Assessing the association of epigenetic age acceleration with osteoarthritis in the Multicenter Osteoarthritis Study (MOST).

PURPOSE: Advancing age is one of the strongest risk factors for osteoarthritis (OA). DNA methylation-based measures of epigenetic age acceleration may provide insights into mechanisms underlying OA. METHODS: We analyzed data from the Multicenter Osteoarthritis Study in a subset of 671 participants ages 45-69 years with no or mild radiographic knee OA. DNA methylation was assessed with the Illumina Infinium MethylationEPIC 850K array. We calculated predicted epigenetic age according to Hannum, Horvath, PhenoAge, and GrimAge epigenetic clocks, then regressed epigenetic age on chronological age to obtain the residuals. Associations between the residuals and knee, hand, and multi-joint OA were assessed using logistic regression, adjusted for chronological age, sex, clinical site, smoking status, and race. RESULTS: Twenty-three percent met criteria for radiographic hand OA, 25% met criteria for radiographic knee OA, and 8% met criteria for multi-joint OA. Mean chronological age (SD) was 58.4 (6.7) years. Mean predicted epigenetic age (SD) according to Horvath, Hannum, PhenoAge, and GrimAge epigenetic clocks was 64.9 (6.4), 68.6 (5.9), 50.5 (7.7), and 67.0 (6.2), respectively. Horvath epigenetic age acceleration was not associated with an increased odds of hand OA, odds ratio (95% confidence intervals) = 1.03 (0.99-1.08), with similar findings for knee and multi-joint OA. We found similar magnitudes of associations for Hannum epigenetic age, PhenoAge, and GrimAge acceleration compared to Horvath epigenetic age acceleration. CONCLUSIONS: Epigenetic age acceleration as measured by various well-validated epigenetic clocks based on DNA methylation was not associated with increased risk of knee, hand, or multi-joint OA independent of chronological age.

Optimal Design of Clinical Trials Involving Persons with Disorders of Consciousness.

BACKGROUND: Limited data exist regarding the optimal clinical trial design for studies involving persons with disorders of consciousness (DoC), and only a few therapies have been tested in high-quality clinical trials. To address this, the Curing Coma Campaign Clinical Trial Working Group performed a gap analysis on the current state of clinical trials in DoC to identify the optimal clinical design for studies involving persons with DoC. METHODS: The Curing Coma Campaign Clinical Trial Working Group was divided into three subgroups to (1) review clinical trials involving persons with DoC, (2) identify unique challenges in the design of clinical trials involving persons with DoC, and (3) recommend optimal clinical trial designs for DoC. RESULTS: There were 3055 studies screened, and 66 were included in this review. Several knowledge gaps and unique challenges were identified. There is a lack of high-quality clinical trials, and most data regarding patients with DoC are based on observational studies focusing on patients with traumatic brain injury and cardiac arrest. There is a lack of a structured long-term outcome assessment with significant heterogeneity in the methodology, definitions of outcomes, and conduct of studies, especially for long-term follow-up. Another major barrier to conducting clinical trials is the lack of resources, especially in low-income countries. Based on the available data, we recommend incorporating trial designs that use master protocols, sequential multiple assessment randomized trials, and comparative effectiveness research. Adaptive platform trials using a multiarm, multistage approach offer substantial advantages and should make use of biomarkers to assess treatment responses to increase trial efficiency. Finally, sound infrastructure and international collaboration are essential to facilitate the conduct of trials in patients with DoC. CONCLUSIONS: Conduct of trials in patients with DoC should make use of master protocols and adaptive design and establish international registries incorporating standardized assessment tools. This will allow the establishment of evidence-based practice recommendations and decrease variations in care.

Pediatric Unintentional Fall-Related Injuries in a Statewide Trauma Registry.

OBJECTIVES: The purpose of the study was to evaluate patterns of fall-related injury through childhood and identify risk factors for more severe fall-related injuries with the goal of informing targeted prevention strategies for different ages. METHODS: The study population consisted of pediatric patients in the Iowa Trauma Registry from January 1, 2010, to December 31, 2014, who sustained an unintentional fall-related injury (N = 3856 patients). Multinomial logistic regression analysis was used to predict injury severity. Adjusted odds ratios were calculated characterizing the relationship between fall severity and age, sex, race, and fall type. RESULTS: More males (62%) sustained a fall-related injury during the study period when compared with females (38%; P < 0.0001). Head injuries were the most common type of injury in the younger than 1 year age group (77%), whereas fractures were the predominant injury type in all other age groups, followed by head injuries. Those younger than 1 year (adjusted odds ratio, 4.0; 95% confidence interval, 2.36-6.90) and aged 15 to 18 years (adjusted odds ratio, 1.9; 95% confidence interval, 1.17-3.03) were more likely to have an Injury Severity Score of ≥16 than those aged 10 to 14 years. CONCLUSIONS: Recommendations and prevention strategies need to focus on specific risk factors to reduce the harm of multilevel falls. As we have shown, patterns of fall injuries presenting to trauma hospitals differ by age, thus suggesting that prevention strategies focus on specific age groups.

Phase 1/2a Trial of ISPASM.

BACKGROUND AND PURPOSE: Microthrombosis could play a role in delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage. Tirofiban has shown promising results in reducing delayed cerebral ischemia in retrospective studies. However, the safety of using tirofiban in aneurysmal subarachnoid hemorrhage is not rigorously established. METHODS: A phase 1/2a double-blinded randomized controlled trial (2:1 randomization) to assess the safety of a 7-day intravenous infusion of tirofiban compared with placebo, in patients with aneurysmal subarachnoid hemorrhage treated with ventriculostomy placed in the operative room and coiling was conducted. The primary end point was any intracranial hemorrhage during the hospital stay. The secondary end points were: incidence of radiographic and clinical vasospasm, incidence of delayed cerebral ischemia, and incidence of cerebral ischemic changes noted on magnetic resonance imaging or computed tomography. RESULTS: Eighteen patients received intravenous tirofiban and 12 received placebo. There was no difference in baseline characteristics except for higher male proportions in the tirofiban group. There was no difference in death, in development of new or change in existing intracranial hemorrhages, in thrombocytopenia, and need for shunts in the two arms. However, the tirofiban arm had a lower incidence of delayed cerebral ischemia compared with placebo (6% [1/18] versus 33% [4/12]; P=0.04), and less radiographic vasospasm as detected by catheter angiogram or computed tomography angiography (P=0.01) and computed tomography perfusion (P=0.01). CONCLUSIONS: The above preliminary results support proceeding with further testing of the safety and efficacy of 7-day intravenous infusion of tirofiban in a pragmatic (placing external ventricular drain by the bedside), multicenter setting, and using a larger population. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03691727.

Common Data Elements for Unruptured Intracranial Aneurysm and Subarachnoid Hemorrhage Clinical Research: Recommendations from the Working Group on Long-Term Therapies.

OBJECTIVES: The goal for the long-term therapies (LTT) working group (WG) of the Unruptured Intracranial Aneurysm (UIA) and Subarachnoid Hemorrhage (SAH) common data elements (CDEs) was to develop a comprehensive set of CDEs, data definitions, case report forms, and guidelines for use in UIA and SAH LTT clinical research, as part of a new joint effort between the National Institute of Neurological Disorders and Stroke (NINDS) and the National Library of Medicine of the US National Institutes of Health. These UIA and SAH CDEs will join other neurological disease-specific CDEs already developed and available for use by research investigators. METHODS: The eight LTT WG members comprised international UIA, and SAH experts reviewed existing NINDS CDEs and instruments, created new elements when needed, and provided recommendations for future LTT clinical research. The recommendations were compiled, internally reviewed by the all UIA and SAH WGs and steering committee members. The NINDS CDE team also reviewed the final version before posting the SAH Version 1.0 CDE recommendations on the NINDS CDE website. RESULTS: The NINDS UIA and SAH LTT CDEs and supporting documents are publicly available on the NINDS CDE ( https://www.commondataelements.ninds.nih.gov/#page=Default ) and NIH Repository ( https://cde.nlm.nih.gov/home ) websites. The subcommittee members discussed and reviewed various parameters, outcomes, and endpoints in UIA and SAH LTT studies. The following meetings with WG members, the LTT WG's recommendations are incorporated into the disease/injury-related events, assessments and examinations, and treatment/intervention data domains. CONCLUSIONS: Noting gaps in the literature regarding medication and rehabilitation parameters in UIA and SAH clinical studies, the current CDE recommendations aim to arouse interest to explore the impact of medication and rehabilitation treatments and therapies and encourage the convergence of LTT clinical study parameters to develop a harmonized standard.

Common Data Elements for Unruptured Intracranial Aneurysms and Subarachnoid Hemorrhage Clinical Research: A National Institute for Neurological Disorders and Stroke and National Library of Medicine Project.

OBJECTIVES: The goal for this project was to develop a comprehensive set of common data elements (CDEs), data definitions, case report forms and guidelines for use in unruptured intracranial aneurysm (UIA) and subarachnoid hemorrhage (SAH) clinical research, as part of a new joint effort between the National Institute of Neurological Disorders and Stroke (NINDS) and the National Library of Medicine of the US National Institutes of Health. These UIA and SAH CDEs will join several other neurological disease-specific CDEs that have already been developed and are available for use by research investigators. METHODS: A Working Group (WG) divided into eight sub-groups and a Steering Committee comprised of international UIA and SAH experts reviewed existing NINDS CDEs and instruments, created new elements when needed and provided recommendations for UIA and SAH clinical research. The recommendations were compiled, internally reviewed by the entire UIA and SAH WG and posted online for 6 weeks for external public comments. The UIA and SAH WG and the NINDS CDE team reviewed the final version before posting the SAH Version 1.0 CDE recommendations. RESULTS: The NINDS UIA and SAH CDEs and supporting documents are publicly available on the NINDS CDE ( https://www.commondataelements.ninds.nih.gov/#page=Default ) and NIH Repository ( https://cde.nlm.nih.gov/home ) websites. The recommendations are organized into domains including Participant Characteristics and Outcomes and Endpoints. CONCLUSION: Dissemination and widespread use of CDEs can facilitate UIA and SAH clinical research and clinical trial design, data sharing, and analyses of observational retrospective and prospective data. It is vital to maintain an international and multidisciplinary collaboration to ensure that these CDEs are implemented and updated when new information becomes available.

Angiographic Features of Intracranial Aneurysms in Ecuador.

BACKGROUND: Most of the literature describing morphological features of intracranial aneurysms (IAs) is from North-America, East-Asia, and Europe. There is limited data from South-America. We describe the epidemiologic and angiographic features of ruptured and unruptured IAs in a cohort of patients from Ecuador. METHODS: We conducted a retrospective analysis of prospectively acquired databases from 3 different tertiary hospitals over a 3-year period (2014-2017). In a per-patient basis, odd ratios (ORs) of ruptured presentation for each variable using a univariate logistic regression model were calculated. An aneurysm-based multivariate analysis was performed to calculate rupture ORs for each variable. RESULTS: Our sample included 557 patients with 761 IAs. Mean patient age was 52.2 years (range 18-82). Sixty-eight percent were women, and almost 90% presented with ruptured aneurysms and concomitant subarachnoid hemorrhage (SAH). Mean size of all the IAs was 6.4 mm ± 3.98 mm. Most IAs were located in anterior circulation (96.6%): 28.4% medial cerebral artery, 24.4% anterior cerebral artery or anterior communicating artery (ACOM), and 23.5% posterior communicating artery (PCOM). Only 6 basilar tip aneurysms (0.8%) were reported. In the adjusted analysis, aneurysms located in the ACOM (OR 1.89, 95% CI 1.29-2.78) and PCOM (OR 1.84, 95% CI 1.25-2.71), size larger than 5 mm (OR 2.84, 95% CI 2.04-3.93) and 7 mm (OR 2.28, 95% CI 1.64-3.19), and those with non-saccular morphology (OR 9.87, 95% CI 2.21-44.14) were significantly associated with ruptured presentation. CONCLUSIONS: The prevalence of posterior circulation IAs in Ecuador, particularly basilar tip aneurysms, is low when compared to previous reports from developed countries. In our sample, IAs greater than 5 mm (and ≥7 mm) in size, ACOM and PCOM locations, and IAs with nonsaccular morphologies (blister and fusiform) were significantly associated with SAH presentation.

Secular Increases in Spontaneous Subarachnoid Hemorrhage during Pregnancy: A Nationwide Sample Analysis.

IMPORTANCE: Understanding of the epidemiology, outcomes, and management of spontaneous subarachnoid hemorrhage (sSAH) during pregnancy is limited. Small, single center series suggest a slight increase in morbidity and mortality. OBJECTIVE: To determine if incidence of sSAH in pregnancy is increasing nationally and also to study the outcomes for this patient population. DESIGN, SETTING, AND PARTICIPANTS: A retrospective analysis was performed utilizing the Nationwide Inpatient Sample (NIS) and Healthcare Cost and Utilization Project for the years 2002-2014 for sSAH hospitalizations. The NIS is a large administrative database designed to produce nationally weighted estimates. Female patients age 15-49 with sSAH were identified using the International Classification of Diseases, 9th Revision, Clinical Modification code 430. Pregnancy and maternal diagnosis were identified using pregnancy related ICD codes validated by previous studies. The Cochran-Armitage trend test and parametric tests were utilized to analyze temporal trends and group comparisons. Main Outcomes and Measures: National trend for incidence of sSAH in pregnancy, age, and race/ethnicity as well as associated risk factors and outcomes. RESULTS: During the time period, there were 73,692 admissions for sSAH in women age 15-49 years, of which 3978 (5.4%) occurred during pregnancy. The proportion of sSAH during pregnancy hospitalizations increased from 4.16 % to 6.33% (P-Trend < .001) during the 12 years of the study. African-American women (8.19%) and Hispanic (7.11%) had higher rates of sSAH during pregnancy than whites (3.83%). In the NIS data, the incidence of sSAH increased from 5.4/100,000 deliveries (2002) to 8.5/100,000 deliveries (2014; P-Trend < .0001). The greatest increase in sSAH was noted to be among pregnant African-American women from (13.4 [2002]) to (16.39 [2014]/100,000 births). Mortality was lower in pregnant women (7.69% versus 17.37%, P < .0001). Pregnant women had a higher likelihood of being discharged to home (69.78% versus 53.66%, P < .0001) and lower likelihood of discharge to long term facility (22.4% versus 28.7%, P < .0001) than nonpregnant women after sSAH hospitalization. CONCLUSIONS AND RELEVANCE: There is an upward trend in the incidence of sSAH occurring during pregnancy. There was disproportionate increase in incidence of sSAH in the African American and younger mothers. Outcomes were better for both pregnant and nonpregnant women treated at teaching hospitals and in pregnant women in general as compared to nonpregnant women.

Disparities in Inter-hospital Helicopter Transportation for Hispanics by Geographic Region: A Threat to Fairness in the Era of Thrombectomy.

BACKGROUND AND PURPOSE: Mechanical thrombectomy (MT) is a time-dependent therapy that is only available at a limited number of hospitals. As such, patients that live at a considerable distance of those specialized centers often require rapid interhospital emergent evacuation with Helicopter Emergency Medical Services (HEMS) to be considered for MT. It is not known whether the use of HEMS is equitable across different groups of patients. METHODS: Acute ischemic stroke patients emergently transferred to another facility were identified in a retrospective review of a large Medicare claims database. Mode of transportation (HEMS, advanced, or basic ground ambulances) was determined by CPT codes. Distance from patient's residence to the closest center with MT capabilities was calculated. Generalized linear mixed logit models were used to determine the odds of HEMS relative to ground services for Hispanic and non-Hispanic black (NHB) patients relative to non-Hispanic white (NHW) patients while controlling for confounders. RESULTS: A total of 8027 patients that underwent emergent interhospital transportation were analyzed. HEMS utilization was 18.1% for NHB, 20.6% for Hispanics, and 21.6% for NHW (P = .054). In adjusted analyses for confounders, including distance to a MT-capable hospital, Hispanic patients were less likely than NHWs to be transported by HEMS. While that association had marginal significance for the whole United States (OR = .76; 95% CI, .57-1.01; P = .055), it was statistically significant for patients living in the southern region of the United States (OR = .6; 95% CI, .40-.92; P = .019). DISCUSSION: Our findings suggest there is a disparity in the use of HEMS in Hispanic stroke patients compared to NHW. Such a disparity may delay arrival to a MT-capable hospital, delay treatment times, or lead to ineligibility for MT altogether. Given the known benefit of MT and known existing disparities in stroke treatment and outcomes, it is important to further investigate and address disparities in mode of interhospital transportation.

Intravenous immune globulin and thromboembolic adverse events in patients with hematologic malignancy.

In patients with hypogammaglobulinemia secondary to chronic lymphocytic leukemia (CLL) or multiple myeloma (MM), intravenous immune globulin (IVIg) may be administered to reduce the risk of infection. Since 2013, IVIg products have carried a boxed safety warning about the risk of thromboembolic events (TEEs), with TEEs reported in 0.5% to 15% of patients treated with IVIg. In this retrospective cohort study of older patients with CLL or MM identified from the Surveillance, Epidemiology, and End Results-Medicare Linked Database, we assessed rates of clinically serious TEEs in 2724 new users of IVIg and a propensity-matched comparison group of 8035 nonusers. For the primary end point, arterial TEE, we observed a transient increased risk of TEE during the day of an IVIg infusion and the day afterward (hazard ration = 3.40; 95% confidence interval [CI]: 1.25, 9.25); this risk declined over the remainder of the 30-day treatment cycle. When considered in terms of absolute risk averaged over a 1-year treatment period, the increase in risk attributable to IVIg was estimated to be 0.7% (95% CI: -0.2%, 2.0%) compared with a baseline risk of 1.8% for the arterial TEE end point. A statistically nonsignificant risk increase of 0.3% (95% CI: -0.4%, 1.5%) compared with a baseline risk of 1.1% was observed for the venous TEE end point. Further research is needed to establish the generalizability of these results to patients receiving higher doses of IVIg for other indications.

Emergency department charges may be associated with mortality in patients with severe sepsis and septic shock: a cohort study.

BACKGROUND: Sepsis severity of illness is challenging to measure using claims, which makes sepsis difficult to study using administrative data. We hypothesized that emergency department (ED) charges may be associated with hospital mortality, and could be a surrogate marker of severity of illness for research purposes. The objective of this study was to measure concordance between ED charges and mortality in admitted patients with severe sepsis or septic shock. METHODS: Cohort study of all adult patients presenting to a 60,000-visit Midwestern academic ED with severe sepsis or septic shock (by ICD-9 codes) between July 1, 2008 and June 30, 2010. Data on demographics, admission APACHE-II score, and disposition was extracted from the medical record, and comorbidities were identified from diagnosis codes using the Elixhauser methodology. Summary statistics were reported and bivariate concordance was tested using Pearson correlation. Logistic regression models for 28-day mortality were developed to measure the independent association with mortality. RESULTS: We included a total of 294 patients in the analysis. We found that ED charges were inversely related to mortality (adjusted OR 0.829 per $1000 increase in total ED charges, 95%CI 0.702-0.980). ED charges were also independently associated with 28-day hospital-free and ICU-free days (0.74 days increase per $1000 additional ED charges, 95%CI 0.06-1.41 and 0.81 days increase per $1000 additional ED charges, 95%CI 0.05-1.56, respectively). ED charges were also associated with APACHE-II score ($34 total ED charges per point increase in APACHE-II score, 95%CI $6-62). CONCLUSIONS: ED charges in administrative data sets are associated with in-hospital mortality and health care utilization, likely related to both illness severity and intensity of early sepsis resuscitation. ED charges may have a role in risk adjustment models using administrative data for acute care research.

Management of Brain Arteriovenous Malformations: A Scientific Statement for Healthcare Professionals From the American Heart Association/American Stroke Association.

PURPOSE: The aim of this statement is to review the current data and to make suggestions for the diagnosis and management of both ruptured and unruptured brain arteriovenous malformations. METHODS: The writing group met in person and by teleconference to establish search terms and to discuss narrative text and suggestions. Authors performed their own literature searches of PubMed, Medline, or Embase, specific to their allocated section, through the end of January 2015. Prerelease review of the draft statement was performed by expert peer reviewers and by the members of the Stroke Council Scientific Oversight Committee and Stroke Council Leadership Committee. RESULTS: The focus of the scientific statement was subdivided into epidemiology; diagnosis; natural history; treatment, including the roles of surgery, stereotactic radiosurgery, and embolization; and management of ruptured and unruptured brain arteriovenous malformations. Areas requiring more evidence were identified. CONCLUSIONS: Brain arteriovenous malformations are a relatively uncommon but important cause of hemorrhagic stroke, especially in young adults. This statement describes the current knowledge of the natural history and treatment of patients with ruptured and unruptured brain arteriovenous malformations, suggestions for management, and implications for future research.

Relationship of Trochlear Morphology and Patellofemoral Joint Alignment to Superolateral Hoffa Fat Pad Edema on MR Images in Individuals with or at Risk for Osteoarthritis of the Knee: The MOST Study.

Purpose To determine the relationship of patellofemoral joint alignment and trochlear morphology to superolateral Hoffa fat pad (SHFP) edema on magnetic resonance (MR) images in older adults with or at risk for osteoarthritis of the knee. Materials and Methods Institutional review board approval and written informed consent were obtained from all subjects. The Multicenter Osteoarthritis Study is a prospective cohort study of older adults with or at risk for osteoarthritis of the knee. Subjects were recruited from Birmingham, Alabama, and Iowa City, Iowa. In this cross-sectional study, patellofemoral joint alignment (bisect offset, patellar tilt angle, and Insall-Salvati ratio), trochlear morphology (sulcus angle, lateral and medial trochlear inclination, and trochlear angle) and SHFP edema were assessed on MR images of the knee. Measures of alignment and morphology were divided into quartiles, and SHFP was determined to be present or absent. Separate logistic regression models were used to determine the relationship of each measure of alignment and morphology to the presence of SHFP edema, with adjustments for age, sex, and body mass index. Results SHFP edema was present in 152 (13.4%) of the 1134 knees that were included. When compared with knees with measurements in the lowest quartile, knees with measurements in the highest quartile for trochlear angle, bisect offset, and Insall-Salvati ratios were 1.6 (95% confidence interval [CI]: 1.0, 2.6), 2.3 (95% CI: 1.3, 4.0), and 8.9 (95% CI: 4.7, 16.9) times more likely to show SHFP edema, respectively. No relationship was found between other measures and SHFP edema. Conclusion A more anterior trochlear facet, a more laterally displaced patella, and knees with patella alta were significantly associated with SHFP edema on MR images in subjects with or at risk for osteoarthritis of the knee. © RSNA, 2017.

Rural Patients With Severe Sepsis or Septic Shock Who Bypass Rural Hospitals Have Increased Mortality: An Instrumental Variables Approach.

OBJECTIVE: To identify factors associated with rural sepsis patients' bypassing rural emergency departments to seek emergency care in larger hospitals, and to measure the association between rural hospital bypass and sepsis survival. DESIGN: Observational cohort study. SETTING: Emergency departments of a rural Midwestern state. PATIENTS: All adults treated with severe sepsis or septic shock between 2005 and 2014, using administrative claims data. INTERVENTIONS: Patients bypassing local rural hospitals to seek care in larger hospitals. MEASUREMENTS AND MAIN RESULTS: A total of 13,461 patients were included, and only 5.4% (n = 731) bypassed a rural hospital for their emergency department care. Patients who initially chose a top-decile sepsis volume hospital were younger (64.7 vs 72.7 yr; p < 0.001) and were more likely to have commercial insurance (19.6% vs 10.6%; p < 0.001) than those who were seen initially at a local rural hospital. They were also more likely to have significant medical comorbidities, such as liver failure (9.9% vs 4.2%; p < 0.001), metastatic cancer (5.9% vs 3.2%; p < 0.001), and diabetes with complications (25.2% vs 21.6%; p = 0.024). Using an instrumental variables approach, rural hospital bypass was associated with a 5.6% increase (95% CI, 2.2-8.9%) in mortality. CONCLUSIONS: Most rural patients with sepsis seek care in local emergency departments, but demographic and disease-oriented factors are associated with rural hospital bypass. Rural hospital bypass is independently associated with increased mortality.

Longitudinal associations between mental health conditions and overactive bladder in women veterans.

BACKGROUND: One in 5 recently deployed US women veterans report overactive bladder symptoms. Mental health conditions such as depression and anxiety commonly co-occur in women with overactive bladder, but temporal relationships between these outcomes have not been well studied, and the mechanism behind this association is unknown. The Women Veterans Urinary Health Study, a nationwide longitudinal study in recently deployed women veterans, was designed to better understand relationships between overactive bladder and mental health conditions. OBJECTIVE: We sought to estimate the 1-year incidence and remission of overactive bladder and to identify the impact of depression, anxiety, posttraumatic stress disorder, and prior sexual assault on 1-year overactive bladder incidence and remission rates. STUDY DESIGN: Participants of this 1-year prospective cohort study were female veterans separated from military service who had returned from Iraq or Afghanistan deployment within the previous 2 years. Eligible women were identified through the Defense Manpower Data Center and recruited by mail and telephone. Telephone screening confirmed participants were ambulatory, community-dwelling veterans and excluded those with urinary tract fistula, congenital abnormality, or cancer; pelvic radiation; spinal cord injury; multiple sclerosis; Parkinson disease; stroke; or current/recent pregnancy. Data collection included computer-assisted telephone interviews performed at enrollment and 1 year later. The interview assessed demographic and military service characteristics; urinary symptoms and treatment; depression, anxiety, and posttraumatic stress disorder symptoms and treatment; and a lifetime history of sexual assault. Overactive bladder was identified if at least moderately bothersome urgency urinary incontinence and/or urinary frequency symptoms were reported on Urogenital Distress Inventory items. Exposures included depression, anxiety, posttraumatic stress disorder, and lifetime sexual assault, assessed at baseline using validated questionnaires (including the Patient Health Questionnaire and Posttraumatic Stress Disorder Checklist). Associations between exposures and overactive bladder incidence and remission were estimated using propensity score adjusted logistic regression models. RESULTS: In all, 1107 (88.0%) of 1258 eligible participants completed 1-year interviews. Median age was 29 (range 20-67) years and 53% were nulliparous. Overactive bladder was identified at baseline in 242 (22%), and 102 (9.2%), 218 (19.7%), 188 (17.0%), and 287 (25.9%) met criteria for baseline depression, anxiety, posttraumatic stress disorder, and lifetime sexual assault, respectively. At 1 year, overactive bladder incidence was 10.5% (95% confidence interval, 8.6-12.8%), and remission of overactive bladder was 36.9% (95% confidence interval, 30.8-43.4%). New overactive bladder occurred more often in women with baseline anxiety (21% vs 9%), posttraumatic stress disorder (19% vs 9%) and lifetime sexual assault (16% vs 9%) (all: P < .01). After adjustment, anxiety (odds ratio, 2.4; 95% confidence interval, 1.4-4.1) and lifetime sexual assault (odds ratio, 1.7; 95% confidence interval, 1.0-2.8) predicted 1-year incident overactive bladder. Overactive bladder remission occurred less often in those with baseline depression (19% vs 41%, P < .01) and anxiety (29% vs 42%, P = .03). After adjustment, depression decreased 1-year overactive bladder remission risk (odds ratio, 0.37; 95% confidence interval, 0.16-0.83). Overactive bladder treatment was uncommon and not associated with remission. CONCLUSION: Anxiety, depression, and prior sexual assault-common postdeployment problems for women veterans-influence the natural history of overactive bladder. Providers should screen for mental health conditions and sexual assault in women with newly diagnosed or persistent overactive bladder.

The Relationship Between US Military Officer Leadership Behaviors and Risk of Sexual Assault of Reserve, National Guard, and Active Component Servicewomen in Nondeployed Locations.

OBJECTIVES: To determine if military leader behaviors are associated with active component and Reserve-National Guard servicewomen's risk of sexual assault in the military (SAIM) for nondeployed locations. METHODS: A community sample of 1337 Operation Enduring Freedom and Operation Iraqi Freedom-era Army and Air Force servicewomen completed telephone interviews (March 2010-December 2011) querying sociodemographic and military characteristics, sexual assault histories, and leader behaviors. We created 2 factor scores (commissioned and noncommissioned) to summarize behaviors by officer rank. RESULTS: A total of 177 servicewomen (13%) experienced SAIM in nondeployed locations. Negative leader behaviors were associated with increased assault risk, at least doubling servicewomen's odds of SAIM (e.g., noncommissioned officers allowed others in unit to make sexually demeaning comments; odds ratio = 2.7; 95% confidence interval = 1.8, 4.1). Leader behavior frequencies were similar, regardless of service type. Negative leadership behavior risk factors remained significantly associated with SAIM risk even after adjustment for competing risk. Noncommissioned and commissioned officer factor scores were highly correlated (r = 0.849). CONCLUSIONS: The association between leader behaviors and SAIM indicates that US military leaders have a critical role in influencing servicewomen's risk of and safety from SAIM.

Sexual assault in the US military: A comparison of risk in deployed and non-deployed locations among Operation Enduring Freedom/Operation Iraqi Freedom active component and Reserve/National Guard servicewomen.

BACKGROUND: To determine whether sexual assault in the military (SAIM) among active component and Reserve/National Guard servicewomen is more likely to occur in deployed or non-deployed locations; and which location poses greater risk for SAIM when time spent in-location is considered. METHODS: A total of 1337 Operation Enduring Freedom/Operation Iraqi Freedom era servicewomen completed telephone interviews eliciting socio-demographics, military and sexual assault histories, including attempted and completed sexual assault. RESULTS: Half of the sample had been deployed (58%). Overall 16% (N = 245) experienced SAIM; a higher proportion while not deployed (15%; n = 208) than while deployed (4%; n = 52). However, the incidence of SAIM per 100 person-years was higher in deployed than in non-deployed locations: 3.5 vs 2.4. Active component and Reserve/National Guard had similar deployment lengths, but Reserve/National Guard had higher SAIM incidence rates/100 person-years (2.8 vs 4.0). CONCLUSIONS: A higher proportion of servicewomen experienced SAIM while not deployed; however, adjusting for time in each location, servicewomen were at greater risk during deployment.

Hysterectomy risk in premenopausal-aged military veterans: associations with sexual assault and gynecologic symptoms.

BACKGROUND: Several gynecological conditions associated with hysterectomy, including abnormal bleeding and pelvic pain, have been observed at increased rates in women who have experienced sexual assault. Previous findings have suggested that one of the unique health care needs for female military veterans may be an increased prevalence of hysterectomy and that this increase may partially be due to their higher risk of sexual assault history and posttraumatic stress disorder (PTSD). Although associations between trauma, PTSD, and gynecological symptoms have been identified, little work has been done to date to directly examine the relationship between sexual assault, PTSD, and hysterectomy within the rapidly growing female veteran population. OBJECTIVES: The objective of the study was to assess the prevalence of hysterectomy in premenopausal-aged female veterans, compare with general population prevalence, and examine associations between hysterectomy and sexual assault, PTSD, and gynecological symptoms in this veteran population. STUDY DESIGN: We performed a computer-assisted telephone interview between July 2005 and August 2008 of 1004 female Veterans Affairs (VA)-enrolled veterans ≤ 52 years old from 2 Midwestern US Veterans Affairs medical centers and associated community-based outreach clinics. Within the veteran study population, associations between hysterectomy and sexual assault, PTSD, and gynecological symptoms were assessed with bivariate analyses using χ(2), Wilcoxon-Mann-Whitney, and Student t tests; multivariate logistic regression analyses were used to look for independent associations. Hysterectomy prevalence and ages were compared with large civilian populations represented in the Behavioral Risk Factor Surveillance System and American College of Surgeons National Surgical Quality Improvement Program databases from similar timeframes using χ(2) and Student t tests. RESULTS: Prevalence of hysterectomy was significantly higher (16.8% vs 13.3%, P = .0002), and mean age at hysterectomy was significantly lower (35 vs 43 years old, P < .0001) in this VA-enrolled sample of female veterans compared with civilian population-based data sets. Sixty-two percent of subjects had experienced attempted or completed sexual assault in their lifetimes. A history of completed lifetime sexual assault with vaginal penetration (LSA-V) was a significant risk factor for hysterectomy (age-adjusted odds ratio, 1.85), with those experiencing their first LSA-V in childhood or in military at particular risk. A history of PTSD was also associated with hysterectomy (age-adjusted odds ratio, 1.83), even when controlling for LSA-V. These associations were no longer significant when controlling for the increased rates of gynecological pain, abnormal gynecological bleeding, and pelvic inflammatory disease seen in those veterans with a history of LSA-V. CONCLUSION: Premenopausal-aged veterans may be at higher overall risk for hysterectomy, and for hysterectomy at younger ages, than their civilian counterparts. Veterans who have experienced completed sexual assault with vaginal penetration in childhood or in military and those with a history of PTSD may be at particularly high risk for hysterectomy, potentially related to their higher risk of gynecological symptoms. If confirmed in future studies, these findings have important implications for women's health care providers and policy makers within both the VA and civilian health care systems related to primary and secondary prevention, costs, and the potential for increased chronic disease and mortality.

Intravenous immune globulin and thromboembolic adverse events: A systematic review and meta-analysis of RCTs.

Prior case reports and observational studies indicate that intravenous immune globulin (IVIg) products may cause thromboembolic events (TEEs), leading the FDA to require a boxed warning in 2013. The effect of IVIg treatment on the risk of serious TEEs (acute myocardial infarction, ischemic stroke, or venous thromboembolism) was assessed using adverse event data reported in randomized controlled trials (RCTs) of IVIg. RCTs of IVIg in adult patients from 1995 to 2015 were identified from Pubmed, Embase, ClinicalTrials.Gov, and two large prior reviews of IVIg's therapeutic applications. Trials at high risk of detection or reporting bias for serious adverse events were excluded. 31 RCTs with a total of 4,129 participants (2,318 IVIg-treated, 1,811 control) were eligible for quantitative synthesis. No evidence was found of increased TEE risk among IVIg-treated patients compared with control patients (odds ratio = 1.10, 95% CI: 0.44, 2.88; risk difference = 0.0%, 95% CI: -0.7%, 0.7%, I(2) = 0%). No significant increase in risk was found when arterial and venous TEEs were analyzed as separate endpoints. Trial publications provided little specific information concerning the methods used to ascertain potential adverse events. Care should be taken in extrapolating the results to patients with higher baseline risks of TEE. Am. J. Hematol. 91:594-605, 2016. © 2016 Wiley Periodicals, Inc.