Design and testing of a humanized porcine donor for xenotransplantation.

Recent human decedent model studies1,2 and compassionate xenograft use3 have explored the promise of porcine organs for human transplantation. To proceed to human studies, a clinically ready porcine donor must be engineered and its xenograft successfully tested in nonhuman primates. Here we describe the design, creation and long-term life-supporting function of kidney grafts from a genetically engineered porcine donor transplanted into a cynomolgus monkey model. The porcine donor was engineered to carry 69 genomic edits, eliminating glycan antigens, overexpressing human transgenes and inactivating porcine endogenous retroviruses. In vitro functional analyses showed that the edited kidney endothelial cells modulated inflammation to an extent that was indistinguishable from that of human endothelial cells, suggesting that these edited cells acquired a high level of human immune compatibility. When transplanted into cynomolgus monkeys, the kidneys with three glycan antigen knockouts alone experienced poor graft survival, whereas those with glycan antigen knockouts and human transgene expression demonstrated significantly longer survival time, suggesting the benefit of human transgene expression in vivo. These results show that preclinical studies of renal xenotransplantation could be successfully conducted in nonhuman primates and bring us closer to clinical trials of genetically engineered porcine renal grafts.

Evaluation of follow-up colposcopy procedures after abnormal cervical screening result across a statewide study in Mississippi.

PURPOSE: Cervical screening is used to detect and treat precancers to prevent invasive cancers. However, successful prevention also requires adequate follow-up and treatment of individuals with abnormal screening results. The aim was to investigate demographics, clinical characteristics, and follow-up status for individuals needing colposcopy after an abnormal screening result. METHODS: The STRIDES (Studying Risk to Improve DisparitiES) cohort comprises individuals undergoing cervical cancer screening and management at a Mississippi Health Department or University of Mississippi clinic. Follow-up status, demographics, and clinical data were assessed from electronic health records and, if necessary, patient navigation on individuals identified as needing a colposcopy after an abnormal screening. RESULTS: Of the 1,458 individuals requiring colposcopy, 43.0% had the procedure within 4 months, 16.4% had a delayed procedure, and 39.5% had no documented colposcopy follow-up, with significant predictors of follow-up identified as age and cytology diagnosis. Individuals 30 + were more likely to have follow up with a colposcopy compared to individuals < 30 years (49% and 38.7%, respectively; p < .001). Individuals with cytology diagnoses of LSIL (52.9%), ASC-H (51.4%), and HSIL (62.3%) had higher percentages of adherence to follow-up guidelines (p < .001). In total, we found that 78% of individuals had some type of follow-up, including a repeat screening visit. CONCLUSION: Despite high cervical cancer screening rates among Mississippians, a substantial proportion did not have adequate next-step intervention. However, it is encouraging that highest risk individuals were more likely to have a colposcopy. Regardless, continuing to understand the underlying causes for incomplete follow-up is crucial for timely secondary targeted interventions to reduce cervical cancer burden, promote awareness, and improve health outcomes.

HNRNPH1 destabilizes the G-quadruplex structures formed by G-rich RNA sequences that regulate the alternative splicing of an oncogenic fusion transcript.

In the presence of physiological monovalent cations, thousands of RNA G-rich sequences can form parallel G-quadruplexes (G4s) unless RNA-binding proteins inhibit, destabilize, or resolve the formation of such secondary RNA structures. Here, we have used a disease-relevant model system to investigate the biophysical properties of the RNA-binding protein HNRNPH1's interaction with G-rich sequences. We demonstrate the importance of two EWSR1-exon 8 G-rich regions in mediating the exclusion of this exon from the oncogenic EWS-FLI1 transcripts expressed in a subset of Ewing sarcomas, using complementary analysis of tumor data, long-read sequencing, and minigene studies. We determined that HNRNPH1 binds the EWSR1-exon 8 G-rich sequences with low nM affinities irrespective of whether in a non-G4 or G4 state but exhibits different kinetics depending on RNA structure. Specifically, HNRNPH1 associates and dissociates from G4-folded RNA faster than the identical sequences in a non-G4 state. Importantly, we demonstrate using gel shift and spectroscopic assays that HNRNPH1, particularly the qRRM1-qRRM2 domains, destabilizes the G4s formed by the EWSR1-exon 8 G-rich sequences in a non-catalytic fashion. Our results indicate that HNRNPH1's binding of G-rich sequences favors the accumulation of RNA in a non-G4 state and that this contributes to its regulation of RNA processing.

Sex-specific associations between self-reported physical activity and PTSD among survivors of sexual violence.

This study examined sex-specific associations between sexual violence (SV) type and physical activity, and identified associations between PTSD symptoms and physical activity, all among cisgender men and women survivors of SV. Cross-sectional data from men (n = 197) and women (n = 356) survivors of SV were analyzed with stratified (men; women) hierarchical logistic regressions. Additionally, fully adjusted models for the total sample included interaction terms to further assess whether associations between SV type as well as PTSD symptoms (sum, clusters) and physical activity differed significantly by sex. Sexual assault was negatively associated with physical activity in the crude model among women (ORs: 0.58; p < 0.05). Harassment was positively associated with physical activity in the crude and adjusted models (ORs:1.92-2.16; ps<0.05) among women. Among men, there were no significant relationships. Regarding PTSD symptoms among women, crude and adjusted stratified models identified significant positive relationships with intrusion (ORs: 1.18-1.22; ps<0.05). Crude and adjusted models revealed significant positive relationships between avoidance and activity (ORs:1.38-1.41; ps<0.05) among men but not women. The interaction term for this difference in the association between avoidance and physical activity by sex was significant (OR: 0.65; 95%CI: 0.48-0.88; p < 0.01). Overall, findings provide evidence for sex-specific associations between SV and physical activity.

Analyzing the concept of toxic positivity for nursing: A dimensional analysis approach.

AIM: To analyze toxic positivity and its relevance to nursing. DESIGN: Concept analysis using Schatzman's dimensional analysis approach. DATA SOURCES: Two searches were conducted using Google Scholar, JSTOR, ProQuest and CINAHL (1990-2023). Keywords included "toxic positivity" (Phase 1) and "emotional suppression," "unrealistic optimism"; "disingenuous happiness," "forced gratitude" and "logical fallacy" (Phase 2). Retained sources (1) were in English (Phases 1 and 2); (2) used 'toxic positivity' as a construct reflecting the purpose of analysis (Phase 1); and (3) demonstrated relevance towards analytical findings (Phase 2). Total analytic sources were 35. METHODS: The analytic phase, identification, elucidated conceptual dimensions and contexts. The analytic phase, logistics, examined relationships among dimensions and contexts through an iterative process resulting in a dimensional matrix/conceptual model. RESULTS: Salient dimension is Emotional Suppression with two sub-dimensions, Logical Fallacy and Forced Gratitude. Other dimensions include Unrealistic Optimism and Disingenuous Happiness. Contexts include intra- and post-paradigmatic societal shifts and intra- and post-traumatic experiences. Analysis reveals toxic positivity as an exchange between a giver and receiver with the receiver experiencing negative outcomes. CONCLUSION: The concept appears consistent in its application and use across contexts and is emerging in nursing literature. IMPLICATIONS FOR THE PROFESSION: Acknowledging toxic positivity in nursing may inform theoretical and future research related to improving nursing burnout, bolstering retention, and enhancing well-being. Nurses across work environments may encounter toxic positivity. Leaders should consider policy adoption and inclusion of trauma-informed practices. IMPACT: Nursing workforce issues require deeper examination of potential contributing factors. Findings suggest toxic positivity may be encountered in work environments impacting nursing at individual and system levels. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution.

Which Types of Stress Are Associated With Accelerated Biological Aging? Comparing Perceived Stress, Stressful Life Events, Childhood Adversity, and Posttraumatic Stress Disorder.

OBJECTIVE: Stress and stressful events are associated with poorer health; however, there are multiple ways to conceptualize and measure stress and stress responses. One physiological mechanism through which stress could result in poorer health is accelerated biological aging. This study tested which types of stress were associated with accelerated biological aging in adulthood. METHODS: Studying 955 participants from the Dunedin Longitudinal Study, we tested whether four types of stress assessed from ages 32 to 45 years-perceived stress, number of stressful life events, adverse childhood experiences, and posttraumatic stress disorder-were associated with accelerated biological aging. RESULTS: Higher levels of all four measures of stress were significantly associated with accelerated aging in separate models. In a combined model, more perceived stress and more stressful life events remained associated with faster aging, and the stress measures explained 6.9% of the variance in aging. The magnitudes of the associations between the four measures of stress and biological aging were comparable to associations for smoking and low education, two established risk factors for accelerated aging. People with high levels of perceived stress, numerous adverse childhood experiences (4+), high stressful life event counts, or posttraumatic stress disorder were aging an additional estimated 2.4 months, 1.1 additional months, 1.4 months, and 1.4 months per year, respectively. CONCLUSIONS: Assessing stress, particularly perceived stress, could help identify people at risk of accelerated aging. Intervening to treat stress or the health-relevant sequelae of stress could potentially slow the rate at which people are aging, improving their health as they age.

Physical Function Assessment of Older Veterans With Serious Mental Illness.

OBJECTIVE: To characterize the physical function of older veterans with serious mental illness (SMI) across endurance, strength, and mobility domains. DESIGN: Retrospective analysis of clinical performance data. SETTING: Gerofit program, a national outpatient supervised exercise program for older veterans, delivered in Veterans Health Administration sites. PARTICIPANTS: Older veterans aged 60 and older (n = 166 with SMI, n = 1,441 without SMI) enrolled across eight national Gerofit sites between 2010 and 2019. MEASUREMENTS: Performance measures of physical function covering endurance (6-minute walk test), strength (chair stands, arm curls), and mobility (10-m walk, 8-foot-up-and-go), were administered at Gerofit enrollment. Baseline data from these measures were analyzed to characterize the functional profiles of older veterans with SMI. One sample t tests were examined to compare functional performance of older veterans with SMI to age- and sex-based reference scores. Propensity score matching (1:3) and linear mixed effects models were used to evaluate differences in function between veterans with and without SMI. RESULTS: Older veterans with SMI performed worse on all measures of function (chair stands, arm curls, 10-m walk, 6-minute walk test, 8-foot-up-and-go) compared to age- and sex-based reference scores with statistically significant differences present in the male sample. Functional performance of those with SMI was also worse compared to propensity-score matched older veterans without SMI with statistically significant differences on chair stands, 6-minute walk test, and 10-m walk. CONCLUSION: Older veterans with SMI have compromised strength, mobility, and endurance. Physical function should be a core component of screening and treatment for this population.

Mothers' accounts of the impact of being in nature on postnatal wellbeing: a focus group study.

BACKGROUND: The postnatal period is a vulnerable time for mothers to experience stress and mental health difficulties. There is increasing evidence that spending time in nature is beneficial for wellbeing. Nature-based interventions have been developed to support mental health, but not specifically tailored for mothers during the postnatal period. Understanding mothers' views and experiences of nature would help determine the suitability for and potential impact of such interventions on postnatal wellbeing. AIMS: To explore mothers' views on the impact of spending time in nature on their postnatal mental wellbeing. METHODS: Focus groups were held with mothers of young children (under five), including mothers from migrant and refugee communities, mothers living with mental health difficulties, and disabled mothers. Data were analysed using reflexive thematic analysis. RESULTS: Four focus groups were held, with a total of 30 participants. Six themes were developed: (1) mothers' experiences of what constitutes 'nature'; (2) sensing nature improves wellbeing; (3) natural spaces facilitate human connection; (4) nature provides escape and relief from daily indoor stressors; (5) nature allows new perspectives; and (6) mothers face a variety of environmental, practical, psychological, physical, socioeconomic, and cultural barriers to spending time in nature during the postnatal period. CONCLUSIONS: Mothers report significant benefits to their postnatal wellbeing when spending time in nature. Further research is warranted to understand whether nature-based interventions have the potential to support postnatal wellbeing, socially, mentally, and physically.

Stimulation of soluble guanylate cyclase exerts antiinflammatory actions in the liver through a VASP/NF-κB/NLRP3 inflammasome circuit.

Soluble guanylate cyclase (sGC) catalyzes the conversion of guanosine triphosphate into cyclic guanosine-3',5'-monophosphate, a key second messenger in cell signaling and tissue homeostasis. It was recently demonstrated that sGC stimulation is associated with a marked antiinflammatory effect in the liver of mice with experimental nonalcoholic steatohepatitis (NASH). Here, we investigated the mechanisms underlying the antiinflammatory effect of the sGC stimulator praliciguat (PRL) in the liver. Therapeutic administration of PRL exerted antiinflammatory and antifibrotic actions in mice with choline-deficient l-amino acid-defined high-fat diet-induced NASH. The PRL antiinflammatory effect was associated with lower F4/80- and CX3CR1-positive macrophage infiltration into the liver in parallel with lower Ly6CHigh- and higher Ly6CLow-expressing monocytes in peripheral circulation. The PRL antiinflammatory effect was also associated with suppression of hepatic levels of interleukin (IL)-1ß, NLPR3 (NACHT, LRR, and PYD domain-containing protein 3), ASC (apoptosis-associated speck-like protein containing a caspase-recruitment domain), and active cleaved-caspase-1, which are components of the NLRP3 inflammasome. In Kupffer cells challenged with the classical inflammasome model of lipopolysaccharide plus adenosine triphosphate, PRL inhibited the priming (expression of Il1b and Nlrp3) and blocked the release of mature IL-1ß. Mechanistically, PRL induced the protein kinase G (PKG)-mediated phosphorylation of the VASP (vasodilator-stimulated phosphoprotein) Ser239 residue which, in turn, reduced nuclear factor-κB (NF-κB) activity and Il1b and Nlrp3 gene transcription. PRL also reduced active cleaved-caspase-1 levels independent of pannexin-1 activity. These data indicate that sGC stimulation with PRL exerts antiinflammatory actions in the liver through mechanisms related to a PKG/VASP/NF-κB/NLRP3 inflammasome circuit.

Finding Themselves, Their Place, Their Way: Uncertainties Identified by Medical Students.

Phenomenon: Navigating uncertainty is a core skill when practicing medicine. Increasingly, the need to better prepare medical students for uncertainty has been recognized. Our current understanding of medical students' perspectives on uncertainty is primarily based on quantitative studies with limited qualitative research having been performed to date. We need to know from where and how sources of uncertainty can arise so that educators can better support medical students learning to respond to uncertainty. This research's aim was to describe the sources of uncertainty that medical students identify in their education. Approach: Informed by our previously published framework of clinical uncertainty, we designed and distributed a survey to second, fourth-, and sixth-year medical students at the University of Otago, Aotearoa New Zealand. Between February and May 2019, 716 medical students were invited to identify sources of uncertainty encountered in their education to date. We used reflexive thematic analysis to analyze responses. Findings: Four-hundred-sixty-five participants completed the survey (65% response rate). We identified three major sources of uncertainty: insecurities, role confusion, and navigating learning environments. Insecurities related to students' doubts about knowledge and capabilities, which were magnified by comparing themselves to peers. Role confusion impacted upon students' ability to learn, meet the expectations of others, and contribute to patient care. Navigating the educational, social, and cultural features of clinical and non-clinical learning environments resulted in uncertainty as students faced new environments, hierarchies, and identified challenges with speaking up. Insights: This study provides an in-depth understanding of the wide range of sources of medical students' uncertainties, encompassing how they see themselves, their roles, and their interactions with their learning environments. These results enhance our theoretical understanding of the complexity of uncertainty in medical education. Insights from this research can be applied by educators to better support students develop the skills to respond to a core element of medical practice.

Physical Function Effects of Live Video Group Exercise Interventions for Older Adults: A Systematic Review and Veteran's Gerofit Group Case Study.

Background: Literature on telehealth interventions for older adults has been primarily on asynchronous interventions. During the COVID-19 pandemic, older adult exercise programs transitioned to an online format. This systematic review and case study examines the effectiveness of older adult live video exercise group interventions on physical health with insights from a Los Angeles VA program, Gerofit. Methods: PubMed was searched for live video older adult exercise groups from database inception to November 2021. All eligible studies included assessments of physical health and were limited to participants with an average age of 65 years or greater. Ten Veterans, who had participated in both in-person and virtual Gerofit sessions, were surveyed in the case study. Results: Nine studies met the inclusion criteria. Four studies included an equivalent in-person group as a comparator to the live video group and reported no significant between-group differences in outcomes, including energy expenditure and 6-minute walking distance test (6MWD). The other five studies reported statistically significant in-group improvement in outcomes including isokinetic knee strength. Case study participants reported similar attendance rates and perceived benefits, such as improved balance, when comparing virtual and in-person sessions. Discussion: Live video exercise groups in older adults demonstrated an improvement in physical function that was not statistically different from the comparison in-person sessions with the added benefit of averaging a higher attendance rate, providing initial support for the use of live video in older adult exercise programs. Insights from the case study supplement this by demonstrating older adults' positive attitude on these groups.

Kidney transplantation from triple-knockout pigs expressing multiple human proteins in cynomolgus macaques.

Porcine cells devoid of three major carbohydrate xenoantigens, αGal, Neu5GC, and SDa (TKO) exhibit markedly reduced binding of human natural antibodies. Therefore, it is anticipated that TKO pigs will be better donors for human xenotransplantation. However, previous studies on TKO pigs using old world monkeys (OWMs) have been disappointing because of higher anti-TKO pig antibodies in OWMs than humans. Here, we show that long-term survival of renal xenografts from TKO pigs that express additional human transgenes (hTGs) can be achieved in cynomolgus monkeys. Kidney xenografts from TKO-hTG pigs were transplanted into eight cynomolgus recipients without pre-screening for low anti-pig antibody titers. Two recipients of TKO-hTG xenografts with low expression of human complement regulatory proteins (CRPs) (TKO-A) survived for 2 and 61 days, whereas six recipients of TKO-hTG xenografts with high CRP expression (TKO-B) survived for 15, 20, 71, 135, 265, and 316 days. Prolonged CD4+ T cell depletion and low anti-pig antibody titers, which were previously reported important for long-term survival of αGal knock-out (GTKO) xenografts, were not always required for long-term survival of TKO-hTG renal xenografts. This study indicates that OWMs such as cynomolgus monkeys can be used as a relevant model for clinical application of xenotransplantation using TKO pigs.

Cost and Quality of Life Outcomes of the STepped Exercise Program for Patients With Knee OsteoArthritis Trial.

OBJECTIVES: This study aimed to evaluate the cost-effectiveness of the randomized clinical trial STEP-KOA (STepped Exercise Program for patients with Knee OsteoArthritis). METHODS: The trial included 230 intervention and 115 control participants from 2 Veterans Affairs (VA) medical centers. A decision tree simulated outcomes for cohorts of patients receiving arthritis education (control) or STEP-KOA (intervention), which consisted of an internet-based exercise training program (step 1), phone counseling (step 2), and physical therapy (step 3) according to patient's response. Intervention costs were assessed from the VA perspective. Quality of life (QOL) was measured using 5-level EQ-5D US utility weights. Incremental cost-effectiveness ratios (ICERs) were calculated as the difference in costs divided by the difference in quality-adjusted life-years (QALYs) between arms at 9 months. A Monte Carlo probabilistic sensitivity analysis was used to generate a cost-effectiveness acceptability curve. RESULTS: The adjusted model found differential improvement in QOL utility weights of 0.042 (95% confidence interval 0.003-0.080; P=.03) for STEP-KOA versus control at 9 months. In the base case, STEP-KOA resulted in an incremental gain of 0.028 QALYs and an incremental cost of $279 per patient for an ICER of $10 076. One-way sensitivity analyses found the largest sources of variation in the ICER were the impact on QOL and the need for a VA-owned tablet. The probabilistic sensitivity analysis found a 98% probability of cost-effectiveness at $50 000 willingness-to-pay per QALY. CONCLUSIONS: STEP-KOA improves QOL and has a high probability of cost-effectiveness. Resources needed to implement the program will decline as ownership of mobile health devices increases.

sGC stimulator praliciguat suppresses stellate cell fibrotic transformation and inhibits fibrosis and inflammation in models of NASH.

Endothelial dysfunction and reduced nitric oxide (NO) signaling are a key element of the pathophysiology of nonalcoholic steatohepatitis (NASH). Stimulators of soluble guanylate cyclase (sGC) enhance NO signaling; have been shown preclinically to reduce inflammation, fibrosis, and steatosis; and thus have been proposed as potential therapies for NASH and fibrotic liver diseases. Praliciguat, an oral sGC stimulator with extensive distribution to the liver, was used to explore the role of this signaling pathway in NASH. We found that sGC is expressed in hepatic stellate cells and stellate-derived myofibroblasts, but not in hepatocytes. Praliciguat acted directly on isolated hepatic stellate cells to inhibit fibrotic and inflammatory signaling potentially through regulation of AMPK and SMAD7. Using in vivo microdialysis, we demonstrated stimulation of the NO-sGC pathway by praliciguat in both healthy and fibrotic livers. In preclinical models of NASH, praliciguat treatment was associated with lower levels of liver fibrosis and lower expression of fibrotic and inflammatory biomarkers. Praliciguat treatment lowered hepatic steatosis and plasma cholesterol levels. The antiinflammatory and antifibrotic effects of praliciguat were recapitulated in human microtissues in vitro. These data provide a plausible cellular basis for the mechanism of action of sGC stimulators and suggest the potential therapeutic utility of praliciguat in the treatment of NASH.

Stepped Exercise Program for Patients With Knee Osteoarthritis : A Randomized Controlled Trial.

BACKGROUND: Evidence-based models are needed to deliver exercise-related services for knee osteoarthritis efficiently and according to patient needs. OBJECTIVE: To examine a stepped exercise program for patients with knee osteoarthritis (STEP-KOA). DESIGN: Randomized controlled trial. (ClinicalTrials.gov: NCT02653768). SETTING: 2 U.S. Department of Veterans Affairs sites. PARTICIPANTS: 345 patients (mean age, 60 years; 15% female; 67% people of color) with symptomatic knee osteoarthritis. INTERVENTION: Participants were randomly assigned in a 2:1 ratio to STEP-KOA or an arthritis education (AE) control group, respectively. The STEP-KOA intervention began with 3 months of an internet-based exercise program (step 1). Participants who did not meet response criteria for improvement in pain and function after step 1 progressed to step 2, which involved 3 months of biweekly physical activity coaching calls. Participants who did not meet response criteria after step 2 went on to in-person physical therapy visits (step 3). The AE group received educational materials via mail every 2 weeks. MEASUREMENTS: Primary outcome was Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score. Scores for the STEP-KOA and AE groups at 9 months were compared by using linear mixed models. RESULTS: In the STEP-KOA group, 65% of participants (150 of 230) progressed to step 2 and 35% (81 of 230) to step 3. The estimated baseline WOMAC score for the full sample was 47.5 (95% CI, 45.7 to 49.2). At 9-month follow-up, the estimated mean WOMAC score was 6.8 points (CI, -10.5 to -3.2 points) lower in the STEP-KOA than the AE group, indicating greater improvement. LIMITATION: Participants were mostly male veterans, and follow-up was limited. CONCLUSION: Veterans in STEP-KOA reported modest improvements in knee osteoarthritis symptoms compared with the control group. The STEP-KOA strategy may be efficient for delivering exercise therapies for knee osteoarthritis. PRIMARY FUNDING SOURCE: Department of Veterans Affairs, Health Services Research and Development Service.

Qualitative Analysis of a Supervised Exercise Program for Older Veterans With PTSD.

OBJECTIVE: Older veterans with post-traumatic stress disorder (PTSD) experience substantial physical and mental health challenges. Given the well-known and wide-reaching benefits of exercise, exploring the impact of interventions designed specifically for this population would be valuable. As such, the present study explored perspectives from older veterans with PTSD who participated in Warrior Wellness, a 12-week supervised exercise intervention designed for older veterans with PTSD. This study was aimed at evaluating 1) facilitators of engagement, 2) perceived benefits from the intervention, and 3) recommendations about possible modifications to the intervention. DESIGN: Qualitative study. SETTING: Face-to-face semistructured interviews conducted after the Warrior Wellness trial was completed. PARTICIPANTS: Fifteen veterans (100% male, 93% African American or Black, 100% non-Hispanic or Latinx, average age = 68.7 years) who completed the Warrior Wellness exercise program. MEASUREMENTS: Semistructured interviews were conducted using an interview guide that assessed veterans' experience in Warrior Wellness and recommendations for future intervention modifications. Interviews were subsequently transcribed and analyzed by thematic analysis. RESULTS: Shared experience, program features, camaraderie during workouts, and accountability emerged as facilitators of engagement. Perceived benefits spanned physical health, mental health, and behavioral domains. Finally, veterans provided several suggestions for modifying the intervention such as increasing its duration, adding a nutritional component, and including significant others in enrollment. CONCLUSIONS: This study offers valuable insights into the intervention and interpersonal factors that veterans view as important for their engagement in exercise, the perceived benefits of exercise, and the ways in which interventions designed for this population can be refined.

Cancer biology functional genomics: From small RNAs to big dreams.

The year 2021 marks the 20th anniversary of the first publications reporting the discovery of the gene silencing mechanism, RNA interference (RNAi) in mammalian cells. Along with the many studies that delineated the proteins and substrates that form the RNAi pathway, this finding changed our understanding of the posttranscriptional regulation of mammalian gene expression. Furthermore, the development of methods that exploited the RNAi pathway began the technological revolution that eventually enabled the interrogation of mammalian gene function-from a single gene to the whole genome-in only a few days. The needs of the cancer research community have driven much of this progress. In this perspective, we highlight milestones in the development and application of RNAi-based methods to study carcinogenesis. We discuss how RNAi-based functional genetic analysis of exemplar tumor suppressors and oncogenes furthered our understanding of cancer initiation and progression and explore how such studies formed the basis of genome-wide scale efforts to identify cancer or cancer-type specific vulnerabilities, including studies conducted in vivo. Furthermore, we examine how RNAi technologies have revealed new cancer-relevant molecular targets and the implications for cancer of the first RNAi-based drugs. Finally, we discuss the future of functional genetic analysis, highlighting the increasing availability of complementary approaches to analyze cancer gene function.

Systematic review of the prospective association of daily step counts with risk of mortality, cardiovascular disease, and dysglycemia.

BACKGROUND: Daily step counts is an intuitive metric that has demonstrated success in motivating physical activity in adults and may hold potential for future public health physical activity recommendations. This review seeks to clarify the pattern of the associations between daily steps and subsequent all-cause mortality, cardiovascular disease (CVD) morbidity and mortality, and dysglycemia, as well as the number of daily steps needed for health outcomes. METHODS: A systematic review was conducted to identify prospective studies assessing daily step count measured by pedometer or accelerometer and their associations with all-cause mortality, CVD morbidity or mortality, and dysglycemia (dysglycemia or diabetes incidence, insulin sensitivity, fasting glucose, HbA1c). The search was performed across the Medline, Embase, CINAHL, and the Cochrane Library databases from inception to August 1, 2019. Eligibility criteria included longitudinal design with health outcomes assessed at baseline and subsequent timepoints; defining steps per day as the exposure; reporting all-cause mortality, CVD morbidity or mortality, and/or dysglycemia outcomes; adults ≥18 years old; and non-patient populations. RESULTS: Seventeen prospective studies involving over 30,000 adults were identified. Five studies reported on all-cause mortality (follow-up time 4-10 years), four on cardiovascular risk or events (6 months to 6 years), and eight on dysglycemia outcomes (3 months to 5 years). For each 1000 daily step count increase at baseline, risk reductions in all-cause mortality (6-36%) and CVD (5-21%) at follow-up were estimated across a subsample of included studies. There was no evidence of significant interaction by age, sex, health conditions or behaviors (e.g., alcohol use, smoking status, diet) among studies that tested for interactions. Studies examining dysglycemia outcomes report inconsistent findings, partially due to heterogeneity across studies of glycemia-related biomarker outcomes, analytic approaches, and sample characteristics. CONCLUSIONS: Evidence from longitudinal data consistently demonstrated that walking an additional 1000 steps per day can help lower the risk of all-cause mortality, and CVD morbidity and mortality in adults, and that health benefits are present below 10,000 steps per day. However, the shape of the dose-response relation is not yet clear. Data are currently lacking to identify a specific minimum threshold of daily step counts needed to obtain overall health benefit.

Prevention of suicide and reduction of self-harm among people with substance use disorder: A systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: People with substance use disorder (SUD) are at significantly greater risk of suicide compared with the general population. In recent years the number of suicides resulting from drug poisoning in England and Wales has increased. We sought to identify and evaluate the effect of interventions to prevent suicide or reduce self-harm among people with SUD. METHODS: We conducted a systematic review of randomised controlled trials (RCTs) of interventions for people with SUD that included suicide or self-harm-related primary outcomes. We searched Cochrane Central Register of Controlled Trials (CENTRAL), PsycINFO, PubMed, Embase and Web of Science from inception until 13th January 2019. Studies were assessed for bias using the Cochrane Risk of Bias 2 tool. A random effects meta-analysis of standardised mean differences (SMD) was conducted. RESULTS: We identified six RCTs from four countries (Australia, Iran, the United States of America and the United Kingdom) comprising 468 participants in total. All but one study investigated psychosocial interventions. On average across studies there was weak evidence of a small positive effect of interventions on suicide or self-harm outcomes (d=-0.20, 95% CI=-0.39-0.00). LIMITATIONS: Studies were heterogeneous in terms of population, intervention, controls and outcome. There were some concerns regarding bias for all trials. All trials were liable to type II error. CONCLUSIONS: Evidence is currently lacking regarding the effectiveness of interventions to prevent suicide and reduce self-harm amongst people with SUD.

Pilot randomized controlled trial of exercise training for older veterans with PTSD.

Exercise training positively impacts mental health, yet remains untested in older adults with posttraumatic stress disorder (PTSD). We conducted a randomized controlled pilot trial to test the feasibility and acceptability of exercise training in older veterans with PTSD. Fifty-four veterans ≥ 60 years, with a DSM-V diagnosis of PTSD, were randomized to supervised exercise (n = 36) or wait-list (WL; n = 18). Primary outcomes included recruitment rates, attendance, satisfaction, and retention. Secondary outcomes included changes in PTSD symptoms, depression, health-related quality of life, and sleep quality; assessed at baseline and 12 weeks. There were no adverse events. Attrition was minimal (14%), and adherence to the exercise intervention was high (82%). Clinically significant improvements in PTSD and related conditions were observed following exercise (Cohen's d = 0.36-0.81). Exercise training is safe and acceptable in older adults with PTSD, may improve PTSD symptoms, and broadly impacts PTSD-related conditions. Future definitive trials are warranted.