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Living with multiple long-term health conditions (multimorbidity) is increasingly common in older age. The more long-term conditions that an individual has, the more medicines they are likely to take. Hospitalisation as a consequence of medication-related harm is increasing and a concerted effort is needed to reduce the burden of harm caused by medication. However, making decisions about the balance between benefit and harm for an older person with multimorbidity and polypharmacy is very complex. There are various clinical tools that can help to identify patients at higher risk of harm and numerous strategies, including medicines optimisation reviews that incorporate personalised health information, to try to reduce risk. Further education and training of the healthcare professionals is needed to equip the multidisciplinary workforce with the skills and knowledge to address these challenges. This article discusses some of the changes that can be implemented now and highlights areas that will require more research before they can be introduced, in order to help patients to get the best out of their medicines.

Purpose: Specific markers of circulating tumor cells may be informative in managing lung cancer. Because the RE-1 silencing transcription factor (REST/NRSF) is a transcriptional repressor that is inactivated in neuroendocrine lung cancer, we identified REST-regulated transcripts (CHGA, CHGB, SCG3, VGF, and PCSK1) for evaluation as biomarkers in peripheral blood.Experimental Design: Transcripts were screened across lung cancer and normal cell lines. Candidates were assessed by reverse transcription-PCR and hybridization of RNA extracted from the peripheral blood of 111 lung cancer patients obtained at clinical presentation and from 27 cancer-free individuals.Results: Expression profiling revealed multiple chromogranin transcripts were readily induced on REST depletion, most notably SCG3 was induced >500-fold. The SCG3 transcript was also overexpressed by 12,000-fold in neuroendocrine compared with nonneuroendocrine lung cancer cells. In peripheral blood of lung cancer patients and cancer-free individuals, we found that SCG3 was more tumor-specific and more sensitive than other chromogranin transcripts as a biomarker of circulating tumor cells. Overall, 36% of small cell lung cancer (SCLC) and 16% of non-SCLC patients scored positively for normalized SCG3 transcript. This correlated with worse survival among SCLC patients with limited disease (n = 33; P = 0.022) but not extensive disease (n = 29; P = 0.459). Interestingly, the subcohort of 6 SCLC patients with resistance to platinum/etoposide chemotherapy all scored positively for peripheral blood SCG3 transcript (P = 0.022).Conclusions: SCG3 mRNA, a component of the REST-dependent neurosecretory transcriptional profile, provides a sensitive prognostic biomarker for noninvasive monitoring of neuroendocrine lung cancer.

Supplementary Figures S1-S2 from SCG3 Transcript in Peripheral Blood Is a Prognostic Biomarker for REST-Deficient Small Cell Lung Cancer

Purpose Therapeutic drug monitoring (TDM) is widely recognised as a key attribute of clinical pharmacologists; yet, the extent to which physicians undertaking postgraduate training in clinical pharmacology (hereafter trainees) are involved in TDM is poorly characterised. Our own experience suggests wide variation in trainee exposure to TDM. Method We performed a Europe-wide cross-sectional internet-based survey of trainees to determine the nature and extent of trainee involvement in TDM. Results There were 43 responses from eight countries analysed. Of the 21 respondents from the UK, all were also training in general internal medicine (GIM), while all of the respondents who were solely training in clinical pharmacology were from outside the UK. Overall, 86.0% of respondents reported access to drug monitoring for clinical care at their affiliated institution, of which 81.0% were personally involved in TDM in some capacity. On average, trainees reported that drug monitoring was available for 16 of the 33 (48%) of the drug/drug classes surveyed. UK-based respondents were involved in requesting drug-level investigations and interpreting the results for patients under their care in 76.2% and 85.7% of cases, respectively, while non-UK respondents supported other healthcare professionals to interpret results in 45.4% of cases. Trainees felt TDM training was generally either insufficient or very inadequate. Conclusion While access to TDM is relatively available at institutions where trainees are based, the role of trainees is variable and affected by a variety of factors including country and training programme. Universally, trainees feel they need more education in TDM.

Cognitive difficulties typically resolve within days to weeks following mild traumatic brain injury (mTBI); however, a sizable proportion of individuals continue to report cognitive symptoms months to years later that are often associated with posttraumatic stress disorder (PTSD) and depression to a greater degree than a history of mTBI. The current study sought to evaluate the prevalence of self-reported cognitive difficulties as well as the relative contributions of demographic, injury-related, and mental health variables in a large study of U.S. military personnel injured during deployment since 2001. Slightly fewer than half (42.0%) of participants reported elevated cognitive difficulties compared with a normative population; however, this was driven primarily by those who screened positive for PTSD or depression. Hierarchical linear regression revealed that various demographic and injury factors, including lower educational attainment, retired or separated military status, enlisted rank, and a history of deployment-related mTBI, were associated with more self-reported cognitive difficulties, f

Introduction Over the last two decades, the conflicts in Iraq and Afghanistan have cost the United States significantly in terms of lives lost, disabling injuries, and budgetary expenditures. This manuscript calculates the differences in costs between veterans with combat injuries vs veterans without combat injuries. This work could be used to project future costs in subsequent studies. Materials and Methods In this retrospective cohort study, we randomly selected 7,984 combat-injured veterans between February 1, 2002, and June 14, 2016, from Veterans Affairs Health System administrative data. We matched injured veterans 1:1 to noninjured veterans on year of birth (± 1 year), sex, and first service branch. We observed patients for a maximum of 10 years. This research protocol was reviewed and approved by the David Grant USAF Medical Center institutional review board (IRB), the University of Utah IRB, and the Research Review Committee of the VA Salt Lake City Health Care System in accordance with all applicable Federal regulations. Results Patients were primarily male (98.1% in both groups) and White (76.4% for injured patients, 72.3% for noninjured patients), with a mean (SD) age of 26.8 (6.6) years for the injured group and 27.7 (7.0) years for noninjured subjects. Average total costs for combat-injured service members were higher for each year studied. The difference was highest in the first year ($16,050 compared to $4,135 for noninjured). These differences remained significant after adjustment. Although this difference was greatest in the first year (marginal effect $12,386, 95% confidence interval $9,736-$15,036; P Conclusions Combat injured patients have significantly higher long-term health care costs compared to their noninjured counterparts. If this random sample is extrapolated to the 53,251 total of combat wounded service members, it implies a total excess cost of $1.6 billion to date after adjustment for covariates and a median follow-up time of 10 years. These costs are likely to increase as injured veterans age and develop additional chronic conditions.

Background Structured Medication Reviews (SMRs) are intended to help deliver the NHS Long Term Plan for medicines optimisation in people living with multiple long-term conditions and polypharmacy. It is challenging to gather the information needed for these reviews due to poor integration of health records across providers and there is little guidance on how to identify those patients most urgently requiring review. Objective To extract information from scattered clinical records on how health and medications change over time, apply interpretable artificial intelligence (AI) approaches to predict risks of poor outcomes and overlay this information on care records to inform SMRs. We will pilot this approach in primary care prescribing audit and feedback systems, and co-design future medicines optimisation decision support systems. Design DynAIRx will target potentially problematic polypharmacy in three key multimorbidity groups, namely, people with (a) mental and physical health problems, (b) four or more long-term conditions taking ten or more drugs and (c) older age and frailty. Structured clinical data will be drawn from integrated care records (general practice, hospital, and social care) covering an ∼11m population supplemented with Natural Language Processing (NLP) of unstructured clinical text. AI systems will be trained to identify patterns of conditions, medications, tests, and clinical contacts preceding adverse events in order to identify individuals who might benefit most from an SMR. Discussion By implementing and evaluating an AI-augmented visualisation of care records in an existing prescribing audit and feedback system we will create a learning system for medicines optimisation, co-designed throughout with end-users and patients.

BACKGROUND: Globally, there is a paucity of multimorbidity and comorbidity data, especially for minority ethnic groups and younger people. We estimated the frequency of common disease combinations and identified non-random disease associations for all ages in a multiethnic population. METHODS: In this population-based study, we examined multimorbidity and comorbidity patterns stratified by ethnicity or race, sex, and age for 308 health conditions using electronic health records from individuals included on the Clinical Practice Research Datalink linked with the Hospital Episode Statistics admitted patient care dataset in England. We included individuals who were older than 1 year and who had been registered for at least 1 year in a participating general practice during the study period (between April 1, 2010, and March 31, 2015). We identified the most common combinations of conditions and comorbidities for index conditions. We defined comorbidity as the accumulation of additional conditions to an index condition over an individual's lifetime. We used network analysis to identify conditions that co-occurred more often than expected by chance. We developed online interactive tools to explore multimorbidity and comorbidity patterns overall and by subgroup based on ethnicity, sex, and age. FINDINGS: We collected data for 3 872 451 eligible patients, of whom 1 955 700 (50.5%) were women and girls, 1 916 751 (49.5%) were men and boys, 2 666 234 (68.9%) were White, 155 435 (4.0%) were south Asian, and 98 815 (2.6%) were Black. We found that a higher proportion of boys aged 1-9 years (132 506 [47.8%] of 277 158) had two or more diagnosed conditions than did girls in the same age group (106 982 [40.3%] of 265 179), but more women and girls were diagnosed with multimorbidity than were boys aged 10 years and older and men (1 361 232 [80.5%] of 1 690 521 vs 1 161 308 [70.8%] of 1 639 593). White individuals (2 097 536 [78.7%] of 2 666 234) were more likely to be diagnosed with two or more conditions than were Black (59 339 [60.1%] of 98 815) or south Asian individuals (93 617 [60.2%] of 155 435). Depression commonly co-occurred with anxiety, migraine, obesity, atopic conditions, deafness, soft-tissue disorders, and gastrointestinal disorders across all subgroups. Heart failure often co-occurred with hypertension, atrial fibrillation, osteoarthritis, stable angina, myocardial infarction, chronic kidney disease, type 2 diabetes, and chronic obstructive pulmonary disease. Spinal fractures were most strongly non-randomly associated with malignancy in Black individuals, but with osteoporosis in White individuals. Hypertension was most strongly associated with kidney disorders in those aged 20-29 years, but with dyslipidaemia, obesity, and type 2 diabetes in individuals aged 40 years and older. Breast cancer was associated with different comorbidities in individuals from different ethnic groups. Asthma was associated with different comorbidities between males and females. Bipolar disorder was associated with different comorbidities in younger age groups compared with older age groups. INTERPRETATION: Our findings and interactive online tools are a resource for: patients and their clinicians, to prevent and detect comorbid conditions; research funders and policy makers, to redesign service provision, training priorities, and guideline development; and biomedical researchers and manufacturers of medicines, to provide leads for research into common or sequential pathways of disease and inform the design of clinical trials. FUNDING: UK Research and Innovation, Medical Research Council, National Institute for Health and Care Research, Department of Health and Social Care, Wellcome Trust, British Heart Foundation, and The Alan Turing Institute.

INTRODUCTION Atrial fibrillation and atrial flutter (AF/AFL), the most common atrial arrhythmias, have never been examined in combat casualties. In this study, we investigated the impact of traumatic injury on AF/AFL among service members with deployment history. METHODS Sampled from the Department of Defense (DoD) Trauma Registry (n = 10,000), each injured patient in this retrospective cohort study was matched with a non-injured service member drawn from the Veterans Affairs/DoD Identity Repository. The primary outcome was AF/AFL diagnosis identified using ICD-9-CM and ICD-10-CM codes. Competing risk regressions based on Fine and Gray subdistribution hazards model with were utilized to assess the association between injury and AF/AFL. RESULTS There were 130 reported AF/AFL cases, 90 of whom were injured and 40 were non-injured. The estimated cumulative incidence rates of AF/AFL for injured was higher compared to non-injured patients (hazards ratio [HR] = 2.04; 95% confidence interval [CI] = 1.44, 2.87). After adjustment demographics and tobacco use, the association did not appreciably decrease (HR = 1.90; 95% CI = 1.23, 2.93). Additional adjustment for obesity, hypertension, diabetes, and vascular disorders, the association between injury and AF/AFL was no longer statistically significant (HR = 1.51; 95% CI = 0.99, 2.52). CONCLUSION Higher AF/AFL incidence rate was observed among deployed service members with combat injury compared to servicemembers without injury. The association did not remain significant after adjustment for cardiovascular-related covariates. These findings highlight the need for combat casualty surveillance to further understand the AF/AFL risk within the military population and to elucidate the potential underlying pathophysiologic mechanisms.

Examinations of risk factors for suicide attempt in United States service members at high risk of mental health diagnoses, such as those with combat injuries, are essential to guiding prevention and intervention efforts.Retrospective cohort study of 8727 combat-injured patients matched to deployed, non-injured patients utilizing Department of Defense and Veterans Affairs administrative records.Combat injury was positively associated with suicide attempt in the univariate model (HR = 1.75, 95% CI 1.5-2.1), but lost significance after adjustment for mental health diagnoses. Utilizing Latent Transition Analysis in the combat-injured group, we identified five mental/behavioral health profiles: (1) Few mental health diagnoses, (2) PTSD and depressive disorders, (3) Adjustment disorder, (4) Multiple mental health comorbidities, and (5) Multiple mental health comorbidities with alcohol use disorder (AUD). Multiple mental health comorbidities with AUD had the highest suicide attempt rate throughout the study and more than four times that of Multiple mental health comorbidities in the first study year (23.4 vs. 5.1 per 1000 person years, respectively).Findings indicate that (1) combat injury's impact on suicide attempt is attenuated by mental health and (2) AUD with multiple mental health comorbidities confers heightened suicide attempt risk in combat-injured service members.

Previous studies have identified combat exposure and combat traumatic experience as problematic drinking risk factors. Increasing evidence suggests that opioid use increases the risk of alcohol use disorder. This study investigated the association between opioid prescription use after injury and (1) alcohol use disorder and (2) severity of alcohol use disorder among deployed military servicemembers.Deidentified health records data of 9,029 deployed servicemembers from a retrospective cohort study were analyzed. Data were randomly selected from the Department of Defense Trauma Registry and included servicemembers with combat injuries during deployment in Iraq or Afghanistan (2002-2016). Pharmacy records and International Classification of Diseases, Ninth and Tenth Revision diagnosis codes were used. Three groups were identified (no opioid prescription use, nonpersistent opioid prescription use, and persistent opioid prescription use) and were compared on the basis of alcohol use disorder risk using Cox proportional hazard models. Data analyses were performed in 2021.Of the 9,029 servicemembers with combat injury, 2,262 developed alcohol use disorder (1,322 developed severe alcohol use disorder). Compared with no opioid prescription use, increased alcohol use disorder risk was associated with persistent opioid prescription use, with a hazard ratio of 1.13 (95% CI=1.02, 1.26). After covariate adjustment, increased risk remained statistically significant (hazards ratio=1.24; 95% CI=1.10, 1.39). There was no significant difference in alcohol use disorder risk between no opioid prescription use and nonpersistent opioid prescription use. The risk of severe alcohol use disorder did not vary by opioid use among servicemembers with alcohol use disorder diagnosis.The findings of the study suggest that the incidence of alcohol use disorder was higher among injured servicemembers with persistent opioid prescription use than among those without opioid use. If replicated in prospective studies, the findings highlight the need for clinicians to consider the current and history of alcohol use of patients in initiating treatment involving opioids.

Objective:Dialysis patients may not have access to conventional renal replacement therapy (RRT) following disasters. We hypothesized that improvised renal replacement therapy (ImpRRT) would be comparable to continuous renal replacement therapy (CRRT) in a porcine acute kidney injury model.Methods:Following bilateral nephrectomies and 2 hours of caudal aortic occlusion, 12 pigs were randomized to 4 hours of ImpRRT or CRRT. In the ImpRRT group, blood was circulated through a dialysis filter using a rapid infuser to collect the ultrafiltrate. Improvised replacement fluid, made with stock solutions, was infused pre-pump. In the CRRT group, commercial replacement fluid was used. During RRT, animals received isotonic crystalloids and norepinephrine.Results:There were no differences in serum creatinine, calcium, magnesium, or phosphorus concentrations. While there was a difference between groups in serum potassium concentration over time (P < 0.001), significance was lost in pairwise comparison at specific time points. Replacement fluids or ultrafiltrate flows did not differ between groups. There were no differences in lactate concentration, isotonic crystalloid requirement, or norepinephrine doses. No difference was found in electrolyte concentrations between the commercial and improvised replacement solutions.Conclusion:The ImpRRT system achieved similar performance to CRRT and may represent a potential option for temporary RRT following disasters.

Introduction We explore disparities in awarding post-traumatic stress disorder (PTSD) service-connected disability benefits (SCDB) to veterans based on gender, race/ethnicity, and misconduct separation. Methods Department of Defense data on service members who separated from October 1, 2001 to May 2017 were linked to Veterans Administration (VA) administrative data. Using adjusted logistic regression models, we determined the odds of receiving a PTSD SCDB conditional on a VA diagnosis of PTSD. Results A total of 1,558,449 (79% of separating service members) had at least one encounter in VA during the study period (12% female, 4.5% misconduct separations). Females (OR 0.72) and Blacks (OR 0.93) were less likely to receive a PTSD award and were nearly equally likely to receive a PTSD diagnosis (OR 0.97, 1.01). Other racial/ethnic minorities were more likely to receive an award and diagnosis, as were those with misconduct separations (award OR 1.3, diagnosis 2.17). Conclusions Despite being diagnosed with PTSD at similar rates to their referent categories, females and Black veterans are less likely to receive PTSD disability awards. Other racial/ethnic minorities and those with misconduct separations were more likely to receive PTSD diagnoses and awards. Further study is merited to explore variation in awarding SCDB.

Introduction Musculoskeletal (MSK) conditions are commonly seen among military service members (SM) and Veterans. We explored correlates of award of MSK-related service-connected disability benefits (SCDB) among SM seeking care in Veterans Affairs (VA) hospitals. Materials and Methods Department of Defense data on SM who separated from October 1, 2001 to May 2017 were linked to VA administrative data. Using adjusted logistic regression models, we determined the odds of receiving MSK SCDB. Results A total of 1,558,449 (79% of separating SM) had at least one encounter in VA during the study period (7.8% disability separations). Overall, 51% of this cohort had at least one MSK SCDB (88% among disability separations, 48% among normal). Those with disability separations (as compared to normal separations) were significantly more likely to receive MSK SCDB (odds ratio 2.37) as were females (compared to males, odds ratio 1.15). Conclusions Although active duty SM with disability separations were more likely to receive MSK-related service-connected disability ratings in the VA, those with normal separations also received such awards. Identifying those at highest risk for MSK-related disability could lead to improved surveillance and prevention strategies in the Department of Defense and VA health care systems to prevent further damage and disability.

Therapeutic drug monitoring (TDM) is widely recognised as a key attribute of clinical pharmacologists; yet, the extent to which physicians undertaking postgraduate training in clinical pharmacology (hereafter trainees) are involved in TDM is poorly characterised. Our own experience suggests wide variation in trainee exposure to TDM.We performed a Europe-wide cross-sectional internet-based survey of trainees to determine the nature and extent of trainee involvement in TDM.There were 43 responses from eight countries analysed. Of the 21 respondents from the UK, all were also training in general internal medicine (GIM), while all of the respondents who were solely training in clinical pharmacology were from outside the UK. Overall, 86.0% of respondents reported access to drug monitoring for clinical care at their affiliated institution, of which 81.0% were personally involved in TDM in some capacity. On average, trainees reported that drug monitoring was available for 16 of the 33 (48%) of the drug/drug classes surveyed. UK-based respondents were involved in requesting drug-level investigations and interpreting the results for patients under their care in 76.2% and 85.7% of cases, respectively, while non-UK respondents supported other healthcare professionals to interpret results in 45.4% of cases. Trainees felt TDM training was generally either insufficient or very inadequate.While access to TDM is relatively available at institutions where trainees are based, the role of trainees is variable and affected by a variety of factors including country and training programme. Universally, trainees feel they need more education in TDM.

STUDY OBJECTIVES: Obstructive sleep apnea is prevalent among military members despite fewer traditional risk factors. We sought to determine the incidence and longitudinal predictors of obstructive sleep apnea in a large population of survivors of combat-related traumatic injury and a matched control group. METHODS: Retrospective cohort study of military service members deployed to conflict zones from 2002–2016 with longitudinal follow-up in the Veterans Affairs and Military Health Systems. Two cohorts of service members were developed: (1) those who sustained combat injuries and (2) matched, uninjured participants. RESULTS: 17,570 service members were retrospectively analyzed for a median of 8.4 years. After adjustment, traumatic brain injury (hazard ratio [HR] 1.39, 95% confidence interval [CI] 1.20–1.60), posttraumatic stress disorder (HR 1.24, 95% CI 1.05–1.46), depression (HR 1.52, 95% CI 1.30–1.79), anxiety (HR 1.40, 95% CI 1.21–1.62), insomnia (HR 1.71, 95% CI 1.44–2.02), and obesity (HR 2.40, 95% CI 2.09–2.74) were associated with development of obstructive sleep apnea. While combat injury was associated with obstructive sleep apnea in the univariate analysis (HR 1.25, 95% CI 1.17–1.33), the direction of this association was reversed in the multivariable model (HR 0.74, 95% CI 0.65–0.84). In a nested analysis, this was determined to be due to the effect of mental health diagnoses. CONCLUSIONS: The incidence of obstructive sleep apnea is higher among injured service members (29.1 per 1,000 person-years) compared to uninjured service members (23.9 per 1,000 person-years). This association appears to be driven by traumatic brain injury and the long-term mental health sequelae of injury. CITATION: Haynes ZA, Stewart IJ, Poltavskiy EA, et al. Obstructive sleep apnea among survivors of combat-related traumatic injury: a retrospective cohort study. J Clin Sleep Med. 2022;18(1):171–179.

The source-sink paradigm has been a powerful tool for focusing theoretical and empirical explorations of population dynamics in heterogeneous landscapes. The prevalence of suspected source-sink dynamics in empirical studies would lead to the conclusion that sources and sinks are common. However, important questions remain about how source-sink dynamics have been assessed in past studies and the degree to which current approaches apply to atypical populations and dynamic landscapes. We reviewed 432 papers that directly addressed source-sink dynamics between 1985 and 2018. We found that the majority of studies focused on birds, mammals, and forested systems. In recent years, however, the number of aquatic invertebrate and marine studies increased, as did the tendency to focus on conservation or management goals and to report population trends. Although 79% of papers claimed to identify source-sink dynamics, only 13% of studies based their assessment on all four measures of reproduction, mortality, immigration, and emigration. Nearly 23% of all studies used neither demographic nor movement metrics to make conclusions about the presence of source-sink dynamics. Source-sink theory and practice has matured and is increasingly relevant for species conservation and management. However, we lack a clear understanding of the conditions under which limited data can defensibly support source-sink assessments and be scaled up to the extent at which resource decisions are made. In the absence of this, future studies will need to take a more rigorous approach to defining sources and sinks to better gauge the prevalence of source-sink dynamics.

Management actions and land-use change can disrupt interdependent population processes, re-define population networks, and change source-sink dynamics. Yet we know little about the types of changes that can de-stabilize source-sink dynamics and how such changes could affect management decisions. We examined the degree to which source-sink status and strength could change under a range of management actions and land-use change scenarios including different patterns and extents of habitat loss, restoration, demographic improvements from parasitism control, and increased frequencies inter-population movement. We developed an empirically-rich, spatially explicit, individual-based model for the formerly endangered Black-capped vireo in Texas. We simulated the network-wide consequences of different kinds of changes and compared the resulting source-sink strength, status, and regional abundance across scenarios. We gauged source-sink stability by the degree to which system changes caused the reversal of source or sink status. The stability of source-sink characterizations differed with the type of change. Source-sink dynamics were less responsive to small changes to population structure and changes that minimally affected demographic conditions. Source-sink status was most responsive to changes that affected habitat patterns and quality. Accurately classifying sources and sinks is challenging, particularly in variable and directionally changing systems. The stability of source-sink classifications depends on the type of management or land-use change. Management actions may need to weigh interventions that improve regional abundance against those that alter regional source-sink dynamics as abundance and source-sink states can be sensitive to different kinds of change.

Introduction Although retrospective analyses have found that combat-injured service members are at high risk for mental and physical health outcomes following injury, relatively little is known about the long-term health of injured service members. To better understand long-term health outcomes after combat injury, a large, prospective observational cohort collecting both subjective and objective health data is needed. Given that a study of this nature would be costly and face many logistical challenges, we first conducted a pilot to assess the feasibility of a larger, definitive study. Materials and Methods We ran a prospective, observational pilot study of 119 combat-injured service members and veterans who completed (1) at least one set of laboratory measurements (blood and urine sample collection and vitals measurements) at Clinical Laboratory Improvement Amendment of 1988 compliant laboratory locations and (2) at least one online assessment for the Wounded Warrior Recovery Project (WWRP), a 15-year examination of patient-reported outcomes among service members injured on combat deployment. We recruited the pilot study cohort from WWRP participants who met eligibility criteria and indicated interest in additional research opportunities. We collected laboratory values and patient-reported outcomes at baseline and again 1 year later, and obtained demographic, injury, and military service data from the Expeditionary Medical Encounter Database. The David Grant USAF Medical Center Institution Review Board (IRB) and the Naval Health Research Center IRB reviewed and approved the study protocols. Results During recruitment for the pilot study, 624 study candidates were identified from WWRP. Of the 397 candidates we contacted about the pilot study, 179 (45.1%) enrolled and 119 (66.4%) of those who enrolled completed the first year of participation. The second study year was suspended due to the coronavirus disease-2019 pandemic. At the time of suspension, 72 (60.5%) participants completed follow-up laboratory appointments, and 111 (93.3%) completed second-year WWRP assessments. Participants in the pilot study were predominately male (95.0%) and non-Hispanic White (55.5%), with a median (interquartile range) age of 38.3 (34.1-45.4) years. Conclusions Collection of patient-reported outcomes and laboratory samples in a geographically dispersed cohort of combat-injured service members is possible. While significant challenges exist, our pilot study results indicate that a larger, longitudinal, cohort study is feasible.

STUDY OBJECTIVES: Insomnia is a diagnosis with broad health and economic implications that has been increasingly recognized in military service members. This trend was concurrent with an increase in traumatic wartime injuries. Accordingly, we sought to determine longitudinal predictors of persistent insomnia in combat veterans who sustained traumatic injuries. METHODS: Retrospective cohort study of service members deployed to conflict zones from 2002 to 2016, with longitudinal follow-up in the Veterans Affairs and Military Health Systems. Two cohorts were derived: (1) service members who sustained traumatic injuries and (2) an age-, sex-, and service component–matched cohort of uninjured service members who deployed to a combat zone. Insomnia was defined using International Classification of Diseases, Ninth Revision or International Classification of Diseases, 10th Revision-Clinical Modification codes. RESULTS: The final population of 17,374 service members was followed from date of injury (or date of matched participant’s injury) for a median of 8.4 (interquartile range, 5.3–10.7) years. Service members with traumatic injury were at significantly greater risk of developing insomnia than uninjured service members (hazard ratio = 1.43; 95% confidence interval, 1.30–1.58) after adjustment. Traumatic brain injury was associated with insomnia compared with patients without traumatic brain injury in the multivariable model: mild/unclassified traumatic brain injury (hazard ratio = 2.07; 95% confidence interval, 1.82–2.35) and moderate/severe/ penetrating traumatic brain injury (hazard ratio = 2.43; 95% confidence interval, 2.06–2.86). Additionally, burn injury (hazard ratio = 1.95; 95% confidence interval, 1.47–2.59) and amputation (hazard ratio = 1.61; 95% confidence interval, 1.26–2.06) significantly increased the risk of a diagnosis. CONCLUSIONS: Traumatic injuries significantly predicted a diagnosis of insomnia after controlling for mental health disorders. Our findings strongly suggest the need for long-term surveillance of sleep disorders in trauma survivors. CITATION: Haynes ZA, Collen JF, Poltavskiy EA, et al. Risk factors of persistent insomnia among survivors of traumatic injury: a retrospective cohort study. J Clin Sleep Med. 2021;17(9):1831–1840.

A growing body of literature on military personnel and veterans’ health suggests that prior military service may be associated with exposures that increase the risk of cardiovascular disease (CVD), which may differ by race/ethnicity. This study examined the hypothesis that differential telomere shortening, a measure of cellular aging, by race/ethnicity may explain prior findings of differential CVD risk in racial/ethnic groups with military service. Data from the first two continuous waves of the National Health and Nutrition Examination Survey (NHANES), administered from 1999–2002 were analyzed. Mean telomere length in base pairs was analyzed with multivariable adjusted linear regression with complex sample design, stratified by sex. The unadjusted mean telomere length was 225.8 base shorter for individuals with prior military service. The mean telomere length for men was 47.2 (95% CI: −92.9, −1.5, p &lt, 0.05) base pairs shorter for men with military service after adjustment for demographic, socioeconomic, and behavioral variables, but did not differ significantly in women with and without prior military service. The interaction between military service and race/ethnicity was not significant for men or women. The results suggest that military service may contribute to accelerated aging as a result of health damaging exposures, such as combat, injury, and environmental contaminants, though other unmeasured confounders could also potentially explain the results.

Background A better understanding of the long-term health effects of combat injury is important for the management of veterans’ health in the Department of Defense (DoD) and Veterans Affairs (VA) health care systems and may have implications for primary care management of civilian trauma patients. Objective To determine the impact of traumatic injury on the subsequent development of hypertension (HTN), diabetes mellitus (DM), and coronary artery disease (CAD) after adjustment for sociodemographic, health behavior, and mental health factors. Design Retrospective cohort study of current and former US military personnel with data obtained from both the DoD and VA health care systems. Participants Combat injured (n = 8727) service members between 1 February 2002 and 14 June 2016 randomly selected from the DoD Trauma Registry matched 1:1 based on year of birth, sex, and branch of service to subjects that deployed to a combat zone but were not injured. Main Measures Traumatic injury, stratified by severity, compared with no documented injury. Diagnoses of HTN, DM, and CAD defined by International Classification of Diseases 9th or 10th Revision Clinical Modification codes. Key Results After adjustment, severe traumatic injury was significantly associated with HTN (HR 2.78, 95% CI 2.18–3.55), DM (HR 4.45, 95% CI 2.15–9.18), and CAD (HR 4.87, 95% CI 2.11–11.25), compared with no injury. Less severe injury was associated with HTN (HR 1.14, 95% CI 1.05–1.24) and CAD (HR 1.62, 95% CI 1.11–2.37). Conclusions Severe traumatic injury is associated with the subsequent development of HTN, DM, and CAD. These findings have profound implications for the primary care of injured service members in both the DoD/VA health systems and may be applicable to civilian trauma patients as well. Further exploration of pathophysiologic, health behavior, and mental health changes after trauma is warranted to guide future intervention strategies.

Accurate assessment of coagulation in porcine studies is essential. We sought to establish normal values for porcine rotational thromboelastometry (ROTEM) according to the American Society for Veterinary Clinical Pathology guidelines and to assess the effects of various preanalytical parameters on those measurements. Healthy Yorkshire-cross pigs (n = 81; 46 males and 35 females) were anesthetized. By using a 18-gauge needle attached to a vacuum phlebotomy tube, blood was acquired from the cranial vena cava. Tubes were filled in the following order: evacuation clot tube, EDTA tube, heparin tube, and 2 citrate tubes. The citrate tubes were randomly assigned to 30 min with or without constant agitation on a rocker. The following parameters were reported according to the manufacturer's recommendations: clotting time, clot formation time, α, (tangent to the clot formation curve when the clot firmness is 20 mm), clot firmness after 10 and 20 min, maximal clot firmness, maximum lysis, and lysis indexes at 30 and 45 min. Reference intervals were reported as mean ± 2 SD (parametric distribution) or 2.5th and 97.5th percentile of the population's results (nonparametric distribution). The effects of sex, sampling order, and agitation on ROTEM results were analyzed through linear regression. Neither sex nor sample agitation influenced any of the ROTEM parameters. Combined reference intervals were established for each ROTEM parameter by pooling data from the nonagitated tubes for both male and female pigs. This study is the first to establish ROTEM reference intervals from a large number of male and female adult Yorkshire-cross pigs and to provide a detailed description of preanalytical sample processing.

Background Although the long-term effects of combat injury are not well understood, there is emerging concern that exposure to combat environments and subsequent injury may increase the risk of hypertension through changes in inflammatory responses, psychological stress and mental health, and health behaviors. Methods Data from the Millennium Cohort Study and the Department of Defense Trauma Registry were used to identify combat-exposed and combat-injured participants. Incident hypertension diagnoses were ascertained from the Millennium Cohort survey. The associations between combat exposure/injury and hypertension risk was estimated using multivariable complementary log-log survival models. Results The final analysis sample consisted of 38 734 participants. Of these, 50.8% deployed but were not exposed to combat, 48.6% deployed and were exposed to combat, and 0.6% had combat injury. Overall prevalence of hypertension was 7.6%. Compared with participants who deployed but did not experience combat (mild exposure), elevated odds of hypertension were observed among those who experienced combat but not wounded (moderate exposure; AOR, 1.28; 95% CI, 1.19-1.38) and those wounded in combat (high exposure; AOR, 1.46; 95% CI, 1.07-2.00). Sleep duration of less than 4 h (AOR, 1.21; 95% CI, 1.03-1.43), sleep duration of 4-6 h (AOR, 1.16; 95% CI, 1.05-1.29), posttraumatic stress disorder (AOR, 1.54; 95% CI, 1.26-1.87), and overweight (AOR, 1.77; 95% CI, 1.61-1.95) and obese (AOR, 2.77; 95% CI, 2.45-3.12) status were also associated with higher odds of hypertension. Conclusion Results support the hypotheses that combat exposure increases hypertension risk and that combat injury exacerbates this risk.

Top predators have cascading effects throughout the food web, but their impacts on scavenger abundance are largely unknown. Gray wolves (Canis lupus) provide carrion to a suite of scavenger species, including the common raven (Corvus corax). Ravens are wide‐ranging and intelligent omnivores that commonly take advantage of anthropogenic food resources. In areas where they overlap with wolves, however, ravens are numerous and ubiquitous scavengers of wolf‐acquired carrion. We aimed to determine whether subsidies provided through wolves are a limiting factor for raven populations in general and how the wolf reintroduction to Yellowstone National Park in 1995–1997 affected raven population abundance and distribution on the Yellowstone's Northern Range specifically. We counted ravens throughout Yellowstone's Northern Range in March from 2009 to 2017 in both human‐use areas and wolf habitat. We then used statistics related to the local wolf population and the winter weather conditions to model raven abundance during our study period and predict raven abundance on the Northern Range both before and after the wolf reintroduction. In relatively severe winters with greater snowpack, raven abundance increased in areas of human use and decreased in wolf habitat. When wolves were able to acquire more carrion, however, ravens increased in wolf habitat and decreased in areas with anthropogenic resources. Raven populations prior to the wolf reintroduction were likely more variable and heavily dependent on ungulate winter‐kill and hunter‐provided carcasses. The wolf recovery in Yellowstone helped stabilize raven populations by providing a regular food supply, regardless of winter severity. This stabilization has important implications for effective land management as wolves recolonize the west and global climate patterns change.

Raptors are wide-ranging, vagile avian predators whose populations can be difficult and costly to monitor on their breeding or winter range. However, monitoring raptors during their annual northbound or southbound migration is a cost-effective and efficient alternative to time-intensive, single-species breeding surveys. In 2010, we observed numerous Swainson’s Hawks (Buteo swainsoni) and Red-tailed Hawks (Buteo jamaicensis) migrating through the Hayden Valley in central Yellowstone National Park, prompting an investigation into raptor migration patterns in the park. Our objectives were to monitor annual autumn raptor migration in Hayden Valley from 2011 to 2015 and to determine the relative role of this undocumented migration site by comparing our observations to simultaneously collected migration data from three other sites in the Rocky Mountain Flyway. From 2011 to 2015, we observed 6441 raptors of 17 species across 170 d and 907 h of observation. Red-tailed Hawks, Swainson’s Hawks, and Golden Eagles (Aquila chrysaetos) accounted for 51% of the total individuals observed over five years. Overall counts from Hayden Valley were comparable to counts from the three migration sites in the Rocky Mountains, although abundance of individual species varied by site. Data from this study suggest that Hayden Valley may serve as a stopover site for migrating raptors and presents an opportunity for future research. By improving our understanding of where raptors migrate and the characteristics of stopover areas in the Rocky Mountains, land managers may develop effective strategies for protecting raptor populations and habitat from threats including development and climate change.

Background: Although rhabdomyolysis has been associated with acute kidney injury and mortality in the short term, the long-term consequences of an episode of rhabdomyolysis remain unknown. We sought to identify the long-term outcomes of rhabdomyolysis, including mortality, renal function, and incidence of hypertension (HTN), among service members initially admitted to the intensive care unit after sustaining a combat injury in Iraq or Afghanistan between February 1, 2002 and February 1, 2011. Methods: Information on age, sex, injury severity score, mechanism of injury, serum creatinine, burn injury, presenting mean arterial pressure, and creatine kinase were retrospectively collected and analyzed for 2,208 patients. Standard descriptive tests were used to compare characteristics of patients with and without rhabdomyolysis. Competing risk Cox proportional hazards models were performed to assess the associated risk of rhabdomyolysis with both HTN and poor renal function. Results: While rhabdomyolysis was associated with HTN on univariate analysis (hazard ratio [HR] 1.30, 95% CI 1.03–1.64; p = 0.029), this difference did not persist on multivariable analysis (HR 1.27, 95% CI 0.99–1.62; p = 0.058). The median estimated glomerular filtration rate (eGFR) was 119 (interquartile range [IQR] 103–128) among those with rhabdomyolysis, compared with 108 (IQR 94–121) in the group without rhabdomyolysis (p < 0.001). Conclusion: After adjustment, patients with rhabdomyolysis were not at an increased risk of HTN compared to patients without rhabdomyolysis. eGFR was paradoxically higher in patients with rhabdomyolysis. There was no association found between rhabdomyolysis and mortality.

Although polygyny is common and regular among a small proportion of North American songbirds, some socially monogamous passerines may also exhibit occasional polygyny. We present evidence for only the second documented case of polygyny within the Vireonidae and the first documentation for polygyny in the endangered songbird the Black-capped Vireo (Vireo atricapilla). We located two simultaneous nests being tended by the same color-banded male vireo in a territory adjacent to an unpaired male. We suspect that differences in territory quality, rather than male quality, unbalanced sex ratios, or asynchronous settlement, were drivers of polygyny in this example.

Trauma-induced acute kidney injury (AKI) has affected many U.S. warfighters throughout history. We seek to provide a historical review of the epidemiology of combat-acquired AKI and to highlight the importance of adapting current renal replacement therapy (RRT) capabilities to prepare for the next armed conflict. While severe AKI was rare in the recent conflicts in Iraq and Afghanistan, an analysis of prior wars suggests that it will be more common in future combat operations characterized by prolonged evacuation times, limited resuscitation capabilities, and delayed aeromedical evacuation. Therefore, the military community must develop RRT capabilities to satisfy the demands of prolonged field care and austere environments. We propose a series of solutions such as re-enforcing forward deployment of conventional RRT capabilities as well as novel therapies such as improvised dialysis systems or sorbent-based RRT.

Objective To determine whether persistent opioid use after injury is associated with subsequent long-term development of clinically recognized opioid abuse. Summary background data Opioid abuse is an epidemic in the United States and trauma can initiate persistent use; however, it remains unclear whether persistent opioid use contributes to the subsequent development of opioid abuse. The care of combat casualties by the Departments of Defense and Veterans Affairs uniquely allows investigation of this long-term outcome. Methods This retrospective cohort study randomly selected 10,000 battle-injured United States military personnel. We excluded patients who died during initial hospitalization or within 180 days of discharge, had a preinjury opioid abuse diagnosis, or had missing data in a preselected variable. We defined persistent opioid use as filling an opioid prescription 3 to 6 months after discharge and recorded clinically recognized opioid abuse using relevant diagnosis codes. Results After exclusion, 9284 subjects were analyzed, 2167 (23.3%) of whom developed persistent opioid use. During a median follow-up time of 8 years, 631 (6.8%) patients developed clinically recognized opioid abuse with a median time to diagnosis of 3 years. Injury severity and discharge opioid prescription amount were associated with persistent opioid use after trauma. After adjusting for patient and injury-specific factors, persistent opioid use was associated with the long-term development of clinically recognized opioid abuse (adjusted hazard ratio, 2.39; 95% confidence interval, 1.99-2.86). Conclusions Nearly a quarter of patients filled an opioid prescription 3 to 6 months after discharge, and this persistent use was associated with long-term development of opioid abuse.

Objective: To determine: 1) rates of cardio­vascular disease (CVD) among individuals with and without prior US military service; and 2) variation in CVD outcomes by race/ ethnicity.Methods: We performed a cross-sectional study of the 2011-2016 Behavioral Risk Fac­tor Surveillance System during 2018-2019. Groups with (n=369,844) and without (n=2,491,784) prior service were compared overall, and by race/ethnicity. CVD odds were compared using logistic regression. Rate-difference decomposition was used to estimate relative contributions of covariates to differences in CVD prevalence.Results: CVD was associated with military service (OR=1.34; P

Risk prediction is important during combat operations because resources are limited and triage decisions must be rapid and accurate. We evaluated 2 point-of-care urinary biomarker tests for risk prediction in combat casualties.This was an observational cohort study of critically injured military personnel admitted to Craig Joint Theater Hospital in Afghanistan from October 2012 to December 2013. We collected urine within 3 hours of admission and measured urinary biomarkers with NephroCheck and a neutrophil gelatinase-associated lipocalin dipstick (NGALds) to evaluate their ability to predict a combined end point of need for renal replacement therapy or death. Odds ratios (ORs) were calculated and receiver operator characteristic curves were generated for both tests.A total of 89 patients were included for analysis. The median Injury Severity Score was 18 and the combined end point occurred in 12 (13.5%) patients. NephroCheck was not associated with the combined end point (OR 1.56; 95% CI 0.81 to 3.03; p = 0.19) and the area under the curve of the receiver operator characteristic curve was 0.65. The NGALds was highly associated with the combined end point (OR 4.93; 95% CI 2.18 to 11.14; p0.001) and the area under the curve of the receiver operator characteristic curve was 0.84. The NGALds remained significantly associated with the combined end point in a logistic regression model that included Injury Severity Score as a covariate (OR 4.10; 95% CI 1.74 to 9.67; p = 0.001).Measurement of urinary biomarkers with an NGALds, but not NephroCheck, predicts poor outcomes in combat casualties. An NGALds is a simple urine dipstick that could be deployed to combat zones to prioritize aeromedical evacuation, help with triage decisions, and predict resource use.

BACKGROUND Potassium-binding polymers have shown promising results in an anephric porcine hyperkalemia model. The benefits of the polymer in a clinically relevant injury model remain unknown. We hypothesized that potassium-binding cartridges would control serum potassium concentration in a porcine hemorrhagic shock model with supraceliac aortic occlusion and a limb crush injury. METHODS Ten Yorkshire-cross swine were anesthetized and instrumented. Pigs underwent splenectomy and bilateral nephrectomy. Hemorrhagic shock was induced for 30 minutes while a leg compression device was applied. Pigs underwent supraceliac aortic occlusion for 60 minutes and were resuscitated with shed blood. The leg compression device was removed 20 minutes after balloon deflation. After 20 minutes of reperfusion, animals were randomized to extracorporeal circulation with (treatment) or without (control) the potassium binding cartridges. In both groups, blood was circulated through a hemodialyzer with a peristaltic pump. In the treatment group, the ultrafiltrate was diverted from the hemodialyzer through cartridges containing the polymer and returned to the extracorporeal circuit. Animals were resuscitated with 0.9% saline boluses and a norepinephrine infusion. The change in serum potassium concentration (ΔK) was calculated as serum [K]T390 - serum [K]T0. RESULTS There was a significant difference in serum potassium concentration between groups (p < 0.001). ΔK was significantly higher in the control than the treatment group (3.75 [3.27-4.42] and 1.15 [0.62-1.59] mmol/L, respectively; p = 0.03). There were no differences in mean arterial pressure (p = 0.14), isotonic crystalloids requirement (p = 0.51), or norepinephrine dose (p = 0.83) between groups. Serum lactate concentration was significantly higher in the control group (p < 0.001). At the end of the experiment, the [K] was reduced by 25% (24.9%-27.8%) across the cartridges. CONCLUSION The cartridges controlled serum potassium concentrations without dialysate and retained potassium binding capabilities over 4 hours. There were no deleterious effects on hemodynamic parameters. Those cartridges might be beneficial adjuncts for hyperkalemia management in austere environments. LEVEL OF EVIDENCE Translational science study, level I.

A thorough understanding of the effects of spatially and temporally variable demographic drivers of population processes is necessary to accurately evaluate potential source-sink dynamics, estimate long-term population viability, and devise effective management practices. The black-capped vireo (Vireo atricapilla) is an endangered songbird that suffers from high rates of parasitism by the brown-headed cowbird (Molothrus ater). The largest breeding population of vireos is located on the Fort Hood Military Installation in central Texas. This large reserve is well studied but its role in vireo metapopulation dynamics is largely unknown. Furthermore, the evolving cowbird control regime across Fort Hood and nearby isolated populations could impact the local source-sink dynamics. From 2011 through 2014, we monitored breeding vireos at eleven sites across central Texas that varied in cowbird control level. From observations of fecundity and survival, we calculated stochastic and deterministic population growth rates and assessed populations as sources or sinks. We also calculated quasi-extinction probabilities and the sensitivity and elasticity of population growth to demographic parameters. Sites with at least some cowbird control had greater nest success than sites with no cowbird control. We identified four source populations, three of which were on the large Fort Hood reserve and had comprehensive cowbird control across all study years. Although not all sites with cowbird control were sources on average, population dynamics were variable between years and the implementation of cowbird management was generally associated with the growth of local populations. Importantly, source and sink populations were not static, revealing a complex and temporally dynamic system driven largely by variations in adult survival and evolving cowbird control regimes.

As urban areas have grown in population, use of nearby natural areas for outdoor recreation has also increased, potentially influencing bird distribution in landscapes managed for conservation. Members of the family Corvidae (crows, ravens, jays, and magpies) have strong interactions with humans and may be directly affected by recreation in wild landscapes. In Mount Rainier National Park, we evaluated the effects of vegetation, visitor use, and the availability of human-subsidized food on the use of landscape features by 4 corvid species: Steller's Jay (Cyanocitta stelleri), Gray Jay (Perisoreus canadensis), Common Raven (Corvus corax), and Clark's Nutcracker (Nucifraga columbiana). We conducted >1,400 point counts across areas that varied in habitat and in the degree of human recreational impact. We calculated predicted occupancy values while allowing for variation in detection probability. In addition to species-specific suites of vegetation and landscape variables, we found that patterns of hu...

The associations between injury severity, posttraumatic stress disorder (PTSD), and development of chronic diseases, such as hypertension, among military service members are not understood. We sought to (1) estimate the prevalence and incidence of PTSD within a severely injured military cohort, (2) assess the association between the presence and chronicity of PTSD and hypertension, and (3) determine whether or not initial injury severity score and PTSD are independent risk factors for hypertension. Administrative and clinical databases were used to conduct a retrospective cohort study of 3846 US military casualties injured in the Iraq and Afghanistan conflicts between February 1, 2002, and February 1, 2011. Development of PTSD and hypertension after combat injury were determined using the International Classification of Diseases, Ninth Revision codes. Multivariable competing risk regression models were used to assess associations between injury severity score, PTSD, and hypertension, while controlling for covariates. Overall prevalence of PTSD was 42.4%, and prevalence of hypertension was 14.3%. Unadjusted risk of hypertension increased significantly with chronicity of PTSD (1–15 diagnoses: hazard ratio, 1.77; 95% confidence interval, 1.46–2.14; P 15 diagnoses: hazard ratio, 2.29; 95% confidence interval, 1.85–2.84; P P P =0.03). In a cohort of service members injured in combat, we found that chronicity of PTSD diagnoses and injury severity were independent risk factors for hypertension.

Red-tailed Hawks (Buteo jamaicensis) are common across North America and are well-adapted to human-altered landscapes. Yellowstone National Park offers an opportunity to study this nearly ubiquitous species in a relatively unaltered and intact temperate ecosystem. In anticipation of future habitat and environmental change, we monitored Red-tailed Hawk territories and nests across the park's northern range to establish a baseline of hawk density, reproduction, and population status. We used a combination of intensive territory monitoring at two different scales and roadside point count surveys, analyzed using detection-dependent density modeling. From 2011 through 2015, we monitored between 17 and 44 territories each year and, in total, documented at least 60 territories in the northern range. Territory density across the northern range was comparable with other regional estimates, but local density was particularly high on the Blacktail Deer Plateau. On average, 87% of territorial pairs (range: 75–100%) laid eggs and breeding success averaged 63% (range: 48–89%). Hawk reproductive rate averaged 1.07 (range: 0.46–1.74) young per occupied territory and brood size averaged 1.73 (range: 1.30–1.96) young per successful nest. Reproductive rate varied significantly between study years but on average was well below the level thought necessary for a stable population, underscoring the importance of continued monitoring to better understand the drivers of population trends.