Epidemiologic Evidence on the Role of Lactobacillus iners in Sexually Transmitted Infections and Bacterial Vaginosis: A Series of Systematic Reviews and Meta-Analyses.

ABSTRACT: Although Lactobacillus crispatus -dominated vaginal microbiotas are thought to protect against bacterial vaginosis (BV) and sexually transmitted infections, the role of Lactobacillus iners -dominated microbiotas is less clear. To better understand the impact of L. iners on common cervicovaginal infections, we conducted systematic reviews of the associations between L. iners compared with L. crispatus and 8 outcomes: Chlamydia trachomatis (Ct), BV, human papillomavirus, cervical dysplasia, human immunodeficiency virus, genital herpes, Trichomonas vaginalis , and Neisseria gonorrhoeae . On April 30, 2021, we searched PubMed, Embase, Cochrane Library, and Web of Science for epidemiologic studies of reproductive-age, nonpregnant, cisgender women that used marker gene sequencing to characterize vaginal microbiota composition and presented an effect estimate for the association between L. iners , compared with L. crispatus , and outcomes of interest. For outcomes with ≥3 eligible results presenting the same form of effect estimate, we conducted random-effects meta-analysis. The review protocol was registered prospectively (PROSPERO CRD42020214775). Six Ct studies were included in meta-analysis, which showed L. iners -dominated microbiotas were associated with 3.4-fold higher odds of Ct compared with L. crispatus -dominated microbiotas (95% confidence interval, 2.1-5.4). Three BV studies were included in meta-analysis, which indicated L. iners -dominated microbiotas were associated with 2.1-fold higher prevalence of BV compared with L. crispatus -dominated microbiotas (95% confidence interval, 0.9-4.9). Evidence was too sparse to perform meta-analysis for the remaining outcomes. L. iners -dominated vaginal microbiotas may be suboptimal compared with L. crispatus -dominated microbiotas for BV and Ct. These reviews highlight evidence gaps regarding the remaining outcomes and opportunities to improve epidemiologic rigor in vaginal microbiome science.

Mind the Gap: Bridging the Divide Between Current Binge Drinking Prevention and the Needs of Hispanic Underage Emerging Adults.

In this article, we highlight the urgent public health need for prevention of heavy episodic drinking among underage Hispanic emerging adults in the USA. We outline the current state of binge drinking prevention programming and contrast it with the unique cultural, social, and developmental realities of this population using an ecodevelopmental framework (Szapocznik and Coatsworth 1999). Finally, we advance specific recommendations for the development and delivery of culturally tailored, multisystemic binge drinking prevention programs for underage Hispanic emerging adults.

Framework for Supporting Adolescent Peer Leaders: A Pilot Using Text Messaging in a School-Based Substance Use Prevention Program.

Training peer leaders (PLs) as implementation agents is a state-of-the-art approach in prevention, but the field lacks frameworks for providing support. Text messaging, a powerful tool for direct intervention, may be useful in this regard. We introduce a conceptual framework for engaging, retaining, and educating adolescent PLs and conduct a pilot test of this framework using text messages for delivery to middle school PLs in a new, peer-led substance use prevention program. Fifty eighth-graders were recruited as PLs. We used a newly-developed framework to create text messages to strengthen peer leaders': (a) mission, agency, and team identity; (b) connection to adult mentors; (c) content knowledge and application to their own lives; and (d) preparation for prevention activities. Thirty-four texts were sent to PLs over 4 months. PL replies and participation were recorded to track engagement. Forty-one PLs (71%) received texts and completed baseline and post-program surveys. Parents and school staff completed post-program questionnaires. Eighty-five percent of PLs responded to at least one text message. Response rates for specific messages varied from 22 to 56%. Students were most likely to reply to texts about preparation for their own prevention activities in the school. Ninety-five percent of PLs said they read messages even when they did not reply. Eighty-three percent of PLs said the messages helped them accomplish their mission. PLs reported that they wanted to receive messages in the future. PL attendance had very little variability in two of the three schools, but replies to texts were associated with better attendance in one school. Our study provides a framework for supporting adolescent peer leaders in a network intervention. Automated text messaging supporting middle school PLs was feasible, engaging, and well-received. Texting activity was associated with participation in school-based activities. Future priorities include systematically varying text support to determine its true effect on implementation and on involvement by less engaged PLs.

Piliation of Lactobacillus rhamnosus GG promotes adhesion, phagocytosis, and cytokine modulation in macrophages.

Recently, spaCBA-encoded pili on the cell surface of Lactobacillus rhamnosus GG were identified to be key molecules for binding to human intestinal mucus and Caco-2 intestinal epithelial cells. Here, we investigated the role of the SpaCBA pilus of L. rhamnosus GG in the interaction with macrophages in vitro by comparing the wild type with surface mutants. Our results show that SpaCBA pili play a significant role in the capacity for adhesion to macrophages and also promote bacterial uptake by these phagocytic cells. Interestingly, our data suggest that SpaCBA pili also mediate anti-inflammatory effects by induction of interleukin-10 (IL-10) mRNA and reduction of interleukin-6 (IL-6) mRNA in a murine RAW 264.7 macrophage cell line. These pili appear to mediate these effects indirectly by promoting close contact with the macrophages, facilitating the exertion of anti-inflammatory effects by other surface molecules via yet unknown mechanisms. Blockage of complement receptor 3 (CR3), previously identified to be a receptor for streptococcal pili, significantly decreased the uptake of pilus-expressing strains in RAW 264.7 cells, while the expression of IL-10 and IL-6 mRNA by these macrophages was not affected by this blocking. On the other hand, blockage of Toll-like receptor 2 (TLR2) significantly reduced the expression of IL-6 mRNA irrespective of the presence of pili.

Rare Pathogenic Variants in Pooled Whole-Exome Sequencing Data Suggest Hyperammonemia as a Possible Cause of Dementia Not Classified as Alzheimer's Disease or Frontotemporal Dementia.

The genetic bases of Alzheimer's disease (AD) and frontotemporal dementia (FTD) have been comprehensively studied, which is not the case for atypical cases not classified into these diagnoses. In the present study, we aim to contribute to the molecular understanding of the development of non-AD and non-FTD dementia due to hyperammonemia caused by mutations in urea cycle genes. The analysis was performed by pooled whole-exome sequencing (WES) of 90 patients and by searching for rare pathogenic variants in autosomal genes for enzymes or transporters of the urea cycle pathway. The survey returned two rare pathogenic coding mutations leading to citrullinemia type I: rs148918985, p.Arg265Cys, C>T; and rs121908641, p.Gly390Arg, G>A in the argininosuccinate synthase 1 (ASS1) gene. The p.Arg265Cys variant leads to enzyme deficiency, whereas p.Gly390Arg renders the enzyme inactive. These variants found in simple or compound heterozygosity can lead to the late-onset form of citrullinemia type I, associated with high ammonia levels, which can lead to cerebral dysfunction and thus to the development of dementia. The presence of urea cycle disorder-causing mutations can be used for the early initiation of antihyperammonemia therapy in order to prevent the neurotoxic effects.

HIV-1 interaction with an O-glycan-specific bacterial lectin enhances virus infectivity and resistance to neutralization by antibodies.

Bacteria dysbiosis has been associated with an increased risk of HIV-1 transmission and acquisition. The prevalent idea is that bacteria dysbiosis compromises mucosal integrity and promotes inflammatory conditions to cause recruitment and activation of immune cells that harbor or are targeted by HIV-1. However, it is also possible that HIV-1 directly binds bacteria or bacterial products to impact virus infectivity and transmissibility. This study evaluated HIV-1 interactions with bacteria through glycan-binding lectins. The Streptococcal Siglec-like lectin SLBR-N, which is part of the fimbriae shrouding the bacteria surface and recognizes α2,3 sialyated O-linked glycans, was noted for its ability to enhance HIV-1 infectivity in the context of cell-free infection and cell-to-cell transfer. Enhancing effects were recapitulated with O-glycan-binding plant lectins, signifying the importance of O-glycans. Conversely, N-glycan-binding bacterial lectins FimH and Msl had no effect. SLBR-N was demonstrated to capture and transfer infectious HIV-1 virions, bind to O-glycans on HIV-1 Env, and increase HIV-1 resistance to broadly neutralizing antibodies targeting different regions of Env. Hence, this study highlights the potential contribution of O-glycans in promoting HIV-1 infection through the exploitation of O-glycan-binding lectins from commensal bacteria at the mucosa.

Inhibition of infection and transmission of HIV-1 and lack of significant impact on the vaginal commensal lactobacilli by carbohydrate-binding agents.

OBJECTIVES: A selection of carbohydrate-binding agents (CBAs) with different glycan specificities were evaluated for their inhibitory effect against HIV infection and transmission, and their interaction with vaginal commensal bacteria. METHODS: Several assays were used for the antiviral evaluation: (i) cell-free virus infection of human CD4+ T lymphocyte C8166 cells; (ii) syncytium formation in co-cultures of persistently HIV-1-infected HUT-78/HIV-1 and non-infected CD4+ SupT1 cells; (iii) DC-SIGN-directed capture of HIV-1 particles; and (iv) transmission of DC-SIGN-captured HIV-1 particles to uninfected CD4+ C8166 cells. CBAs were also examined for their interaction with vaginal commensal lactobacilli using several viability, proliferation and adhesion assays. RESULTS: The CBAs showed efficient inhibitory activity in the nanomolar to low-micromolar range against four events that play a crucial role in HIV-1 infection and transmission: cell-free virus infection, fusion between HIV-1-infected and non-infected cells, HIV-1 capture by DC-SIGN and transmission of DC-SIGN-captured virus to T cells. As candidate microbicides should not interfere with the normal human microbiota, we examined the effect of CBAs against Lactobacillus strains, including a variety of vaginal strains, a gastrointestinal strain and several non-human isolates. None of the CBAs included in our studies inhibited the growth of these bacteria in several media, affected their viability or had any significant impact on their adhesion to HeLa cell monolayers. CONCLUSIONS: The CBAs in this study were inhibitory to HIV-1 in several in vitro infection and transmission models, and may therefore qualify as potential microbicide candidates. The lack of significant impact on commensal vaginal lactobacilli is an important property of these CBAs in view of their potential microbicidal use.

The highly autoaggregative and adhesive phenotype of the vaginal Lactobacillus plantarum strain CMPG5300 is sortase dependent.

Lactobacilli are important for the maintenance of a healthy ecosystem in the human vagina. Various mechanisms are postulated but so far are poorly substantiated by molecular studies, such as mutant analysis. Bacterial autoaggregation is an interesting phenomenon that can promote adhesion to host cells and displacement of pathogens. In this study, we report on the identification of a human vaginal isolate, Lactobacillus plantarum strain CMPG5300, which shows high autoaggregative and adhesive capacity. To investigate the importance of sortase-dependent proteins (SDPs) in these phenotypes, a gene deletion mutant was constructed for srtA, the gene encoding the housekeeping sortase that covalently anchors these SDPs to the cell surface. This mutant lost the capacity to autoaggregate, showed a decrease in adhesion to vaginal epithelial cells, and lost biofilm-forming capacity under the conditions tested. These results indicate that the housekeeping sortase SrtA of CMPG5300 is a key determinant of the peculiar surface properties of this vaginal Lactobacillus strain.

Emotion regulation difficulties, youth-adult relationships, and suicide attempts among high school students in underserved communities.

To develop and refine interventions to prevent youth suicide, knowledge is needed about specific processes that reduce risk at a population level. Using a cross-sectional design, the present study tested hypotheses regarding associations between self-reported suicide attempts, emotion regulation difficulties, and positive youth-adult relationships among 7,978 high-school students (48.6% male, 49.9% female) in 30 high schools from predominantly rural, low-income communities. 683 students (8.6%) reported a past-year suicide attempt. Emotion regulation difficulties and a lack of trusted adults at home and school were associated with increased risk for making a past-year suicide attempt, above and beyond the effects of depressive symptoms and demographic factors. The association between emotion regulation difficulties and suicide attempts was modestly lower among students who perceived themselves as having higher levels of trusted adults in the family, consistent with a protective effect. Having a trusted adult in the community (outside of school and family) was associated with fewer suicide attempts in models that controlled only for demographic covariates, but not when taking symptoms of depression into account. These findings point to adolescent emotion regulation and relationships with trusted adults as complementary targets for suicide prevention that merit further intervention studies. Reaching these targets in a broad population of adolescents will require new delivery systems and "option rich" (OR) intervention designs.

Emerging issues in probiotic safety: 2023 perspectives.

Probiotics are used for both generally healthy consumers and in clinical settings. However, theoretical and proven adverse events from probiotic consumption exist. New probiotic strains and products, as well as expanding use of probiotics into vulnerable populations, warrants concise, and actionable recommendations on how to work toward their safe and effective use. The International Scientific Association for Probiotics and Prebiotics convened a meeting to discuss and produce evidence-based recommendations on potential acute and long-term risks, risks to vulnerable populations, the importance for probiotic product quality to match the needs of vulnerable populations, and the need for adverse event reporting related to probiotic use. The importance of whole genome sequencing, which enables determination of virulence, toxin, and antibiotic resistance genes, as well as clear assignment of species and strain identity, is emphasized. We present recommendations to guide the scientific and medical community on judging probiotic safety.

What is the context? Probiotics, available to healthy consumers as both dietary supplements and foods, are also used by some patient populations. The goal of this paper is to determine if any new factors have emerged that would impact current views about probiotic safety for both these populations.What is new? The authors conclude that established practices are sensibly addressing factors important to the safety of traditional probiotics used by the general population. They also make recommendations regarding emerging safety considerations. Probiotics targeted for patient populations should undergo stringent testing to meet quality standards appropriate for that population, preferably verified by an independent third party. The safety of probiotics derived from species without a history of safe use must be considered on a case-by-case basis. Research is needed to address some gaps, for example which best animal models to use for safety assessment of live microbes, the possibility of antibiotic resistance gene transfer via transformation, and potential impact of probiotic-induced changes in microbiomes, interactions with drugs, and probiotic colonization.What is the impact? Probiotics of sufficient quality for patient populations are being developed and should be used accordingly. Long-term safety assessments for probiotics should be consistent with, and not more stringent than, current regulatory requirements for biologic drugs, including fecal microbial transplants. Rigor in collecting and reporting data on adverse events is needed. The authors confirm the need for understanding the entire genetic makeup of a probiotic as a cornerstone for assessing its safety.

New sorafenib derivatives: synthesis, antiproliferative activity against tumour cell lines and antimetabolic evaluation.

Sorafenib is a relatively new cytostatic drug approved for the treatment of renal cell and hepatocellular carcinoma. In this report we describe the synthesis of sorafenib derivatives 4a-e which differ from sorafenib in their amide part. A 4-step synthetic pathway includes preparation of 4-chloropyridine-2-carbonyl chloride hydrochloride (1), 4-chloro-pyridine-2-carboxamides 2a-e, 4-(4-aminophenoxy)-pyridine-2-carboxamides 3a-e and the target compounds 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]-phenoxy]-pyridine-2-carboxamides 4a-e. All compounds were fully chemically characterized and evaluated for their cytostatic activity against a panel of carcinoma, lymphoma and leukemia tumour cell lines. In addition, their antimetabolic potential was investigated as well. The most prominent antiproliferative activity was obtained for compounds 4a-e (IC(50) = 1-4.3 µmol·L-1). Their potency was comparable to the potency of sorafenib, or even better. The compounds inhibited DNA, RNA and protein synthesis to a similar extent and did not discriminate between tumour cell lines and primary fibroblasts in terms of their anti-proliferative activity.

Associations between suicidal high school students' help-seeking and their attitudes and perceptions of social environment.

Suicide is a leading cause of death among adolescents, many of whom fail to disclose suicide concerns to adults who might help. This study examined patterns and predictors of help-seeking behavior among adolescents who seriously considered suicide in the past year. 2,737 students (50.9 % female, 46.9 % male; racial distribution 79.5 % Caucasian, 11.9 % Hispanic/Latino, and 3.6 % Black/African-American) from 12 high schools in rural/underserviced communities were surveyed to assess serious suicide ideation (SI) in the past year, disclosure of SI to adults and peers, attempts to get help, attitudes about help-seeking, perceptions of school engagement, and coping support. Help-seeking was defined as both disclosing SI to an adult and perceiving oneself as seeking help. The relationship between adolescents' help-seeking disclosure and (1) help-seeking attitudes and (2) perceptions of social resources was examined among suicidal help-seeking youth, suicidal non-help-seeking youth, and non-suicidal youth. Of the 381 (14 %) students reporting SI, only 23 % told an adult, 29 % sought adult help, and 15 % did both. Suicidal help-seekers were similar to non-suicidal peers on all measures of help-seeking attitudes and social environment perceptions. Positive attitudes about help-seeking from adults at school, perceptions that adults would respond to suicide concerns, willingness to overcome peer secrecy requests, and greater coping support and engagement with the school were associated with students' increased disclosure of SI and help-seeking. This study supports prevention strategies that change student norms, attitudes and social environments to promote help-seeking among adolescents with SI. Promising intervention targets include increasing students' perceptions of the availability and capability of adults to help them, and strengthening students' understanding of how existing resources can help them cope.

Effect of the COVID-19 Pandemic on Stimulant Use and Antiretroviral Therapy Adherence Among Men Who Have Sex With Men Living With HIV: Qualitative Focus Group Study.

BACKGROUND: Evidence suggests that economic, social, and psychological circumstances brought about by the COVID-19 pandemic may have a serious impact on behavioral health. Men who have sex with men (MSM) are disproportionally impacted by HIV and stimulant use, the co-occurrence of which heightens HIV transmission risk and undermines nationwide treatment strategies as prevention efforts for ending the HIV epidemic. There is a paucity of information regarding the potential impact of the COVID-19 pandemic on the substance use and HIV medication adherence in this key vulnerable population-MSM who use stimulants and are living with HIV. OBJECTIVE: The aim of this qualitative study was to identify ways in which the COVID-19 pandemic has affected stimulant use and antiretroviral therapy (ART) adherence among a sample of MSM living with HIV. METHODS: Two focus groups were conducted in August 2020 via videoconferencing technology compliant with the Health Insurance Portability and Accountability Act. Potential participants from an established research participant registry at State University of New York Downstate Health Sciences University were invited and screened for study participation on the basis of inclusion criteria. A semistructured interview guide was followed. A general inductive approach was used to analyze the data. Findings in two general areas of interest, the impact of the COVID-19 pandemic on stimulant use and ART adherence, emerged directly from the raw data. RESULTS: A total of 12 ethnically diverse participants over the age of 25 years took part in the study. Results were heterogeneous in terms of the effects of the pandemic on both stimulant use and ART adherence among MSM living with HIV. Some men indicated increased or sustained stimulant use and ART adherence, and others reported decreased stimulant use and ART adherence. Reasons for these behavioral changes ranged from concerns about their own health and that of their loved ones to challenges brought about by the lack of daily structure during the lockdown phase of the pandemic and emotion regulation difficulties. CONCLUSIONS: The COVID-19 pandemic has had a differential impact on stimulant use and ART medication adherence among MSM living with HIV. The reasons for behavioral change identified in this study may be salient intervention targets to support ART medication adherence and lower stimulant use among MSM in the aftermath of the of the COVID-19 pandemic, as well as beyond.

Predictors of COVID-19 Fatality: A Worldwide Analysis of the Pandemic over Time and in Latin America.

SARS-CoV-2 has infected over one hundred million people worldwide and has affected Latin America particularly severely in terms of both cases and deaths. This study aims to determine the association between SARS-CoV-2 testing and COVID-19 fatality rate worldwide over 8 months and to examine how this relationship differs between Latin America and all other countries. This cross-sectional study used March 2021 data from 169 countries. Multivariate regressions predicted COVID-19 fatality (outcome) from the number of SARS-CoV-2 tests (exposure), while controlling for other predictors. Results for March 2021 were compared to results from June 2020. Additionally, results for Latin America were also compared to all other countries except Latin American for March 2021. SARS-CoV-2 testing was associated with a significant decrease in COVID-19 fatality rate in both June 2020 and March 2021 (RR = 0.92; 95% CI 0.87-0.96 and RR = 0.86; 95% CI 0.74-1.00, respectively). SARS-CoV-2 testing was associated with a significant decrease in COVID-19 fatality rate in Latin American countries but not in all other countries (RR = 0.45; 95% CI 0.23-0.89 and RR = 0.95; 95% CI 0.82-1.11, respectively). However, the difference between the risk ratios for June 2020 and March 2021 and between the risk ratios for Latin America and all other countries were not statistically significant. Increased SARS-CoV-2 testing may be a significant predictor of lower COVID-19 case fatality rate, specifically in Latin American countries, due to the existence of a strong association, which may have driven the worldwide results.

Lacticaseibacillus rhamnosus GR-1, a.k.a. Lactobacillus rhamnosus GR-1: Past and Future Perspectives.

Lacticaseibacillus rhamnosus GR-1 (LGR-1) (previously classified as Lactobacillus rhamnosus GR-1) is the most researched probiotic strain for women's health. Its various urogenital health effects, including a reduction in the recurrence of bacterial vaginosis and urinary-tract infection, are well documented. The strain has also been safely used by HIV-positive subjects, a portion of whom have reported reduced diarrhea and increased CD4 counts. Unlike most probiotic strains used for urogenital health, LGR-1 has been extensively studied for its properties, including its genomic and metabolic traits and its surface properties. This review aims to highlight the totality of research performed with LGR-1, to act as a rigorous scientific benchmark for probiotic microbes, especially for application to women's health.

Shaping the Future of Probiotics and Prebiotics.

Recent and ongoing developments in microbiome science are enabling new frontiers of research for probiotics and prebiotics. Novel types, mechanisms, and applications currently under study have the potential to change scientific understanding as well as nutritional and healthcare applications of these interventions. The expansion of related fields of microbiome-targeted interventions, and an evolving landscape for implementation across regulatory, policy, prescriber, and consumer spheres, portends an era of significant change. In this review we examine recent, emerging, and anticipated trends in probiotic and prebiotic science, and create a vision for broad areas of developing influence in the field.

An outcome evaluation of the Sources of Strength suicide prevention program delivered by adolescent peer leaders in high schools.

OBJECTIVES: We examined the effectiveness of the Sources of Strength suicide prevention program in enhancing protective factors among peer leaders trained to conduct schoolwide messaging and among the full population of high school students. METHODS: Eighteen high schools--6 metropolitan and 12 rural--were randomly assigned to immediate intervention or the wait-list control. Surveys were administered at baseline and 4 months after program implementation to 453 peer leaders in all schools and to 2675 students selected as representative of the 12 rural schools. RESULTS: Training improved the peer leaders' adaptive norms regarding suicide, their connectedness to adults, and their school engagement, with the largest gains for those entering with the least adaptive norms. Trained peer leaders in larger schools were 4 times as likely as were untrained peer leaders to refer a suicidal friend to an adult. Among students, the intervention increased perceptions of adult support for suicidal youths and the acceptability of seeking help. Perception of adult support increased most in students with a history of suicidal ideation. CONCLUSIONS: Sources of Strength is the first suicide prevention program involving peer leaders to enhance protective factors associated with reducing suicide at the school population level.

Lactobacillus rhamnosus probiotic prevents airway function deterioration and promotes gut microbiome resilience in a murine asthma model.

Allergic asthma is a highly prevalent inflammatory disease of the lower airways, clinically characterized by airway hyperreactivity and deterioration of airway function. Immunomodulatory probiotic bacteria are increasingly being explored to prevent asthma development, alone or in combination with other treatments. In this study, wild-type and recombinant probiotic Lactobacillus rhamnosus GR-1 were tested as preventive treatment of experimental allergic asthma in mice. Recombinant L. rhamnosus GR-1 was designed to produce the major birch pollen allergen Bet v 1, to promote allergen-specific immunomodulation. Administration of wild-type and recombinant L. rhamnosus GR-1 prevented the development of airway hyperreactivity. Recombinant L. rhamnosus GR-1 also prevented elevation of airway total cell counts, lymphocyte counts and lung IL-1ß levels, while wild-type L. rhamnosus GR-1 inhibited airway eosinophilia. Of note, a shift in gut microbiome composition was observed after asthma development, which correlated with the severity of airway inflammation and airway hyperreactivity. In the groups that received L. rhamnosus GR-1, this asthma-associated shift in gut microbiome composition was not observed, indicating microbiome-modulating effects of this probiotic. These data demonstrate that L. rhamnosus GR-1 can prevent airway function deterioration in allergic asthma. Bet v 1 expression by L. rhamnosus GR-1 further contributed to lower airway inflammation, although not solely through the expected reduction in T helper 2-associated responses, suggesting involvement of additional mechanisms. The beneficial effects of L. rhamnosus GR-1 correlate with increased gut microbiome resilience, which in turn is linked to protection of airway function, and thus further adds support to the existence of a gut-lung axis.

Effect of the Wingman-Connect Upstream Suicide Prevention Program for Air Force Personnel in Training: A Cluster Randomized Clinical Trial.

Importance: Suicide has been a leading manner of death for US Air Force personnel in recent years. Universal prevention programs that reduce suicidal thoughts and behaviors in military populations have not been identified. Objectives: To determine whether the Wingman-Connect program for Airmen-in-training reduces suicidal ideation, depression, and occupational problems compared with a stress management program and to test the underlying network health model positing that cohesive, healthy units are protective against suicidal ideation. Design, Setting, and Participants: This cluster randomized clinical trial was conducted from October 2017 to October 2019 and compared classes of personnel followed up for 6 months. The setting was a US Air Force technical training school, with participants studied to their first base assignment, whether US or international. Participants in 216 classes were randomized, with an 84% retention rate. Data analysis was performed from November 2019 to May 2020. Interventions: The Wingman-Connect program used group skill building for cohesion, shared purpose, and managing career and personal stressors (3 blocks of 2 hours each). Stress management training covered cognitive and behavioral strategies (2 hours). Both conditions had a 1-hour booster session, plus text messages. Main Outcomes and Measures: The primary outcomes were scores on the suicidal ideation and depression scales of the Computerized Adaptive Test for Mental Health and self-reports of military occupational impairment. Class network protective factors hypothesized to mediate the effect of Wingman-Connect were assessed with 4 measures: cohesion assessed perceptions that classmates cooperate, work well together, and support each other; morale was measured with a single item used in other studies with military samples; healthy class norms assessed perceptions of behaviors supported by classmates; and bonds to classmates were assessed by asking each participant to name classmates whom they respect and would choose to spend time with. Results: A total of 215 classes including 1485 individuals (1222 men [82.3%]; mean [SD] age, 20.9 [3.1] years) participated; 748 individuals were enrolled in the Wingman-Connect program and 737 individuals were enrolled in the stress management program. At 1 month, the Wingman-Connect group reported lower suicidal ideation severity (effect size [ES], -0.23; 95% CI, -0.39 to -0.09; P = .001) and depression symptoms (ES, -0.24; 95% CI, -0.41 to -0.08; P = .002) and fewer occupational problems (ES, -0.14; 95% CI, -0.31 to -0.02; P = .02). At 6 months, the Wingman-Connect group reported lower depression symptoms (ES, -0.16; 95% CI, -0.34 to -0.02; P = .03), whereas the difference in suicidal ideation severity was not significant (ES, -0.13; 95% CI, -0.29 to 0.01; P = .06). The number needed to treat to produce 1 fewer participant with elevated depression at either follow-up point was 21. The benefits of the training on occupational problems did not extend past 1 month. The Wingman-Connect program strengthened cohesive, healthy class units, which helped reduce suicidal ideation severity (estimate, -0.035; 95% CI, -0.07 to -0.01; P = .02) and depression symptom scores (estimate, -0.039; 95% CI, -0.07 to -0.01; P = .02) at 1 month. Conclusions and Relevance: Wingman-Connect is the first universal prevention program to reduce suicidal ideation and depression symptoms in a general Air Force population. Group training that builds cohesive, healthy military units is promising for upstream suicide prevention and may be essential for ecological validity. Extension of the program to the operational Air Force is recommended for maintaining continuity and testing the prevention impact on suicidal behavior. Trial Registration: ClinicalTrials.gov Identifier: NCT04067401.