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Research Briefs February 2019

NLHBI Puts Heart Trial on Hold

Out of “an abundance of caution,” the National Heart, Lung, and Blood Institute (NHLBI) has “paused” CONCERT-HF, a phase 2 trial investigating whether c-kit+ cells, alone or in combination with mesenchymal stem cells, can safely benefit patients with chronic heart failure. The reason? NHLBI says the recent controversy about certain journal articles in cell therapy research have raised concerns, although none of the articles in question are about the CONCERT-HF trial itself.

The New England Journal of Medicine recently retracted one article and expressed concern about others on work led by Piero Anversa, MD. Anversa left Harvard Medical School amid claims that much of his published data had been manipulated or was fraudulent; he has subsequently blamed a former lab member for the fraud.

While the c-kit+ cells being studied in CONCERT-HF are the same type of cell used in Anversa’s laboratory, they were manufactured in the University of Miami Miller School of Medicine’s Interdisciplinary Stem Cell Institute. Further, the cell therapies being tested in CONCERT-HF are under an investigational, new drug designation overseen by the Food and Drug Administration (FDA). The scientific basis of CONCERT-HF is supported by several preclinical models in a number of studies and a variety of laboratories, the NHLBI says, and it was reviewed by a Protocol Review Committee independent of the trial.

In an interview with tctMD.com., Timothy Henry, MD, one of the trial investigators, said he thought the decision to stop the trial without scientific evidence was “unethical.” Dr. Henry has said he thinks it’s dangerous for the National Institutes of Health (NIH) to let publicity or politics within the NIH drive its decisions.

The NHLBI convened CONCERT-HF’s Data and Safety Monitoring Board (DSMB) to ensure the study “continues to meet the highest standards for participant safety and scientific integrity.” Pausing the study allows the DSMB to complete its review, which will inform NHLBI’s future actions. In the meantime, NHLBI will honor its commitment to study participants and continue the follow-up protocol for all those who have already been treated.

Source: tctMD., November 2, 2018

Suicide Prevention on the Job

Many adults spend a large part of their time at work, making the workplace an important but underused location for suicide prevention, say Centers for Disease Control and Prevention (CDC) researchers, who analyzed data on 22,053 suicides in 17 states. The U.S. suicide rate among working adults (16–64 years old) rose 34% between 2000 and 2016, from 12.9 per 100,000 to 17.3 per 100,000.

Suicide rates rose in many occupational groups between 2012 and 2015, but identifying the specific role that occupational factors might play in suicide risk is complicated: Both work (e.g., little job control, job insecurity) and nonwork (e.g., relationship conflict) factors are associated with psychological distress and suicide. Factors such as access to lethal means while at work play a part as well.

The group with the highest male suicide rate was Construction and Extraction (from 43.6% in 2012 to 53.2% in 2015). The Arts, Design, Entertainment, Sports, and Media group had the highest female suicide rate (15.6%, up from 11.7%).

Healthcare Support, ranked 12th in 2015, actually saw a drop in the male suicide rate (19.5/100,000 in 2015, vs. 22.1/100,000 in 2012). However, the female suicide rate rose 31% in the same period (8.4/100,000 to 11.0/100,000), making the category 3rd among women.

With a 13% decrease in female suicides (10.3/100,000 vs. 9.0/100,000), Healthcare Practitioners and Technical dropped from 4th to 6th place. Among men, the category ranked 8th, with an increase of 23% (20.8/100,000 to 25.6/100,000).

The researchers say a better understanding of how suicides are distributed by occupational group might help inform prevention programs and policies. The CDC recommends a comprehensive approach, including strategies such as:

  • enhancing social connectedness
  • strengthening state or local economic supports
  • implementing practices that encourage help-seeking and reduce stigma
  • providing referrals to mental health and other services, and
  • reducing access to lethal means among people at risk.

The CDC also encourages decision makers, such as employers, to create a response plan, in the event that someone in their organization commits suicide.

Source: CDC MMWR., November 16, 2018

Protecting Against Cyber Threats in Health Care

Over 400 major cybersecurity breaches in the health care sector were reported between 2017 and 2018. The hacks potentially threatened sensitive medical data and equipment, and intellectual property. To address such threats, the Department of Health and Human Services (HHS) created the Health Sector Cybersecurity Coordination Center (HC3), which was officially dedicated in October 2018 as part of National Cybersecurity Awareness Month. The event coordinated with the rollout of the National Cyber Strategy, intended to bolster the health sector’s cybersecurity defenses.

HC3’s mission is to coordinate with health care practitioners, organizations, and cybersecurity information-sharing organizations. A main goal is to cultivate “cybersecurity resilience” by providing timely and actionable intelligence to health organizations and to develop strategic partnerships among the organizations.

“We believe that when a risk is shared across sectors, the only way to manage that risk successfully is to manage it collectively,” said Jeanette Manfra, Assistant Secretary for Cybersecurity and Communications in the Department of Homeland Security. She added that HC3 “is a vital capability for the early detection and coordination of information between the private sector and the federal government, and with cyber professionals across the federal government.”

Source: HHS, October 30, 2018

Mapping the Pathway of Pain

What causes our response to pain? What makes us pull our hand away from a hot stove or flinch at a pinprick? Researchers from the National Center for Complementary and Integrative Health (NCCIH) say they’ve identified the activity in the brain that governs these reactions.

Alexander Chesler, PhD, senior author of the study, says we already know a lot about local spinal-cord circuits for simple reflexive responses, but “the mechanisms underlying more complex behaviors remain poorly understood.”

Using heat as the source of discomfort in their experiments, the researchers found a predictable sequence of behaviors— akin to walking cautiously on a hot beach, then hopping as the heat intensifies, then running to a water source. “This kind of ‘feed-forward’ circuitry is unique because it is an upward spiral,” says Arnab Barik, PhD, one of the study authors. “The more this pathway is activated by harmful activity, the more it reacts, leading to dramatic behavioral responses.”

The experiments showed that the brainstem parts involved in this circuit are the parabrachial nucleus (PBNI) and the dorsal reticular formation in the medulla (MdD). Standing on a hot surface activated a group of nerve cells in the PBNI, triggering escape responses through connections to the MdD. (Interestingly, PBNI cells express a gene that codes for substances that also contribute to multiple disease processes.)

“Our data provide evidence that the PBNI produces streams of information with distinct functional significance,” says Dr. Barik. “The brainstem-spinal cord pathway identified in this study selectively controls pain response and elicits appropriate behaviors based on sensory input.”

Further investigation could help us understand how pain is encoded in the brain. The study findings may also offer opportunities to understand how the body becomes dysregulated during chronic pain.

Source: NCCIH., November 16, 2018

A “Low-Burden” Tool to Screen for Intimate Partner Violence

Estimates of intimate partner violence (IPV) perpetration among veterans range from 14% to 60%, rates that are up to triple of those in civilian populations, say researchers from the VA Connecticut Healthcare System, Yale University, the VA Boston Healthcare System, and Boston University. Surprisingly, a recent study of women who served in Iraq and Afghanistan suggests that rates among women veterans may be as high as 73%. But in general, research has been conducted among men.

The National Institute of Science and U.S. Preventive Services Task Force are among the agencies calling for routine IPV-victimization screening in health care settings, including the Veterans Health Administration. However, researchers say there’s limited evidence to inform practice and policy. They also note that such screening in a busy medical setting requires a method that’s accurate but also quick and easy to use.

They suggest that screening with the five-item Modified Extended-Hurt/Insult/Threaten/Scream (Modified E-HITS) scale may fit the bill: It demonstrates good accuracy, and is fast (delivered in a couple of minutes), easy to score, and acceptable to women veterans. To test it, the researchers administered the test to 187 women. Thirty-one of them reported IPV perpetration in the past six months on the Conflict Tactics Scales. The test’s overall accuracy was good, and the majority of respondents found the questions acceptable and appropriate.

The tool is clinically useful, researchers say, with a cut score of 7 or 6. When the primary priority is maximizing detection, a lower cut score of 6 would make the instrument more sensitive. However, that also might mean more false positives, which would increase the burden on patients and the system by requiring more follow-up.

The researchers say the Modified E-HITS can help identify potential perpetrators early, so that intervention—education, information, resources, and referrals—can be offered at an early stage. The tool is also a good conversation starter, allowing for brief counseling interventions that could lead to treatment and the prevention of future incidents.

Source: Women’s Health Issues., September–October 2018

Service Dogs and Saliva

People who love dogs know intuitively that being with a dog can lower stress levels. And research backs that up: When they “positively interact” with a dog, healthy adults secrete significantly less cortisol in their saliva.

For veterans with PTSD, dogs are more than stress-reducing companions, they’re important complementary treatment. Plenty of quantitative and qualitative studies have suggested that PTSD service dogs can confer “unique benefits,” say researchers from Purdue University, Arizona State University, University of California-Irvine, and Johns Hopkins. Research has documented significant effects on self-reports of PTSD symptoms, depression, quality of life, and emotional health. Service dogs can also reduce hypervigilance by, for instance, standing behind the vet to “watch their back,” and redirecting the vet’s attention during a distressing episode.

These effects can be measured through the cortisol profile. For example, cortisol output can often attenuate over time among individuals with PTSD, the researchers say, presumably because of the unremitting fight-or-flight response. Moreover, studies have also shown that cortisol activity and reactivity can change with PTSD treatment. These researchers decided to find out whether the effect of service dogs on cortisol secretion or the cortisol awakening response (CAR) can be quantified in the context of PTSD.

Their study included 73 post-9/11 military veterans with PTSD. Of those, 45 had a service dog and 28 were on the waitlist to receive one. The researchers collected saliva samples from the veterans on two consecutive weekday mornings upon awakening and 30 minutes later.

Having a service dog was associated with a significantly higher CAR and area under the plasma drug concentration-time curve, compared with the waitlisted group. The service dog was not a predictor of waking cortisol values, but was specifically associated with a larger magnitude of the awakening response. A higher CAR may be indicative of better health and well-being, the researchers say.

Veterans with a service dog also reported significantly lower anxiety, anger, and sleep disturbance, and less alcohol abuse.

However, PTSD severity and cortisol outcomes were not significantly related, suggesting that the psychosocial and physiological effects of a service dog may be independent of each other. The researchers say it remains unclear how changes in PTSD symptoms and hyperarousal relate to changes in hypothalamic–pituitary–adrenocortical activity. They suggest that future research should incorporate physiological measurement using longitudinal designs.

Source: Psychoneuroendocrinology., December 2018

Military Service Poses Special Concerns in Pregnancy

Many women in America are at high risk for pregnancy complications—U.S. maternal and infant morbidity rates are among the highest in the industrialized world—but women who have served in the military have a different kind of risk profile, according to researchers from the University of Washington and VA Puget Sound Health Care System.

The researchers analyzed data from the 2013 and 2014 Behavioral Risk Factor Surveillance System (BRFSS) questionnaires. Of 109,197 women who met the study criteria— aged 18 to 44 years, not currently pregnant, known military status—2,436 were of childbearing age and had undergone military service.

Service members and veterans had higher rates of poor sleep and depression, compared with women who had not served. Higher rates of insufficient sleep could be due to a number of factors, the researchers say, such as disruption in circadian rhythm because of work assignments and PTSD from combat-related trauma and military sexual trauma. (The researchers note that the BRFSS did not include data on PTSD.)

The higher risk of depression puts women at risk for perinatal depression and adverse obstetrical outcomes. Further, pharmacological treatments for insomnia and depression present safety concerns in pregnancy. PTSD screening may also inform referral guidelines, since perinatal depression alone may require less intensive treatment than perinatal depression with comorbid PTSD.

Younger service members also had higher rates of smoking.

Regarding physical activity and obesity, the service members were in better shape, thanks to the “healthy soldier effect.” However, that seemed to wear off over time, as the oldest women did not have the same health advantage.

It’s essential to screen women not only for risk factors but for their military service history, the researchers conclude, especially since many women in this population get their health care from non-VA providers. Alos, screening for PTSD in addition to depression is critical for optimal preconception care in this high-risk population.

Source: Women’s Health Issues., November–December 2018

NIH Study Will Test Male Contraceptive Gel

“A safe, highly effective, and reversible method of male contraception would fill an important public health need,” says Diana Blithe, PhD, chief of the Contraceptive Development Program at the National Institute of Child Health and Human Development.

To that end, the NIH is funding a clinical trial to test NES/T, a male contraceptive skin gel that combines a progestin compound (segesterone acetate [Nestorone]) and testosterone. The progestin blocks natural testosterone production in the testes, reducing sperm production to low or nonexistent levels. The replacement testosterone maintains normal sex drive and other functions dependent on testosterone levels.

Researchers plan to enroll approximately 420 couples in the study. The men will apply NES/T daily for 4 to 12 weeks to evaluate tolerability. If sperm levels haven’t sufficiently declined, the men will use the gel for up to 16 weeks. When sperm levels are low enough for contraception, the men will enter the 52-week efficacy phase to test the gel’s pregnancy-prevention strength. Each couple will rely solely on the man’s application of the gel for contraception. The men will remain in the study for another 24 weeks after they stop using the gel.

The study will be conducted at the Los Angeles Biomedical Research Institute, the University of California Los Angeles Medical Center, and the University of Washington in Seattle.

Source: NIH., November 28, 2018

Ibrutinib + Rituximab = “New Standard” of CLL Care

“Practice-changing” results are in from a study of ibrutinib plus rituximab in patients with previously untreated chronic lymphocytic leukemia (CLL), according to researchers with the ECOG-ACRIN Cancer Research Group.

Ibrutinib and rituximab are a targeted treatment: Ibrutinib interferes with the survival of lymphocytic leukemia cells, and rituximab enhances the immune system’s ability to destroy the cells. Until now, the standard treatment combined fludarabine and cyclophosphamide with rituximab (FCR).

In the study (E1912), 529 patients aged 70 years and younger were randomly assigned to receive either ibrutinib–rituximab therapy or FCR. The first planned interim analysis for progression-free survival was made in September 2018. At a median of 33.4 months, results already showed that the ibrutinib combination reduced the risk of disease progression by 65%—exceeding the trial design target. Overall survival was also better in the ibrutinib group.

Lead investigator Tait Shanafelt, MD, said the study results “immediately establish ibrutinib and rituximab as the new standard of care” for patients 70 years of age and younger with CLL.

The findings were so remarkable that the data and safety monitoring board overseeing the trial recommended that they be released immediately. The outcome has been disclosed to all participants and their physicians, and patients already receiving ibrutinib can continue the therapy for as long as it remains effective. All patients assigned to FCR have completed treatment and are being monitored. Quality-of-life data are awaiting analysis.

Source: NCI., December 4, 2018