter to the CMS, the American Hospital Association said putting these measures in place have been difficult even for the most sophisticated hospitals. It's not an easy process to automate because the estimates need to be tailored to each patient.

"The regulation grossly underestimates the administrative burden of these requirements," the AHA said in a letter to the CMS dated March 4.

Making it even more confusing is that people with insurance could be considered uninsured in certain circumstances, according to Deborah Kantar Gardner, partner with law firm Ropes & Gray, who also is working on compliance with provider clients.

If insurance doesn't cover a particular benefit such as a cosmetic procedure, that patient would be considered uninsured in this circumstance and entitled to a good-faith estimate. At the same time, a patient who decides not to use their insurance benefits would also be entitled to an estimate, according to the American Medical Association.

"Even that determination about whether or not somebody has a benefit actually could be very difficult to figure out," Kantar Gardner said

https://www.healthcaredive.com/news/surprise-billing-compliance-good-faith-estimate/620895/