Lessons on the use of real-world data in medical device research: findings from the National Evaluation System for Health Technology Test-Cases.

Aim: Although the US FDA encourages manufacturers of medical devices to submit real-world evidence (RWE) to support regulatory decisions, the ability of real-world data (RWD) to generate evidence suitable for decision making remains unclear. The 2017 Medical Device User Fee Amendments (MDUFA IV), authorized the National Evaluation System for health Technology Coordinating Center (NESTcc) to conduct pilot projects, or 'Test-Cases', to assess whether current RWD captures the information needed to answer research questions proposed by industry stakeholders. We synthesized key lessons about the challenges conducting research with RWD and the strategies used by research teams to enhance their ability to generate evidence from RWD based on 18 Test-Cases conducted between 2020 and 2022. Materials & methods: We reviewed study protocols and reports from each Test-Case team and conducted 49 semi-structured interviews with representatives of participating organizations. Interview transcripts were coded and thematically analyzed. Results: Challenges that stakeholders encountered in working with RWD included the lack of unique device identifiers, capturing key data elements and their appropriate meaning in structured data, limited reliability of diagnosis and procedure codes in structured data, extracting information from unstructured electronic health record (EHR) data, limited capture of long-term study end points, missing data and data sharing. Successful strategies included using manufacturer and supply chain data, leveraging clinical registries and registry reporting processes to collect and aggregate data, querying standardized EHR data, implementing natural language processing algorithms and using multidisciplinary research teams. Conclusion: The Test-Cases identified numerous challenges working with RWD but also opportunities to address these challenges and improve researchers' ability to use RWD to generate evidence on medical devices.

Harmine and exendin-4 combination therapy safely expands human ß cell mass in vivo in a mouse xenograft system.

Five hundred thirty-seven million people globally suffer from diabetes. Insulin-producing ß cells are reduced in number in most people with diabetes, but most individuals still have some residual ß cells. However, none of the many diabetes drugs in common use increases human ß cell numbers. Recently, small molecules that inhibit dual tyrosine-regulated kinase 1A (DYRK1A) have been shown to induce immunohistochemical markers of human ß cell replication, and this is enhanced by drugs that stimulate the glucagon-like peptide 1 (GLP1) receptor (GLP1R) on ß cells. However, it remains to be demonstrated whether these immunohistochemical findings translate into an actual increase in human ß cell numbers in vivo. It is also unknown whether DYRK1A inhibitors together with GLP1R agonists (GLP1RAs) affect human ß cell survival. Here, using an optimized immunolabeling-enabled three-dimensional imaging of solvent-cleared organs (iDISCO+) protocol in mouse kidneys bearing human islet grafts, we demonstrate that combination of a DYRK1A inhibitor with exendin-4 increases actual human ß cell mass in vivo by a mean of four- to sevenfold in diabetic and nondiabetic mice over 3 months and reverses diabetes, without alteration in human α cell mass. The augmentation in human ß cell mass occurred through mechanisms that included enhanced human ß cell proliferation, function, and survival. The increase in human ß cell survival was mediated, in part, by the islet prohormone VGF. Together, these findings demonstrate the therapeutic potential and favorable preclinical safety profile of the DYRK1A inhibitor-GLP1RA combination for diabetes treatment.

Amygdala-liver signaling orchestrates rapid glycemic responses to stress and drives stress-induced metabolic dysfunction.

Behavioral adaptations to environmental threats are crucial for survival and necessitate rapid deployment of energy reserves. The amygdala coordinates behavioral adaptations to threats, but little is known about its involvement in underpinning metabolic adaptations. Here, we show that acute stress activates medial amygdala (MeA) neurons that innervate the ventromedial hypothalamus (MeAVMH neurons), which precipitates hyperglycemia and hypophagia. The glycemic actions of MeAVMH neurons occur independent of adrenal or pancreatic glucoregulatory hormones. Instead, using whole-body virus tracing, we identify a polysynaptic connection from MeA to the liver, which promotes the rapid synthesis of glucose by hepatic gluconeogenesis. Repeated stress exposure disrupts MeA control of blood glucose and appetite, resulting in diabetes-like dysregulation of glucose homeostasis and weight gain. Our findings reveal a novel amygdala-liver axis that regulates rapid glycemic adaptations to stress and links recurrent stress to metabolic dysfunction.

RANKL/RANK is required for cytokine-induced beta cell death; osteoprotegerin, a RANKL inhibitor, reverses rodent type 1 diabetes.

Treatment for type 1 diabetes (T1D) requires stimulation of functional ß cell regeneration and survival under stress. Previously, we showed that inhibition of the RANKL/RANK [receptor activator of nuclear factor kappa Β (NF-κB) ligand] pathway, by osteoprotegerin and the anti-osteoporotic drug denosumab, induces rodent and human ß cell proliferation. We demonstrate that the RANK pathway mediates cytokine-induced rodent and human ß cell death through RANK-TRAF6 interaction and induction of NF-κB activation. Osteoprotegerin and denosumab protected ß cells against this cytotoxicity. In human immune cells, osteoprotegerin and denosumab reduce proinflammatory cytokines in activated T-cells by inhibiting RANKL-induced activation of monocytes. In vivo, osteoprotegerin reversed recent-onset T1D in nonobese diabetic/Ltj mice, reduced insulitis, improved glucose homeostasis, and increased plasma insulin, ß cell proliferation, and mass in these mice. Serum from T1D subjects induced human ß cell death and dysfunction, but not α cell death. Osteoprotegerin and denosumab reduced T1D serum-induced ß cell cytotoxicity and dysfunction. Inhibiting RANKL/RANK could have therapeutic potential.

Magnetogenetic cell activation using endogenous ferritin.

The ability to precisely control the activity of defined cell populations enables studies of their physiological roles and may provide therapeutic applications. While prior studies have shown that magnetic activation of ferritin-tagged ion channels allows cell-specific modulation of cellular activity, the large size of the constructs made the use of adeno-associated virus, AAV, the vector of choice for gene therapy, impractical. In addition, simple means for generating magnetic fields of sufficient strength have been lacking. Toward these ends, we first generated a novel anti-ferritin nanobody that when fused to transient receptor potential cation channel subfamily V member 1, TRPV1, enables direct binding of the channel to endogenous ferritin in mouse and human cells. This smaller construct can be delivered in a single AAV and we validated that it robustly enables magnetically induced cell activation in vitro . In parallel, we developed a simple benchtop electromagnet capable of gating the nanobody-tagged channel in vivo . Finally, we showed that delivering these new constructs by AAV to pancreatic beta cells in combination with the benchtop magnetic field delivery stimulates glucose-stimulated insulin release to improve glucose tolerance in mice in vivo . Together, the novel anti-ferritin nanobody, nanobody-TRPV1 construct and new hardware advance the utility of magnetogenetics in animals and potentially humans.

Psychological Harms and Treatment of Sexual Assault and Sexual Harassment in Adults: Systematic and Scoping Reviews to Inform Improved Care for Military Populations.

Victims of sexual assault and sexual harassment often experience a variety of psychological outcomes and mental health symptoms related to posttraumatic stress disorder (PTSD), depression, anxiety, substance abuse, suicidal ideation, and self-harm. Sexual trauma also might affect careers. Despite a need to address these harms, some service members have reported that connecting to health care or mental health services following sexual assault or sexual harassment can be difficult-in part because of a lack of leadership support. Given these persistent challenges, the Psychological Health Center of Excellence identified an urgent need to better understand research that is pertinent to sexual assault and sexual harassment during military service so that the U.S. Department of Defense and the military services can improve the health care response for service members. RAND researchers investigated and synthesized relevant research in three topic areas: (1) the effectiveness of psychotherapy treatments designed for adult victims of sexual assault or sexual harassment in military settings; (2) barriers faced by U.S. military members to accessing and remaining in mental health care settings; and (3) associations between sexual assault or sexual harassment and mental health conditions.

Evaluation of Mental Health First Aid in New York City.

More than 155,000 New Yorkers were trained in Mental Health First Aid (MHFA) between 2016 and 2020. Free citywide trainings were made available to all New Yorkers and were disseminated through city agencies and community-based settings. RAND Corporation researchers conducted a mixed-methods study that included a web-based survey of past trainees and a series of focus groups with leaders of community-based organizations and city agency staff to assess the impact of the MHFA trainings and needs for future training. In this article, the authors describe the evaluation activities that took place; the methods behind them; and the results at the individual, agency, and community levels. They also offer recommendations for ways to improve future mental health education efforts. Respondents applied MHFA skills extensively and broadly across their social networks. Nine in ten respondents had contact with an individual with a mental health problem in the past six months. Among those who had contact, 84 percent indicated using their MHFA skills to help a friend or family member, and nearly half reported applying skills with a co-worker, neighbor, or acquaintance. Because MHFA was offered through city agency workplaces and community-based settings, tens of thousands of New Yorkers were given tools to come to the aid of individuals in their personal and professional lives. MHFA may be a promising approach to building supportive social networks, organizations, and communities that are primed to recognize and assist those experiencing mental health challenges.

Does removing menthol cigarettes in convenience stores reduce susceptibility to cigarette smoking? An experimental investigation in young people.

BACKGROUND: Evidence for the effectiveness of menthol cigarette bans comes mostly from studies of adults that smoke. This experiment evaluated whether the absence of menthol products from a convenience store influenced young people's susceptibility to cigarette smoking after they shopped in the store. METHODS: This experiment took place in the RAND StoreLab (RSL), a life-sized research convenience store. A three-group, between-subjects design was used. Study conditions differed in the mix of flavored tobacco products the RSL displayed: 1) All tobacco-, sweet-, and menthol-flavors displayed; 2) only tobacco- and menthol-flavors displayed; and 3) only tobacco-flavors displayed. Participants were randomly assigned to shop in the RSL under one of these conditions and after shopping, completed measures of their susceptibility to cigarette smoking, one measure for menthol cigarettes and one for unflavored cigarettes (scores on each susceptibility measure was dichotomized: 0 = not susceptible; 1 = susceptible). RESULTS: Multivariable logistic regression assessed the main effects of condition on susceptibility to smoking menthol and unflavored cigarettes. There was no condition effect on susceptibility to smoking unflavored cigarettes. However, removing menthol-flavored products significantly increased participants' susceptibility to smoking menthol cigarettes compared to when all flavored products were available (OR = 3.66, 95% CI [1.33, 10.03]). This significant effect was only found among young people with some pre-existing risk of cigarette smoking (OR = 5.92, 95% CI [1.81, 19.39]). CONCLUSION: Results suggest the need to consider that menthol bans could unintentionally increase the appeal of menthol cigarettes among youth already at risk of smoking.

An experimental evaluation of the effects of banning the sale of flavored tobacco products on adolescents' and young adults' future nicotine vaping intentions.

BACKGROUND: Some U.S. states and municipalities have banned the sale of flavored tobacco products to help curb youth vaping. However, evidence supporting such bans is limited. This experiment tested whether removing flavored tobacco products from a retail setting diminished adolescents' (ages 11-20) future intentions to use vaping products. METHODS: The study was implemented in the RAND StoreLab, a life-sized model convenience store. The display of flavored tobacco products in the store was manipulated with these conditions: 1) tobacco, sweet, and menthol/mint flavors displayed; 2) only tobacco and menthol/mint displayed; and 3) only tobacco flavors displayed. Participants were randomly assigned to shop in one of these conditions and completed measures of future vaping intentions post-shopping. Separate logistic regression models assessed effect of condition on future intentions to use different flavors (tobacco-, menthol/mint-, and sweet-flavored) and any flavor (composite score across flavor categories) of vaping products. RESULTS: Study condition was not associated with intentions to use menthol/mint-, sweet-flavored, or any flavor. Compared to the condition in which all flavored products were displayed, removing menthol/mint- and sweet-flavored products significantly increased future intentions to use tobacco-flavored vaping products (OR = 3.97, 95 % CI [1.01, 15.58], p < .05). This effect was only observed among adolescents with history of vaping (OR = 11.30, 95 % CI [1.42, 89.96], p = .02). CONCLUSIONS: Flavor bans may not affect adolescents' intentions to use menthol/mint, sweet, or "any" flavor of vaping products but may increase intentions to use tobacco-flavored products for teens who have already started vaping.

Diversity in U.S. Military Families: An Environmental Scan of the Peer-Reviewed Literature on Race and Ethnic Variation for Select Well-Being Outcomes.

Researchers explore the literature on race and ethnicity (R/E) in relation to U.S. military service member well-being in the areas of mental health, behavioral health, family violence, marital satisfaction, and financial stress to uncover whether past research has focused on R/E differences in outcomes as a driving research question; the variables used to capture R/E; and the quality of research in terms of design, data, and analysis. The Department of Defense (DoD) has expressed commitment to improving diversity and inclusion in the military. If leaders seek to do this based on existing evidence, they will find that information about how R/E intersects with the well-being of service members and their families is extremely limited. DoD should consider developing a deliberate, strategic, and comprehensive research agenda on R/E diversity in service member and family well-being outcomes. This will help DoD identify where differences exist and where policies and programs can address those gaps.