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Background: Improving a patient's ability to self-monitor and manage changes in chronic obstructive pulmonary disease (COPD) symptoms may improve outcomes.Objective: To determine the efficacy of a comprehensive care management program (CCMP) in reducing the risk for COPD hospitalization.Design: A randomized, controlled trial comparing CCMP with guideline-based usual care. (ClinicalTrials.gov registration number: NCT00395083) SETTING: 20 Veterans Affairs hospital-based outpatient clinics.Participants: Patients hospitalized for COPD in the past year.Intervention: The CCMP included COPD education during 4 individual sessions and 1 group session, an action plan for identification and treatment of exacerbations, and scheduled proactive telephone calls for case management. Patients in both the intervention and usual care groups received a COPD informational booklet; their primary care providers received a copy of COPD guidelines and were advised to manage their patients according to these guidelines. Patients were randomly assigned, stratifying by site based on random, permuted blocks of variable size.Measurements: The primary outcome was time to first COPD hospitalization. Staff blinded to study group performed telephone-based assessment of COPD exacerbations and hospitalizations, and all hospitalizations were blindly adjudicated. Secondary outcomes included non-COPD health care use, all-cause mortality, health-related quality of life, patient satisfaction, disease knowledge, and self-efficacy.Results: Of the eligible patients, 209 were randomly assigned to the intervention group and 217 to the usual care group. Citing serious safety concerns, the data monitoring committee terminated the intervention before the trial's planned completion after 426 (44%) of the planned total of 960 patients were enrolled. Mean follow-up was 250 days. When the study was stopped, the 1-year cumulative incidence of COPD-related hospitalization was 27% in the intervention group and 24% in the usual care group (hazard ratio, 1.13 [95% CI, 0.70 to 1.80]; P= 0.62). There were 28 deaths from all causes in the intervention group versus 10 in the usual care group (hazard ratio, 3.00 [CI, 1.46 to 6.17]; P= 0.003). Cause could be assigned in 27 (71%) deaths. Deaths due to COPD accounted for the largest difference: 10 in the intervention group versus 3 in the usual care group (hazard ratio, 3.60 [CI, 0.99 to 13.08]; P= 0.053).Limitations: Available data could not fully explain the excess mortality in the intervention group. Ability to assess the quality of the educational sessions provided by the case managers was limited.Conclusion: A CCMP in patients with severe COPD had not decreased COPD-related hospitalizations when the trial was stopped prematurely. The CCMP was associated with unanticipated excess mortality, results that differ markedly from similar previous trials. A data monitoring committee should be considered in the design of clinical trials involving behavioral interventions. [ABSTRACT FROM AUTHOR]

While research linking work organization factors to work-related musculoskeletal disorders has been increasing, there is still a need to delineate specific dimensions to be targeted by intervention programs. The present cross-sectional investigation identified work organization risk factors for low back (LB) and upper extremity (UE) symptoms and determined the magnitudes of such associations. Questionnaires containing items on ergonomic, individual psychosocial, and occupational psychosocial factors were administered to a sample of workers (n = 248 U.S. Marines) in previously identified high-risk job categories for musculoskeletal disorders. Study participants were categorized into groups of either having LB symptoms only, UE symptoms only, concurrent LB and UE symptoms, or being asymptomatic on the basis of self-report. Additionally, measures of pain intensity, physical function, and mental health were obtained. Linear regression analyses adjusting for demographics, ergonomic factors, and individual psychosocial factors indicated that decision authority and experienced responsibility for work were significant correlates for pain intensity during the week. Logistic regression analyses indicated that ergonomic stressors were a risk factor for all symptomatic groups (OR = 1.02 per point increase; 95% CI: 1.0-1.1). Time pressure (OR = 1.2 per point increase; 95% CI: 1.0-1.4) was also a significant risk factor for all symptomatic groups, while cognitive processing placed workers at higher risks for concurrent LB and UE symptoms (OR = 1.2; 95% CI: 1.0-1.4). Interpersonal demands placed individuals at a lower risk for LB symptoms (OR = 0.8; 95% CI: 0.5-1.0). Findings highlight the importance of intervention approaches that address time pressure, cognitive processing factors, and interpersonal demands at work. In light of past biobehavioral studies, these results also suggest that job redesign and interventions that address a worker's workstyle when faced with increased work demands may help reduce the likelihood of musculoskeletal symptoms and/or their intensity. [ABSTRACT FROM AUTHOR]

An integrated case management (ICM) approach (ergonomic and problem-solving intervention) to work-related upper-extremity disorders was examined in relation to patient satisfaction, future symptom severity, function, and return to work (RTW). Federal workers with work-related upper-extremity disorder workers' compensation claims (n = 205) were randomly assigned to usual care or ICM intervention. Patient satisfaction was assessed after the 4-month intervention period. Questionnaires on clinical outcomes and ergonomic exposure were administered at baseline and at 6- and 12-months postintervention. Time from intervention to RTW was obtained from an administrative database. ICM group assignment was significantly associated with greater patient satisfaction. Regression analyses found higher patient satisfaction levels predicted decreased symptom severity and functional limitations at 6 months and a shorter RTW. At 12 months, predictors of positive outcomes included male gender, lower distress, lower levels of reported ergonomic exposure, and receipt of ICM. Findings highlight the utility of targeting workplace ergonomic and problem solving skills. [ABSTRACT FROM AUTHOR]

This study prospectively examined the extent to which a set of medical, physical, ergonomic, occupational psychosocial, and individual psychosocial variables would predict clinical outcome associated with a diverse set of work-related upper extremity disorders in recently diagnosed individuals. This investigation was designed to develop a tool for use in a clinical setting to assist in identifying patients at risk for poorer outcome. Outcome was measured at 1, 3, and 12 months after completing a baseline questionnaire. Outcome status was based on a median split of a standardized composite index (symptoms, function, workdays lost, and mental health). Logistic regression indicated that predictors of poorer outcome at 1 month were: upper extremity comorbidity (risk ratio [RR], 1.58), pain severity (RR, 1.45), ergonomic risk exposure (RR, 1.07), low job support (RR, 1.03), and pain coping style (RR, 1.54). At 3 months, poorer outcome was predicted by: symptom severity (RR, 10.46), job stress (RR, 1.20), and pain coping style (RR, 1.98). The number of prior treatments/providers (RR, 1.77), past recommendation for surgery (RR, 6.43), and pain coping style were found to predict poorer outcome at 12 months. Sensitivity and specificity, respectively, for the models were 77.4% and 71.8% at 1 month, 80.6% and 82.4% at 3 months, and 80.6% and 83.3% at 12 months. The results indicate that baseline measures of ergonomic and psychosocial stress, pain severity, and pain coping style predict clinical outcome at shorter intervals, whereas number of past treatments/providers, recommendation for surgery and pain coping style predict longer-term outcome. The resulting prognostic screen provides a simple tool that assesses the multidimensional nature of work-related upper extremity disorders and predicts clinical outcome. Furthermore, the findings suggest the importance of early intervention that addresses both physical and psychosocial stressors at work. Specific recommendations to reduce the impact of observed risk factors are discussed. [ABSTRACT FROM AUTHOR]

The Americans with Disabilities Act (ADA) was designed, in part, to assist in work re-entry for the disabled. ADA-related complaints that are more difficult to resolve and consequently reach the litigation stage may provide useful insights into the challenges associated with the re-integration of disabled workers into the workplace. The present study identified pattems of impairments and areas of dispute from all ADA litigation (n = 189) between 1990 to 1996. While HIV/AIDS was the most common single impairment category (18.8%), combined musculoskeletal-related (ie., back and upper extremity) impairments comprised the largest group of impairments (23.4% of total) involved in litigation. The top two areas of dispute were termination and alleged failure to provide reasonable accommodation, respectively. The distribution of musculoskeletal- and nonmusculoskeletal-related cases were similar for these two areas of dispute. These findings highlight the direction upon which effective work re-entry strategies for workers with musculoskeletal-related disabilities must focus. Efforts to provide effective accommodation for these workers should improve return-to-work outcomes and reduce the risk of litigation. Specific recommendations for such efforts are provided. [ABSTRACT FROM AUTHOR]

Background: Nirmatrelvir-ritonavir is recommended for persons at risk for severe coronavirus disease 2019 (COVID-19) but remains underutilized. Information on which eligible groups are likely to benefit from treatment is needed., Methods: We conducted a target trial emulation study in the Veterans Health Administration comparing nirmatrelvir-ritonavir treated versus matched untreated veterans at risk for severe COVID-19 who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from April 2022 through March 2023. We measured incidence of any hospitalization or all-cause mortality at 30 days. Outcomes were measured for the entire cohort, as well as among subgroups defined by 30-day risk of death or hospitalization, estimated using an ensemble risk prediction model., Results: Participants were 87% male with median age 66 years and 16% unvaccinated. Compared with matched untreated participants, those treated with nirmatrelvir-ritonavir (n = 24 205) had a lower 30-day risk for hospitalization (1.80% vs 2.30%; risk difference [RD], -0.50% points [95% confidence interval {CI}: -.69 to -.35]) and death (0.11% vs 0.30%; RD, -0.20 [95% CI: -.24 to -.13]). The greatest reductions in combined hospitalization or death were observed in the highest risk quartile (RD -2.85 [95% CI: -3.94 to -1.76]), immunocompromised persons (RD -1.91 [95% CI: -3.09 to -.74]), and persons aged ≥75 years (RD -1.16 [95% CI: -1.73 to -.59]). No reductions were observed in the 2 lowest risk quartiles or persons younger than 65 years., Conclusions: Nirmatrelvir-ritonavir was effective in reducing 30-day hospitalization and death in older veterans, those at highest predicted risk for severe outcomes, and immunocompromised groups. Benefit was not observed in younger veterans or groups at lower predicted risk for hospitalization and death., Competing Interests: Potential conflicts of interest. D. H. reports consulting fees from Quality Insights, research consulting co-ownership in Van-Breemen & Hynes, LLC, and a subcontract at Oregon State University for a PCORI grant through the University of North Carolina, grants from VA Health Services Research and Development (HSRD), Quality Insight. G. I. reports grants from Department of Veterans Affairs. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2024.)

Importance: Robotic exoskeletons leverage technology that assists people with spinal cord injury (SCI) to walk. The efficacy of home and community exoskeletal use has not been studied in a randomized clinical trial (RCT)., Objective: To examine whether use of a wheelchair plus an exoskeleton compared with use of only a wheelchair led to clinically meaningful net improvements in patient-reported outcomes for mental and physical health., Design, Setting, and Participants: This RCT of veterans with SCI was conducted at 15 Veterans Affairs medical centers in the US from September 6, 2016, to September 27, 2021. Data analysis was performed from March 10, 2022, to June 20, 2024., Interventions: Participants were randomized (1:1) to standard of care (SOC) wheelchair use or SOC plus at-will use of a US Food and Drug Administration (FDA)-cleared exoskeletal-assisted walking (EAW) device for 4 months in the home and community., Main Outcomes and Measures: Two primary outcomes were studied: 4.0-point or greater improvement in the mental component summary score on the Veterans RAND 36-Item Health Survey (MCS/VR-36) and 10% improvement in the total T score of the Spinal Cord Injury-Quality of Life (SCI-QOL) physical and medical health domain and reported as the proportion who achieved clinically meaningful changes. The primary outcomes were measured at baseline, post randomization after advanced EAW training sessions, and at 2 months and 4 months (primary end point) in the intervention period. Device usage, reasons for not using, and adverse events were collected., Results: A total of 161 veterans with SCI were randomized to the EAW (n = 78) or SOC (n = 83) group; 151 (94%) were male, the median age was 47 (IQR, 35-56) years, and median time since SCI was 7.3 (IQR, 0.5 to 46.5) years. The difference in proportion of successes between the EAW and SOC groups on the MCS/VR-36 (12 of 78 [15.4%] vs 14 of 83 [16.9%]; relative risk, 0.91; 95% CI, 0.45-1.85) and SCI-QOL physical and medical health domain (10 of 78 [12.8%] vs 11 of 83 [13.3%]; relative risk, 0.97; 95% CI, 0.44-2.15) was not statistically different. Device use was lower than expected (mean [SD] distance, 1.53 [0.02] miles per month), primarily due to the FDA-mandated companion being unavailable 43.9% of the time (177 of 403 instances). Two EAW-related foot fractures and 9 unrelated fractures (mostly during wheelchair transfers) were reported., Conclusions and Relevance: In this RCT of veterans with SCI, the lack of improved outcomes with EAW device use may have been related to the relatively low device usage. Solutions for companion requirements and user-friendly technological adaptations should be considered for improved personal use of these devices., Trial Registration: ClinicalTrials.gov Identifier: NCT02658656.

Purpose: The phase 3 Veterans Affairs Lung Cancer Surgery Or Stereotactic Radiotherapy study implemented centralized quality assurance (QA) to mitigate risks of protocol deviations. This report summarizes the quality and compliance of the first 100 participants treated with stereotactic body radiation therapy (SBRT) in this study., Methods and Materials: A centralized QA program was developed to credential and monitor study sites to ensure standard-of-care lung SBRT treatments are delivered to participants. Requirements were adapted from protocols established by the National Cancer Institute's Image and Radiation Oncology Core, which provides oversight for clinical trials sponsored by the National Cancer Institute's National Clinical Trials Network., Results: The first 100 lung SBRT treatment plans were reviewed from April 2017 to October 2022. Tumor contours were appropriate in all submissions. Planning target volume (PTV) expansions were less than the minimum 5 mm requirement in 2% of cases. Critical organ-at-risk structures were contoured accurately for the proximal bronchial tree, trachea, esophagus, spinal cord, and brachial plexus in 75%, 92%, 100%, 100%, and 95% of cases, respectively. Prescriptions were appropriate in 98% of cases; 2 central tumors were treated using a peripheral tumor dose prescription while meeting organ-at-risk constraints. PTV V100% (the percentage of target volume that receives 100% or more of the prescription) values were above the protocol-defined minimum of 94% in all but 1 submission. The median dose maximum (Dmax) within the PTV was 125.4% (105.8%-149.0%; SD ± 8.7%), where values reference the percentage of the prescription dose. High-dose conformality (ratio of the volume of the prescription isodose to the volume of the PTV) and intermediate-dose compactness [R50% (ratio of the volume of the half prescription isodose to the volume of the PTV) and D2cm (the maximum dose beyond a 2 cm expansion of the PTV expressed as a percentage of the prescription dose)] were acceptable or deviation acceptable in 100% and 94% of cases, respectively., Conclusions: The first 100 participants randomized to SBRT in this study were appropriately treated without safety concerns. A response to the incorrect prescriptions led to preventative measures without further recurrences. The program was developed in a health care system without prior experience with a centralized radiation therapy QA program and may serve as a reference for other institutions., Competing Interests: Disclosures Timothy A. Ritter reports salary support from the VA Cooperative Studies Program (CSP), Hines, IL, as an employee of the Veterans Health Administration. Robert D. Timmerman reports grant support from Varian Medical Systems, Elekta Oncology, and Accuray, Inc. Domenic J. Reda reports support from the Department of Veterans Affairs; support for attending meetings and/or travel from the Society for Clinical Trials; participation on a Data Safety Monitoring Board or Advisory Board for Abeona Therapeutics, D-CARE, and GWICTIC; an unpaid leadership or fiduciary role for the Society for Clinical Trials; and support from the University of Illinois at Chicago for his role as an instructor. Catherine R Sears reports support from VA CSP and VA BLR&D. Lorraine D. Cornwell reports support from VA CSP and support for travel to training and educational events from Edwards, Angiodynamics, Medtronic, Abbott, and Intuitive. Jatinder Palta reports contract support from Senior Medical Physics Services to VHA National Radiation Oncology 11SPEC 22 and a Chair role with the Intranational Council of AAPM. Drew Moghanaki reports support from the VA CSP, payment or honoraria for presentations from Varian Medical Systems, and support for attending meetings and/or travel from Varian Medical Systems. The other authors have nothing to disclose. No artificial intelligence tools were used in the preparation of this manuscript., (Published by Elsevier Inc.)

Large-scale genome-wide association studies of schizophrenia have uncovered hundreds of associated loci but with extremely limited representation of African diaspora populations. We surveyed electronic health records of 200,000 individuals of African ancestry in the Million Veteran and All of Us Research Programs, and, coupled with genotype-level data from four case-control studies, realized a combined sample size of 13,012 affected and 54,266 unaffected persons. Three genome-wide significant signals - near PLXNA4 , PMAIP1 , and TRPA1 - are the first to be independently identified in populations of predominantly African ancestry. Joint analyses of African, European, and East Asian ancestries across 86,981 cases and 303,771 controls, yielded 376 distinct autosomal loci, which were refined to 708 putatively causal variants via multi-ancestry fine-mapping. Utilizing single-cell functional genomic data from human brain tissue and two complementary approaches, transcriptome-wide association studies and enhancer-promoter contact mapping, we identified a consensus set of 94 genes across ancestries and pinpointed the specific cell types in which they act. We identified reproducible associations of schizophrenia polygenic risk scores with schizophrenia diagnoses and a range of other mental and physical health problems. Our study addresses a longstanding gap in the generalizability of research findings for schizophrenia across ancestral populations, underlining shared biological underpinnings of schizophrenia across global populations in the presence of broadly divergent risk allele frequencies.

Objective: This study aimed to assess the impact of a lung-protective ventilation strategy utilizing transpulmonary driving pressure titrated positive end-expiratory pressure (PEEP) on the prognosis [mechanical ventilation duration, hospital stay, 28-day mortality rate and incidence of ventilator-associated pneumonia (VAP), survival outcome] of patients with Acute Respiratory Distress Syndrome (ARDS)., Methods: A total of 105 ARDS patients were randomly assigned to either the control group (n = 51) or the study group (n = 53). The control group received PEEP titration based on tidal volume [A tidal volume of 6 mL/kg, flow rate of 30-60 L/min, frequency of 16-20 breaths/min, constant flow rate, inspiratory-to-expiratory ratio of 1:1 to 1:1.5, and a plateau pressure ≤ 30-35 cmH 2 O. PEEP was adjusted to maintain oxygen saturation (SaO 2 ) at or above 90%, taking into account blood pressure], while the study group received PEEP titration based on transpulmonary driving pressure (Esophageal pressure was measured as a surrogate for pleural pressure using an esophageal pressure measurement catheter connected to the ventilator. Tidal volume and PEEP were adjusted based on the observed end-inspiratory and end-expiratory transpulmonary pressures, aiming to maintain a transpulmonary driving pressure below 15 cmH 2 O during mechanical ventilation. Adjustments were made 2-4 times per day). Statistical analysis and comparison were conducted on lung function indicators [oxygenation index (OI), arterial oxygen tension (PaO2), arterial carbon dioxide tension (PaCO2)] as well as other measures such as heart rate, mean arterial pressure, and central venous pressure in two groups of patients after 48 h of mechanical ventilation. The 28-day mortality rate, duration of mechanical ventilation, length of hospital stay, and ventilator-associated pneumonia (VAP) incidence were compared between the two groups. A 60-day follow-up was performed to record the survival status of the patients., Results: In the control group, the mean age was (55.55 ± 10.51) years, with 33 females and 18 males. The pre-ICU hospital stay was (32.56 ± 9.89) hours. The mean Acute Physiology and Chronic Health Evaluation (APACHE) II score was (19.08 ± 4.67), and the mean Murray Acute Lung Injury score was (4.31 ± 0.94). In the study group, the mean age was (57.33 ± 12.21) years, with 29 females and 25 males. The pre-ICU hospital stay was (33.42 ± 10.75) hours. The mean APACHE II score was (20.23 ± 5.00), and the mean Murray Acute Lung Injury score was (4.45 ± 0.88). They presented a homogeneous profile (all P > 0.05). Following intervention, significant improvements were observed in PaO 2 and OI compared to pre-intervention values. The study group exhibited significantly higher PaO 2 and OI compared to the control group, with statistically significant differences (all P < 0.05). After intervention, the study group exhibited a significant increase in PaCO2 (43.69 ± 6.71 mmHg) compared to pre-intervention levels (34.19 ± 5.39 mmHg). The study group's PaCO2 was higher than the control group (42.15 ± 7.25 mmHg), but the difference was not statistically significant (P > 0.05). There were no significant differences in hemodynamic indicators between the two groups post-intervention (all P > 0.05). The study group demonstrated significantly shorter mechanical ventilation duration and hospital stay, while 28-day mortality rate and incidence of ventilator-associated pneumonia (VAP) showed no significant differences. Kaplan-Meier survival analysis revealed a significantly better survival outcome in the study group at the 60-day follow-up (HR = 0.565, 95% CI: 0.320-0.999)., Conclusion: Lung-protective mechanical ventilation using transpulmonary driving pressure titrated PEEP effectively improves lung function, reduces mechanical ventilation duration and hospital stay, and enhances survival outcomes in patients with ARDS. However, further study is needed to facilitate the wider adoption of this approach., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Persons diagnosed with schizophrenia (SCZ) or bipolar I disorder (BPI) are at high risk for self-injurious behavior, suicidal ideation, and suicidal behaviors (SB). Characterizing associations between diagnosed health problems, prior pharmacological treatments, and polygenic scores (PGS) has potential to inform risk stratification. We examined self-reported SB and ideation using the Columbia Suicide Severity Rating Scale (C-SSRS) among 3,942 SCZ and 5,414 BPI patients receiving care within the Veterans Health Administration (VHA). These cross-sectional data were integrated with electronic health records (EHRs), and compared across lifetime diagnoses, treatment histories, follow-up screenings, and mortality data. PGS were constructed using available genomic data for related traits. Genome-wide association studies were performed to identify and prioritize specific loci. Only 20% of the veterans who reported SB had a corroborating ICD-9/10 EHR code. Among those without prior SB, more than 20% reported new-onset SB at follow-up. SB were associated with a range of additional clinical diagnoses, and with treatment with specific classes of psychotropic medications (e.g., antidepressants, antipsychotics, etc.). PGS for externalizing behaviors, smoking initiation, suicide attempt, and major depressive disorder were associated with SB. The GWAS for SB yielded no significant loci. Among individuals with a diagnosed mental illness, self-reported SB were strongly associated with clinical variables across several EHR domains. Analyses point to sequelae of substance-related and psychiatric comorbidities as strong correlates of prior and subsequent SB. Nonetheless, past SB was frequently not documented in health records, underscoring the value of regular screening with direct, in-person assessments, especially among high-risk individuals., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Depression is one of the primary global public health issues, and there has been a dramatic increase in depression levels among young people over the past decade. The neuroplasticity theory of depression postulates that a malfunction in neural plasticity, which is responsible for learning, memory, and adaptive behavior, is the primary source of the disorder's clinical manifestations. Nevertheless, the impact of depression symptoms on associative learning remains underexplored., Methods: We used the differential fear conditioning paradigm to investigate the effects of depressive symptoms on fear acquisition and extinction learning. Skin conductance response (SCR) is an objective evaluation indicator, and ratings of nervousness, likeability, and unconditioned stimuli (US) expectancy are subjective evaluation indicators. In addition, we used associability generated by a computational reinforcement learning model to characterize the skin conductance response., Results: The findings indicate that individuals with depressive symptoms exhibited significant impairment in fear acquisition learning compared to those without depressive symptoms based on the results of the skin conductance response. Moreover, in the discrimination fear learning task, the skin conductance response was positively correlated with associability, as estimated by the hybrid model in the group without depressive symptoms. Additionally, the likeability rating scores improved post-extinction learning in the group without depressive symptoms, and no such increase was observed in the group with depressive symptoms., Conclusion: The study highlights that individuals with pronounced depressive symptoms exhibit impaired fear acquisition and extinction learning, suggesting a possible deficit in associative learning. Employing the hybrid model to analyze the learning process offers a deeper insight into the associative learning processes of humans, thus allowing for improved comprehension and treatment of these mental health problems., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Luo, Su, Zhao, Cao, Liao, Xue, Huang and Yang.)

Introduction: Older military veterans often present with unique and complex risk factors for Alzheimer's disease (AD) and related dementias. Increasing veteran participation in research studies offers one avenue to advance the field and improve health outcomes., Methods: To this end, the National Institute on Aging (NIA) and Department of Veterans Affairs (VA) partnered to build infrastructure, improve collaboration, and intensify targeted recruitment of veterans. This initiative, INviting Veterans InTo Enrollment in Alzheimer's Disease Research Centers (INVITE-ADRC), provided funding for five sites and cross-site organizing structure. Diverse and innovative recruitment strategies were used., Results: Across five sites, 172 veterans entered registries, and 99 were enrolled into ADRC studies. Of the enrolled, 39 were veterans from historically underrepresented racial and ethnic groups., Conclusions: This initiative laid the groundwork to establish sustainable relationships between the VA and ADRCs. The partnership between both federal agencies demonstrates how mutual interests can accelerate progress. In turn, efforts can help our aging veterans., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Our previous study showed that the abscisic acid receptor lanthionine synthetase C-like 2 (LanCL2) is a significant prognostic factor for overall survival in young glioblastoma patients. However, the role of LanCL2 in glioblastoma remains unclear yet., Objectives: This study aims to investigate the role of LanCL2 in regulating in-vitro cell invasion and in-vivo tumor progression of glioblastoma and its underlying mechanism., Methods: Tyrosine 198 or 295 residue of LanCL2 was mutated using site-directed mutagenesis to block its phosphorylation. The role of LanCL2 in glioblastoma was investigated using transwell or 3D invasion assay, matrix degradation assay and intracranial xenograft model., Results: This study showed that nuclear transport of LanCL2 was enhanced by overexpression of LanCL2 or its ligand abscisic acid in glioblastoma cells. Knockdown of LanCL2 suppressed migration, invasion and invadopodia formation of glioblastoma cells, whereas overexpression of wild-type LanCL2 enhanced them. Blocking of Tyr295 residue phosphorylation of LanCL2 impeded its nuclear transport, retarded glioblastoma cell motility and invadopodia formation, and deceased the phosphorylation of Cortactin and STAT3. c-Met was identified as the upstream tyrosine kinase of Tyr295 residue of LanCL2, and inhibition of c-Met markedly suppressed the nuclear transport of LanCL2. Moreover, overexpression of wild-type LanCL2 significantly promoted orthotopic tumor growth of glioblastoma in vivo and led to poor survival of mice with median survival time of 33.5 days, whereas Tyr295 mutation rescued it with median survival time of 49 days., Conclusion: Our findings suggested that Tyr295 phosphorylation is crucial to the activation and nuclear transport of LanCL2, as well as invadopodia formation and tumor progression of glioblastoma, providing the evidence of a novel signaling axis c-Met/LanCL2/STAT3/Cortactin and the first observation of the importance of Tyr295 phosphorylation to LanCL2., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Production and hosting by Elsevier B.V.)

Estrogen regulates a wide range of neuronal functions in the brain, such as dendritic spine formation, remodeling of synaptic plasticity, cognition, neurotransmission, and neurodevelopment. Estrogen interacts with intracellular estrogen receptors (ERs) and membrane-bound ERs to produce its effect via genomic and non-genomic pathways. Any alterations in these pathways affect the number, size, and shape of dendritic spines in neurons associated with psychiatric diseases. Increasing evidence suggests that estrogen fluctuation causes changes in dendritic spine density, morphology, and synapse numbers of excitatory and inhibitory neurons differently in males and females. In this review, we discuss the role of estrogen hormone in rodents and humans based on sex differences. First, we explain estrogen role in learning and memory and show that a high estrogen level alleviates the deficits in learning and memory. Secondly, we point out that estrogen produces a striking difference in emotional memories in men and women, which leads them to display sex-specific differences in underlying neuronal signaling. Lastly, we discuss that fluctuations in estrogen levels in men and women are related to neuropsychiatric disorders, including schizophrenia, autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), bipolar disorder (BPD), major depressive disorder (MDD), substance use disorder (SUD), and anxiety disorders., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

The olfactory working memory capacity (OWMC) paradigm is able to detect cognitive deficits in 5XFAD mice (an animal model of Alzheimer's disease [TG]) as early as 3 months of age, while other behavioral paradigms detect cognitive deficits only at 4-5 months of age. Therefore, we aimed to demonstrate that the OWMC paradigm is more sensitive and consistent in the early detection of declines in cognitive function than other commonly used behavioral paradigms. The prefrontal cortex (PFC), retrosplenial cortex (RSC), subiculum (SUB), and amygdala (AMY) of 5XFAD mice were harvested and subjected to immunostaining to detect the expression of β-amyloid (Aβ). Additionally, we compared the performance of 3-month-old male 5XFAD mice on common behavioral paradigms for assessing cognitive function (i.e., the open field [OF] test, novel object recognition [NOR] test, novel object location [NOL] test, Y-maze, and Morris water maze [MWM]) with that on the OWMC task. In the testing phase of the OWMC task, we varied the delay periods to evaluate the working memory capacity (WMC) of wild-type (WT) mice. Significant amyloid plaque deposition was observed in the PFC, RSC, SUB, and AMY of 3-month-old male 5XFAD mice. However, aside from the OWMC task, the other behavioral tests failed to detect cognitive deficits in 5XFAD mice. Additionally, to demonstrate the efficacy of the OWMC task in assessing WMC, we varied the retention delay periods; we found that the WMC of WT mice decreased with longer delay periods. The OWMC task is a sensitive and robust behavioral assay for detecting changes in cognitive function., (© 2023 Wiley Periodicals LLC.)

Post-traumatic stress disorder (PTSD) is a stress-associated complex and debilitating psychiatric disorder due to an imbalance of neurotransmitters in response to traumatic events or fear. PTSD is characterized by re-experiencing, avoidance behavior, hyperarousal, negative emotions, insomnia, personality changes, and memory problems following exposure to severe trauma. However, the biological mechanisms and symptomatology underlying this disorder are still largely unknown or poorly understood. Considerable evidence shows that PTSD results from a dysfunction in highly conserved brain systems involved in regulating stress, anxiety, fear, and reward circuitry. This review provides a contemporary update about PTSD, including new data from the clinical and preclinical literature on stress, PTSD, and fear memory consolidation and extinction processes. First, we present an overview of well-established laboratory models of PTSD and discuss their clinical translational value for finding various treatments for PTSD. We then highlight the research progress on the neural circuits of fear and extinction-related behavior, including the prefrontal cortex, hippocampus, and amygdala. We further describe different molecular mechanisms, including GABAergic, glutamatergic, cholinergic, and neurotropic signaling, responsible for the structural and functional changes during fear acquisition and fear extinction processes in PTSD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Iqbal, Huang, Xue, Yang and Jia.)

Background: The US Department of Veterans Affairs (VA) Office of Research and Development (ORD) supports an extensive clinical trials enterprise. Until recently, external partnerships were limited. The VA's potential value as a partner became more apparent during the COVID-19 pandemic because of its large health care system, diverse patient population, and expertise in conducting clinical trials., Observations: By leveraging its infrastructure, the VA was able to participate in 7 large-scale COVID-19 therapeutic and vaccine trials. A key aspect of this enterprise approach is the ability to provide centralized direction and coordination. The VA's partnerships with external groups offered insights into the challenges associated with conducting important trials, especially when rapidity and coordination were essential. The ORD also developed solutions for reducing study startup time that could be established as best practices. We offer lessons for the challenges VA faced: site infrastructure needs and capabilities; study management roles and responsibilities; educational resources; local review; study design demands; contracting and budgeting; central-level systems; and communication., Conclusions: VA participation in major COVID-19 therapeutic and vaccine trials represented a significant part of its research response to the pandemic. These contributions extended beyond the participants, scientists, and data that helped inform subsequent regulatory approvals. The VA also had an opportunity to directly develop partnerships with non-VA groups. These groups became more familiar with the VA while enabling us to gain more experience in the diverse practices used to conduct multisite clinical studies. Ultimately, these efforts empower the VA to further serve the broader scientific and clinical communities., Competing Interests: Author disclosures: The authors report no actual or potential conflicts of interest or outside sources of funding with regard to this article., (Copyright © 2023 Frontline Medical Communications Inc., Parsippany, NJ, USA.)

Background: Within a year of the start of the COVID-19 pandemic, the US Department of Veterans Affairs (VA) was managing about 300 COVID-19-related research projects across roughly 100 facilities, which has since grown to more than 900 projects. This robust set of activities arose from an existing enterprise strategy and aimed at identifying needs for supporting the clinical care mission, more rapidly leveraging resources, and coordinating research across the VA. The VA's efforts to implement an enterprise strategy before March 2020 positioned its research community to dynamically partner with other federal agencies, academic institutions, and industry in addressing a national public health emergency., Observations: The VA research enterprise involves a broad range of functions, scientific and clinical leaders, and organizational resources to enhance the health and care of veterans and the nation. The scope of research activities enables it to support its priorities while also partnering with others who share in mutual commitments to veteran health. Moving toward being the nation's learning health care system, the VA's leadership support, staff, patient volunteers, and partners were key contributors to a national response to COVID-19. Swift action and consistent communication helped address the complexities of the pandemic and strengthened the VA's ability to prepare and mobilize for emergencies and other potential disease outbreaks. Documenting strategies and practices can enhance future opportunities aimed at addressing the most challenging health care needs while also focusing on the primary mission to serve veterans., Conclusions: The COVID-19 pandemic contributed to critical knowledge and lessons that enabled the VA to advance enterprise goals, particularly in the context of its health care system. Sharing these unique processes and experiences will inform current and future partnerships among research, clinical, and public health communities oriented to serve veterans and the nation through scientific innovation., Competing Interests: Author disclosures: The authors report no actual or potential conflicts of interest or outside sources of funding with regard to this article., (Copyright © 2023 Frontline Medical Communications Inc., Parsippany, NJ, USA.)

Background: COVID-19 has been linked to the development of many post-COVID-19 conditions (PCCs) after acute infection. Limited information is available on the effectiveness of oral antivirals used to treat acute COVID-19 in preventing the development of PCCs., Objective: To measure the effectiveness of outpatient treatment of COVID-19 with nirmatrelvir-ritonavir in preventing PCCs., Design: Retrospective target trial emulation study comparing matched cohorts receiving nirmatrelvir-ritonavir versus no treatment., Setting: Veterans Health Administration (VHA)., Participants: Nonhospitalized veterans in VHA care who were at risk for severe COVID-19 and tested positive for SARS-CoV-2 during January through July 2022., Intervention: Nirmatrelvir-ritonavir treatment for acute COVID-19., Measurements: Cumulative incidence of 31 potential PCCs at 31 to 180 days after treatment or a matched index date, including cardiac, pulmonary, renal, thromboembolic, gastrointestinal, neurologic, mental health, musculoskeletal, endocrine, and general conditions and symptoms., Results: Eighty-six percent of the participants were male, with a median age of 66 years, and 17.5% were unvaccinated. Baseline characteristics were well balanced between participants treated with nirmatrelvir-ritonavir and matched untreated comparators. No differences were observed between participants treated with nirmatrelvir-ritonavir ( n = 9593) and their matched untreated comparators in the incidence of most PCCs examined individually or grouped by organ system, except for lower combined risk for venous thromboembolism and pulmonary embolism (subhazard ratio, 0.65 [95% CI, 0.44 to 0.97]; cumulative incidence difference, -0.29 percentage points [CI, -0.52 to -0.05 percentage points])., Limitations: Ascertainment of PCCs using International Classification of Diseases, 10th Revision, codes may be inaccurate. Evaluation of many outcomes could have resulted in spurious associations with combined thromboembolic events by chance., Conclusion: Out of 31 potential PCCs, only combined thromboembolic events seemed to be reduced by nirmatrelvir-ritonavir., Primary Funding Source: U.S. Department of Veterans Affairs., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M23-1394.

Estrogen (E2) modulates the synaptic structure and plasticity in the hippocampus. Previous studies showed that E2 fluctuations during various phases of the menstrual cycle produce subtle neurosynaptic changes that impact women's behavior, emotion, and cognitive functions. In this study, we explored the transcriptome of the hippocampus via RNA-seq (RNA-sequencing) between proestrus (PE) and diestrus (DE) stages in young female rats to determine the effect of E2 of PE and DE stages on hippocampal gene expression. We identified 238 genes (at 1.5-fold-change selection criteria, FDR adjusted p-value < 0.05) as differentially expressed genes (DEGs) that responded to E2 between PE and DE stages. Functional analysis based on Gene Ontology (GO) revealed that a higher E2 level corresponded to an increase in gene transcription among most of the DEGs, suggesting biological mechanisms operating differentially in the hippocampus of female rats between PE and DE stages in the estrus cycle; while analysis with Kyoto Encyclopedia of Genes and Genomes database (KEGG) found that the DEGs involving neuroactive ligand-receptor interaction, antigen processing, cell adhesion molecules, and presentation were upregulated in PE stage, whereas DEGs in pathways relating to bile secretion, coagulation cascades, osteoclast differentiation, cysteine and methionine metabolism were upregulated in DE stage of the estrus cycle. The high-fold expression of DEGs was confirmed by a follow-up quantitative real-time PCR. Our findings in this current study have provided fundamental information for further dissection of neuro-molecular mechanisms in the hippocampus in response to E2 fluctuation and its relationship with disorders., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Working memory capacity impairment is an early sign of Alzheimer's disease, but the underlying mechanisms remain unclear. Clarifying how working memory capacity is affected will help us better understand the pathological mechanism of Alzheimer's disease. We used the olfactory working memory capacity paradigm to evaluate memory capacity in 3-month-old 5XFAD (an animal model of Alzheimer's disease) mice. Immunofluorescence staining of the prefrontal cortex was performed to detect the number of FOS-positive neurons, calmodulin-dependent protein kinase II-positive neurons, and glutamate decarboxylase-positive neurons in the prelimbic cortex and infralimbic cortex. A chemogenetic method was then used to modulate the inhibition and activation of excitatory neurons in the prelimbic cortex of wild-type and 5XFAD mice and to measure the memory capacity of mice., Results: Working memory capacity was significantly diminished in 5XFAD mice compared to littermate wild-type mice. Neuronal activation of the prelimbic cortex, but not the infralimbic cortex, was attenuated in 5XFAD mice performing the olfactory working memory capacity task. Subsequently, the FOS-positive neurons were co-localized with both calmodulin-dependent protein kinase II-positive neurons and glutamate decarboxylase-positive neurons. The results showed that the activation of excitatory neurons in the prelimbic cortex was correlated with working memory capacity in mice. Our results further demonstrate that the chemogenetic inhibition of prelimbic cortex excitatory neurons resulted in reduced working memory capacity in wild-type mice, while the chemogenetic activation of prelimbic cortex excitatory neurons improved the working memory capacity of 5XFAD mice., Conclusion: The diminished activation of prelimbic cortex excitatory neurons in 5XFAD mice during task performance is associated with reduced working memory capacity, and activation modulation of excitatory neurons by chemogenetic methods can improve memory capacity impairment in 5XFAD mice. These findings may provide a new direction for exploring Alzheimer's disease therapeutic approaches., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Importance: Several pharmacotherapies have been authorized to treat nonhospitalized persons with symptomatic COVID-19. Longitudinal information on the use of these therapies is needed., Objective: To analyze trends and factors associated with prescription of outpatient COVID-19 pharmacotherapies within the Veterans Health Administration (VHA)., Design, Setting, and Participants: This cohort study evaluated nonhospitalized veterans in VHA care who tested positive for SARS-CoV-2 from January 2022 through January 2023 using VHA and linked Community Care and Medicare databases., Exposures: Demographic characteristics, underlying medical conditions, COVID-19 vaccination, and regional and local systems of care, including Veterans Integrated Services Networks (VISNs)., Main Outcomes and Measures: Monthly receipt of any COVID-19 pharmacotherapy (nirmatrelvir-ritonavir, molnupiravir, sotrovimab, or bebtelovimab) was described. Multivariable logistic regression was used to identify factors independently associated with receipt of any vs no COVID-19 pharmacotherapy., Results: Among 285 710 veterans (median [IQR] age, 63.1 [49.9-73.7] years; 247 358 males [86.6%]; 28 444 Hispanic [10.0%]; 61 269 Black [21.4%] and 198 863 White [69.6%]) who tested positive for SARS-CoV-2 between January 2022 and January 2023, the proportion receiving any pharmacotherapy increased from 3285 of 102 343 veterans (3.2%) in January 2022 to 5180 of 21 688 veterans (23.9%) in August 2022. The proportion declined to 2194 of 10 551 veterans (20.8%) by January 2023. Across VISNs, the range in proportion of patients who tested positive who received nirmatrelvir-ritonavir or molnupiravir during January 2023 was 41 of 692 veterans (5.9%) to 106 of 494 veterans (21.4%) and 2.1% to 120 of 1074 veterans (11.1%), respectively. Veterans receiving any treatment were more likely to be older (adjusted odds ratio [aOR] for ages 65-74 vs 50-64 years, 1.18; 95% CI, 1.14-1.22; aOR for ages ≥75 vs 50-64 years, 1.19; 95% CI, 1.15-1.23) and have a higher Charlson Comorbidity Index score (aOR for CCI ≥6 vs 0, 1.52; 95% CI, 1.44-1.59). Compared with White veterans, Black veterans (aOR, 1.06; 95% CI, 1.02-1.09) were more likely to receive treatment, and compared with non-Hispanic veterans, Hispanic veterans (aOR 1.06; 95% CI, 1.01-1.11) were more likely to receive treatment., Conclusions and Relevance: This study found that prescription of outpatient COVID-19 pharmacotherapies in the VHA peaked in August 2022 and declined thereafter. There were large regional differences in patterns of nirmatrelvir-ritonavir and molnupiravir use.

Objective: This work aimed to assess the therapeutic and economic benefits of service dogs versus emotional support dogs for veterans with posttraumatic stress disorder (PTSD)., Methods: Veterans with PTSD (N=227) participating in a multicenter trial were randomly assigned to receive a service or emotional support dog; 181 veterans received a dog and were followed up for 18 months. Primary outcomes included overall functioning (assessed with World Health Organization Disability Assessment Scale II [WHODAS 2.0]) and quality of life (Veterans RAND 12-Item Health Survey [VR-12]). Secondary outcomes included PTSD symptoms (PTSD Checklist for DSM-5), suicidal ideation, depression, sleep quality, health care costs and utilization, medication adherence, employment, and productivity., Results: Participants paired with a dog had a mean±SD age of 50.6±13.6 years (range 22-79), and most were male (80%), White (66%), and non-Hispanic (91%). Adjusted linear mixed repeated-measures models indicated no difference between the two groups on WHODAS 2.0 or VR-12 scores. Participants with service dogs had a 3.7-point greater reduction in PTSD symptoms versus participants with emotional support dogs (p=0.036). No reduced health care utilization or cost was associated with receiving a service dog. Veterans with service dogs had an increase of 10 percentage points in antidepressant adherence compared with those with emotional support dogs (p<0.01)., Conclusions: Both groups appeared to benefit from having a service or emotional support dog. No significant differences in improved functioning or quality of life were observed between the groups. Those in the service dog group had a greater reduction in PTSD symptoms and better antidepressant adherence, improvements that should be explored further.

Due to its extremely complex pathogenesis, no effective drugs to prevent, delay progression, or cure Alzheimer's disease (AD) exist at present. The main pathological features of AD are senile plaques composed of β-amyloid, neurofibrillary tangles formed by hyperphosphorylation of the tau protein, and degeneration or loss of neurons in the brain. Many risk factors associated with the onset of AD, including gene mutations, aging, traumatic brain injury, endocrine and cardiovascular diseases, education level, and obesity. Growing evidence points to chronic stress as one of the major risk factors for AD, as it can promote the onset and development of AD-related pathologies via a mechanism that is not well known. The use of murine stress models, including restraint, social isolation, noise, and unpredictable stress, has contributed to improving our understanding of the relationship between chronic stress and AD. This review summarizes the evidence derived from murine models on the pathological features associated with AD and the related molecular mechanisms induced by chronic stress. These results not only provide a retrospective interpretation for understanding the pathogenesis of AD, but also provide a window of opportunity for more effective preventive and identifying therapeutic strategies for stress-induced AD.

The present study aimed to investigate the inhibitory effect and mechanism of Isodon terricolous-medicated serum on lipopolysaccharide(LPS)-induced hepatic stellate cell(HSC) activation. LPS-induced HSCs were divided into a blank control group, an LPS model group, a colchicine-medicated serum group, an LPS + blank serum group, an I. terricolous-medicated serum group, a Toll-like receptor 4(TLR4) blocker group, and a TLR4 blocker + I. terricolous-medicated serum group. HSC proliferation was detected by methyl thiazolyl tetrazolium(MTT) assay. Enzyme-linked immunosorbent assay(ELISA) was used to measure type Ⅰ collagen(COL Ⅰ), COL Ⅲ, transforming growth factor-β1(TGF-β1), intercellular adhesion molecule-1(ICAM-1), α-smooth muscle actin(α-SMA), vascular cell adhesion molecule-1(VCAM-1), cysteinyl aspartate-specific proteinase-1(caspase-1), and monocyte chemotactic protein-1(MCP-1). Real-time PCR(RT-PCR) was used to detect mRNA expression of TLR4, IκBα, and NOD-like receptor thermal protein domain associated protein 3(NLRP3), nuclear factor-κB(NF-κB) p65, gasdermin D(GSDMD), and apoptosis-associated speck-like protein containing a CARD(ASC) in HSCs. Western blot(WB) was used to detect the protein levels of TLR4, p-IκBα, NF-κB p65, NLRP3, ASC, and GSDMD in HSCs. The results showed that I. terricolous-medicated serum could inhibit the proliferation activity of HSCs and inhibit the secretion of COL Ⅰ, COL Ⅲ, α-SMA, TGF-β1, caspase-1, MCP-1, VCAM-1, and ICAM-1 in HSCs. Compared with the LPS model group, the I. terricolous-medicated serum group, the colchicine-medicated serum group, and the TLR4 blocker group showed down-regulated expression of p-IκBα, NLRP3, NF-κB p65, GSDMD, and ASC, and up-regulated expression of IκBα. Compared with the TLR4 blocker group, the TLR4 blocker + I. terricolous-medicated serum group showed decreased expression of TLR4, p-IκBα, NLRP3, NF-κB p65, GSDMD, and ASC, and increased expression of IκBα. In conclusion, I. terricolous-medicated serum down-regulates HSC activation by inhibiting the TLR4/NF-κB/NLRP3 signaling pathway.

In the summer of 2020, multiple efforts were undertaken to establish safe and effective vaccines to combat the spread of the coronavirus disease (COVID-19). In the United States (U.S.), Operation Warp Speed (OWS) was the program designated to coordinate such efforts. OWS was a partnership between the Department of Health and Human Services (HHS), the Department of Defense (DOD), and the private sector, that aimed to help accelerate control of the COVID-19 pandemic by advancing development, manufacturing, and distribution of vaccines, therapeutics, and diagnostics. The U.S. Department of Veterans Affairs' (VA) was identified as a potential collaborator in several large-scale OWS Phase III clinical trial efforts designed to evaluate the safety and efficacy of various vaccines that were in development. Given the global importance of these trials, it was recognized that there would be a need for a coordinated, centralized effort within VA to ensure that its medical centers (sites) would be ready and able to efficiently initiate, recruit, and enroll into these trials. The manuscript outlines the partnership and start-up activities led by two key divisions of the VA's Office of Research and Development's clinical research enterprise. These efforts focused on site and enterprise-level requirements for multiple trials, with one trial serving as the most prominently featured of these studies within the VA. As a result, several best practices arose that included designating clinical trial facilitators to study sites to support study initiation activities and successful study enrollment at these locations in an efficient and timely fashion., Competing Interests: The authors report no conflicts of interest.

Background: Information about the effectiveness of oral antivirals in preventing short- and long-term COVID-19-related outcomes in the setting of Omicron variant transmission and COVID-19 vaccination is limited., Objective: To measure the effectiveness of nirmatrelvir-ritonavir and molnupiravir for outpatient treatment of COVID-19., Design: Three retrospective target trial emulation studies comparing matched cohorts of nirmatrelvir-ritonavir versus no treatment, molnupiravir versus no treatment, and nirmatrelvir-ritonavir versus molnupiravir., Setting: Veterans Health Administration (VHA)., Participants: Nonhospitalized veterans in VHA care who were at risk for severe COVID-19 and tested positive for SARS-CoV-2 during January through July 2022., Intervention: Nirmatrelvir-ritonavir or molnupiravir pharmacotherapy., Measurements: Incidence of any hospitalization or all-cause mortality at 30 days and from 31 to 180 days., Results: Eighty-seven percent of participants were male; the median age was 66 years, and 18% were unvaccinated. Compared with matched untreated control participants, those treated with nirmatrelvir-ritonavir ( n  = 9607) had lower 30-day risk for hospitalization (22.07 vs. 30.32 per 1000 participants; risk difference [RD], -8.25 [95% CI, -12.27 to -4.23] per 1000 participants) and death (1.25 vs. 5.47 per 1000 participants; RD, -4.22 [CI, -5.45 to -3.00] per 1000 participants). Among persons alive at day 31, reductions were seen in 31- to 180-day incidence of death (hazard ratio, 0.66 [CI, 0.49 to 0.89]) but not hospitalization (subhazard ratio, 0.90 [CI, 0.79 to 1.02]). Molnupiravir-treated participants ( n  = 3504) had lower 30-day and 31- to 180-day risks for death (3.14 vs. 13.56 per 1000 participants at 30 days; RD, -10.42 [CI, -13.49 to -7.35] per 1000 participants; hazard ratio at 31 to 180 days, 0.67 [CI, 0.48 to 0.95]) but not hospitalization. A difference in 30-day or 31- to 180-day risk for hospitalization or death was not observed between matched nirmatrelvir- or molnupiravir-treated participants., Limitation: The date of COVID-19 symptom onset for most veterans was unknown., Conclusion: Nirmatrelvir-ritonavir was effective in reducing 30-day hospitalization and death. Molnupiravir was associated with a benefit for 30-day mortality but not hospitalization. Further reductions in mortality from 31 to 180 days were observed with both antivirals., Primary Funding Source: U.S. Department of Veterans Affairs., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M22-3565.

Background: Chronic low back pain (cLBP) is a common and highly disabling problem world-wide. Although many treatment options exist, it is unclear how to best sequence the multitude of care options to provide the greatest benefit to patients., Methods: The Sequential and Comparative Evaluation of Pain Treatment Effectiveness Response (SCEPTER) trial uses a pragmatic, randomized, stepped design. Enrollment targets 2529 participants from 20 Veterans Affairs (VA) medical centers. Participants with chronic low back pain will first be randomized to one of three options: 1) an internet-based self-management program (Pain EASE); 2) a tailored physical therapy program (Enhanced PT); or 3) continued care with active monitoring (CCAM), a form of usual care. Participants not achieving a 30% or 2-point reduction on the study's primary outcome (Brief Pain Inventory Pain Interference (BPI-PI) subscale), 3 months after beginning treatment may undergo re-randomization in a second step to cognitive behavioral therapy for chronic pain, spinal manipulation therapy, or yoga. Secondary outcomes include pain intensity, back pain-related disability, depression, and others. Participants will be assessed every three months until 12 months after initiating their final trial therapy. Companion economic and implementation analyses are also planned., Results: The SCEPTER trial is currently recruiting and enrolling participants., Conclusions: Trial results will inform treatment decisions for the stepped management of chronic low back pain - a common and disabling condition. Additional analyses will help tailor treatment selection to individual patient characteristics, promote efficient resource use, and identify implementation barriers of interventions., Trial Registration: clinicaltrials.gov Identifier: NCT04142177., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Inc.)

Dihydroartemisinin (DHA) has anticancer effects on multiple tumors, including those associated with breast cancer. This study aimed to investigate the mechanism causing DHA-reversing cisplatin (DDP) resistance in breast cancer. Relative mRNA and protein levels were tested using a qRT-PCR and western blot assay. Cell proliferation, viability, and apoptosis were evaluated using colony formation, MTT, and flow cytometry assays, respectively. Interaction of STAT3 and DDA1 was measured via a dual-luciferase reporter assay. The results showed that DDA1 and p-STAT3 levels were dramatically elevated in DDP-resistant cells. DHA treatment repressed proliferation and induced apoptosis of DDP-resistant cells by suppressing STAT3 phosphorylation; the inhibition ability was positively proportional to the DHA concentration. DDA1 knockdown inhibited cyclin expression, promoted G0/G1 phase arrest, restrained cell proliferation, and induced apoptosis of DDP-resistant cells. Furthermore, knockdown of STAT3 restrained proliferation and induced apoptosis and G0/G1 cell cycle arrest of DDP-resistant cells by targeting DDA1. DHA could restrain tumor proliferation of breast cancer via enhancing drug sensitivity of DDP-resistant cells through the STAT3/DDA1 signaling pathway.

Background: Whether chlorthalidone is superior to hydrochlorothiazide for preventing major adverse cardiovascular events in patients with hypertension is unclear., Methods: In a pragmatic trial, we randomly assigned adults 65 years of age or older who were patients in the Department of Veterans Affairs health system and had been receiving hydrochlorothiazide at a daily dose of 25 or 50 mg to continue therapy with hydrochlorothiazide or to switch to chlorthalidone at a daily dose of 12.5 or 25 mg. The primary outcome was a composite of nonfatal myocardial infarction, stroke, heart failure resulting in hospitalization, urgent coronary revascularization for unstable angina, and non-cancer-related death. Safety was also assessed., Results: A total of 13,523 patients underwent randomization. The mean age was 72 years. At baseline, hydrochlorothiazide at a dose of 25 mg per day had been prescribed in 12,781 patients (94.5%). The mean baseline systolic blood pressure in each group was 139 mm Hg. At a median follow-up of 2.4 years, there was little difference in the occurrence of primary-outcome events between the chlorthalidone group (702 patients [10.4%]) and the hydrochlorothiazide group (675 patients [10.0%]) (hazard ratio, 1.04; 95% confidence interval, 0.94 to 1.16; P = 0.45). There were no between-group differences in the occurrence of any of the components of the primary outcome. The incidence of hypokalemia was higher in the chlorthalidone group than in the hydrochlorothiazide group (6.0% vs. 4.4%, P<0.001)., Conclusions: In this large pragmatic trial of thiazide diuretics at doses commonly used in clinical practice, patients who received chlorthalidone did not have a lower occurrence of major cardiovascular outcome events or non-cancer-related deaths than patients who received hydrochlorothiazide. (Funded by the Veterans Affairs Cooperative Studies Program; ClinicalTrials.gov number, NCT02185417.)., (Copyright © 2022 Massachusetts Medical Society.)

Purpose: This study explores the relationship between physical exercise and older people's subjective well-being and the mediating role of a sense of meaning in life and self-esteem by using a structural equation modeling (SEM) approach, in order to provide some suggestions for improving older people's subjective well-being., Methods: In this study, a cross-sectional survey was conducted offline using a simple random method of collection, and the Physical Activity Rating Scale (PARS-3), the Subjective Well-being Scale (SWB), the Meaningfulness of Life Scale (MLQ), and the Self-Esteem Scale (SES) were applied to 419 older adults who participated in physical exercise from Chengdu (Qingyang District, Wuhou District, and Chenghua District), Sichuan Province, China, with the voluntary participation of the subjects. 197 males and 222 females, with a mean age of 72.49 (SD = 1.57). The study used SPSS 25.0 and Process 3.5 plug-in for statistical processing of the data, Cronbach's alpha coefficient for intra-variate consistency testing, Harman's one-way test for common method bias testing and multiple covariance diagnosis, and finally regression analysis and Bootstrap sampling test for significance of mediating effects., Results: Physical exercise was able to have a positive effect on the level of subjective well-being of older adults ( β  = 0.0305; 95% confidence interval (CI): 0.0226, 0.0384; p  < 0.05), and a mediation analysis of sense of meaning in life and self-esteem revealed that they were able to have independent and chained mediation effects, with four pathways: first, physical exercise directly affected subjective well-being of older adults ( β  = 0.0149; 95% CI: 0.0072, 0.0226; p  < 0.05; β  = 0.0149; 95% CI: 0.0072, 0.0226; p  < 0.05); secondly, sense of meaning in life mediated the relationship between physical exercise and subjective well-being of older adults ( β  = 0.0075; 95% CI: 0.0041, 0.0115; p  < 0.05); thirdly, self-esteem mediated the relationship between physical exercise and subjective well-being of older adults ( β  = 0.0075; 95% CI: 0.0041, 0.0115; p  < 0.05). (β = 0.0061; 95% CI: 0.0034, 0.0094; p  < 0.05); fourth, a chain mediating effect of sense of meaning in life and self-esteem in the relationship between physical exercise and subjective well-being in older adults ( β  = 0.0021; 95% CI: 0.0010, 0.0035; p  < 0.05)., Conclusion and Prospects: As indicated by the results, physical exercise can enhance the subjective well-being of older adults through sense of meaning in life and self-esteem, therefore, in order to be able to enhance the subjective well-being of older adults, enhancing the level of sense of meaning in life and self-esteem of older adults is an effective means., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chen, Liu, Huang and Wu.)

Importance: Older adults and individuals with medical comorbidities are at increased risk for severe COVID-19. Several pharmacotherapies demonstrated to reduce the risk of COVID-19-related hospitalization and death have been authorized for use., Objective: To describe factors associated with receipt of outpatient COVID-19 pharmacotherapies in the Veterans Affairs (VA) health care system., Design, Settings, and Participants: This cohort study assessed outpatient veterans with risk factors for severe COVID-19 who tested positive for SARS-CoV-2 during January and February 2022. The setting was the VA health care system, the largest integrated health care system in the US., Exposures: Demographic characteristics, place of residence, underlying medical conditions, and COVID-19 vaccination., Main Outcomes and Measures: The odds of receipt of any COVID-19 pharmacotherapy, including sotrovimab, nirmatrelvir boosted with ritonavir, molnupiravir, or remdesivir were estimated using multivariable logistic regression., Results: Among 111 717 veterans included in this study (median [IQR] age, 60 [46-72] years; 96 482 [86.4%] male, 23 362 [20.9%] Black, 10 740 [9.6%] Hispanic, 75 973 [68.0%] White) who tested positive for SARS-CoV-2 during January to February 2022, 4233 (3.8%) received any COVID-19 pharmacotherapy, including 2870 of 92 396 (3.1%) in January and 1363 of 19 321 (7.1%) in February. Among a subset of 56 285 veterans with documented COVID-19-related symptoms in the 30 days preceding a positive SARS-CoV-2 test, 3079 (5.5%) received any COVID-19 pharmacotherapy. Untreated veterans had a median (IQR) age of 60 (46-71) years and a median (IQR) of 3 (2-5) underlying medical conditions. Veterans receiving any treatment were more likely to be older (aged 65 to 74 years vs 50 to 64 years: adjusted odds ratio [aOR], 1.66 [95% CI, 1.52-1.80]; aged at least 75 years vs 50 to 64 years: aOR, 1.67 [95% CI, 1.53-1.84]) and have a higher number of underlying conditions (at least 5 conditions vs 1 to 2 conditions: aOR, 2.17 [95% CI, 1.98-2.39]). Compared with White veterans, Black veterans (aOR, 0.65 [95% CI, 0.60-0.72]) were less likely to receive treatment; and compared with non-Hispanic veterans, Hispanic veterans (aOR, 0.88 [95% CI, 0.77-0.99]) were less likely to receive treatment. There were 16 546 courses of sotrovimab, nirmatrelvir, and molnupiravir allocated across the VA during this period., Conclusions and Relevance: In this cohort study of veterans who tested positive for SARS-CoV-2 during January and February when supply of outpatient COVID-19 pharmacotherapies was limited, prescription of these pharmacotherapies was underused, and many veterans with risk factors for severe COVID-19 did not receive treatment. Veterans from minority racial and ethnic groups were less likely to receive any pharmacotherapy.

Implementation assessment plans are crucial for clinical trials to achieve their full potential. Without a proactive plan to implement trial results, it can take decades for one-fifth of effective interventions to be adopted into routine care settings. The Veterans Health Administration Office of Research and Development is undergoing a systematic transformation to embed implementation planning in research protocols through the Cooperative Studies Program, its flagship clinical research program. This manuscript has two objectives: 1) to introduce an Implementation Planning Assessment (IPA) Tool that any clinical trialist may use to facilitate post-trial implementation of interventions found to be effective and 2) to provide a case study demonstrating the IPA Tool's use. The IPA Tool encourages study designers to initially consider rigorous data collection to maximize acceptability of the intervention by end-users. It also helps identify and prepare potential interested parties at local and national leadership levels to ensure, upon trial completion, interventions can be integrated into programs, technologies, and policies in a sustainable way. The IPA Tool can alleviate some of the overwhelming nature of implementation science by providing a practical guide based on implementation science principles for researchers desiring to scale up and spread effective, clinical trial-tested interventions to benefit patients., (© The Author(s) 2022.)

Importance: Serious mental illnesses, including schizophrenia, bipolar disorder, and depression, are heritable, highly multifactorial disorders and major causes of disability worldwide., Objective: To benchmark the penetrance of current neuropsychiatric polygenic risk scores (PRSs) in the Veterans Health Administration health care system and to explore associations between PRS and broad categories of human disease via phenome-wide association studies., Design, Setting, and Participants: Extensive Veterans Health Administration's electronic health records were assessed from October 1999 to January 2021, and an embedded cohort of 9378 individuals with confirmed diagnoses of schizophrenia or bipolar 1 disorder were found. The performance of schizophrenia, bipolar disorder, and major depression PRSs were compared in participants of African or European ancestry in the Million Veteran Program (approximately 400 000 individuals), and associations between PRSs and 1650 disease categories based on ICD-9/10 billing codes were explored. Last, genomic structural equation modeling was applied to derive novel PRSs indexing common and disorder-specific genetic factors. Analysis took place from January 2021 to January 2022., Main Outcomes and Measures: Diagnoses based on in-person structured clinical interviews were compared with ICD-9/10 billing codes. PRSs were constructed using summary statistics from genome-wide association studies of schizophrenia, bipolar disorder, and major depression., Results: Of 707 299 enrolled study participants, 459 667 were genotyped at the time of writing; 84 806 were of broadly African ancestry (mean [SD] age, 58 [12.1] years) and 314 909 were of broadly European ancestry (mean [SD] age, 66.4 [13.5] years). Among 9378 individuals with confirmed diagnoses of schizophrenia or bipolar 1 disorder, 8962 (95.6%) were correctly identified using ICD-9/10 codes (2 or more). Among those of European ancestry, PRSs were robustly associated with having received a diagnosis of schizophrenia (odds ratio [OR], 1.81 [95% CI, 1.76-1.87]; P < 10-257) or bipolar disorder (OR, 1.42 [95% CI, 1.39-1.44]; P < 10-295). Corresponding effect sizes in participants of African ancestry were considerably smaller for schizophrenia (OR, 1.35 [95% CI, 1.29-1.42]; P < 10-38) and bipolar disorder (OR, 1.16 [95% CI, 1.11-1.12]; P < 10-10). Neuropsychiatric PRSs were associated with increased risk for a range of psychiatric and physical health problems., Conclusions and Relevance: Using diagnoses confirmed by in-person structured clinical interviews and current neuropsychiatric PRSs, the validity of an electronic health records-based phenotyping approach in US veterans was demonstrated, highlighting the potential of PRSs for disentangling biological and mediated pleiotropy.

Purpose: Severe community-acquired pneumonia (CAP) requiring intensive care unit admission is associated with significant acute and long-term morbidity and mortality. We hypothesized that downregulation of systemic and pulmonary inflammation with prolonged low-dose methylprednisolone treatment would accelerate pneumonia resolution and improve clinical outcomes., Methods: This double-blind, randomized, placebo-controlled clinical trial recruited adult patients within 72-96 h of hospital presentation. Patients were randomized in 1:1 ratio; an intravenous 40 mg loading bolus was followed by 40 mg/day through day 7 and progressive tapering during the 20-day treatment course. Randomization was stratified by site and need for mechanical ventilation (MV) at the time of randomization. Outcomes included a primary endpoint of 60-day all-cause mortality and secondary endpoints of morbidity and mortality up to 1 year of follow-up., Results: Between January 2012 and April 2016, 586 patients from 42 Veterans Affairs Medical Centers were randomized, short of the 1420 target sample size because of low recruitment. 584 patients were included in the analysis. There was no significant difference in 60-day mortality between the methylprednisolone and placebo arms (16% vs. 18%; adjusted odds ratio 0.90, 95% CI 0.57-1.40). There were no significant differences in secondary outcomes or complications., Conclusions: In patients with severe CAP, prolonged low-dose methylprednisolone treatment did not significantly reduce 60-day mortality. Treatment was not associated with increased complications., (© 2022. This is a U.S. Goverment work and not under copyright protection in the US; foreign protection ma apply.)

Background: Working memory capacity (WMC) is the ability to maintain information over a few seconds. Although it has been extensively studied in healthy subjects and neuropsychiatric patients, few tasks have been developed to measure such changes in rodents. Many procedures have been used to measure WM in rodents, including the radial arm maze, the WM version of the Morris swimming task, and various delayed matching and nonmatching-to-sample tasks. It should be noted, however, that the memory components assessed in these procedures do not include memory capacity., Methods: We developed an olfactory working memory capacity (OWMC) paradigm to assess the WMC of 3-month-old 5×FAD mice, a mouse model of Alzheimer's disease. The task is divided into five phases: context adaptation, digging training, rule learning for nonmatching to a single sample odor (NMSS), rule learning for nonmatching to multiple sample odors (NMMS), and capacity testing., Results: In the NMSS rule-learning phase, there was no difference between wild-type (WT) mice and 5×FAD mice in the performance correct rate, correct option rate, and correct rejection rate. The WT mice and 5×FAD mice showed similar memory capacity in the NMMS rule-learning phase. After capacity test, we found that the WMC was significantly diminished in 5×FAD mice. As the memory load increased, 5×FAD mice also made significantly more errors than WT mice., Conclusion: The OWMC task, based on a nonmatch-to-sample rule, is a sensitive and robust behavioral assay that we validated as a reliable method for measuring WMC and exploring different components of memory in mice., (© 2022 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

The specific mechanism of gingerol in cerebral ischemia remains unknown. A neuroprotective function for miR-210 in cerebral ischemia has been identified. The brain-derived neurotrophic factor (BDNF)-mediated signaling pathway protects against cerebral ischemic injury. This investigation aimed to determine whether gingerol plays a neuroprotective role in cerebral ischemia via the miR-210/BDNF axis. N2a cells subjected to 10 h of hypoxia and 4 h of reoxygenation were treated with 5, 10, or 20 μmol/L gingerol. The levels of viability, apoptosis, and proteins in N2a cells were determined using MTT assays, flow cytometry, and western blotting, respectively. The binding relationship between BDNF and miR-210 was studied using a dual luciferase reporter assay. The expression levels of miR-210 and BDNF were determined using qPCR. Gingerol repressed the increase in apoptosis and decrease in viability observed in response to hypoxia/reoxygenation. Gingerol increased Bcl-2, BDNF, and TrkB levels and reduced Bax and cleaved caspase 3 levels after hypoxia/reoxygenation. Gingerol evoked decreased expression of miR-210. Inhibition of miR-210 resulted in increased viability and reduced apoptosis along with increased levels of Bcl-2, BDNF, and TrkB and reduced levels of Bax and cleaved caspase 3 after hypoxia/reoxygenation. Additionally, the miR-210 mimic reversed changes induced by gingerol. The cotransfection of the miR-210 mimic and wild type BDNF led to decreased luciferase activity. BDNF was negatively regulated by miR-210. BDNF siRNA reversed these changes evoked by miR-210 inhibition. Gingerol ameliorated hypoxia/reoxygenation-stimulated neuronal damage by regulating the miR-210/BDNF axis, indicating that gingerol is worthy of further application in cerebral ischemia therapy., (© 2021 The Authors. The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia, Ltd on behalf of Kaohsiung Medical University.)

Background: Hypoxic-ischemic encephalopathy (HIE) occurs when an infant's brain has not received adequate oxygen and blood supply, resulting in ischemic and hypoxic damage. Currently, supportive care and hypothermia therapy have been the standard treatment for HIE. However, there are still over 20% of treated infants died and 19-30% survived with significant disability. HIE animal model was first established by Rice et al., involving the ligation of one common carotid artery followed by hypoxia. In this study, we investigated human umbilical cord blood (HUCB) and its two components mononuclear cell (MNC) and red cell fraction (RCF) in both short and long term study using a modified HIE rat model., Methods: In this modified HIE model, both common carotid arteries were occluded, breathing 8% oxygen in a hypoxic chamber for 60-min, followed by the release of the common carotid arteries ligature, mimicking reperfusion injury. For cell therapeutic study, cells were intravenously injected to HIE rat pups, and both behavioral and histological changes were assessed at selected time points., Result: Statistically significant behavioral improvements were demonstrated on Day 7 and 1 month between saline treated HIE rats and UCB/MNC treated rats. However, at 3 months, the therapeutic improvements were only showed between saline treated HIE animals and MNC treated HIE rats. For histological analysis 1 month after cell injection, the number of functional neurons were statistically increased between saline treated HIE and UCB/MNC/RCF treated HIE rats. At 3 months, the significant increase in functional neurons was only present in MNC treated HIE rats., Conclusion: We have used a bilateral temporary occlusion of 60 min, a moderately brain damaged model, for cell therapeutic studies. HUCB mononuclear cell (MNC) therapy showed benefits in neonatal HIE rats in both short and long term behavioral and histological assessments., Competing Interests: WC was employed by the company Mononuclear Therapeutics Limited. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lyu, Sun, Ng, Cheng, Chen, He, Lam, Zheng, Huang, Wang, Young and Poon.)

Objective: Diffusion spectrum imaging (DSI) was used to quantitatively study the changes in the trigeminal cistern segment in patients with trigeminal neuralgia (TN) and to further explore the value of acquiring DSI data from patients with TN., Methods: To achieve high-resolution fiber tracking, 60 patients with TN and 35 healthy controls (HCs) were scanned with conventional magnetic resonance imaging (MRI) and DSI. The patients and the members of the control group were compared within and between groups. The correlations between quantitative parameters of DSI and the visual analog scale (VAS), and symptom duration and responsible vessel types were analyzed., Results: Compared with unaffected side of patients in the TN group, the affected side showed significantly decreased quantitative anisotropy (QA) ( p < 0.001), fractional anisotropy (FA) ( p = 0.001), and general FA (GFA) ( p < 0.001). The unaffected side exhibited significantly decreased QA ( p + 0.001), FA ( p = 0.001), and GFA ( p < 0.001) and significantly increased axial diffusivity (AD) ( p = 0.036) compared with the affected side of patients in the TN group and the average values of HCs. There were significantly decreased QA ( p = 0.046) and FA ( p = 0.008) between the unaffected side of patients and the average values of HCs. GFA can evidently distinguish arteries, veins, and features of unaffected side in TN patients., Conclusion: Using high-resolution fiber tracking technology, DSI can provide quantitative information that can be used to detect the integrity of trigeminal white matter in patients with TN and can improve the understanding of the disease mechanism., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Luo, Chen, Zhang, Lin, Huang and Lei.)

Importance: Posttraumatic stress disorder (PTSD) is a prevalent and serious mental health problem. Although there are effective psychotherapies for PTSD, there is little information about their comparative effectiveness., Objective: To compare the effectiveness of prolonged exposure (PE) vs cognitive processing therapy (CPT) for treating PTSD in veterans., Design, Setting, and Participants: This randomized clinical trial assessed the comparative effectiveness of PE vs CPT among veterans with military-related PTSD recruited from outpatient mental health clinics at 17 Department of Veterans Affairs medical centers across the US from October 31, 2014, to February 1, 2018, with follow-up through February 1, 2019. The primary outcome was assessed using centralized masking. Tested hypotheses were prespecified before trial initiation. Data were analyzed from October 5, 2020, to May 5, 2021., Interventions: Participants were randomized to 1 of 2 individual cognitive-behavioral therapies, PE or CPT, delivered according to a flexible protocol of 10 to 14 sessions., Main Outcomes and Measures: The primary outcome was change in PTSD symptom severity on the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) from before treatment to the mean after treatment across posttreatment and 3- and 6-month follow-ups. Secondary outcomes included other symptoms, functioning, and quality of life., Results: Analyses were based on all 916 randomized participants (730 [79.7%] men and 186 [20.3%] women; mean [range] age 45.2 [21-80] years), with 455 participants randomized to PE (mean CAPS-5 score at baseline, 39.9 [95% CI, 39.1-40.7] points) and 461 participants randomized to CPT (mean CAPS-5 score at baseline, 40.3 [95% CI, 39.5-41.1] points). PTSD severity on the CAPS-5 improved substantially in both PE (standardized mean difference [SMD], 0.99 [95% CI, 0.89-1.08]) and CPT (SMD, 0.71 [95% CI, 0.61-0.80]) groups from before to after treatment. Mean improvement was greater in PE than CPT (least square mean, 2.42 [95% CI, 0.53-4.31]; P = .01), but the difference was not clinically significant (SMD, 0.17). Results for self-reported PTSD symptoms were comparable with CAPS-5 findings. The PE group had higher odds of response (odds ratio [OR], 1.32 [95% CI, 1.00-1.65]; P < .001), loss of diagnosis (OR, 1.43 [95% CI, 1.12-1.74]; P < .001), and remission (OR, 1.62 [95% CI, 1.24-2.00]; P < .001) compared with the CPT group. Groups did not differ on other outcomes. Treatment dropout was higher in PE (254 participants [55.8%]) than in CPT (215 participants [46.6%]; P < .01). Three participants in the PE group and 1 participant in the CPT group were withdrawn from treatment, and 3 participants in each treatment dropped out owing to serious adverse events., Conclusions and Relevance: This randomized clinical trial found that although PE was statistically more effective than CPT, the difference was not clinically significant, and improvements in PTSD were meaningful in both treatment groups. These findings highlight the importance of shared decision-making to help patients understand the evidence and select their preferred treatment., Trial Registration: ClinicalTrials.gov Identifier: NCT01928732.

Importance: Suicide and suicide attempts are persistent and increasing public health problems. Observational studies and meta-analyses of randomized clinical trials have suggested that lithium may prevent suicide in patients with bipolar disorder or depression., Objective: To assess whether lithium augmentation of usual care reduces the rate of repeated episodes of suicide-related events (repeated suicide attempts, interrupted attempts, hospitalizations to prevent suicide, and deaths from suicide) in participants with bipolar disorder or depression who have survived a recent event., Design, Setting, and Participants: This double-blind, placebo-controlled randomized clinical trial assessed lithium vs placebo augmentation of usual care in veterans with bipolar disorder or depression who had survived a recent suicide-related event. Veterans at 29 VA medical centers who had an episode of suicidal behavior or an inpatient admission to prevent suicide within 6 months were screened between July 1, 2015, and March 31, 2019., Interventions: Participants were randomized to receive extended-release lithium carbonate beginning at 600 mg/d or placebo., Main Outcomes and Measures: Time to the first repeated suicide-related event, including suicide attempts, interrupted attempts, hospitalizations specifically to prevent suicide, and deaths from suicide., Results: The trial was stopped for futility after 519 veterans (mean [SD] age, 42.8 [12.4] years; 437 [84.2%] male) were randomized: 255 to lithium and 264 to placebo. Mean lithium concentrations at 3 months were 0.54 mEq/L for patients with bipolar disorder and 0.46 mEq/L for patients with major depressive disorder. No overall difference in repeated suicide-related events between treatments was found (hazard ratio, 1.10; 95% CI, 0.77-1.55). No unanticipated safety concerns were observed. A total of 127 participants (24.5%) had suicide-related outcomes: 65 in the lithium group and 62 in the placebo group. One death occurred in the lithium group and 3 in the placebo group., Conclusions and Relevance: In this randomized clinical trial, the addition of lithium to usual Veterans Affairs mental health care did not reduce the incidence of suicide-related events in veterans with major depression or bipolar disorders who experienced a recent suicide event. Therefore, simply adding lithium to existing medication regimens is unlikely to be effective for preventing a broad range of suicide-related events in patients who are actively being treated for mood disorders and substantial comorbidities., Trial Registration: ClinicalTrials.gov Identifier: NCT01928446.