Heart studies allegedly manipulated data, saying a blood thinner had healing effects

 Three medical journals recently launched independent investigations of possible data manipulation in heart studies led by Temple University researchers, Reuters has learned, adding new scrutiny to a misconduct inquiry by the university and the U.S. government.

The Journal of Molecular and Cellular Cardiology and the Journal of Biological Chemistry is investigating five papers authored by Temple scientists, the journals told Reuters.

A third journal owned by the Journal of American College of Cardiology (JACC), last month retracted a paper by Temple researchers on its website after determining that there was evidence of data manipulation. The retracted paper had originally concluded that the widely-used blood thinner, Xarelto, could have a healing effect on hearts.

“We are committed to preserving the integrity of the scholarly record,” Elsevier, which owns the Journal of Molecular and Cellular Cardiology and publishes the two other journals on behalf of medical societies, said in a statement to Reuters.

Philadelphia-based Temple began its own inquiry in September 2020 at the request of the U.S. Office of Research Integrity (ORI), which oversees misconduct investigations into federally funded research, according to a lawsuit filed by one of the researchers.

According to court records, Temple University professor Abdel Karim Sabri supervised nine out of the 15 involved papers that were published between 2008 and 2020.

Temple University

The Temple investigation involves 15 papers published between 2008 and 2020 and supported by grants from the U.S. National Institutes of Health, according to the court records. Nine of the studies were supervised by Abdel Karim Sabri, a professor at Temple’s Cardiovascular Research Center.

His colleague Steven Houser, senior associate dean of research at Temple and former president of the American Heart Association, is listed as an author of five studies supervised by Sabri. Houser was also involved in four additional papers under scrutiny.

Houser sued in federal court last year to stop the university’s inquiry, saying Temple sought to discredit him and steal his discoveries.

Houser “has not engaged in scientific or other misconduct, has not falsified data, and has not participated in any bad acts with any other scientist or academic,” Houser’s lawyer, Christopher Ezold, said in a statement to Reuters. Houser helped review and edit the text portions of the Sabri-supervised studies and did not provide or analyze the data, Ezold said.

A Temple spokesperson said the university is “aware of the allegations and is reviewing them.” He would not comment further or discuss interactions with medical journals. ORI also declined comment. Sabri and Houser did not respond to questions.

Several research experts said that Houser, as one of the multiple co-authors, cannot be assumed to be involved in potential misconduct. The ultimate responsibility for a study usually lies with the supervising scientist and any researcher who contributed the specific data under scrutiny.

Expression of Concern

The probes highlight concerns over potential fabrication in medical research and the federal funds supporting it. A Reuters investigation published in June found that the NIH spent hundreds of millions of dollars on heart stem cell research despite fraud allegations against several leading scientists in the field.

The Temple inquiry also reveals a lack of consensus within the scientific community over how such concerns should be communicated, to prevent potentially bad science from informing future work and funding, according to half a dozen research experts interviewed by Reuters.

Temple did not notify the medical journals that it was conducting an inquiry at the request of the U.S. government agency, the journals told Reuters. They said that they began their inquiries independently.

Xarelto’s manufacturer, the Janssen Pharmaceuticals division of Johnson & Johnson, also told Reuters the supervising researchers at Temple did not notify the company about the investigation or the retraction by the JACC journal, though two of its employees were listed as co-authors on the paper. Janssen said their contribution to the paper was not questioned in the retraction.

Senior associate dean of research at Temple University, Steven Houser, is listed as an author of five studies that were supervised by Sabri.

Temple University

In some misconduct inquiries, universities have notified scientific journals that an investigation is underway. That has allowed journals to issue an “expression of concern” about specific studies, telling readers that there may be a reason to question the results. If there is a finding of data manipulation, the journals would be expected to retract the paper.

None of the journals that published the papers under scrutiny by Temple have issued expressions of concern. They would not comment to Reuters as to why they decided not to.

“It’s murky because of a lack of resources for these investigations, there’s no standardization worldwide,” said Arthur Caplan, head of medical ethics at New York University’s Grossman School of Medicine.

Other journals are not scrutinizing the Temple researchers’ work. Five papers flagged by ORI were published in the AHA journals Circulation, Circulation: Heart Failure, and Circulation Research, where Houser is a senior advisory editor.

The AHA said it had not been notified by the U.S. agency or by Temple about their inquiry, and that it does not view itself as responsible for investigating further. The AHA said it had issued a correction of data on one paper at the authors’ request. The paper was the sole study under scrutiny that listed Houser as supervising researcher.

“The American Heart Association is not a regulatory body or agency,” the AHA said in a statement to Reuters.

Federal Funding

Researchers and their institutions can be forced to return federal funding that supported work tainted by data manipulation.

Houser has received nearly $40 million in NIH funding and Sabri has received nearly $10 million since 2000, according to a Reuters analysis of NIH grants. Houser’s lawyer said that none of his NIH funding supported the papers supervised by Sabri.

The JACC journal said in its retraction of the Xarelto research that it launched its investigation after receiving a complaint from a reader. In response, the researchers issued a correction of some image data in the paper, which was supervised by Sabri and listed Houser as an author.

However, the journal said that the correction raised further concerns, prompting it to hire an unidentified outside expert to review them.

According to the retraction notice, the expert evaluation found evidence of manipulation in seven images using a technique known as Western blot, which determines concentrations of a specific protein in cells or tissues under different experimental conditions. As a result, the journal said its ethics board voted to retract the paper.

NIH, ORI, and Temple declined to comment on whether Temple would be required to return any federal funding for the work retracted by the JACC publication.

https://nypost.com/2022/09/13/5-heart-studies-allegedly-manipulated-data-blood-thinner-had-healing-effects/

Tackling cancer while battling the insurance system

 When you take up residency in Cancerland, as I did when I was diagnosed with Stage 4 lung cancer in 2020, you regularly hear yourself described as “battling” cancer. With my one-pill-a-day biomarker-directed therapy, I prefer to say that I’m “tackling” cancer. But if I am at war, it’s with an insurance system that works more like an extortion scheme.

In mid-January 2022, my phone rang early in the morning. This is my recollection of that call.

“Hi, this is Unintelligible Name from SaveOn.”

“Who? I don’t use Sav-On pharmacy.”

“We’re not Sav-On pharmacy, we’re SaveOnSP, specialty pharmacy.” SaveOn is pronounced exactly the same as Sav-On, just to be more confusing.

“I just changed insurers,” I said, “and I’ve been in close contact with my new plan. They contract with Express Scripts, who’ve assigned Accredo as my specialty pharmacy.”

“Yes, and we’re your specialty pharmacy’s specialty pharmacy. If you don’t sign up through us you’ll be charged the full amount of your co-pay of $4,500 every month for your specialty medication. We have all your information. You just have to verbally consent to let us manage your account.”

I was stunned and so sure this was a scam call that I neglected to ask how they had arrived at this $4,500 co-pay, and how that could even be possible because that number was larger than my plan’s deductible and out-of-pocket maximum.

“You’ll receive a bill, but don’t pay it,” my caller continued. “Working with us ensures that you have a zero co-pay.”

“Okay?” I replied. Was there a real choice? I’ve had lengthier consent discussions for a one-time hookup. I promptly forgot about the call and received no paperwork, but a few weeks later my monthly shipment of medication arrived along with an invoice from Express Scripts for $4,445. It noted that I might not owe this amount; nevertheless, it had a detachable payment slip, and a return envelope was provided. Remembering the caller’s assurances, I tossed the bill into my ever-expanding, supersize file I’ve labeled “insurance gobbledygook.” But when I visited an ATM the next day, my balance was significantly lower than I expected. $4,445 had been deducted by Express Scripts.

After I discovered that ginormous deduction from my account, I spent the majority of my waking hours that week ping-ponging between customer service representatives of my insurer, Express Scripts and Accredo. (The name SaveOnSP appeared neither on my invoice nor on my account portals at Express Scripts and Accredo.) I was transferred so many times in my crusade to satisfy the gods that govern the peculiar ecosystems of customer service call centers — which require you to offer up your member ID, Social Security number, date of birth, Zip code and sacrifice of the first born, and shriek “operator” over and over into the void — that I can’t remember which representative informed me that they didn’t show me as being enrolled with SaveOnSP.

Nor was I enrolled, they said, in the co-pay assistance program I had been participating in for more than a year — one sponsored by AstraZeneca, which manufactures my medication, osimertinib, which is sold under the brand name Tagrisso. Like many pharmaceutical companies, AstraZeneca offers several types of assistance designed to help patients pay for costly medications. The program I’m enrolled in provides up to $26,000 per patient per calendar year for Tagrisso, which retails at $14,000 per month.

(A representative of SaveOnSP later told The Post, “Plan participants sign up independently with copay assistance programs, not through SaveOnSP; SaveOnSP monitors consenting participants’ pharmacy accounts on behalf of plans.”)

My previous insurer had billed the AstraZeneca program and the funds they received were applied toward my deductible, and my insurance plan covered the remaining cost of the prescription. When I switched over to Express Scripts, they had initially done the same. If any of the math seems like it doesn’t make a lick of sense, it’s because insurers work out deals with pharma companies that are closely guarded secrets. What’s certain is that they’re not paying the sticker price for drugs like mine. My plan had a pricey monthly premium, but I’d never been charged an out-of-pocket co-pay, and the system operated so seamlessly that I felt fortunate.

Many hours of my cancer-shortened life span were expended before Express Scripts agreed to a refund and acknowledged the screw-up. I was issued a provisional credit, minus a bank-processing fee that came out of my pocket, natch, and it took several weeks before the refund was fully secured.

I was able to weather the $4,445 debit, but more than half of Americans can’t afford a $1,000 emergency. This could have had catastrophic consequences for another family who might have missed a mortgage payment or been unable to put food on the table.

Then, in mid-March, a representative from the AstraZeneca co-pay assistance program called me in a state of agitated confusion.

Previously, the program had been billed $250 a month in co-pay assistance for an annual total of $3,000; now it was being billed $4,500 every month. Had I changed insurers? “A third party is now adjusting my benefits,” I said, and she got very quiet and stopped asking questions. Now I wanted to know what had happened and what I could expect.

As I would learn from longtime industry observer Adam J. Fein, founder of Drug Channels Institute, I’d been entangled in an increasingly exploitative scheme. In what’s become a standard industry practice, pharmacy benefit managers (PBMs) contract with secretive third-party adjusters commonly called co-pay accumulators and maximizer programs to process “specialty medication” prescriptions, including biomarker-targeted therapies for lung cancer and other chronic and deadly diseases. Once a plan engages a co-pay accumulator or maximizer, these entities reclassify these medications (some of the priciest on the market) as “nonessential.” This allows plans to exploit a loophole in the Affordable Care Act: Coverage can be denied for therapies that a plan labels “nonessential,” and a plan can reset the member’s pharmaceutical benefit deductible and out-of-pocket maximum to any amount of their choosing.

Accumulators typically first bill the co-pay assistance program up to a patient’s deductible, and then, because they aren’t obligated to apply this to the deductible, double dip and bill the patient up to the amount of their deductible before providing coverage, often with a newly inflated co-payment rate. “Maximizers are even sneakier,” Fein explained. “They extract the maximum amount allowable from the assistance program before the plan picks up the rest of the cost” ($4,445 turned out to be the maximum amount billable per month from my co-pay assistance program).

“Patients are generally unaware of the complex and confusing benefit design,” according to Fein. Sure enough, I discovered that my co-pay assistance was no longer being applied to my deductible. Had I missed a mention of this program in my insurance plans’ summary of benefits? Nope. The information packet I received included no mention of a third-party maximizer. So much for shopping as an informed consumer in the insurance market.

Making matters more opaque, companies don’t refer to themselves as accumulators or maximizers. SaveOnSP describes itself as a “cost-saving healthcare solution” that focuses on “helping plan sponsors and their participants manage the skyrocketing costs of specialty pharmaceutical drugs.” At the same time, PBMs are pushing back on growing concerns. In a web posting titled “Copay Accumulator Programs Level the Out-of-Pocket Playing Field,” Express Scripts refers to its “Out of Pocket Protection Program” as a way “to ensure an equal benefit for all members.” It reads, “Plan sponsors believe it is not fair to allow one member to utilize outside funding to satisfy their deductible while another has to meet it entirely with their own money.” That’s like complaining that one person has a wealthy aunt who contributes to their care and another doesn’t, pitting plan members against one another like a hunger games. The purported benefit of signing up through SaveOnSP was that there would be zero co-pay for my specialty medication, but I’d already had a zero co-pay — and now it would take me longer to meet my deductible and out-of-pocket maximum, which meant an outlay of more cash for my other health-care costs.

(A representative of SaveOnSP told The Post, “Drug manufacturers keep increasing specialty drug prices. Employer-sponsored health plans bear most of those costs. Plans hire SaveOn to implement plan designs that take full advantage of drug makers’ copay assistance programs and ensure plan participants get specialty drugs for no or little cost. SaveOnSP is glad that the participant received a refund for the pharmacy’s erroneous charge and got her specialty drugs at no cost.”)

I began hearing similar horror stories from patient advocates, such as Carl Schmid, the executive director of the HIV+Hepatitis Policy Institute. “To me, co-pay accumulators very much seem like extortion,” Schmid told me. “And they lead to a decrease in adherence since people can no longer afford their drugs.”

“What’s more,” he said — and this was something I hadn’t realized — “the out-of-pocket obligations patients must pay to meet their deductible and any coinsurance are based on the drug’s undiscounted, pre-rebate list price, not the pharmacy’s actual negotiated price.” Not that anyone knows the rates insurers negotiate; it’s a more closely guarded secret than the identity of Satoshi Nakamoto, but we know it’s substantially less than the sticker price.

Anna Hyde, vice president of advocacy and access at the Arthritis Foundation, wasn’t surprised by my experience. Ever since co-pay accumulators entered the marketplace in 2017, she’s been hearing from patients worried about “interruptions in care and whose co-pays were ballooning.” Hyde alerted me to H.R. 5801, the Help Ensure Lower Patient Copays Act, introduced to Congress in November 2021 by Reps. A. Donald McEachin (D-Va.) and Rodney Davis (R-Ill.) along with more than 50 co-sponsors. The bill “requires health insurance plans to apply certain payments made by, or on behalf of, a plan enrollee toward a plan’s cost-sharing requirements.” In plain English, this means money that plans collect from a patient’s co-pay assistance fund must count toward the patient’s deductible and out-of-pocket maximum. Fourteen states already have banned co-pay accumulators.

Alas, California, where I live, is not one of those states, and H.R. 5801 is still pending in the House. In late August, the HIV+Hepatitis Policy Institute partnered with the Diabetes Leadership Council and the Diabetes Patient Advocacy Coalition to file a suit challenging the US Department of Health and Human Services May 2020 ruling that allows plans to avoid counting co-pay assistance toward deductibles and out-of-pocket maximums. But the difficulties remain in place for now.

“It’s always a scramble,” sighed Lia (who asked to be identified by only her first name out of fear of retribution from future insurers), who lives in Georgia and was diagnosed with lung cancer at age 49. She takes a specialty medication that’s similar to mine, and when her current insurer engaged a maximizer she lost her deductible credit, which has had a dramatic impact on the family’s finances. She has another preexisting condition that’s most effectively treated with a compounded medication that isn’t covered under her plan.

“Each time we change insurances, I hold my breath,” she told me.

“And we know that’s not easy!” I joked. This is what we call “living with lung cancer humor.”

Not long after I spoke with Lia, I learned that I’d have to change my insurance once again. The kicker: SaveOnSP ran through my annual allotment of $26,000 in assistance in only six months, which means I could face a gap period of vastly inflated medication costs. How could I even prepare? When I phoned another insurer, I was informed that they couldn’t determine the cost unless I was already enrolled in the plan. The representative’s best guess was that I’d be responsible for 20 percent of the cost of the medication, up to $750 dollars per order.

“Okay, do you contract with a maximizer?”

“I don’t know,” the customer service representative admitted. Based on my experience, the information is so siloed it’s possible that she really didn’t know.

Before collapsing into an exhausted sleep, I picked up my dog-eared copy of Yuval Harari’s “Sapiens.” I’d been rereading about ancient forager societies over the summer as a tonic to the slings and arrows of Cancerland contingencies. When an old woman in the Aché tribe, hunter-gathers who foraged the jungles of Paraguay, became “a liability to the band,” one of the younger men would sneak behind her and kill her with an ax-blow to the head. How far we’ve come, I’d marveled during my first reading in 2015, long before I learned that the cells in my body were conspiring against me. Now, as I weighed my options, it hit me: I’m the old woman in the modern retelling of this story, and to a PBM, I’m a liability, so until science finds a cure, I can expect many more soul-sucking hours of haggling over insurance benefits. Sometimes, an ax to the head seems preferable.

This essay was underwritten with a grant from the Economic Hardship Reporting Project.

Annabelle Gurwitch is an actress and the author, most recently, of "You're Leaving When?: Adventures in Downward Mobility," now in paperback from Counterpoint.

https://www.washingtonpost.com/outlook/2022/09/09/insurance-copay-specialty-medications-cancer/

Twice-daily nasal irrigation reduces COVID-related illness, death

 Starting twice daily flushing of the mucus-lined nasal cavity with a mild saline solution soon after testing positive for COVID-19 can significantly reduce hospitalization and death, investigators report.

They say the technique that can be used at home by mixing a half teaspoon each of salt and baking soda in a cup of boiled or distilled water then putting it into a sinus rinse bottle is a safe, effective and inexpensive way to reduce the risk of severe illness and death from coronavirus infection that could have a vital public health impact.

"What we say in the emergency room and surgery is the solution to pollution is dilution," says Dr. Amy Baxter, emergency medicine physician at the Medical College of Georgia at Augusta University and corresponding author of the study in Ear, Nose & Throat Journal.

"By giving extra hydration to your sinuses, it makes them function better.

If you have a contaminant, the more you flush it out, the better you are able to get rid of dirt, viruses and anything else," says Baxter.

"We found an 8.5-fold reduction in hospitalizations and no fatalities compared to our controls," says senior author Dr. Richard Schwartz, chair of the MCG Department of Emergency Medicine. "Both of those are pretty significant endpoints."

The study appears to be the largest, prospective clinical trial of its kind and the older, high-risk population they studied—many of whom had preexisting conditions like obesity and hypertension—may benefit most from the easy, inexpensive practice, the investigators say.

They found that less than 1.3% of the 79 study subjects age 55 and older who enrolled within 24-hours of testing positive for COVID-19 between Sept. 24 and Dec. 21, 2020, experienced hospitalization. No one died.

Among the participants, who were treated at MCG and the AU Health System and followed for 28 days, one participant was admitted to the hospital and another went to the emergency room but was not admitted.

By comparison, 9.47% of patients were hospitalized and 1.5% died in a group with similar demographics reported by the Centers for Disease Control and Prevention during the same timeframe, which began about nine months after SARS-CoV-2 first surfaced in the United States.

"The reduction from 11% to 1.3% as of November 2021 would have corresponded in absolute terms to over 1 million fewer older Americans requiring admission," they write. "If confirmed in other studies, the potential reduction in morbidity and mortality worldwide could be profound."

Schwartz says Baxter brought him the idea early in the pandemic and he liked that it was inexpensive, easy to use and could potentially impact millions at a time where, like other health care facilities, the Emergency Department of the AU Health System was starting to see a lot of SARS-CoV-2-positive patients.

"We were really looking at what options we had available for treatment," Schwartz says. The first COVID-19 vaccines were given in December 2020 and the first treatment, the antiviral remdesivir was approved by the Food and Drug Administration in October 2020.

They knew that the more virus that was present in your body, the worse the impact, Baxter says. "One of our thoughts was: If we can rinse out some of the virus within 24 hours of them testing positive, then maybe we can lower the severity of that whole trajectory," she says, including reducing the likelihood the virus could get into the lungs, where it was doing permanent, often lethal damage to many.

Additionally, the now-infamous spiky SARS-CoV-2 is known to attach to the ACE2 receptor, which is pervasive throughout the body and in abundance in locations like the nasal cavity, mouth and lungs. Drugs that interfere with the virus' ability to attach to ACE2 have been pursued, and Baxter says the nasal irrigation with saline helps decrease the usual robust attachment. Saline appears to inhibit the virus' ability to essentially make two cuts in itself, called furin cleavage, so it can better fit into an ACE2 receptor once it spots one.

Participants self-administered nasal irrigation using either povidone-iodine, that brown antiseptic that gets painted on your body before surgery, or sodium bicarbonate, or baking soda, which is often used as a cleanser, mixed with water that had the same salt concentration normally found in the body.

While the investigators found the additives really added no value, previous research had indicated they might help, for example, make it more difficult for the virus to attach to the ACE2 receptor. But their experience indicates the saline solution alone sufficed. "It's really just the rinsing and the quantity that matter," Baxter says.

The investigators also wanted to know any impact on symptom severity, like chills and loss of taste and smell. Twenty-three of the 29 participants who consistently irrigated twice daily had zero or one symptom at the end of two weeks compared to 14 of the 33 who were less diligent.

Those who completed nasal irrigation twice daily reported quicker resolution of symptoms regardless of which of two common antiseptics they were adding to the saline water.

Sixty-two of the participants completed a daily survey, reporting 1.8 irrigations daily; 11 reported irrigation-related complaints and four discontinued use.

Study participants and those used as controls had similar ages and rates of common conditions including one or more preexisting health problems.

Older adults, those with obesity and excess weight, who are physically inactive and those with underlying medical conditions are considered most at risk for serious complications and hospitalization from COVID-19. A body mass index, or BMI, which measures weight in relation to height, between 18.5 and 24.9, is considered ideal, and study participants had a mean BMI of 30.3; over 30 indicates obesity.

Others have shown the nasal irrigation, also called lavage, can also be effective in reducing duration and severity of infection by a family of viruses that include the coronaviruses, which are also known to cause the common cold, as well as the influenza viruses, the investigators write. "SARS-CoV-2 infection was another perfect situation for it," Baxter says.

In fact, nasal irrigation is something that has been done for millennia in Southeast Asia, and Baxter had noted lower death rates from COVID-19 in countries like Laos, Vietnam and Thailand. "Those were places that I knew from having been there where they use nasal irrigation as a normal part of hygiene just like brushing their teeth," she says. A 2019 pre-COVID study provided evidence that regular nasal irrigation in Thailand can improve nasal congestion, decrease postnasal drip, improve sinus pain or headache, improve taste and smell and improve sleep quality.

Schwartz said the simplicity and safety of the treatment had him recommending nasal irrigation to positive patients early on and the published results make him even more confident in recommending nasal irrigation to essentially anyone who tests positive.

Baxter noted the skepticism of the medical community before the results could be peer reviewed and published and her frustration with this relatively simple approach not being used when so many were sick and dying.

"Many of the people who have been using this now for months have told me their seasonal allergies have gone away, that it really makes a huge difference in any of the things that go through the nose that are annoying."

A study released in September 2020 indicated that gargling with a saline-based solution can reduce viral load in COVID-19, and another released in 2021 suggested that saline works multiple ways to reduce cold symptoms related to infection with other coronaviruses and might work as well as a first-line intervention for COVID-19.

Despite the two nostrils, the nasal sinus is just one cavity, so the water is pushed into one side and comes out the other, Baxter notes.

---

Explore further

Theophylline nasal irrigation studied in COVID-19-related smell loss

---

More information: Amy L Baxter et al, Rapid initiation of nasal saline irrigation to reduce severity in high-risk COVID+ outpatients, Ear, Nose & Throat Journal (2022). DOI: 10.1177/01455613221123737

https://medicalxpress.com/news/2022-09-twice-daily-nasal-irrigation-covid-related-illness.html

Drug that mimics effects of exercise on muscle and bone IDd

 Maintaining a regular workout routine can help you look and feel great—but did you know that exercise also helps maintain your muscles and bones? People who are unable to engage in physical activity experience weakening of the muscles and bones, a condition known as locomotor frailty. Recently, researchers in Japan have identified a new drug that may aid in the treatment of locomotor frailty by inducing similar effects as exercise.

Physical inactivity can result in a weakening of the muscles (known as sarcopenia) and bones (known as osteoporosis). Exercise dispels these frailties, increasing muscle strength and promoting bone formation while suppressing bone resorption. However, exercise therapy cannot be applied to all the clinical cases. Drug therapy may be helpful in treating sarcopenia and osteoporosis, especially when the patients have cerebrovascular disease, dementia or when they have already become bedridden. However, there is no single drug that addresses both issues simultaneously.

In a new study published in Bone Research, researchers from Tokyo Medical and Dental University (TMDU) developed a novel drug screening system to identify a compound that mimics the changes in muscle and bone that occur as a result of exercise. Using the screening system, the researchers identified the aminoindazole derivative locamidazole (LAMZ). LAMZ was capable of stimulating the growth of muscle cells and bone-forming cells (osteoblasts), while suppressing the growth of bone-resorbing cells (osteoclasts).

When LAMZ was administrated to mice orally, it was successfully transmitted into the blood, without no obvious side effects. "We were pleased to find that LAMZ-treated mice exhibited larger muscle fiber width, greater maximal muscle strength, a higher rate of bone formation, and lower bone resorption activity," says lead author of the study Takehito Ono.

The research team further addressed the mode of function of LAMZ and found that LAMZ mimics calcium and PGC-1α signaling pathways. These pathways are activated during exercise and stimulate expression of downstream molecules that are involved in the maintenance of muscle and bone.

The TMDU-led team asked if LAMZ can treat locomotor frailty, LAMZ was administrated to an animal model that has sarcopenia and osteoporosis. "Both oral and subcutaneous administration of drug improved the muscle and bone of mice with locomotor frailty," says senior author Tomoki Nakashima.

Taken together, the research team's findings show that LAMZ represents a potential therapeutic method for the treatment of locomotor frailty by mimicking exercise.

---

Explore further

How load stimulates bone formation via the expression of osteocrin

---

More information: Takehito Ono et al, Simultaneous augmentation of muscle and bone by locomomimetism through calcium-PGC-1α signaling, Bone Research (2022). DOI: 10.1038/s41413-022-00225-w

https://medicalxpress.com/news/2022-09-scientists-drug-mimics-effects-muscle.html

Preventing 'chemo brain' with antioxidants targeting spinal fluid

 Up to three quarters of patients receiving cancer chemotherapy suffer from "chemo brain"—a long-term side effect that makes it harder to remember things, maintain attention, and learn new information. When it strikes children, whose brains are still developing, their schoolwork and self-esteem may suffer.

"When we meet with parents and talk about the life-saving therapy we are proposing for their child's cancer, one of the most distressing potential side effects we sometimes describe is cognitive loss," says pediatric oncologist Lisa Diller, MD, chief medical officer for the Dana-Farber/Boston Children's Cancer and Blood Disorders Center. "If we had preventive treatments that could be delivered during therapy, or later in the survivorship phase of care, that would be game-changing."

In a study published in the journal Neuron on September 6, collaborators Maria Lehtinen, Ph.D. and Naama Kanarek, Ph.D., in the Department of Pathology at Boston Children's Hospital, take a first step in that direction. Their vision: treating the cerebrospinal fluid (CSF) that bathes the brain and spinal cord to protect the brain from chemotherapy's toxic effects.

"If we can treat the CSF, which is easy to target, we can potentially treat the brain itself," says Kanarek.

Investigating chemo's effects on the brain

Lehtinen has conducted pioneering studies showing the importance of the CSF in promoting brain health and growth, together with the choroid plexus, the little-known brain tissue that produces CSF. Separately, Kanarek has been studying the metabolic effects of the chemotherapy drug methotrexate on cancer cells. Methotrexate is used in children with acute lymphoblastic leukemia that has spread to the brain, as well as osteosarcoma and certain tumors of the central nervous system. It is also used in adults to treat leukemia, lymphoma, breast cancer, and lung cancer.

The two labs teamed up. In an initial study of mice, they found that exposure to methotrexate caused oxidative damage—a metabolic imbalance leading to the production of toxic oxygen molecules—to both the CSF and the choroid plexus. Nerve cells in the hippocampus, the brain's main center of learning and memory, were also damaged. And in behavioral testing, the mice showed increased anxiety and impairment on tasks involving short-term learning and memory.

Using advanced laboratory tools, Lehtinen, Kanarek, and colleagues further showed that methotrexate prevented the choroid plexus from secreting a key enzyme, superoxide dismutase 3 (SOD3), into the CSF. SOD3 is a natural antioxidant that normally protects cells in the brain and other tissues by helping break down potentially toxic oxygen molecules. The researchers think that without SOD3 delivered by the CSF, brain cells are more susceptible to damage.

Reversing toxic brain effects of methotrexate

Do the same effects happen in humans? The researchers first studied human neurons generated from stem cells. When they exposed the neurons to methotrexate, they produced less SOD and showed evidence of oxidative damage.

They also studied CSF samples from 11 adult cancer patients who had received methotrexate chemotherapy for lymphomas affecting their central nervous system. Compared with 12 cancer-free controls who did not receive methotrexate, these patients had reduced levels of SOD3 in their CSF and an increase in markers of oxidative damage.

So could adding SOD3 back protect the brain? Using a gene therapy approach in the mice, the research team boosted SOD3 production in the choroid plexus. When they then gave the mice methotrexate, the animals' CSF and brain tissue were largely free of oxidative damage, and there was less evidence of anxiety and memory impairment.

"With more work in the future, these findings have the potential to prevent or treat one of the most concerning late effects of methotrexate, a cancer drug we use frequently," says Diller, who was not part of the study.

Exploring treatment possibilities

Lehtinen and Kanarek now want to explore the effects of other chemotherapy drugs on the CSF and choroid plexus. They also want to better understand how methotrexate and antioxidants affect other parts of the brain, and test the efficacy of antioxidants given directly, rather than through gene therapy, in alleviating chemo brain.

Antioxidant treatments could potentially come in the form of an IV injection, a nasal spray, or an intrathecal injection, through a spinal tap, directly into the CSF. Such treatments could possibly be given together with the chemotherapy itself. The most immediate opportunity might be in patients who are receiving intrathecal methotrexate for brain cancer, or for leukemia or lymphoma with brain involvement, says Kanarek.

Another potential approach, yet to be tested, is simply providing antioxidants through antioxidant-rich foods or dietary supplements.

"This first study is just the tip of the iceberg," says Lehtinen. "If we could correct the collateral damage of chemotherapy and make even a small improvement in the trajectory of patients' lives, that would be really exciting."

---

Explore further

Choroid plexus volume linked to Alzheimer's disease

---

More information: Ahram Jang et al, Choroid plexus-CSF-targeted antioxidant therapy protects the brain from toxicity of cancer chemotherapy, Neuron (2022). DOI: 10.1016/j.neuron.2022.08.009

https://medicalxpress.com/news/2022-09-chemo-brain-antioxidants-spinal-fluid.html

Health care researchers must be wary of misusing AI

 An international team of researchers, writing in the journal Nature Medicine, advises that strong care needs to be taken not to misuse or overuse machine learning (ML) in health care research.

"I absolutely believe in the power of ML but it has to be a relevant addition," said neurosurgeon-in-training and statistics editor Dr. Victor Volovici, first author of the comment, from Erasmus MC University Medical Center, The Netherlands. "Sometimes ML algorithms do not perform better than traditional statistical methods, leading to the publication of papers that lack clinical or scientific value."

Real world examples have shown that the misuse of algorithms in health care could perpetuate human prejudices or inadvertently cause harm when the machines are trained on biased datasets.

"Many believe ML will revolutionize health care because machines make choices more objectively than humans. But without proper oversight, ML models may do more harm than good," said Associate Professor Nan Liu, senior author of the comment, from the Center for Quantitative Medicine and Health Services & Systems Research Program at Duke-NUS Medical School, Singapore.

"If, through ML, we uncover patterns that we otherwise would not see—like in radiology and pathology images—we should be able to explain how the algorithms got there, to allow for checks and balances."

Together with a group of scientists from the U.K. and Singapore, the researchers highlight that although guidelines have been formulated to regulate the use of ML in clinical research, these guidelines are only applicable once a decision to use ML has been made and do not ask whether or when its use is appropriate in the first place.

For example, companies have successfully trained ML algorithms to recognize faces and road objects using billions of images and videos. But when it comes to their use in health care settings, they are often trained on data in the tens, hundreds or thousands. "This underscores the relative poverty of big data in health care and the importance of working toward achieving sample sizes that have been attained in other industries, as well as the importance of a concerted, international big data sharing effort for health data," the researchers write.

Another issue is that most ML and deep learning algorithms (that do not receive explicit instructions regarding the outcome) are often still regarded as a "black box." For example, at the start of the COVID-19 pandemic, scientists published an algorithm that could predict coronavirus infections from lung photos. Afterwards, it turned out that the algorithm had drawn conclusions based on the imprint of the letter "R" (for "Right Lung") in the photos, which was always found in a slightly different spot on the scans.

"We have to get rid of the idea that ML can discover patterns in data that we cannot understand," said Dr. Volovici about the incident. "ML can very well discover patterns that we cannot see directly, but then you have to be able to explain how you came to that conclusion. In order to do that, the algorithm has to be able to show what steps it took, and that requires innovation."

The researchers advise that ML algorithms should be evaluated against traditional statistical approaches (when applicable) before they are used in clinical research. And when deemed appropriate, they should complement clinician decision-making, rather than replace it. "ML researchers should recognize the limits of their algorithms and models in order to prevent their overuse and misuse, which could otherwise sow distrust and cause patient harm," the researchers write.

The team is working on organizing an international effort to provide guidance on the use of ML and traditional statistics, and also to set up a large database of anonymized clinical data that can harness the power of ML algorithms.

---

Explore further

Using AI to detect cancer from patient data securely

---

More information: Victor Volovici et al, Steps to avoid overuse and misuse of machine learning in clinical research, Nature Medicine (2022). DOI: 10.1038/s41591-022-01961-6

https://medicalxpress.com/news/2022-09-health-wary-misusing-ai.html