Amplification of positivity for depression and anxiety: Neural prediction of treatment response.

Psychosocial treatments targeting the positive valence system (PVS) in depression and anxiety demonstrate efficacy in enhancing positive affect (PA), but response to treatment varies. We examined whether individual differences in neural activation to positive and negative valence incentive cues underlies differences in benefitting from a PVS-targeted treatment. Individuals with clinically elevated depression and/or anxiety (N = 88, ages 18 to 55) participated in one of two randomized, waitlist-controlled trials of Amplification of Positivity (AMP; NCT02330627, NCT03196544), a cognitive and behavioral intervention targeting the PVS. Participants completed a monetary incentive delay (MID) task during fMRI acquisition at baseline measuring neural activation to the possibility of gaining or losing money. Change in PA from before to after treatment was assessed using the Positive and Negative Affect Schedule. No significant associations were observed between baseline neural activation during gain anticipation and AMP-related changes in PA in regions of interest (striatum and insula) or whole-brain analyses. However, higher baseline striatal and insula activation during loss anticipation was associated with greater increases in PA post-AMP. This study provides preliminary evidence suggesting neural reactivity to negative valence cues may inform who stands to benefit most from treatments targeting the PVS.

Polygenic liability for anxiety in association with comorbid anxiety in multiple sclerosis.

OBJECTIVE: Comorbid anxiety occurs often in MS and is associated with disability progression. Polygenic scores offer a possible means of anxiety risk prediction but often have not been validated outside the original discovery population. We aimed to investigate the association between the Generalized Anxiety Disorder 2-item scale polygenic score with anxiety in MS. METHODS: Using a case-control design, participants from Canadian, UK Biobank, and United States cohorts were grouped into cases (MS/comorbid anxiety) or controls (MS/no anxiety, anxiety/no immune disease or healthy). We used multiple anxiety measures: current symptoms, lifetime interview-diagnosed, and lifetime self-report physician-diagnosed. The polygenic score was computed for current anxiety symptoms using summary statistics from a previous genome-wide association study and was tested using regression. RESULTS: A total of 71,343 individuals of European genetic ancestry were used: Canada (n = 334; 212 MS), UK Biobank (n = 70,431; 1,390 MS), and the USA (n = 578 MS). Meta-analyses identified that in MS, each 1-SD increase in the polygenic score was associated with ~50% increased odds of comorbid moderate anxious symptoms compared to those with less than moderate anxious symptoms (OR: 1.47, 95% CI: 1.09-1.99). We found a similar direction of effects in the other measures. MS had a similar anxiety genetic burden compared to people with anxiety as the index disease. INTERPRETATION: Higher genetic burden for anxiety was associated with significantly increased odds of moderate anxious symptoms in MS of European genetic ancestry which did not differ from those with anxiety and no comorbid immune disease. This study suggests a genetic basis for anxiety in MS.

PTSD, Comorbidities, Gender, and Increased Risk of Cardiovascular Disease in a Large Military Cohort.

Importance: Posttraumatic stress disorder (PTSD) is a prevalent mental health problem that increases risk of cardiovascular disease (CVD). It is not known whether gender or comorbidities modify associations between PTSD and CVD. Objective: To assess risk of hypertension and atherosclerotic CVD (ASCVD) associated with PTSD in a predominantly young military population, and determine if gender or PTSD comorbidities modify these associations. Design setting and participants: Using administrative medical records, this longitudinal, retrospective cohort study assessed relationships of PTSD, gender, comorbidities (metabolic risk factors [MRF], behavioral risk factors [BRF], depression, and sleep disorders) to subsequent hypertension and ASCVD among 863,993 active-duty U.S. Army enlisted soldiers (86.2% male; 93.7%

Application of an egocentric social network approach to examine changes in social connections following treatment for anxiety and depression: A novel measurement tool for clinical trials research?

The epidemic of loneliness and social isolation has been recognized as a public health crisis warranting the same prioritization as other public health issues today, such as obesity, substance use disorders, and tobacco use. Social disconnection is particularly prevalent and disabling among individuals with anxiety and depression, yet it is inadequately evaluated and addressed in most clinical psychology treatment research. Studies generally employ global measures of perceived connectedness, loneliness, or relationship satisfaction, limiting understanding about elements of one's social network that may change with treatment. This study examined changes in the degree (number of people nominated) and quality of one's social network from pre-to post-treatment using an egocentric social network approach in 59 adults (mean age = 30.8 years, range = 18 to 54) with clinically elevated anxiety or depression who were randomized to a cognitive and behavioral positive valence treatment versus waitlist. Participants (egos) named people in their lives (alters) with whom they discussed important issues or spent free time. For each alter, participants rated how close they felt, how close they thought the alter felt to them, and how frequently they communicated. Linear regressions, which included treatment group as a predictor, revealed no group differences in changes in network degree, perceived alter feelings of closeness, or communication frequency, despite prior findings from this sample indicating larger increases in perceived global connectedness in the treatment group. Unexpectedly, the control group reported a greater increase in perceived closeness to alters. Post-hoc analyses revealed this was explained by the treatment group identifying more distal social ties (e.g., extended family, colleagues, roommates) as alters following treatment - an outcome positively associated with global improvements in connectedness. This proof-of-concept study suggests egocentric social network surveys may provide unique information on treatment-related changes in social functioning. Suggestions are provided for adaptations to facilitate application of social network surveys to mental health treatment research.

Disease-modifying therapies in systemic lupus erythematosus for extrarenal manifestations.

Our 2022 published working definition of disease modification in systemic lupus erythematosus (SLE) was 'minimising disease activity with the fewest treatment-associated toxicities and slowing or preventing organ damage progression'. The objective of this review was to classify current SLE treatments according to the proposed non-renal disease modification criteria excluding toxicities. Based on a review of select clinical trial (n=32) and observational study (n=54) publications for 14 SLE medications across different therapeutic classes, and the authors' clinical experience, we evaluated disease modification potential as per the proposed framework at three time points. Specific criteria used to determine disease modification potential included a drug's capacity to reduce: (1) non-renal disease activity, (2) severe flares, (3) use of steroids/immunosuppressants and (4) organ damage accrual. Criteria 1-3 were assessed at 1 year and 2-5 years and, when positive, were considered evidence for disease modification potential; criterion 4 was used to confirm disease modification at >5 years. Each treatment received one of four mutually exclusive designations at each time point: (a) criterion met, (b) indications of criterion met despite insufficient evidence in the literature, (c) inconclusive and (d) no available supportive data. This review excludes an assessment of potential toxicities. Eight of the 14 SLE treatments met ≥1 disease modification criteria up to year 5. Hydroxychloroquine improved overall survival at >5 years, suggesting long-term disease modification, but no data on specific organ systems were reported. Belimumab was the only treatment to meet all criteria. Belimumab and hydroxychloroquine met disease modification definitions across three time points. Evidence for other SLE therapies was incomplete, particularly at >5 years. Future studies are warranted for other treatments to meet the disease modification criteria. We discuss challenges to classification and possible updates to our published criteria.

Remission and low disease activity are associated with lower healthcare costs: results from the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort.

OBJECTIVES: This study aims to determine the independent impact of definitions of remission/low disease activity (LDA) on direct/indirect costs (DCs, ICs) in a multicentre inception cohort. METHODS: Patients from 31 centres in 10 countries were enrolled within 15 months of diagnosis and assessed annually. Five mutually exclusive disease activity states (DAS) were defined as (1) remission off-treatment: clinical (c) SLEDAI-2K=0, without prednisone/immunosuppressants; (2) remission on-treatment: cSLEDAI-2K=0, prednisone ≤5 mg/day and/or maintenance immunosuppressants; (3) LDA-Toronto Cohort (TC): cSLEDAI-2K≤2, without prednisone/immunosuppressants; (4) modified lupus LDA state (mLLDAS): SLEDAI-2K≤4, no activity in major organs/systems, no new activity, prednisone ≤7.5 mg/day and/or maintenance immunosuppressants and (5) active: all remaining assessments.At each assessment, patients were stratified into the most stringent DAS fulfilled and the proportion of time in a DAS since cohort entry was determined. Annual DCs/ICs (2021 Canadian dollars) were based on healthcare use and lost workforce/non-workforce productivity over the preceding year.The association between the proportion of time in a DAS and annual DC/IC was examined through multivariable random-effects linear regressions. RESULTS: 1692 patients were followed a mean of 9.7 years; 49.0% of assessments were active. Remission/LDA (per 25% increase in time in a remission/LDA state vs active) were associated with lower annual DC/IC: remission off-treatment (DC -$C1372; IC -$C2507), remission on-treatment (DC -$C973; IC -$C2604,) LDA-TC (DC -$C1158) and mLLDAS (DC -$C1040). There were no cost differences between remission/LDA states. CONCLUSIONS: Our data suggest that systemic lupus erythematosus patients who achieve remission, both off and on-therapy, and reductions in disease activity incur lower costs than those experiencing persistent disease activity.

Genetic influences and causal pathways shared between cannabis use disorder and other substance use traits.

Cannabis use disorder (CanUD) has increased with the legalization of the use of cannabis. Around 20% of individuals using cannabis develop CanUD, and the number of users has grown with increasing ease of access. CanUD and other substance use disorders (SUDs) are associated phenotypically and genetically. We leveraged new CanUD genomics data to undertake genetically-informed analyses with unprecedented power, to investigate the genetic architecture and causal relationships between CanUD and lifetime cannabis use with risk for developing SUDs and substance use traits. Analyses included calculating local and global genetic correlations, genomic structural equation modeling (genomicSEM), and Mendelian Randomization (MR). Results from the genetic correlation and genomicSEM analyses demonstrated that CanUD and cannabis use differ in their relationships with SUDs and substance use traits. We found significant causal effects of CanUD influencing all the analyzed traits: opioid use disorder (OUD) (Inverse variant weighted, IVW ß = 0.925 ± 0.082), problematic alcohol use (PAU) (IVW ß = 0.443 ± 0.030), drinks per week (DPW) (IVW ß = 0.182 ± 0.025), Fagerström Test for Nicotine Dependence (FTND) (IVW ß = 0.183 ± 0.052), cigarettes per day (IVW ß = 0.150 ± 0.045), current versus former smokers (IVW ß = 0.178 ± 0.052), and smoking initiation (IVW ß = 0.405 ± 0.042). We also found evidence of bidirectionality showing that OUD, PAU, smoking initiation, smoking cessation, and DPW all increase risk of developing CanUD. For cannabis use, bidirectional relationships were inferred with PAU, smoking initiation, and DPW; cannabis use was also associated with a higher risk of developing OUD (IVW ß = 0.785 ± 0.266). GenomicSEM confirmed that CanUD and cannabis use load onto different genetic factors. We conclude that CanUD and cannabis use can increase the risk of developing other SUDs. This has substantial public health implications; the move towards legalization of cannabis use may be expected to increase other kinds of problematic substance use. These harmful outcomes are in addition to the medical harms associated directly with CanUD.

Anti-KIF20B autoantibodies are associated with cranial neuropathy in systemic lupus erythematosus.

BACKGROUND: Cranial neuropathies (CN) are a rare neuropsychiatric SLE (NPSLE) manifestation. Previous studies reported that antibodies to the kinesin family member 20B (KIF20B) (anti-KIF20B) protein were associated with idiopathic ataxia and CN. We assessed anti-KIF20B as a potential biomarker for NPSLE in an international SLE inception cohort. METHODS: Individuals fulfilling the revised 1997 American College of Rheumatology (ACR) SLE classification criteria were enrolled from 31 centres from 1999 to 2011 and followed annually in the Systemic Lupus Erythematosus International Collaborating Clinics inception cohort. Anti-KIF20B testing was performed on baseline (within 15 months of diagnosis or first annual visit) samples using an addressable laser bead immunoassay. Logistic regression (penalised maximum likelihood and adjusting for confounding variables) examined the association between anti-KIF20B and NPSLE manifestations (1999 ACR case definitions), including CN, occurring over the first 5 years of follow-up. RESULTS: Of the 1827 enrolled cohort members, baseline serum and 5 years of follow-up data were available on 795 patients who were included in this study: 29.8% were anti-KIF20B-positive, 88.7% female, and 52.1% White. The frequency of anti-KIF20B positivity differed only for those with CN (n=10) versus without CN (n=785) (70.0% vs 29.3%; OR 5.2, 95% CI 1.4, 18.5). Compared with patients without CN, patients with CN were more likely to fulfil the ACR haematological (90.0% vs 66.1%; difference 23.9%, 95% CI 5.0%, 42.8%) and ANA (100% vs 95.7%; difference 4.3%, 95% CI 2.9%, 5.8%) criteria. In the multivariate analysis adjusting for age at baseline, female, White race and ethnicity, and ACR haematological and ANA criteria, anti-KIF20B positivity remained associated with CN (OR 5.2, 95% CI 1.4, 19.1). CONCLUSION: Anti-KIF20B is a potential biomarker for SLE-related CN. Further studies are needed to examine how autoantibodies against KIF20B, which is variably expressed in a variety of neurological cells, contribute to disease pathogenesis.

Effects of genetically predicted posttraumatic stress disorder on autoimmune phenotypes.

Observational studies suggest that posttraumatic stress disorder (PTSD) increases risk for various autoimmune diseases. Insights into shared biology and causal relationships between these diseases may inform intervention approaches to PTSD and co-morbid autoimmune conditions. We investigated the shared genetic contributions and causal relationships between PTSD, 18 autoimmune diseases, and 3 immune/inflammatory biomarkers. Univariate MiXeR was used to contrast the genetic architectures of phenotypes. Genetic correlations were estimated using linkage disequilibrium score regression. Bi-directional, two-sample Mendelian randomization (MR) was performed using independent, genome-wide significant single nucleotide polymorphisms; inverse variance weighted and weighted median MR estimates were evaluated. Sensitivity analyses for uncorrelated (MR PRESSO) and correlated horizontal pleiotropy (CAUSE) were also performed. PTSD was considerably more polygenic (10,863 influential variants) than autoimmune diseases (median 255 influential variants). However, PTSD evidenced significant genetic correlation with nine autoimmune diseases and three inflammatory biomarkers. PTSD had putative causal effects on autoimmune thyroid disease (p = 0.00009) and C-reactive protein (CRP) (p = 4.3 × 10-7). Inferences were not substantially altered by sensitivity analyses. Additionally, the PTSD-autoimmune thyroid disease association remained significant in multivariable MR analysis adjusted for genetically predicted inflammatory biomarkers as potential mechanistic pathway variables. No autoimmune disease had a significant causal effect on PTSD (all p values > 0.05). Although causal effect models were supported for associations of PTSD with CRP, shared pleiotropy was adequate to explain a putative causal effect of CRP on PTSD (p = 0.18). In summary, our results suggest a significant genetic overlap between PTSD, autoimmune diseases, and biomarkers of inflammation. PTSD has a putative causal effect on autoimmune thyroid disease, consistent with existing epidemiologic evidence. A previously reported causal effect of CRP on PTSD is potentially confounded by shared genetics. Together, results highlight the nuanced links between PTSD, autoimmune disorders, and associated inflammatory signatures, and suggest the importance of targeting related pathways to protect against disease and disability.

Isolated Traumatic Subarachnoid Hemorrhage on Head Computed Tomography Scan May Not Be Isolated: A TRACK-TBI Study.

Isolated traumatic subarachnoid hemorrhage (tSAH) after traumatic brain injury (TBI) on head computed tomography (CT) scan is often regarded as a "mild" injury, with reduced need for additional workup. However, tSAH is also a predictor of incomplete recovery and unfavorable outcome. This study aimed to evaluate the characteristics of CT-occult intracranial injuries on brain magnetic resonance imaging (MRI) scan in TBI patients with emergency department (ED) arrival Glasgow Coma Scale (GCS) score 13-15 and isolated tSAH on CT. The prospective, 18-center Transforming Research and Clinical Knowledge in Traumatic Brain Injury Study (TRACK-TBI; enrollment years 2014-2019) enrolled participants who presented to the ED and received a clinically-indicated head CT within 24 hours (h) of TBI. A subset of TRACK-TBI participants underwent venipuncture within 24h for plasma glial fibrillary acidic protein (GFAP) analysis, and research MRI at 2-weeks post-injury. In the current study, TRACK-TBI participants aged ≥17 years with ED arrival GCS 13-15, isolated tSAH on initial head CT, plasma GFAP level, and 2-week MRI data were analyzed. In 57 participants, median age was 46.0 years [quartile 1 to 3 (Q1-Q3): 34-57] and 52.6% were male. At ED disposition, 12.3% were discharged home, 61.4% were admitted to hospital ward, and 26.3% to intensive care unit. MRI identified CT-occult traumatic intracranial lesions in 45.6% (26 of 57 participants; 1 additional lesion type: 31.6%; 2 additional lesion types: 14.0%); of these 26 participants with CT-occult intracranial lesions, 65.4% had axonal injury, 42.3% had subdural hematoma, and 23.1% had intracerebral contusion. GFAP levels were higher in participants with CT-occult MRI lesions compared to without (median: 630.6 pg/ml, Q1-Q3: [172.4-941.2] vs. 226.4 [105.8-436.1], p=0.049), and were associated with axonal injury (no: median 226.7 pg/ml [109.6-435.1], yes: 828.6 pg/ml [204.0-1194.3], p=0.009). Our results indicate that isolated tSAH on head CT is often not the sole intracranial traumatic injury in GCS 13-15 TBI. Forty-six percent of patients in our cohort (26 of 57 participants) had additional CT-occult traumatic lesions on MRI. Plasma GFAP may be an important biomarker for the identification of additional CT-occult injuries, including axonal injury. These findings should be interpreted cautiously given our modest sample size and await validation from larger studies.

Migraine Prevalence, Environmental Risk, and Comorbidities in Men and Women Veterans.

Importance: Migraine is a prevalent and debilitating condition that substantially impacts quality of life. Investigating migraine prevalence, associated comorbidities, and potential military service exposures in veterans, focusing on gender differences, is crucial for targeted interventions and management strategies. Objective: To determine the prevalence of migraine, associated health comorbidities, and potential military service and environmental exposures among men and women US veterans using a large-scale epidemiological sample from the Million Veteran Program (MVP). Design, Setting, and Participants: This cross-sectional study analyzed self-report survey data from the MVP, a large epidemiological sample of US veterans that was started in 2011 and has ongoing enrollment. Eligible participants were selected from the MVP database in 2023. The study included 491 604 veterans to examine migraine prevalence, health comorbidities, demographic characteristics, military service history, and environmental exposures. Data were analyzed from December 2022 to July 2023. Exposures: Military service and environmental factors, such as chemical or biological warfare exposure, were considered. Main Outcomes and Measures: The primary outcome was migraine prevalence among men and women veterans, assessed through self-reported diagnoses. Secondary outcomes included the association between migraine and health comorbidities, demographic characteristics, military service history, and environmental exposures. Results: Of the 491 604 veterans included in this study, 450 625 (91.8%) were men and 40 979 (8.2%) were women. The lifetime prevalence of migraine was significantly higher in women (12 324 of 40 979 [30.1%]) than in men (36 816 of 450 625 [8.2%]). Migraine prevalence varied by race and ethnicity, with the highest prevalence in Hispanic or Latinx women (1213 of 3495 [34.7%]). Veterans with migraine reported worse general health, higher levels of pain, increased pain interference with work, a higher likelihood of psychiatric and neurological health conditions, and greater lifetime opioid use. Specific aspects of military service, including service post-September 2001 and deployment in Operation Enduring Freedom and Operation Iraqi Freedom, and environmental factors, including Agent Orange, chemical and biological welfare, and antinerve agent pills history, were significantly associated with migraine prevalence. Conclusions and Relevance: In this cross-sectional study of migraine, the results highlighted gender differences in migraine prevalence and associated health comorbidities among US veterans. The findings emphasized the need for interdisciplinary approaches to migraine management, increased awareness and education efforts, and population-based screening strategies, particularly for women and Hispanic veterans who are at greater risk. Our findings encourage further research into tailored interventions for specific subpopulations and the impact of military service and environmental exposures on migraine and related health conditions.

Advancing Artificial Intelligence Integration Into the Pathology Workflow: Exploring Opportunities in Gastrointestinal Tract Biopsies.

This review aims to present a comprehensive overview of the current landscape of artificial intelligence (AI) applications in the analysis of tubular gastrointestinal biopsies. These publications cover a spectrum of conditions, ranging from inflammatory ailments to malignancies. Moving beyond the conventional diagnosis based on hematoxylin and eosin-stained whole-slide images, the review explores additional implications of AI, including its involvement in interpreting immunohistochemical results, molecular subtyping, and the identification of cellular spatial biomarkers. Furthermore, the review examines how AI can contribute to enhancing the quality and control of diagnostic processes, introducing new workflow options, and addressing the limitations and caveats associated with current AI platforms in this context.

The relationship between expressive suppression, therapeutic bond, and treatment outcomes of a positive affect intervention for adults with anxiety and/or depression.

Expressive suppression (ES; reducing emotional expression) is linked with reduced social connectedness in individuals with anxiety or depression. One implication is that people who use ES may have difficulty establishing a bond with their therapist which may impede clinical improvement. We examined this hypothesis in 33 adults with clinically elevated anxiety or depression receiving treatment focused on enhancing positive thoughts, emotions, and behaviors. At baseline, participants rated ES for positive and negative emotions during a standardized conversation task designed to generate connectedness. They also rated measures of early (session 3) perceived therapeutic bond and treatment outcomes (i.e. positive affect and social connectedness). ES of positive (r = -.39, p = .018), but not negative (r = .06, p = .747), emotions was negatively associated with therapeutic bond. Therapeutic bond mediated the relationship between greater ES of positive emotions during affiliation and lower post-treatment positive affect, 95% bias-corrected bootstrap confidence interval [-0.021, -0.000], adjusted for pre-treatment positive affect, as well as lower post-treatment social connectedness [-0.397, -0.015]; however, the indirect effect was not significant when accounting for pre-treatment social connectedness (p > .05). ES of positive emotions may be an important factor in the development of therapeutic bond and therefore treatment outcomes for individuals with anxiety or depression.

Vulnerabilities in social anxiety: Integrating intra- and interpersonal perspectives.

What are the major vulnerabilities in people with social anxiety? What are the most promising directions for translational research pertaining to this condition? The present paper provides an integrative summary of basic and applied translational research on social anxiety, emphasizing vulnerability factors. It is divided into two subsections: intrapersonal and interpersonal. The intrapersonal section synthesizes research relating to (a) self-representations and self-referential processes; (b) emotions and their regulation; and (c) cognitive biases: attention, interpretation and judgment, and memory. The interpersonal section summarizes findings regarding the systems of (a) approach and avoidance, (b) affiliation and social rank, and their implications for interpersonal impairments. Our review suggests that the science of social anxiety and, more generally, psychopathology may be advanced by examining processes and their underlying content within broad psychological systems. Increased interaction between basic and applied researchers to diversify and elaborate different perspectives on social anxiety is necessary for progress.

Impact of PTSD treatment on postconcussive symptoms in veterans: A comparison of sertraline, prolonged exposure, and their combination.

Many Veterans who served in Iraq and Afghanistan struggle with posttraumatic stress disorder (PTSD) and the effects of traumatic brain injuries (TBI). Some people with a history of TBI report a constellation of somatic, cognitive, and emotional complaints that are often referred to as postconcussive symptoms (PCS). Research suggests these symptoms may not be specific to TBI. This study examined the impact of PTSD treatment on PCS in combat Veterans seeking treatment for PTSD. As part of a larger randomized control trial, 198 Operation Iraqi Freedom, Operation Enduring Freedom, Operation New Dawn (OIF/OEF/OND) Veterans with PTSD received Prolonged Exposure Therapy, sertraline, or the combination. Potential deployment related TBI, PCS, PTSD and depression symptoms were assessed throughout treatment. Linear mixed models were used to predict PCS change over time across the full sample and treatment arms, and the association of change in PTSD and depression symptoms on PCS was also examined. Patterns of change for the full sample and the subsample of those who reported a head injury were examined. Results showed that PCS decreased with treatment. There were no significant differences across treatments. No significant differences were found in the pattern of symptom change based on TBI screening status. Shifts in PCS were predicted by change PTSD and depression. Results suggest that PCS reduced with PTSD treatment in this population and are related to shift in depression and PTSD severity, further supporting that reported PCS symptoms may be better understood as non-specific symptoms.

Toward personalized care for insomnia in the US Army: a machine learning model to predict response to cognitive behavioral therapy for insomnia.

STUDY OBJECTIVES: The standard of care for military personnel with insomnia is cognitive behavioral therapy for insomnia (CBT-I). However, only a minority seeking insomnia treatment receive CBT-I, and little reliable guidance exists to identify those most likely to respond. As a step toward personalized care, we present results of a machine learning (ML) model to predict CBT-I response. METHODS: Administrative data were examined for n=1,449 nondeployed US Army soldiers treated for insomnia with CBT-I who had moderate-severe baseline Insomnia Severity Index (ISI) scores and completed one or more follow-up ISIs 6-12 weeks after baseline. An ensemble ML model was developed in a 70% training sample to predict clinically significant ISI improvement (reduction of at least two standard deviations on the baseline ISI distribution). Predictors included a wide range of military administrative and baseline clinical variables. Model accuracy was evaluated in the remaining 30% test sample. RESULTS: 19.8% of patients had clinically significant ISI improvement. Model AU-ROC (SE) was 0.60 (0.03). The 20% of test sample patients with highest probabilities of improvement were twice as likely to have clinically significant improvement as the remaining 80% (36.5% versus 15.7%; χ21=9.2, p=.002). Nearly 85% of prediction accuracy was due to ten variables, the most important of which were baseline insomnia severity and baseline suicidal ideation. CONCLUSIONS: Pending replication, the model could be used as part of a patient-centered decision-making process for insomnia treatment. Parallel models will be needed for alternative treatments before such a system is of optimal value.

Whole-exome sequencing in UK Biobank reveals rare genetic architecture for depression.

Nearly two hundred common-variant depression risk loci have been identified by genome-wide association studies (GWAS). However, the impact of rare coding variants on depression remains poorly understood. Here, we present whole-exome sequencing analyses of depression with seven different definitions based on survey, questionnaire, and electronic health records in 320,356 UK Biobank participants. We showed that the burden of rare damaging coding variants in loss-of-function intolerant genes is significantly associated with risk of depression with various definitions. We compared the rare and common genetic architecture across depression definitions by genetic correlation and showed different genetic relationships between definitions across common and rare variants. In addition, we demonstrated that the effects of rare damaging coding variant burden and polygenic risk score on depression risk are additive. The gene set burden analyses revealed overlapping rare genetic variant components with developmental disorder, autism, and schizophrenia. Our study provides insights into the contribution of rare coding variants, separately and in conjunction with common variants, on depression with various definitions and their genetic relationships with neurodevelopmental disorders.

Genetic contribution to the comorbidity between attention-deficit/hyperactivity disorder and substance use disorders.

We characterized the genetic architecture of the attention-deficit hyperactivity disorder-substance use disorder (ADHD-SUD) relationship by investigating genetic correlation, causality, pleiotropy, and common polygenic risk. Summary statistics from genome-wide association studies (GWAS) were used to investigate ADHD (Neff = 51,568), cannabis use disorder (CanUD, Neff = 161,053), opioid use disorder (OUD, Neff = 57,120), problematic alcohol use (PAU, Neff = 502,272), and problematic tobacco use (PTU, Neff = 97,836). ADHD, CanUD, and OUD GWAS meta-analyses included cohorts with case definitions based on different diagnostic criteria. PAU GWAS combined information related to alcohol use disorder, alcohol dependence, and the items related to alcohol problematic consequences assessed by the alcohol use disorders identification test. PTU GWAS was generated a multi-trait analysis including information regarding Fagerström Test for Nicotine Dependence and cigarettes per day. Linkage disequilibrium score regression analyses indicated positive genetic correlation with CanUD, OUD, PAU, and PTU. Genomic structural equation modeling showed that these genetic correlations were related to two latent factors: one including ADHD, CanUD, and PTU and the other with OUD and PAU. The evidence of a causal effect of PAU and PTU on ADHD was stronger than the reverse in the two-sample Mendelian randomization analysis. Conversely, similar strength of evidence was found between ADHD and CanUD. CADM2 rs62250713 was a pleiotropic SNP between ADHD and all SUDs. We found seven, one, and twenty-eight pleiotropic variants between ADHD and CanUD, PAU, and PTU, respectively. Finally, OUD, CanUD, and PAU PRS were associated with increased odds of ADHD. Our findings demonstrated the contribution of multiple pleiotropic mechanisms to the comorbidity between ADHD and SUDs.

Predicting Homelessness Among Transitioning U.S. Army Soldiers.

INTRODUCTION: This study develops a practical method to triage Army transitioning service members (TSMs) at highest risk of homelessness to target a preventive intervention. METHODS: The sample included 4,790 soldiers from the Study to Assess Risk and Resilience in Servicemembers-Longitudinal Study (STARRS-LS) who participated in 1 of 3 Army STARRS 2011-2014 baseline surveys followed by the third wave of the STARRS-LS online panel surveys (2020-2022). Two machine learning models were trained: a Stage-1 model that used administrative predictors and geospatial data available for all TSMs at discharge to identify high-risk TSMs for initial outreach; and a Stage-2 model estimated in the high-risk subsample that used self-reported survey data to help determine highest risk based on additional information collected from high-risk TSMs once they are contacted. The outcome in both models was homelessness within 12 months after leaving active service. RESULTS: Twelve-month prevalence of post-transition homelessness was 5.0% (SE=0.5). The Stage-1 model identified 30% of high-risk TSMs who accounted for 52% of homelessness. The Stage-2 model identified 10% of all TSMs (i.e., 33% of high-risk TSMs) who accounted for 35% of all homelessness (i.e., 63% of the homeless among high-risk TSMs). CONCLUSIONS: Machine learning can help target outreach and assessment of TSMs for homeless prevention interventions.

Perspectives of suicide loss survivors: Qualitative analysis of data from a psychological autopsy study of U.S. Army soldiers.

INTRODUCTION: Suicide loss survivors can provide information not otherwise available about the circumstances preceding a suicide. In this study, we analyzed interview data from suicide loss survivors collected as part of a psychological autopsy study of U.S. Army soldiers. METHODS: Next-of-kin (NOK) (n = 61) and Army supervisors (SUP) (n = 107) of suicide decedents (n = 135) who had died in the last 2-3 months answered open-ended questions about suicide risk factors, ideas for improving suicide prevention, and the impact of the suicide. Responses were coded using conventional content analysis methods to identify common themes. RESULTS: Many NOK (30%) and SUP (50%) did not observe any signs of risk preceding the soldier's suicide. The most common idea regarding suicide prevention from SUP was that the suicide was inevitable, whereas NOK were more likely to emphasize the importance of increasing mental health treatment and reducing stigma. Both NOK and SUP reported negative effects of the suicide, but SUP reported some positive effects (e.g., increased unit connectedness). CONCLUSIONS: Results underscore the challenges of using informants to identify soldiers at high risk of suicide, given many respondents did not observe any warning signs. Findings also highlight attitudinal barriers present in the military that, if targeted, may increase soldiers' help-seeking and willingness to disclose their risk.