All-cause and cause-specific mortality rates after severe extremity injuries among previously deployed active duty service members.

BACKGROUND: Previous research has shown that active duty military personnel who sustain extremity injuries while in service are at elevated risk for serious physical and psychological health issues that could affect their long-term functioning and quality of life yet longer-term mortality has not been studied in this population. OBJECTIVE: To determine whether rates of all-cause and cause-specific mortality are elevated for active duty U.S. service members who sustained traumatic limb injuries in service, compared to the broader population of deploying service members. To assess differences in mortality rates between service members with traumatic limb injuries that did versus did not result in amputation. DESIGN: Retrospective cohort study; archival Department of Defense deployment, personnel, medical, and death records were combined and analyzed. Standardized mortality ratios (SMR) adjusted for age, sex, and ethnoracial group, along with associated 95% confidence intervals (CIs), were calculated to directly compare all-cause and cause-specific mortality rates in each of the two injury groups to rates in the total study population. SETTING: Not applicable. PARTICIPANTS: Service members who deployed in support of the global war on terror between 2001 and 2016 were eligible for inclusion; the final sample included 1,875,206 individuals surveilled through 2019. INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: All-cause and cause-specific mortality rates. RESULTS: Overall, the number of deaths was over three times higher than expected among service members with amputations (SMR = 3.01; CI: 2.36-3.65), and nearly two times higher among those with serious limb injuries not resulting in amputation (SMR = 1.72; CI: 1.54-1.90) when compared to the larger study population. Rates for both internal and external causes of death were significantly elevated among those with limb injuries. CONCLUSIONS: Long-term mortality rates are elevated among service members with traumatic limb injuries, though mortality patterns may differ based on whether the injury results in amputation. Although further research into causal mechanisms is needed, these results may inform the development of interventions to improve long-term health outcomes among injured military personnel.

Immunomodulatory effects of colchicine on peripheral blood mononuclear cell subpopulations in human obesity: Data from a randomized controlled trial.

OBJECTIVE: Colchicine is known to reduce inflammation and improve endothelial cell function and atherosclerosis in obesity, but there is little knowledge of the specific circulating leukocyte populations that are modulated by colchicine. METHODS: A secondary analysis of a double-blind randomized controlled trial of colchicine 0.6 mg or placebo twice daily for 3 months on circulating leukocyte populations and regulation of the immune secretome in 35 adults with obesity was performed. RESULTS: Colchicine altered multiple innate immune cell populations, including dendritic cells and lymphoid progenitor cells, monocytes, and natural killer cells when compared with placebo. Among all subjects and within the colchicine group, changes in natural killer cells were significantly positively associated with reductions in biomarkers of inflammation, including cyclooxygenase 2, pulmonary surfactant-associated protein D, myeloperoxidase, proteinase 3, interleukin-16, and resistin. Changes in dendritic cells were positively correlated with changes in serum heart-type fatty acid-binding protein concentrations. Additionally, colchicine treatment reduced cluster of differentiation (CD) CD4+ T effector cells and CD8+ T cytotoxic cells. Conversely, colchicine increased CD4+ and CD8+ T central memory cells and activated CD38High CD8+ T cells. Changes in CD4+ T effector cells were associated with changes in serum heart-type fatty acid-binding protein. CONCLUSIONS: In adults with obesity, colchicine significantly affects circulating leukocyte populations involved in both innate and adaptive immune systems along with the associated inflammatory secretome.

Gender differences in disorders comorbid with posttraumatic stress disorder among U.S. Sailors and Marines.

Psychological comorbidity, the co-occurrence of mental health disorders, is more often the rule than the exception among individuals with posttraumatic stress disorder (PTSD). Research shows that prevalence estimates for specific psychological disorders differ by gender; however, little is known about whether these patterns persist in the presence of a comorbid PTSD diagnosis. This study examined gender differences in prevalence estimates for conditions comorbid with PTSD using medical records for 523,626 active duty U.S. Sailors and Marines who entered the military over an 8-year period. Using chi-square tests of independence, we detected statistically significant gender differences for specific comorbid conditions in the subsample of 9,447 service members with a PTSD diagnosis. Women were more likely than men to have PTSD with comorbid adjustment, OR = 1.35; depressive, OR = 1.71; and generalized anxiety or other anxiety disorders, OR = 1.16, with the largest effects for eating, OR = 12.60, and personality disorders, OR = 2.97. In contrast, women were less likely than men to have a diagnosis of PTSD with comorbid alcohol use, OR = 0.69, and drug use disorders, OR = 0.72, with the largest effects for insomnia, OR = 0.42, and traumatic brain injury, OR = 0.17. No significant gender differences emerged for comorbid bipolar, obsessive-compulsive, panic/phobic, psychotic, or somatoform/dissociative disorders, ps = .029-.314. The results show gender differences in conditions comorbid with PTSD generally align with internalizing and externalizing dimensions. Differences in comorbidities with PTSD between women and men could have implications for treatment development and delivery.

Effects of colchicine on lipolysis and adipose tissue inflammation in adults with obesity and metabolic syndrome.

OBJECTIVE: The aim of this study was to examine whether colchicine's anti-inflammatory effects would improve measures of lipolysis and distribution of leukocyte populations in subcutaneous adipose tissue (SAT). METHODS: A secondary analysis was conducted for a double-blind, randomized, placebo-controlled pilot study in which 40 adults with obesity and metabolic syndrome (MetS) were randomized to colchicine 0.6 mg or placebo twice daily for 3 months. Non-insulin-suppressible (l0 ), insulin-suppressible (l2 ), and maximal (l0 +l2 ) lipolysis rates were calculated by minimal model analysis. Body composition was determined by dual-energy x-ray absorptiometry. SAT leukocyte populations were characterized by flow cytometry analysis from biopsied samples obtained before and after the intervention. RESULTS: Colchicine treatment significantly decreased l2 and l0 +l2 versus placebo (p < 0.05). These changes were associated with a significant reduction in markers of systemic inflammation, including high-sensitivity C-reactive protein, resistin, and circulating monocytes and neutrophils (p < 0.01). Colchicine did not significantly alter SAT leukocyte population distributions (p > 0.05). CONCLUSIONS: In adults with obesity and MetS, colchicine appears to improve insulin regulation of lipolysis and reduce markers of systemic inflammation independent of an effect on local leukocyte distributions in SAT. Further studies are needed to better understand the mechanisms by which colchicine affects adipose tissue metabolic pathways in adults with obesity and MetS.

Predictors of Symptom Increase in Subsyndromal PTSD Among Previously Deployed Military Personnel.

INTRODUCTION: Subsyndromal PTSD (sub-PTSD) is associated with functional impairment and increased risk for full PTSD. This study examined factors associated with progression from sub-PTSD to full PTSD symptomatology among previously deployed military veterans. MATERIALS AND METHODS: Data were drawn from a longitudinal survey of Navy and Marine Corps personnel leaving military service between 2007 and 2010 administered immediately before separation (baseline) and ~1 year later (follow-up). Survey measures assessed PTSD symptoms at both times; the baseline survey also assessed potential predictors of symptom change over time. Logistic regression models were used to identify predictors of progression from sub-PTSD to full PTSD status. RESULTS: Compared to those with no or few PTSD symptoms at baseline, individuals with sub-PTSD were almost three times more likely to exhibit full PTSD symptomatology at follow-up. Risk factors for symptom increase among those with sub-PTSD included moderate or high levels of combat exposure and utilization of fewer positive coping behaviors. Use of prescribed psychotropic medication was protective against symptom increase. CONCLUSION: This study identified several predictors of symptom increase in military veterans with sub-PTSD. Interventions targeting modifiable risk factors for symptom escalation, including behavioral and pharmacological treatments, may reduce rates of new-onset PTSD in this population.

Associations of GlycA and high-sensitivity C-reactive protein with measures of lipolysis in adults with obesity.

BACKGROUND: Obesity-associated inflammation promotes metabolic dysfunction. However, it is unclear how different inflammatory biomarkers predict dysregulation in specific tissues/organs, particularly adipose tissue. OBJECTIVE: The aim of our study was to examine whether GlycA, a nuclear magnetic resonance-measured biomarker of inflammation, is a better predictor of insulin-suppressible lipolysis and other measures of metabolic dysfunction compared with high-sensitivity C-reactive protein (hsCRP) in human obesity. METHODS: This was a cross-sectional study of 58 nondiabetic adults with obesity (body mass index: 39.8 ± 7.0 kg/m2, age 46.5 ± 12.2 years, 67.2% female) who underwent a frequently sampled intravenous glucose tolerance test in the fasted state. Noninsulin-suppressible (l0), insulin-suppressible (l2), and maximal (l0+l2) lipolysis rates, as well as insulin sensitivity and acute insulin response to glucose, were calculated by minimal model analysis. Nuclear magnetic resonance was used to measure GlycA. Body composition was determined by dual-energy X-ray absorptiometry. RESULTS: GlycA was strongly correlated with hsCRP (r = +0.46; P < .001). GlycA and hsCRP were positively associated with l2, l0+l2, and fat mass (Ps < .01). In linear regression models accounting for age, race, sex, and fat mass, GlycA remained significantly associated with l2 and l0+l2 (Ps < .05), whereas hsCRP did not (Ps ≥ .20). Neither GlycA nor hsCRP was associated with l0, insulin sensitivity, or acute insulin response to glucose. CONCLUSIONS: GlycA was associated with elevated lipolysis, independent of adiposity, in adults with obesity. Our findings suggest that GlycA and hsCRP have distinct inflammation-mediated metabolic effects, with GlycA having a greater association with adipose tissue dysfunction. Further studies are warranted to investigate the mechanisms underlying these associations.

Colchicine's effects on metabolic and inflammatory molecules in adults with obesity and metabolic syndrome: results from a pilot randomized controlled trial.

OBJECTIVE: Recent clinical trials have demonstrated that colchicine may have metabolic and cardiovascular and benefits in at-risk patients; however, the mechanisms through which colchicine may improve outcomes are still unclear. We sought to examine colchicine's effects on circulating inflammatory and metabolic molecules in adults with obesity and metabolic syndrome (MetS). METHODS: Blood samples were collected pre- and post-intervention during a double-blind randomized controlled trial in which 40 adults with obesity and MetS were randomized to colchicine 0.6 mg or placebo twice-daily for 3 months. Serum samples were analyzed for 1305 circulating factors using the SomaScan Platform. The Benjamini-Hochberg procedure was used to adjust the false discovery rate (FDR) for multiple testing. RESULTS: At baseline, age (48.0 ± 13.8 vs. 44.7 ± 10.3 years) and BMI (39.8 ± 6.4 vs. 41.8 ± 8.2 kg/m2) were not different between groups. After controlling for the FDR, 34 molecules were significantly changed by colchicine. Colchicine decreased concentrations of multiple inflammatory molecules, including C-reactive protein, interleukin 6, and resistin, in addition to vascular-related proteins (e.g., oxidized low-density lipoprotein receptor, phosphodiesterase 5A). Conversely, relative to placebo, colchicine significantly increased concentrations of eight molecules including secreted factors associated with metabolism and anti-thrombosis. CONCLUSIONS: In adults with obesity, colchicine significantly affected concentrations of proteins involved in the innate immune system, endothelial function and atherosclerosis, uncovering new mechanisms behind its cardiometabolic effects. Further research is warranted to investigate whether colchicine's IL-6 suppressive effects may be beneficial in COVID-19.

Bacitracin attenuates haemolysis-induced insulin degradation during insulin sensitivity testing: Repurposing an old drug for use in metabolic research.

Haemolysis of serially collected insulin serum samples frequently causes falsely-low measured concentrations because of the release of intracellular insulin degrading enzyme (IDE). We investigated if bacitracin, an in vitro IDE inhibitor, could prevent haemolysis-induced insulin degradation during insulin sensitivity testing. Blood samples were collected from adults undergoing serial sampling for insulin sensitivity. A dose-finding study measured insulin from experimentally haemolysed samples containing five bacitracin concentrations (0-2.5 g/L) and from non-experimentally haemolysed samples. To confirm the utility of bacitracin in the clinical setting, we compared insulin in samples collected with and without 1 g/L bacitracin from a frequently sampled intravenous glucose tolerance test (FSIVGTT), where haemolysis often occurs accidentally. In the dose-finding study, bacitracin 0.25, 1 and 2.5 g/L all maximally prevented insulin degradation in experimentally haemolysed samples. Among FSIVGTT unintentionally haemolysed samples, insulin concentrations from bacitracin-containing samples were significantly higher than from those without bacitracin (P < .01), and not different from non-haemolysed samples obtained simultaneously from a second intravenous catheter (P = .07). Bacitracin did not significantly alter insulin concentrations in non-haemolysed samples. Bacitracin attenuates haemolysis-associated insulin degradation in clinical samples, enabling a more accurate assessment of insulin sensitivity and glucose homeostasis.

Colchicine's effects on lipoprotein particle concentrations in adults with metabolic syndrome: A secondary analysis of a randomized controlled trial.

BACKGROUND: Colchicine has received renewed interest for its potential beneficial effects in secondary prevention of cardiovascular disease. This was presumed to be primarily because of its anti-inflammatory effects; however, limited data exist regarding colchicine's impact on other cardiovascular risk factors. OBJECTIVE: The aim of this study was to examine if colchicine's anti-inflammatory actions would lead to reduced circulating concentrations of oxidized low-density lipoprotein (oxLDL) in metabolically unhealthy individuals. We also examined if colchicine would improve concentrations of other atherogenic lipoprotein subfractions. METHODS: This is a secondary analysis of a double-blind, randomized, placebo-controlled pilot study in which 40 adults with metabolic syndrome were randomized to colchicine 0.6 mg or placebo twice daily for 3 months. Blood samples were collected in the fasted state. OxLDL was measured using enzyme-linked immunosorbent assay. Nuclear magnetic resonance spectroscopy was used to measure other lipoprotein particle subfraction concentrations. RESULTS: Compared with placebo, colchicine reduced markers of inflammation, including C-reactive protein, erythrocyte sedimentation rate, and GlycA (P < .01). Concentrations of oxLDL (P = .019) and small LDL (P = .022) appeared significantly increased in the colchicine arm. Colchicine had no significant effect on other lipoprotein subfractions or lipoprotein particle sizes (all P > .05). CONCLUSION: Although colchicine may have benefit in secondary prevention of cardiovascular disease in at-risk individuals, we found no evidence that these effects are because of improvements in circulating atherogenic lipoprotein particle concentrations. Further studies are needed to confirm whether colchicine increases circulating oxLDL and small LDL levels in adults with metabolic syndrome. If true, additional research is warranted to elucidate the mechanisms underlying these associations.

Effects of colchicine in adults with metabolic syndrome: A pilot randomized controlled trial.

AIM: To evaluate the efficacy and safety of colchicine for improving metabolic and inflammatory outcomes in people with obesity and metabolic syndrome (MetS). MATERIALS AND METHODS: Adults with obesity and MetS, but who did not have diabetes, were randomized to colchicine 0.6 mg or placebo capsules twice daily for 3 months. The primary outcome was change in insulin sensitivity (SI ) as estimated by insulin-modified frequently sampled intravenous glucose tolerance tests. Secondary outcomes included changes in other metabolic variables and inflammatory markers. RESULTS: Of 40 participants randomized (21 colchicine, 19 placebo), 37 completed the trial. Compared with placebo, colchicine significantly reduced C-reactive protein (P <0.005), erythrocyte sedimentation rate (P <0.01), white blood cell count (P <0.005), and absolute neutrophil count (P <0.001). Change in SI was not significantly different between colchicine and placebo arms (difference: +0.21 × 10-5 ; CI -1.70 to +2.13 × 10-5 min-1 mU-1 mL; P = 0.82). However, changes in some secondary outcomes, including homeostatic model assessment of insulin resistance (P = 0.0499), fasting insulin (P = 0.07) and glucose effectiveness (P = 0.08), suggested metabolic improvements in the colchicine versus placebo group. Adverse events were generally mild and similar in both groups. CONCLUSIONS: This pilot study found colchicine significantly improved obesity-associated inflammatory variables and showed a good safety profile among adults with obesity and MetS who did not have diabetes. These results suggest a larger, adequately powered study should be conducted to determine whether colchicine improves insulin resistance and other measures of metabolic health in at-risk individuals.

Prevalence of Posttraumatic Stress Disorder and Psychological Comorbidities Among U.S. Active Duty Service Members, 2006-2013.

Among active duty service members, posttraumatic stress disorder (PTSD) diagnoses have increased dramatically since 2000. Because psychiatric comorbidity is more common for PTSD than for other mental health disorders, we examined the prevalence estimates of disorders comorbid or trimorbid with PTSD in this study. The medical records of 523,626 female and male active duty Sailors and Marines who entered the U.S. military between 2006 and 2013 were examined for diagnoses of PTSD and 14 potentially comorbid disorders. Results showed that 1.8% of military members had a PTSD diagnosis; among those with PTSD, 83.3% had a comorbid mental health disorder, and 62.2% had a third (i.e., trimorbid) disorder. Most frequently, PTSD co-occurred with depressive disorder (49.0%), adjustment disorder (37.0%), generalized anxiety disorder (36.1%), and alcohol use disorder (26.9%). All disorders we examined were significantly more likely to be diagnosed in service members with PTSD than in those without PTSD, odds ratios = 1.52-29.63. For service members with PTSD, comorbid mental health disorders are the rule rather than the exception. Consequently, it is important that clinicians also assess for other disorders and select treatment options that address both PTSD and comorbid conditions.

Subcutaneous adipose tissue imaging of human obesity reveals two types of adipocyte membranes: Insulin-responsive and -nonresponsive.

In adipose tissue, resistance to insulin's ability to increase glucose uptake can be induced by multiple factors, including obesity. Impaired insulin action may take place at different spatial loci at the cellular or subcellular level. To begin to understand the spatial response to insulin in human subcutaneous adipose tissue (hSAT), we developed a quantitative imaging method for activation of a major signaling node in the glucoregulatory insulin signaling pathway. After treatment with insulin or control media, biopsied tissues were immunostained for Akt phosphorylation at Thr-308/9 (pAkt) and then imaged by confocal fluorescence microscopy automated to collect a large grid of high resolution fields. In hSAT from 40 men and women with obesity, substantial heterogeneity of pAkt densities in adipocyte membranes were quantified in each image mosaic using a spatial unit of at least twice the size of the point spread function. Statistical analysis of the distribution of pAkt spatial units was best fit as the weighted sum of two separate distributions, corresponding to either a low or high pAkt density. A "high pAkt fraction" metric was calculated from the fraction of high pAkt distributed units over the total units. Importantly, upon insulin stimulation, tissues from the same biopsy showed either a minimal or a substantial change in the high pAkt fraction. Further supporting a two-state response to insulin stimulation, subjects with similar insulin sensitivity indices are also segregated into either of two clusters identified by the amount of membrane-localized pAkt.

A follow-up comparative safety analysis of pandemic H1N1 vaccination during pregnancy and risk of infant birth defects among U.S. military mothers.

OBJECTIVE: To update a previous assessment of birth defects among infants born to active duty U.S. military mothers who received the 2009-2010 pandemic H1N1 vaccine, in comparison to the 2008-2009 seasonal influenza vaccine, during pregnancy. Here, we updated the previous comparative analyses with a more refined definition for birth defects using an additional year of follow-up data from both inpatient and outpatient medical encounters. METHODS: The study population included 15,510 live born infants born to active duty mothers vaccinated during pregnancy with either the 2009-2010 pandemic H1N1 vaccine (n = 9033) or the 2008-2009 seasonal influenza vaccine (n = 6477). Birth defect cases were defined as those infants who received a birth defect diagnosis on one inpatient record or two outpatient records on different days within the first year of life. Multivariable logistic regression models were conducted to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) for the association between birth defects and maternal vaccination during pregnancy with pandemic H1N1 vaccine versus seasonal influenza vaccine. RESULTS: Infants born to mothers vaccinated during pregnancy with the pandemic H1N1 vaccine, versus the seasonal influenza vaccine, were not at increased odds of birth defects in univariable (OR: 1.13, 95% CI: 0.95-1.34) or multivariable (OR: 1.14, 95% CI: 0.96-1.35) models. Findings were not significant when further limited to first trimester exposure. Multivariable models were adjusted for infant sex and plurality; maternal age, race/ethnicity, marital status, service branch, military rank, and occupation; timing of vaccination; and receipt of vaccination(s) not routinely recommended during pregnancy. CONCLUSION: Comparable to our previous analyses assessing birth defects diagnosed at birth, no significant association was found between the pandemic H1N1 vaccination during pregnancy and birth defects, versus the seasonal influenza vaccine. These findings are reassuring and provide additional support for H1N1-containing seasonal influenza vaccination during pregnancy.

Postpartum depression and timing of spousal military deployment relative to pregnancy and delivery.

OBJECTIVE: This study aimed to determine the relationship between spousal deployment and postpartum depression diagnosis among U.S. military wives, accounting for the timing of deployment with respect to pregnancy and delivery. METHODS: A retrospective cohort study was conducted to evaluate the association between spousal deployment and postpartum depression among pregnant wives of active-duty service members. Electronic medical records for 161,454 births occurring between 2004 and 2009 were used to define postpartum depression. Three non-mutually exclusive exposure variables were created to categorize deployments as occurring before, during, or after the infant's delivery. A multivariable logistic regression model mutually adjusted for these exposure variables was fitted, producing an odds ratio for each of the three timing categories. RESULTS: A modest significant association was detected only in those whose husbands deployed in pregnancy and returned after delivery (i.e., deployed during delivery) [odds ratio (OR) 1.10, 95 % confidence interval (CI) 1.04-1.15]. An interactive effect between preexisting depression or anxiety and deployment during delivery was also detected in the data (OR 1.13, 95 % CI 1.07-1.20 for those without a preexisting diagnosis; OR 0.87, 95 % CI 0.80-0.95 for those with a preexisting diagnosis). CONCLUSION: Health care providers should continue to be aware of spousal deployment as a military-unique stressor in this population and rigorously screen for potential symptoms of postpartum depression, especially among those whose husbands are absent at delivery.