Towards a blood-based diagnostic panel for bipolar disorder.

BACKGROUND: Bipolar disorder (BD) is a costly, devastating and life shortening mental disorder that is often misdiagnosed, especially on initial presentation. Misdiagnosis frequently results in ineffective treatment. We investigated the utility of a biomarker panel as a diagnostic test for BD. METHODS AND FINDINGS: We performed a meta-analysis of eight case-control studies to define a diagnostic biomarker panel for BD. After validating the panel on established BD patients, we applied it to undiagnosed BD patients. We analysed 249 BD, 122 pre-diagnostic BD, 75 pre-diagnostic schizophrenia and 90 first onset major depression disorder (MDD) patients and 371 controls. The biomarker panel was identified using ten-fold cross-validation with lasso regression applied to the 87 analytes available across the meta-analysis studies. We identified 20 protein analytes with excellent predictive performance [area under the curve (AUC)⩾0.90]. Importantly, the panel had a good predictive performance (AUC 0.84) to differentiate 12 misdiagnosed BD patients from 90 first onset MDD patients, and a fair to good predictive performance (AUC 0.79) to differentiate between 110 pre-diagnostic BD patients and 184 controls. We also demonstrated the disease specificity of the panel. CONCLUSIONS: An early and accurate diagnosis has the potential to delay or even prevent the onset of BD. This study demonstrates the potential utility of a biomarker panel as a diagnostic test for BD.

Predictors of the Onset of Schizophrenia in US Military Personnel.

Alterations in immune response may be an important component in the etiopathogenesis of schizophrenia and bipolar disorder. We examined the associations of pentraxin-3 (PTX3) with the onset of schizophrenia or bipolar disorder. We tested preonset serum specimens from 160 US military service members who were later diagnosed with schizophrenia or bipolar disorder and 160 matched controls without psychiatric disorders. Lower serum levels of PTX3 were predictive of schizophrenia but not of bipolar disorder. Subjects with below-median PTX3 levels had a 3.0 odds ratio (confidence interval, 1.6-5.7) for schizophrenia onset in the multivariable logistic regression model controlling for demographic and military variables. The test for trends was significant (p = 0.002), with the likelihood increasing as the levels of PTX3 decreased. Crude and adjusted categorized levels were not predictive of bipolar disorder. A lower level of inflammatory response indicated by PTX3 might be implicated in developing schizophrenia.

Trends in the epidemiology of disability related to traumatic brain injury in the US Army and Marine Corps: 2005 to 2010.

BACKGROUND: Traumatic brain injury (TBI) has been recognized as a major public health issue for several decades. Despite technological advancements in protective equipment and medical care available during recent military conflicts, TBI is the most common neurological condition among Soldiers and Marines evaluated for discharge from service. This study describes the demographic, service-related, and disability characteristics of Soldiers and Marines referred for combat-related TBI disability evaluation. METHODS: Cross-sectional analysis of Soldiers and Marines evaluated for combat-related disability between October 1, 2004 and September 30, 2010 was performed. Traumatic brain injury cases were identified using the Veterans Affairs Schedule for Rating Disabilities code for TBI and compared with other combat-related disabilities. RESULTS: Combat-related TBI disability rates have significantly increased in both the Army and the Marine Corps since 2005. Significantly more unfitting conditions are present on average in combat-related TBI cases than in other combat-related disability cases. Combat-related TBI disability cases are more likely to be medically retired than other types of combat-related disability. CONCLUSIONS: Because veterans with combat-related TBI disabilities are likely to require chronic care for TBI-associated medical conditions, disability evaluation policy and programs must ensure that combat-related TBI disabilities are accurately identified and compensated, and the potential long-term care needs are addressed.

Smoking and multiple sclerosis risk in black people: A nested case-control study.

BACKGROUND: Smoking is a well-established risk factor for MS; however, it is not known whether its effect on disease risk varies by race/ethnicity. METHODS: We conducted a nested case-control study among US military personnel who have serum samples stored at the Department of Defense Serum Repository. We measured serum cotinine levels, a marker of tobacco smoke exposure, in 157 Black and 23 White individuals who developed MS during follow-up. Controls were randomly selected and matched to each case by age, sex, race/ethnicity, dates of sample collection, and branch of military service. RESULTS: Smoking was not associated with an increased risk of MS in Black people (RR: 1.08, 95 % CI: 0.63-1.85). The results remained similar in analyses restricted to smoking status at baseline, to samples collected 5 years before symptom onset, and using different cut-off levels in cotinine to define smoking status. Smoking was not statistically significantly associated with MS risk in White people, but the point estimate was similar to what has previously been reported in other studies (RR: 1.85, 95 % CI: 0.56-6.16). CONCLUSIONS: Smoking was not associated with MS risk in Black people. Given the consistent association between smoking and MS risk in predominantly White populations, this may suggest that the association between smoking and MS varies by race/ethnicity.

Serologic Response to the Epstein-Barr Virus Peptidome and the Risk for Multiple Sclerosis.

Importance: It remains unclear why only a small proportion of individuals infected with the Epstein-Barr virus (EBV) develop multiple sclerosis (MS) and what the underlying mechanisms are. Objective: To assess the serologic response to all EBV peptides before the first symptoms of MS occur, determine whether the disease is associated with a distinct immune response to EBV, and evaluate whether specific EBV epitopes drive this response. Design, Setting, and Participants: In this prospective, nested case-control study, individuals were selected among US military personnel with serum samples stored in the US Department of Defense Serum Repository. Individuals with MS had serum collected at a median 1 year before onset (reported to the military in 2000-2011) and were matched to controls for age, sex, race and ethnicity, blood collection, and military branch. No individuals were excluded. The data were analyzed between September 1, 2022, and August 31, 2023. Exposure: Antibodies (enrichment z scores) to the human virome measured using VirScan (phage-displayed immunoprecipitation and sequencing). Main Outcome and Measure: Rate ratios (RRs) for MS for antibodies to 2263 EBV peptides (the EBV peptidome) were estimated using conditional logistic regression, adjusting for total anti-EBV nuclear antigen 1 (EBNA-1) antibodies, which have consistently been associated with a higher MS risk. The role of antibodies against other viral peptides was also explored. Results: A total of 30 individuals with MS were matched with 30 controls. Mean (SD) age at sample collection was 27.8 (6.5) years; 46 of 60 participants (76.7%) were male. The antibody response to the EBV peptidome was stronger in individuals with MS, but without a discernible pattern. The antibody responses to 66 EBV peptides, the majority mapping to EBNA antigens, were significantly higher in preonset sera from individuals with MS (RR of highest vs lowest tertile of antibody enrichment, 33.4; 95% CI, 2.5-448.4; P for trend = .008). Higher total anti-EBNA-1 antibodies were also associated with an elevated MS risk (top vs bottom tertile: RR, 27.6; 95% CI, 2.3-327.6; P for trend = .008). After adjusting for total anti-EBNA-1 antibodies, risk estimates from most EBV peptides analyses were attenuated, with 4 remaining significantly associated with MS, the strongest within EBNA-6/EBNA-3C, while the association between total anti-EBNA-1 antibodies and MS persisted. Conclusion and Relevance: These findings suggest that antibody response to EBNA-1 may be the strongest serologic risk factor for MS. No single EBV peptide stood out as being selectively targeted in individuals with MS but not controls. Larger investigations are needed to explore possible heterogeneity of anti-EBV humoral immunity in MS.

Pre-enlistment hearing loss and hearing loss disability among US soldiers and marines.

Hearing loss is a common condition among US adults, with some evidence of increasing prevalence in young adults. Noise-induced hearing loss attributable to employment is a significant source of preventable morbidity world-wide. The US military population is largely comprised of young adult males serving in a wide variety of occupations, many in high noise-level conditions, at least episodically. To identify accession and service-related risk factors for hearing-related disability, matched case-control study of US military personnel was conducted. Individuals evaluated for hearing loss disability in the US Army and Marine Corps were frequency matched to controls without history of disability evaluation on service and enlistment year. Conditional logistic regression was used to examine the association between accession and service-related factors and hearing-related disability evaluations between October 2002 and September 2010. Individuals with medically disqualifying audiograms or hearing loss diagnoses at application for military service were 8 and 4 times more likely, respectively, to have a disability evaluation related to hearing loss, after controlling for relevant accession, demographic, and service-related factors. Conservative hearing loss thresholds on pre-enlistment audiograms, stricter hearing loss medical waiver policies or qualified baseline audiograms pre-enlistment are needed in the U.S military. Industrial corporations or labor unions may also benefit from identifying individuals with moderate hearing loss at the time of employment to ensure use of personal protective equipment and engineer controls of noise.

National estimates of seroincidence and seroprevalence for herpes simplex virus type 1 and type 2 among US military adults aged 18 to 29 years.

BACKGROUND: While population-based seroprevalence studies of herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) are widespread, seroincidence studies are largely limited to select or high-risk populations. The US military offers a potential population to derive national seroincidence rate estimates for young adults (ages 18-29). METHODS: We used banked, longitudinal serum specimens collected in a cohort of 1094 military personnel aged 18 to 30 years who served between 1989 and 2005 to estimate national HSV-1 and HSV-2 seroincidence and seroprevalence for the young, adult military population, weighted according to the US Census. Serum was tested with indirect ELISA (enzyme-linked immunosorbent assay). RESULTS: Estimated national seroincidence rates for the US young, adult military population were 9.1 per 100 person-years (95% confidence interval: 4.6-13.5) for HSV-1 and 6.2 (95% confidence interval: 3.1-9.3) for HSV-2. Female sex and black race were associated with significantly higher HSV-2 seroconversion rates. Our estimated HSV1/2 seroprevalences were comparable to US national data provided by National Health and Nutrition Examination Surveys' serosurveys except for non-Hispanic blacks and Hispanics. CONCLUSION: Although these US 2000 Census-weighted estimates of HSV-1 and HSV-2 seroincidence apply only to young, military adults, they nonetheless supply, to our knowledge, the only national figures that might be used to predict US national HSV1/2 seroincidence in young adults. Thus, we believe that our findings in this military population can be used to inform the planning of HSV-1 and 2 prevention measures in the general, young-adult US population.

Temporal trends in the epidemiology of disabilities related to posttraumatic stress disorder in the U.S. Army and Marine Corps from 2005-2010.

Since the start of Operation Iraqi Freedom and Operation Enduring Freedom, over 2 million U.S. military members were deployed to Iraq and Afghanistan. The estimated prevalence of posttraumatic stress disorder (PTSD) among soldiers and Marines returning from combat zones varies from 5%-20%; little is known about those individuals whose PTSD renders them unfit for duty. This report describes the rates and correlates of PTSD in soldiers and Marines evaluated for disability. Data for service members who underwent disability evaluation between fiscal years 2005-2010 were analyzed for trends in disability rates, ratings, retirement, and comorbid disability. PTSD rates varied by age, sex, race, rank, branch of service, and component. Most cases were deployed and were considered combat-related. Over the study period, the rate and severity of disability from PTSD increased substantially. Significant increases in disability from PTSD incidence, rating, and retirement were observed in both services. Other medical conditions, largely musculoskeletal and neurological, were present in the majority of cases indicating many cases also experienced disabling physical injuries. Further research is needed to target interventions accurately for redeploying service members to minimize comorbidity associated with disability from PTSD and facilitate continuation in military service or successful transition to civilian life.

Risk factors for medical disability in U.S. enlisted Marines: fiscal years 2001 to 2009.

OBJECTIVE: To assess factors associated with medical disability in the U.S. Marine Corps. METHODS: Case-control study enrolling 11,554 medical disability cases of U.S. enlisted Marines referred to the Physical Evaluation Board fiscal year 2001 to 2009 and 42,216 controls frequency matched to cases in a 4:1 ratio on year of accession into the service were analyzed utilizing bivariate and multivariate logistic regression analysis. RESULTS: Increased age and body mass index at accession were associated with higher odds of medical disability. Females (odds ratio adjusted [OR(adj)] = 1.3, 95% confidence interval [CI] = 1.2-1.3) have higher odds of disability than males. "Healthy Warrior Effect" was observed in that those who deployed (OR(adj) = 0.48, 95% CI = 0.46-0.50) had decreased odds of medical disability than those who did not deploy. Medical waivers at accession (OR(adj) = 1.12, 95% CI = 1.01-1.23) increased the odds of medical disability. CONCLUSIONS: Continued surveillance of the disability evaluation system is needed to help develop preventive measures and to help policy makers establish evidence-based policies on accession, deployment, and retention standards over the lifecycle of service members.

Physical training injuries and interventions for military recruits.

Low physical fitness levels are associated with increased musculoskeletal injury risk and attrition among military recruits. The authors review physical fitness trends, injury risk factors, and Department of the Army initiatives to address recruit fitness, injuries, and attrition. Initiatives include the Fitness Assessment Program, which reduced injury risk and attrition among low-fit trainees, and the Assessment of Recruit Motivation and Strength, which enabled the Army to enlist individuals exceeding body composition accession standards without increasing attrition. Physical Readiness Training (PRT) is the Army's primary initiative to address training-related injuries and attrition. PRT's inherent injury control and exercise progression components are designed to address low fitness levels across entry-level training. PRT has been shown to decrease injury rates, but low-fit recruits remain at increased risk regardless of program design. The authors recommend resuming pre-enlistment fitness screening and fitness programming before low-fit recruits begin entry-level training. The decision whether to screen for fitness before beginning entry-level training could be based upon the existing recruiting environment in terms of applicant supply and the demand for recruits. However, the Army should anticipate increased injury and attrition rates when discontinuing screening and/or fitness programming for low-fit recruits.

A noncognitive temperament test to predict risk of mental disorders and attrition in U.S. Army recruits.

UNLABELLED: U.S. military accession mental health screening includes cognitive testing and questions regarding the applicants' past mental health history. This process relies on applicants' knowledge of and willingness to disclose symptoms and conditions. Applicants have a strong incentive to appear qualified, which has resulted in a long history of frequent mental health conditions presenting during recruit training. OBJECTIVE: To assess the predictive value of a pre-enlistment noncognitive temperament test score for risk of mental disorders and attrition in the first year of service. METHODS: A retrospective cohort study was conducted on non-high school diploma U.S. Army active duty recruits who took the Assessment of Individual Motivation (AIM). Multivariate logistic regression models were used to determine associations between AIM score quintiles, mental disorders, and attrition. RESULTS: AIM scorers in the lowest quintile were at increased risk for a mental disorder (OR, 1.44; 95% CI, 1.35-1.53) and of discharge (OR, 1.65; 95% CI, 1.44-1.68) compared to AIM scorers in the highest quintile, with significant linear trends for decreased risk with increasing AIM score. CONCLUSIONS: AIM offers the potential to improve screening of military applicants and reduce mental disorders and attrition in new recruits beyond the current process.

Temporary disability retirement cases: variations in time to final disposition and disability rating by service and medical condition.

OBJECTIVE: Service members undergoing disability evaluation are placed on the temporary disability retirement list (TDRL) when their disabling medical condition(s) may change in severity over time. Information is sparse on the epidemiology of the TDRL population and factors influencing time spent on the TDRL or changes in compensation ratings before final disability outcome. METHODS: A cross-sectional study was conducted on U.S. Army, Navy, and Marine Corps personnel placed on the TDRL between fiscal years 2005 to 2009. RESULTS: Approximately 85% of cases were finalized at first re-evaluation and more than 75% were permanently retired. Overall, about 50% of cases retained the same disability rating throughout the process. Cases with medical conditions within two or more body systems were more likely to be permanently retired and receive a change in disability rating than those with medical condition(s) within a single body system. CONCLUSIONS: Most cases retained the same disability rating and were permanently retired by the first re-evaluation. Important areas of future research include cost-benefit analyses to determine if length of time currently allowable on the TDRL can be shortened or if repeated evaluations are necessary and exploration of specific medical conditions likely to change in severity over time.

Recommendations for Population-Based Applications of the Adverse Childhood Experiences Study: Position Statement by the American College of Preventive Medicine.

Introduction: Childhood adversity profoundly influences health, well-being, and longevity. Prevention and interventions to mitigate its harmful effects are essential. The American College of Preventive Medicine reviewed the research literature and other professional and governmental statements about adverse childhood experiences to support the development of evidence-based and population-focused recommendations about prevention, screening, and mitigation interventions for childhood adversity. Methods: We performed an umbrella review to find, assess and synthesize the evidence from systematic reviews focused on 3 key questions: the prevention or mitigation of the effects of adverse childhood experiences; the association of screening for adverse childhood experiences with various benefits, including health outcomes; and the effectiveness and harms of interventions in individuals with elevated adverse childhood experience scores. Adverse childhood experience‒related recommendations from 6 professional and governmental organizations were also reviewed. On the basis of these reviews, the American College of Preventive Medicine developed a position statement through consensus. Results: A total of 8 systematic reviews, including 260 studies in total, were identified and combined with adverse childhood experiences‒related recommendations from 6 professional organizations to support the American College of Preventive Medicine recommendations. The American College of Preventive Medicine offers 7 adverse childhood experiences‒related recommendations focused on screening, education/training, policy/practice, and research: 2 are evidence-based, and 5 are based on expert opinion. Notably, regarding secondary prevention of adverse childhood experiences, the American College of Preventive Medicine endorses population-level surveillance and research around childhood adversity but not adverse childhood experience screening in individual clinical encounters. Conclusions: Despite limitations in the heterogeneity and quality of the published systematic reviews, the extant literature supports the American College of Preventive Medicine recommendations. Interventions to enhance protective factors and prevent and mitigate the consequences of adverse childhood experiences and other childhood adversity are promising and require further implementation and research.

Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system of unknown etiology. We tested the hypothesis that MS is caused by Epstein-Barr virus (EBV) in a cohort comprising more than 10 million young adults on active duty in the US military, 955 of whom were diagnosed with MS during their period of service. Risk of MS increased 32-fold after infection with EBV but was not increased after infection with other viruses, including the similarly transmitted cytomegalovirus. Serum levels of neurofilament light chain, a biomarker of neuroaxonal degeneration, increased only after EBV seroconversion. These findings cannot be explained by any known risk factor for MS and suggest EBV as the leading cause of MS.

Quality of life among testicular cancer survivors: a case-control study in the United States.

INTRODUCTION: Evidence from previous studies has suggested there may be physical and mental changes in health among testicular cancer survivors. No studies have been conducted in the United States, however. METHODS: Study participants were initially enrolled in the US Servicemen's Testicular Tumor Environmental and Endocrine Determinants (STEED) study between 2002 and 2005. A total of 246 TGCT (testicular germ cell tumor) cases and 236 non-testicular cancer controls participated in the current study, and completed a self-administered questionnaire. Mean time since diagnosis for cases was 14 years, and no less than five for all cases. Component scores determined from responses to questions about physical and mental health on SF36 were tabulated to yield two summary measures, physical component scores (PCS), and mental component scores (MCS). Component and summary scores were normalized to a score of 50 with a standard deviation of 10 by a linear T-score transformation. RESULTS: Overall, cases may not suffer greatly in different quality of life than controls. When all cases and controls are compared, TGCT cases had lower PCS (mean: 51.9 95% CI: 50.6-53.2, P value: 0.037) than controls (mean: 53.6 95% CI: 52.7-54.6). MCS were not significantly different (P value: 0.091). In multivariate analyses, several physical health components were worse for TGCT cases such as role-physical (OR 1.19, 95% CI: 1.01-1.39) and general health (OR 1.26, 95% CI: 1.07-1.49) compared to controls. However, TGCT cases treated with chemotherapy had lower PCS (cases: 50.2, 95% CI: 47.6-52.8; controls: 53.6, 95% CI: 52.7-54.6, P value: 0.0032) and MCS (cases: 49.3, 95% CI: 46.5-52.1; controls: 52.0, 95% CI: 50.9-53.2, P value: 0.039). TGCT cases who received treatments other than chemotherapy did not differ from controls in either PCS or MCS. DISCUSSION: Physical and general health limitations may affect testicular cancer survivors. Men treated with chemotherapy, however, may be most likely to suffer adverse health outcomes due to a combination of body-wide effects on physical and mental factors which affect various aspects of physical health, mental health, and overall quality of life. And in particular, physical functioning, role-physical, and general health are strongly affected.

Descriptive epidemiology and natural history of idiopathic venous thromboembolism in U.S. active duty enlisted personnel, 1998-2007.

The estimated incidence of idiopathic venous thromboembolism (IVTE) cases in the United States ranges from 24,000 to 282,000/year. This analysis explores the incidence and prevalence of IVTE in the military and if cases experience increased attrition. The Defense Medical Surveillance System was searched for incident IVTE cases from 1998 through 2007. Enlisted cases were each matched to 3 controls. Kaplan-Meier survival analysis and Cox proportional hazard modeling were performed. We matched 463 cases to 1,389 controls. Outpatient IVTE rates have increased markedly from 1998 through 2007. Cases of all-cause attrition risk (0.56 [95% CI = 0.44, 0.72]) and rates were significantly less than controls (p < 0.0001), and cases of medical attrition risk (1.64 [95% CI = 1.13, 2.37]) and rates were significantly higher (p < 0.01). Increasing rates with lower attrition suggests increasing case prevalence. Health care providers must maintain a high index of suspicion for venous thromboembolism to minimize adverse sequelae affecting health, unit readiness, and medical costs.

Self-reported physical activity and preaccession fitness testing in U.S. Army applicants.

The Assessment of Recruit Motivation and Strength (ARMS) study evaluated a physical fitness screening test for Army applicants before basic training. This report examines applicants' self-reported physical activity as a predictor of objective fitness measured by ARMS. In 2006, the ARMS study administered a fitness test and physical activity survey to Army applicants during their medical evaluation, using multiple logistic regression for comparison. Among both men and women, "qualified" and "exceeds-body-fat" subjects who met American College of Sports Medicine adult physical activity guidelines were more likely to pass the fitness test. Overall, subjects who met physical activity recommendations, watched less television, and played on sports teams had a higher odds of passing the ARMS test after adjustment for age, race, and smoking status. This study demonstrates that self-reported physical activity was associated with physical fitness and may be used to identify those at risk of failing a preaccession fitness test.

U.S. military recruits waived for pathological curvature of the spine: increased risk of discharge from service.

Selective accession waivers for medically disqualifying conditions like spinal curvature are one way the military meets its manpower needs. We evaluated retention patterns during the first 2 years of service of a cohort of military recruits with waivers for pathological curvature of the spine (spinal curvature). Recruits waived for spinal curvature (n = 417), who accessed from 1998 to 2005 were identified and matched with 3 qualified recruits. Kaplan-Meier survival analysis and Cox proportional hazards model were used to compare survival patterns and adjusted attrition hazard estimates. Waived recruits experienced significantly increased risk of "all cause" discharge (relative risk = 1.3; 95% confidence interval: 1.1, 1.5) and "existing prior to service" discharge (relative risk = 2.4; confidence interval: 1.6, 3.5). Despite the increased risk of discharge, current waiver criteria allowed a majority with spinal curvature to complete at least 2 years of service. Policy makers must consider risks and benefits before modifying the current accession standard for spinal curvature.

Risk factors for disability retirement among healthy adults joining the U.S. Army.

OBJECTIVE: From 2001 to 2006, the Army deployed over 717,000 personnel to Iraq and Afghanistan, with over 15,000 troops wounded. Little is known about the impact of military and demographic factors, particularly deployment, occupation, and pre-existing medical status, on disability retirement. METHODS: A nested case-control study of first time, active duty personnel entering from 1997 to 2004. Cases, individuals granted a medical disability retirement from 1997 to 2006, were identified by the Army Physical Disability Agency. Five controls were matched by year of entrance to each case. RESULTS: Several factors were associated with increased risk of disability retirement, including sex, age, Hispanic ethnicity, body mass index, and military occupation; deployment was associated with a lower risk. CONCLUSIONS: The reasons for increased risk among some groups are unknown. The decreased risk associated with deployment probably reflects a "healthy warrior effect," whereas the increased risk for combat arms may reflect combat exposures among the deployed and more rigorous training among the nondeployed.