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Thursday, July 4, 2019

Soccer headgear may not reduce sport-related concussion

In season-long tests, soccer headgear didn’t reduce the overall number or severity of concussions experienced by high school players, U.S. researchers say.
Some of the five headgear models used in the trial, however, may have been better at reducing impact forces that lead to concussions, particularly among female players, the study authors report in the British Journal of Sports Medicine.
“Female soccer is late to the party in terms of recognizing the number of injuries. So much focus has been on football that we haven’t recognized that females are more at risk for knee injuries and concussions,” said Timothy McGuine of the University of Wisconsin School of Medicine and Public Health in Madison, who led the study.
High school female soccer players have about double the rate of concussions as males, he said, and based on participation numbers, that’s about the same rate reported among football players.
“Athletic trainers at schools have been saying this for years, but we couldn’t get people to take it seriously,” he told Reuters Health in a phone interview. “Now parents tell us their daughters have experienced two or three concussions during a season and missed a month of school.”
Few studies have looked at the efficacy of protective headgear during soccer practices and matches, especially among high school athletes, McGuine noted. So, he and his colleagues studied 2,766 high school players, two thirds of them girls, over two academic years.
The researchers assigned about half the teams to wear headgear during an entire season while the rest did not. Individuals were allowed to choose which headgear model to wear from among five models that met American Society for Testing Materials International standards and were approved for use by the National Federation of State High School Associations.
Licensed athletic trainers at the schools recorded information about concussions and other injuries.

Overall, there were 130 sport-related concussions during the study, with 108 of these in girls. Twelve participants, including 11 girls, were medically disqualified from soccer for the rest of the season. The others spent about five days in a return-to-play protocol and missed about 13 days from soccer during a season.
But there was no difference in rates of sport-related concussions among those who wore headgear and those who didn’t. The number of days lost due to sport-related concussion also didn’t differ between the groups.
“Most safety devices haven’t been studied beyond a company’s lab settings,” McGuine said. “We weren’t able to formally study the brands, but we did see a discrepancy in the rates between different headgear.”
About the same number of players wore a model called the Storelli ExoShield, for example, as wore one called the Ultra Forcefield Sweatband, but half as many concussions were among players wearing the Storelli model.
Future studies will need more in-depth analysis of different types of headgear, which can become expensive to test, McGuine said. Researchers and national soccer associations should work together to discuss rule changes and technique changes to help high school athletes reduce these injuries and concussions in the first place, he added, both for high school teams and local club teams.
“Many schools are required to have athletic trainers who can recognize concussions, but there’s no mandate for clubs to do that, and we’re finding two-thirds of girls don’t have access to the safety or care that they need,” he said. “As a parent, ask your coaches if they’re aware of this and if they do baseline testing.”
As studies continue, parents should consider the risks of sport-related concussion versus the benefits of physical activity and team participation, said Doug Martini of Oregon Health and Science University in Portland, who wasn’t involved in the study

In his own research looking at long-term issues after high school concussions, he didn’t consistently find long-lasting effects, Martini notes. As heading techniques change and concussion protocols improve, the benefits of sport will likely outweigh the risks, he added.
SOURCE: bit.ly/2J9Qdp0 British Journal of Sports Medicine, online May 14, 2019.
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Opioid drug defendants ask Oklahoma judge to end case

The defendants in Oklahoma’s trial against drugmakers are asking a judge to rule in their favour, arguing the state has failed to prove they’re responsible for the opioid epidemic.
Attorneys for consumer products giant Johnson & Johnson and Janssen Pharmaceuticals filed a motion for judgment Wednesday after the state rested its case.
Oklahoma called its last witness on Tuesday, a former sales representative for Johnson & Johnson. The drugmakers’ case is expected to take about four more weeks.
Oklahoma Attorney General Mike Hunter has called Johnson & Johnson and its subsidiaries a “kingpin” responsible for the state’s ongoing opioid epidemic.
Johnson & Johnson attorney John Sparks says the state is seeking damages from the company without any evidence that it caused the problem.
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Using CRISPR to eliminate HIV

Antiretroviral therapy (ART) is the standard of care for HIV. These drugs can prevent HIV from replicating but they can’t clear the virus from the body altogether. Now, in a step closer to a possible cure for the infection, a team of scientists has removed HIV from mice using the CRISPR-Cas9 gene-editing technology and long-acting ART.
HIV integrates its genetic material into the genomes of the host’s cells, which currently available ART can’t target. In a study in Nature Communications, scientists at Temple University and the University of Nebraska Medical Center said the combination of CRISPR and a newly developed ART successfully eliminated HIV DNA from about 30% of infected mice.
Excision BioTherapeutics, a biotech focused on using CRISPR to treat viral infections, has licensed the gene-editing technology from Temple University, with a plan to advance the platform into human clinical trials. Senior author Kamel Khalili, Ph.D., professor and chair of neuroscience at Temple’s Lewis Katz School of Medicine at Temple University, is the founder and principal scientific advisor of Philadelphia-based Excision.
Khalili and his Temple colleagues previously used CRISPR to cut off large fragments of HIV DNA from infected immune cells. However, similar to ART, gene editing alone didn’t completely eliminate HIV. So they figured that a CRISPR-based system could be more effective when the HIV viral load is already controlled at low levels.
For the study, Khalili’s team used a new therapeutic called long-acting slow effective release antiviral therapy (LASER ART), which was co-developed by Howard Gendelman and Benson Edagwa at UNMC. LASER ART packages HIV drugs into nanoparticles that target tissues where latent HIV resides. It dissolves and releases ART slowly, with a higher proportion of the drug entering the circulation, the researchers said. That also helps lessen off-target toxicity.
To test their idea, the team built a mouse model that was engineered to resemble human HIV infection. In two separate experiments, infected mice received either the combination therapy, solo CRISPR or solo LASER ART, or they were left untreated. In the combo group, LASER ART was given used to suppress HIV growth, and then CRISPR was used to eliminate the remaining HIV DNA.
Eight weeks following the last administration of LASER ART and five weeks after the single CRISPR treatment, the animals were observed for evidence of viral rebound. Notably, about one-third of the rodents that got the combo therapy showed no sign of HIV, according to the team. DNA and RNA analysis of the spleen, bone marrow, gut, brain, liver, kidney and lung tissues of the rodents showed no traces of the virus’ genomic material. What’s more, the researchers also found no off-target effects that could be attributed to CRISPR.

The use of CRISPR in HIV stirred up much controversy after Chinese scientist He Jiankui claimed to have used the technology to edit human embryos, resulting in the birth of babies with a mutated form of the CCR5 gene that rendered them resistant to HIV. However, in the current research, CRISPR was not used for germline editing as it was in the China study.
Khalili, Gendelman and colleagues believe that their new approach marks the first time that replication-competent HIV DNA has been eliminated from the genomes of living animals.
“The big message of this work is that it takes both CRISPR-Cas9 and virus suppression through a method such as LASER ART, administered together, to produce a cure for HIV infection,” Khalili said in a statement. “We now have a clear path to move ahead to trials in non-human primates and possibly clinical trials in human patients within the year.”
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Purdue hires Ducharme as CSO to aid expansion beyond opioids


Purdue Pharma CSO Julie Ducharme. (Mundipharma)

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Novartis struggles for payer coverage for $2.1M gene therapy Zolgensma: analysts

Only about one-third of the top 30 U.S. insurance companies have made their decisions about how to cover Novartis’ new $2.1 million gene therapy to treat spinal muscular atrophy (SMA), Zolgensma, but analysts at one influential Wall Street firm are already worried.
Ronny Gal and his colleagues at Bernstein collected early coverage decisions on Zolgensma from 11 payers and found them to be “surprisingly restricted,” the firm said in a Tuesday note to clients.
“The restriction reflects unexpected and material payer resistance to the Zolgensma price point” and suggests that even if Novartis produces more data from ongoing clinical trials of the product, “payers will only grudgingly expand coverage and penetration into the broader population,” they wrote.
A spokesperson for Novartis said via email that the company does not believe Bernstein’s analysis represents “an accurate picture of the reimbursement situation or decisions that are occurring on the ground.” “[M]ultiple patients across different SMA types, weights and ages” have been treated and covered, the spokesman added, and the company will provide additional details when it releases its second-quarter earnings results on July 18.
Zolgensma kicked up a pricing controversy long before the FDA approved it, after one Novartis executive suggested the gene therapy would be cost-effective at a price of $4 million to $5 million. Then the Institute for Clinical and Economic Review (ICER) released a report saying Zolgensma would not be cost-effective at any price higher than $1.5 million.
But after Zolgensma was approved and priced, Novartis won over the cost watchdogs by saying it would work with payers to develop outcomes-based installment payments spread over five years. That would bring the per-year cost to $425,000, half what it would cost to treat a patient with the leading chronic drug therapy, Biogen’s Spinraza, for 10 years, Novartis said at the time. ICER subsequently said Zolgensma is worth up to $2.1 million.

Nevertheless, the initial coverage moves are more restrictive than Zolgensma’s label is. For example, Horizon Blue Cross of New Jersey is not covering the gene therapy for patients previously treated with Spinraza, Bernstein found, and nine of the companies won’t allow concurrent treatment with Spinraza. Health Net is requiring any patient who’d used Spinraza to prove their disease progressed while on treatment before it will cover Zolgensma.
Four of the insurers Bernstein surveyed are refusing to treat presymptomatic SMA patients—a major red flag, Gal and colleagues wrote.
Gene therapy, after all, is meant to be a cure. Treating children before they develop symptoms offers the potential for a healthy life many can’t achieve with chronic drug therapy. And even though clinical trials ahead of Zolgensma’s approval focused on symptomatic patients, the FDA approval allows its use in those who haven’t developed symptoms yet.
Therefore, Bernstein analysts said, “by making coverage choices that may be legally defensible but deny Zolgensma to patients who could clearly benefit, the payers are sending a clear signal that they are very unhappy with the price of Zolgensma.”

Payer resistance may be bad news for Novartis, but it’s a boon for Biogen, at least in the short term. Bernstein’s analysis of Zolgensma coverage decisions prompted the firm to boost its estimates for Spinraza, which has a sticker price of $750,000 for the first year and $375,000 per year after that. Bernstein now projects Spinraza sales of nearly $1.4 billion by 2024, not $1 billion as it previously estimated.
Other Wall Street firms are even more optimistic about Spinraza’s ability to compete with Novartis’ pricey Zolgensma. The consensus estimate places sales of Spinraza at $2.2 billion this year, with receipts growing slightly each year until 2023, when it peaks at $2.3 billion in sales.
So can Novartis overcome early resistance from payers? Absolutely, Bernstein said. The company is running additional trials, which could deliver data to persuade insurance companies to ease up on their coverage restrictions. Novartis is also working with patient advocacy groups to “apply pressure to ICER,” the analysts wrote, in the hopes that the cost watchdog will increase its estimate of a fair Zolgensma price.
For Novartis, “it is a long path ahead,” Bernstein concluded.
But the broader message from payers about gene therapy is clear, the analysts said: If there is competition on the market, expect pushback on price.
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Risk of dementia rises with prostate cancer hormone-blocking therapy

Prostate cancer patients who received hormone-lowering therapy were at higher risk of developing dementia and Alzheimer’s disease later on than men who didn’t get this treatment, a large U.S. study finds.
Researchers who followed nearly 155,000 men with prostate cancer found that overall, those given so-called androgen-deprivation therapy were at a 20% higher risk of being diagnosed with dementia and at 14% higher risk of an Alzheimer’s diagnosis in the next 10 years. The risk continued to rise with increasing doses of androgen-deprivation drugs.
The results suggest that in cases where the prostate cancer is localized, androgen-deprivation therapy may not be a good choice, said the study’s lead author, Ravishankar Jayadevappa, a research associate professor in the department of medicine at the University of Pennsylvania’s Perelman School of Medicine in Philadelphia.
Even in patients at high risk, there needs to be a discussion about the elevated risk of dementia and Alzheimer’s disease during long-term follow-up, Jayadevappa said.
The most common androgens found in the male body are testosterone and dihydrotestosterone (DHT). According to the American Cancer Society, doctors may choose to prescribe androgen-lowering therapy because it can result in slower growth – or even shrinkage – of prostate tumors.
Studies on the cognitive impacts of androgen-deprivation therapy have had mixed results, Jayadevappa and his colleagues note in JAMA Network Open.
In an attempt to arrive at a more definitive result, the researchers pored over data from a National Cancer Institute database that collects information on cancer incidence, treatment and mortality from 18 sites, encompassing 28% of the U.S. population, and links it with Medicare data.

The researchers focused on men who were aged 66 and older and diagnosed with localized or advanced prostate cancer between 1996 and 2003. The men were followed until 2013, so all had at least 10 years of follow-up. Out of 154,089 men in the study, 62,330 received androgen deprivation therapy within two years of their diagnosis.
The study team found that 13.1% of men who got hormone-lowering therapy and 9.4% of those who didn’t were diagnosed with Alzheimer’s disease during the follow-up period. Similarly, 21.6% of those who got androgen deprivation and 15.8% of those who didn’t were diagnosed with other forms of dementia.
Greater exposure was also tied to greater risk: Men who got one to four doses of androgen deprivation therapy had a 19% higher risk for Alzheimer’s or dementia, while those who had eight or more doses had a 24% higher risk of developing Alzheimer’s and a 21% higher risk of developing dementia.
Dr. Catherine Marshall welcomed the new study. “We know there are many negative side effects of ADT (androgen-deprivation therapy), including many long-term side effects,” said Marshall, an assistant professor at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore, Maryland. “While this question of a link between ADT and Alzheimer’s disease and dementia has been explored before, this is quite possibly the largest study to address this issue. Because of that, it adds important information about the risk of Alzheimer’s disease and dementia for men being treated.”
Studies like this one are very important because “our clinical trials are not always as long as this study and may not capture the long-term consequences of these treatments,” Marshall said in an email. “Delaying the start of ADT until the disease is more advanced may be a reasonable option for many men and would help to ultimately shorten the total duration of treatment.”
The new study is very interesting and “it may lead to prevention trials for Alzheimer’s disease,” said Dr. Oscar Lopez, director of the University of Pittsburgh Alzheimer Disease Research Center in Pennsylvania.

But there are some caveats, Lopez said in an email. “The use of a Medicare database to determine the presence of Alzheimer’s disease is a limitation since the mild cases are usually not captured by these types of registries,” he said.
SOURCE: bit.ly/2XpGjIp JAMA Network Open, online July 3, 2019.
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Sports playbook helps doctors predict cancer patient outcomes

In this season of global soccer competitions and hotly contested political primaries, bookies and pundits are scouring every evolving scrap of information and sifting through mountains of data in an effort to predict the outcome of the next game or election. These predictions can change on a dime, however, based on a player’s poor pass or a candidate’s stellar debate performance.
Statisticians refer to the technique of incorporating a variety of continuously generated information—who is on the bench, who was injured in the first half of the match, who polled well in Iowa yesterday—as calculating in-game win probability, and it’s been used for decades to predict the outcome of ongoing sports matches or elections.
Now researchers at the Stanford University School of Medicine have taken a page from this playbook to generate more accurate prognoses for . They’ve done so by designing a computer algorithm that can integrate many different types of predictive data—including a tumor’s response to treatment and the amount of cancer DNA circulating in a patient’s blood during therapy—to generate a single, dynamic risk assessment at any point in time during a patient’s course of treatment. Such an advance could be deeply meaningful for patients and their doctors.
“When we care for our patients, we are walking on eggshells for a profound period of time while we try to determine whether the cancer is truly gone, or if it is likely to return,” said associate professor of medicine Ash Alizadeh, MD, Ph.D. “And patients are wondering ‘Should I be planning to attend my child’s wedding next summer, or should I prioritize making my will?’ We are trying to come up with a better way to predict at any point during a patient’s course of treatment what their outcome is likely to be.”
Surprisingly, the researchers have also found that the approach, which they’ve termed CIRI for Continuous Individualized Risk Index, may also help doctors to pinpoint people who might benefit from early, more aggressive treatments as well as those who are likely to be cured by standard methods.
The study will be published online July 4 in Cell. Alizadeh, a Stanford Health Care oncologist who specializes in treating patients with blood cancers, shares senior authorship with associate professor of radiation oncology Maxmilian Diehn, MD, Ph.D. Instructor of medicine David Kurtz, MD, Ph.D., and postdoctoral scholars Mohammad Esfahani, Ph.D., and Florian Scherer, MD, are the lead authors.
Getting a more complete picture
The researchers began their study by looking at people previously diagnosed with diffuse large B-cell lymphoma, which is the most common blood cancer in the United States. Although nearly two-thirds of adults with DLBCL are cured with standard treatment protocols, the remaining third will likely die from the disease.
When a DLBCL patient is diagnosed, clinicians like Alizadeh, Diehn and Kurtz assess the initial symptoms, the cell type from which the cancer originated and the size and location of the tumor after the first imaging scan to generate an initial prognosis. More recently, clinicians have also been able to assess the amount of tumor DNA circulating in a patient’s blood after the first one or two rounds of therapy to determine how the tumor is responding and estimate a patient’s overall risk of succumbing to their disease.
But each of these situations gives a risk based on a snapshot in time rather than aggregating all the data available to generate a single, dynamic risk assessment that can be updated throughout the course of a patient’s treatment.
“What we’re doing now is somewhat like trying to predict the outcome of a basketball game by tuning in at halftime to check the score, or by watching only the tipoff,” Diehn said, “when in reality we know that there are any number of things that could have happened during the first half that we aren’t taking into account. We wanted to learn if it’s best to look at the latest information available about a patient, the earliest information we gathered, or whether it’s best to aggregate all of this data over many time points.”
Alizadeh and his colleagues gathered data on more than 2,500 DLBCL patients from 11 previously published studies for whom the three most common predictors of prognosis were available. They used the data to train a computer algorithm to recognize patterns and combinations likely to affect whether a patient lived for at least 24 months after seemingly successful treatment without experiencing a recurrence of their disease. They also included information from 132 patients for whom data about circulating tumor DNA levels were available prior to and after the first and second rounds of treatment.
“Our standard methods of predicting prognoses in these patients are not that accurate,” Kurtz said. “Using standard baseline variables it becomes almost a crystal ball exercise. If a perfectly accurate test has a score of 1, and a test that assigns patients randomly to one of two groups has a score of 0.5—essentially a coin toss—our current methods score at about 0.6. But CIRI’s score was around 0.8. Not perfect, but markedly better than we’ve done in the past.”
Identifying better treatment options
The researchers next tested CIRI’s performance on data from previously published panels of people with a common leukemia and another on breast cancer patients. Although the prognostic indicators varied for each disease, they found that, by serially integrating the predictive information over time, CIRI outperformed the standard methods. Furthermore, it suggested that it might be useful to identify patients who might need more aggressive intervention within one or two rounds of rather than waiting to see if the disease recurs.
“What I didn’t expect was that aggregating all this information through time may also be predictive,” Alizadeh said. “It might tell us ‘you’re going down the wrong path with this therapy, and this other therapy might be better.’ Now we have a mathematical model that might help us identify subsets of  who are unlikely to do well with standard treatments.”
The researchers are next planning to test CIRI’s predictive capabilities in people recently diagnosed with aggressive lymphoma.
Explore further
Journal information: Cell
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