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Iron deficiency (ID) during neurodevelopment is associated with lasting cognitive and socioemotional deficits and increased risk for neuropsychiatric disease throughout the lifespan. These neurophenotypical changes are underlain by gene dysregulation in the brain that outlasts the period of ID; however, the mechanisms by which ID establishes and maintains gene expression changes are incompletely understood. The epigenetic modification of 5-hydroxymethylcytosine (5hmC), or DNA hydroxymethylation, is one candidate mechanism because of its dependence on iron-containing TET enzymes. The aim of the present study was to determine the effect of fetal-neonatal ID on regional brain TET activity, Tet expression, and 5hmC in the developing rat hippocampus and cerebellum and to determine whether changes are reversible with dietary iron treatment. Timed pregnant Sprague Dawley rats were fed iron-deficient diet (ID; 4 mg/kg Fe) from gestational day 2 to generate iron-deficient anemic (IDA) offspring. Control dams were fed iron-sufficient diet (IS; 200 mg/kg Fe). At postnatal day (P)7, a subset of ID-fed litters was randomized to IS diet, generating treated IDA (TIDA) offspring. At P15, the hippocampus and cerebellum were isolated for subsequent analysis. TET activity was quantified by ELISA from nuclear proteins. Expression of Tet1, Tet2, and Tet3 was quantified by qPCR from total RNA. Global %5hmC was quantified by ELISA from genomic DNA. ID increased DNA hydroxymethylation (p = 0.0105), with a corresponding increase in TET activity (p < 0.0001) and Tet3 expression (p < 0.0001) in the P15 hippocampus. In contrast, ID reduced TET activity (p = 0.0016) in the P15 cerebellum, with minimal effect on DNA hydroxymethylation. Neonatal dietary iron treatment resulted in partial normalization of these changes in both brain regions. These results demonstrate that the TET/DNA hydroxymethylation system is disrupted by developmental ID in a brain region-specific manner. Differential regional disruption of this epigenetic system may contribute to the lasting neural circuit dysfunction and neurobehavioral dysfunction associated with developmental ID.

Background: Despite advances in surgery and pharmacotherapy, there remains significant residual ischemic risk after coronary artery bypass grafting surgery. Methods: In REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial), a multicenter, placebo-controlled, double-blind trial, statin-treated patients with controlled low-density lipoprotein cholesterol and mild to moderate hypertriglyceridemia were randomized to 4 g daily of icosapent ethyl or placebo. They experienced a 25% reduction in risk of a primary efficacy end point (composite of cardiovascular death, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina) and a 26% reduction in risk of a key secondary efficacy end point (composite of cardiovascular death, myocardial infarction, or stroke) when compared with placebo. The current analysis reports on the subgroup of patients from the trial with a history of coronary artery bypass grafting. Results: Of the 8179 patients randomized in REDUCE-IT, a total of 1837 (22.5%) had a history of coronary artery bypass grafting, with 897 patients randomized to icosapent ethyl and 940 to placebo. Baseline characteristics were similar between treatment groups. Randomization to icosapent ethyl was associated with a significant reduction in the primary end point (hazard ratio [HR], 0.76 [95% CI, 0.63–0.92]; P =0.004), in the key secondary end point (HR, 0.69 [95% CI, 0.56–0.87]; P =0.001), and in total (first plus subsequent or recurrent) ischemic events (rate ratio, 0.64 [95% CI, 0.50–0.81]; P =0.0002) compared with placebo. This yielded an absolute risk reduction of 6.2% (95% CI, 2.3%–10.2%) in first events, with a number needed to treat of 16 (95% CI, 10–44) during a median follow-up time of 4.8 years. Safety findings were similar to the overall study: beyond an increased rate of atrial fibrillation/flutter requiring hospitalization for at least 24 hours (5.0% vs 3.1%; P =0.03) and a nonsignificant increase in bleeding, occurrences of adverse events were comparable between groups. Conclusions: In REDUCE-IT patients with a history of coronary artery bypass grafting, treatment with icosapent ethyl was associated with significant reductions in first and recurrent ischemic events. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01492361.

OBJECTIVE To assess the efficacy of erenumab at the ≥50%, ≥75%, and 100% reduction in monthly migraine days (MMD) response thresholds, using data from the 6-month double-blind treatment phase (DBTP) of the Study to Evaluate the Efficacy and Safety of Erenumab in Migraine Prevention (STRIVE) pivotal clinical trial. METHODS Enrolled patients with episodic migraine (EM; ≥4 MMD and

BACKGROUND AND PURPOSE: Cavernous malformations occur most often in the brain but can occur in the spinal cord. Small studies of patients with familial cerebral cavernous malformations suggested a prevalence of spinal cord cavernous malformations of 20%–42%. We aimed to review our familial cohort and prospectively estimate the prevalence of spinal cord cavernous malformations. MATERIALS AND METHODS: We initially reviewed our familial cerebral cavernous malformations cohort for spinal cord cavernous malformations and reviewed clinical spine MR imaging examinations for sequence sensitivity. We then prospectively performed research MR imaging of the spinal cord in 29 patients from the familial cohort to estimate the prevalence. RESULTS: Gradient-based sequences identified the most spinal cord cavernous malformations on clinical MR images, forming the basis for developing our screening MR imaging. Screening spinal cord MR imaging demonstrated a prevalence of 72.4%, and a positive correlation with patient age and number of cerebral cavernous malformations. CONCLUSIONS: Spinal cord cavernous malformations occur commonly in the familial cerebral cavernous malformation population. Gradient-based sequences are the most sensitive and should be used when spinal cord cavernous malformations are suspected. This study establishes the prevalence in the familial population at around 70% and supports the idea that this condition is a progressive systemic disease that affects the entire central nervous system.

While total hip arthroplasty (THA) is extremely successful, early failures do occur. The purpose of this study was to determine the cause of revision in specific patient demographic groups at 3 time points to potentially help decrease the revision risk.Data for cases performed between 2012 and 2018 from a statewide, quality improvement arthroplasty registry were used. The database included 79,205 THA cases and 1,433 revisions with identified etiology (1,584 in total). All revisions performed at5 years from the primary THA were reviewed. Six groups, men/women,65, 65-75, and75 years, were compared at revision time points6 months,1 year, and5 years.There were obvious and significant differences between subgroups based on demographics and time points (P.0001). Seven hundred and fifty-six (53%) of all revisions occurred within 6 months. The most common etiologies within 6 months (756 revisions) were fracture (316, 41.8%), dislocation/instability (194, 25.7%), and infection (98, 12.9%). At this early time point, the most common revision cause was fracture for all age/gender-stratified groups, ranging from 27.6% in young men to 60% in older women. Joint instability became the leading cause for revision after 1 year in all groups.This quality improvement project demonstrated clinically meaningful differences in the reason for THA revision between gender, age, and time from surgery. Strategies based on these data should be employed by surgeons to minimize the factors that lead to revision.

Iron deficiency (ID) anemia is the foremost micronutrient deficiency worldwide, affecting around 40% of pregnant women and young children. ID during the prenatal and early postnatal periods has a pronounced effect on neurodevelopment, resulting in long-term effects such as cognitive impairment and increased risk for neuropsychiatric disorders. Treatment of ID has been complicated as it does not always resolve the long-lasting neurodevelopmental deficits. In animal models, developmental ID results in abnormal hippocampal structure and function associated with dysregulation of genes involved in neurotransmission and synaptic plasticity. Dysregulation of these genes is a likely proximate cause of the life-long deficits that follow developmental ID. However, a direct functional link between iron and gene dysregulation has yet to be elucidated. Iron-dependent epigenetic modifications are one mechanism by which ID could alter gene expression across the lifespan. The jumonji and AT-rich interaction domain-containing (JARID) protein and the Ten-Eleven Translocation (TET) proteins are two families of iron-dependent epigenetic modifiers that play critical roles during neural development by establishing proper gene regulation during critical periods of brain development. Therefore, JARIDs and TETs can contribute to the iron-mediated epigenetic mechanisms by which early-life ID directly causes stable changes in gene regulation across the life span.

Uncertainty remains surrounding the use of aspirin as a sole chemoprophylactic agent to reduce the risk of venous thromboembolism (deep vein thrombosis or pulmonary embolism) and bleeding after primary total hip arthroplasty.We performed a non-inferiority analysis of a retrospective cohort of patients undergoing total hip arthroplasty from April 1, 2013 to December 31, 2018. Cases were retrieved from the Michigan Arthroplasty Registry Collaborative Quality Initiative database and performed by 355 surgeons at 61 hospitals throughout Michigan. Surgical setting ranged from small community hospitals to large academic and non-academic centers. The primary outcomes were post-operative venous thromboembolism event or death and bleeding event.Of the 59,747 patients included, 32,878 (55.03%) were female, and the mean age was 64.5. A total of 462 (0.77%) composite venous thromboembolism events occurred. There were 221 (0.71%) and 129 (0.80%) venous thromboembolism events in patients receiving aspirin only and anticoagulants only, respectively. Aspirin was non-inferior to anticoagulants for composite venous thromboembolism events (odds ratio 0.99, 95% confidence interval 0.79-1.26, P.001). Bleeding events occurred in 767 (1.28%) patients, with 304 (0.97%) and 281 (1.74%) bleeding events in patients receiving aspirin only and anticoagulants only, respectively. Aspirin was non-inferior to anticoagulants for bleeding events (odds ratio 0.62, 95% confidence interval 0.52-0.74, P.001).Aspirin is not inferior to other anticoagulants as pharmacologic venous thromboembolism prophylaxis with regards to post-operative risk of venous thromboembolism or bleeding. Sole use of aspirin for venous thromboembolism prophylaxis after total hip arthroplasty should be considered in the appropriate patient.

Background The Michigan Arthroplasty Registry Collaborative Quality Initiative (MARCQI) has monitored discharge disposition, after total hip and knee arthroplasties, since inception in 2012 and found the standardized risk of extended care facility (ECF) placement to be highly variable between hospitals. Methods The variation in standardized risks of ECF placement among MARCQI member sites was reported to the collaborative. At the May 2, 2014 quarterly meeting, a quality initiative was started, emphasizing the wide variability between hospitals, the contribution of hospital and surgeon to that variability using median odds ratios, and the need for outlier hospitals to initiate quality improvement (QI) processes. Patients from 29 hospitals that were members of MARCQI before the intervention were included in this analysis. We compared standardized risks before and after the intervention in the entire cohort, and for 3 hospitals that implemented institution-specific QI projects. We report changes in ECF placement, length of stay, emergency room visits, and readmissions over time. Results This study includes 31,347 patients before and 20,879 patients after the implementation of the quality initiative. The range in standardized risk dropped from 9.4%-46.1% to 9.4%-32.4% and the average dropped from 23.0% to 19.6%. Three outlier hospitals decreased their absolute risk of ECF placement by 12.2%, 8.9%, and 12.4% after QI, without increases in adverse outcomes. Conclusion Discharge to ECF after primary hip and knee arthroplasties is highly variable and influenced by hospital and surgeon practices. Hospital-level QI measures can decrease ECF admissions.

Extended care facility use is a primary driver of variation in hospitalization-associated health care payments and is increasingly a focus for savings under episode-based payment. However, concerns remain that extended care facility limits could incur rising readmissions, emergency department use, or other costs. We analyzed the effects of a statewide value improvement initiative to decrease extended care facility use after lower extremity arthroplasty on extended care facility use, readmission, emergency department use, and payments.We performed a retrospective cohort study using complete claims from the Michigan Value Collaborative for patients undergoing lower extremity joint replacement. We compared the change in extended care facility use before (2012-2013) and after (2016-2017) the aforementioned statewide initiative with 90-day postacute care, readmission, and emergency department rates and payments using t tests.Of the patients included, 68,537 underwent total knee arthroplasty; 27,131 underwent total hip arthroplasty. Statewide, extended care facility use and postacute care payments decreased (extended care facility: 27.5% before vs 18.1% after, payments: $4,999 vs $3,832, P.0001) without increased readmission rates (8.0% vs 7.6%, P = .10) or payments ($1,087 vs $1,026, P = .14). Emergency department use increased (7.8% vs 8.9%, P.0001). Per hospital, there was no association between extended care facility use change and readmission rate change (r = 0.05). Hospital change in extended care facility use ranged from +2.3% (no extended care facility decrease group) to -16.6% (large extended care facility decrease group) and was associated with lower total episode payments without differences in change in readmission rate/payments or emergency department use.Despite decreased use of extended care facilities, there was no compensatory increase in readmission rate or payments. Reducing excess use of extended care facilities after joint replacement may be an important opportunity for savings in episode-based reimbursement.

Background Models of health care coverage with varying degrees of patient cost-sharing have been shown to influence health care behaviors for chronic conditions including medication adherence. The effect of insurance cost-sharing subsidies on the probability of postoperative opioid refill, however, is unclear. Methods This retrospective cohort study examined 100% Medicare claims data among patients (N = 21,781) ages 65 and older undergoing orthopedic procedures in Michigan between January 2013 and September 2016. Patients were classified based on the presence of low-income subsidy and on prior opioid exposure using Medicare Part D prescription files of drug events. We investigated the association of these factors with the probability of both initial and second postoperative opioid fill within 90 days from the date of discharge. Results In this cohort, 84.6% of patients filled an initial opioid prescription, and 66.4% refilled an opioid prescription. Patients with a full low-income subsidy had greater odds of refill within the postoperative 90 days compared with those patients without a low-income subsidy (odds ratio 1.38, 95% confidence interval 1.18–1.60). Among opioid naive patients with a full low-income subsidy, the adjusted refill rate was 61.3% (95% confidence interval 58.0–64.7%) compared with 57.6% (95% confidence interval 51.4–63.7%) among those with partial low-income subsidy and 54.2% (95% confidence interval 52.8–55.6%) among patients without low-income subsidy. Conclusion Among Medicare patients undergoing orthopedic procedures, a full medication subsidy is associated with an increased probability of opioid refill when compared with no subsidy. Going forward, it is critical to lessen financial barriers to ensure all patients have equitable access to postoperative analgesia, including both opioid and nonopioid analgesics by decreasing the patient burden of cost-sharing.

The increasing readmission risk of primary total knee arthroplasty (TKA) represents a significant economic burden and public health challenge. Many have investigated the predictors of readmissions after TKA while little work has studied the associated readmission costs. This article investigated the factors affecting readmission cost after primary TKA at the time of initial discharges using clinical and resource-use information and compared the factors between 2 payer groups (Medicare-or-Medicaid and non-Medicare-nor-Medicaid groups).We used data from the Michigan State Inpatient Database of the Healthcare Cost and Utilization Project, Agency for Healthcare Research and Quality. We identified readmissions after primary TKA in 2012 using International Classification of Diseases, Ninth Revision, code 81.54. Total readmission cost was modeled using multivariate regression to identify predictors.Of 1358 readmissions after primary TKA, 949 were in the Medicare-or-Medicaid group, and 409 were in the non-Medicare-nor-Medicaid group. The overall mean and median total readmission costs were $9335 (standard deviation $10,528) and $6810, respectively. Significant predictors of total readmission cost for the Medicare-or-Medicaid group included length of stay (P.001), discharge disposition (P.001), number of chronic conditions (P = .001), and total cost of initial admission (P.001). Only total cost of initial admission was significant in predicting total readmission cost for the non-Medicare-nor-Medicaid group (P.001).Total cost of initial admission was a significant predictor of total readmission cost in both Medicare-or-Medicaid and non-Medicare-nor-Medicaid groups, independent of length of stay and number of chronic conditions.

Objective While psychosocial factors have been associated with poorer outcomes after knee and hip arthroplasty, we hypothesized that augmented pain perception, as occurs in conditions such as fibromyalgia, may account for decreased responsiveness to primary knee and hip arthroplasty. Methods A prospective, observational cohort study was conducted. Preoperative phenotyping was conducted using validated questionnaires to assess pain, function, depression, anxiety, and catastrophizing. Participants also completed the 2011 fibromyalgia survey questionnaire, which addresses the widespread body pain and comorbid symptoms associated with characteristics of fibromyalgia. Results Of the 665 participants, 464 were retained 6 months after surgery. Since individuals who met criteria for being classified as having fibromyalgia were expected to respond less favorably, all primary analyses excluded these individuals (6% of the cohort). In the multivariate linear regression model predicting change in knee/hip pain (primary outcome), a higher fibromyalgia survey score was independently predictive of less improvement in pain (estimate −0.25, SE 0.044; P

Guidelines for cardiopulmonary resuscitation recommend a chest compression rate of at least 100 compressions/min. A recent clinical study reported optimal return of spontaneous circulation with rates between 100 and 120/min during cardiopulmonary resuscitation for out-of-hospital cardiac arrest. However, the relationship between compression rate and survival is still undetermined.Prospective, observational study.Data is from the Resuscitation Outcomes Consortium Prehospital Resuscitation IMpedance threshold device and Early versus Delayed analysis clinical trial.Adults with out-of-hospital cardiac arrest treated by emergency medical service providers.None.Data were abstracted from monitor-defibrillator recordings for the first five minutes of emergency medical service cardiopulmonary resuscitation. Multiple logistic regression assessed odds ratio for survival by compression rate categories (80, 80-99, 100-119, 120-139, ≥140), both unadjusted and adjusted for sex, age, witnessed status, attempted bystander cardiopulmonary resuscitation, location of arrest, chest compression fraction and depth, first rhythm, and study site. Compression rate data were available for 10,371 patients; 6,399 also had chest compression fraction and depth data. Age (mean±SD) was 67±16 years. Chest compression rate was 111±19 per minute, compression fraction was 0.70±0.17, and compression depth was 42±12 mm. Circulation was restored in 34%; 9% survived to hospital discharge. After adjustment for covariates without chest compression depth and fraction (n=10,371), a global test found no significant relationship between compression rate and survival (p=0.19). However, after adjustment for covariates including chest compression depth and fraction (n=6,399), the global test found a significant relationship between compression rate and survival (p=0.02), with the reference group (100-119 compressions/min) having the greatest likelihood for survival.After adjustment for chest compression fraction and depth, compression rates between 100 and 120 per minute were associated with greatest survival to hospital discharge.

Background— The impact of patient age on the risks of death or rehospitalization after primary prevention implantable cardioverter-defibrillator (ICD) placement is uncertain. Methods and Results— Data from 5 major ICD trials were merged: the Multicenter Automatic Defibrillator Implantation Trial I (MADIT-I), the Multicenter UnSustained Tachycardia Trial (MUSTT), the Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II), the Defibrillators in Nonischemic Cardiomyopathy Treatment Evaluation Trial (DEFINITE), and the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT). Median age at enrollment was 62 (interquartile range 53–70) years. Compared with their younger counterparts, older patients had a greater burden of comorbid illness. In unadjusted exploratory analyses, ICD recipients were less likely to die than nonrecipients in all age groups: among patients aged Conclusions— In this analysis, the survival benefit of the ICD exists but is attenuated with increasing age. The latter finding may be because of the higher burden of comorbid illness, competing causes of death, or limited sample size of older patients. There was no evidence that age modifies the association between ICD treatment and rehospitalization.

ObjectiveSocio-economic status (SES) has been positively associated with physical activity (PA) levels in adolescents. In order to tackle these social inequalities, information is needed about the underlying mechanisms of this association. The present study aimed to investigate the potential mediating role of psychosocial correlates of PA on the relationship between SES and PA in European adolescents.DesignCross-sectional study testing the mediating role of psychosocial correlates in the SES–PA association using the product-of-coefficients test of MacKinnon.SettingTen European cities in nine different countries, the HELENA (Healthy Lifestyle in Europe by Nutrition in Adolescence) Study.SubjectsAdolescents (n 2780) aged 12·5–17·49 years self-reported on PA (moderate-to-vigorous intensity PA and total PA), SES indicators (education of the mother and Family Affluence Scale) and psychosocial correlates of PA (stage of change, attitudes, awareness, modelling, social support, self-efficacy, benefits, barriers and environmental correlates).ResultsSES (Family Affluence Scale) was significantly associated with moderate-to-vigorous intensity PA. According to single-mediator models, this association was significantly mediated by stage of change (t = 3·6, P ≤ 0·001), awareness (t = 2·7, 0·001 < P ≤ 0·01), modelling (t = 4·8, P ≤ 0·001), self-efficacy (t = 2·5, 0·01

Background The Michigan Arthroplasty Registry Collaborative Quality Initiative (MARCQI) noted wide variability between member hospitals in blood transfusion rates after primary total hip and knee arthroplasty (THA and TKA). Blood transfusion has substantial risks and accepted recommendations exist to guide transfusion practices. MARCQI began an initiative to decrease unnecessary transfusions by identifying/reporting outliers, discussing conservative transfusion practices, and recommending transfusion guidelines. There was a later recommendation to consider intraoperative use of tranexamic acid. Methods All MARCQI-registered unilateral TKA and THA cases from the 28 member hospitals (pre-November 2013) were included. For 3 time periods (before November 13, 2013; November 13, 2013, to November 12, 2014; and after November 12, 2014), we calculated average risk and range of transfusion, transfusion with nadir hemoglobin >8 g/dL, mean length of stay, and 90-day risk of discharge to nursing home, readmission, deep infection, and emergency department visits. Results For THA, risk and range of transfusion decreased over the 3 time periods: 12.6% (2.5%-36.2%), 7.6% (2.2%-23.8%), and 4.5% (0.7%-14.4%); for TKA, 6.3% (1.3%-15.6%), 3.1% (0%-12.5%), and 1.3% (0%-7.4%). Decreases were also noted for transfusion with a nadir hemoglobin >8 g/dL with a near elimination of “unnecessary” transfusions. There was no evidence of increase in length of stay, discharge to nursing home, readmission, deep infection, or emergency department visits. Conclusion A simple intervention can decrease unnecessary blood transfusions during and after elective primary unilateral THA or TKA. A collaborative registry can be used effectively to improve the quality of patient care and set a new benchmark for transfusion.

Germ cell tumors (GCT) are a rare form of childhood cancer that originate from the primordial germ cell. Recent genome-wide association studies (GWAS) have identified susceptibility alleles for adult testicular GCT (TGCT). We test whether these SNPs are associated with GCT in pediatric and adolescent populations. This case-parent triad study includes individuals with GCT diagnosed between ages 0 and 19. We evaluated 26 SNPs from GWAS of adult TGCT and estimated main effects for pediatric GCT within complete trios (N = 366) using the transmission disequilibrium test. We used Estimation of Maternal, Imprinting and interaction effects using Multinomial modelling to evaluate maternal effects in non-Hispanic white trios and dyads (N = 244). We accounted for multiple comparisons using a Bonferroni correction. A variant in SPRY4 (rs4624820) was associated with reduced risk of GCT (OR [95% CI]: 0.70 [0.57, 0.86]). A variant in BAK1 (rs210138) was positively associated with GCT (OR [95% CI]: 1.70 [1.32, 2.18]), with a strong estimated effect for testis tumors (OR [95% CI]: 3.31 [1.89, 5.79]). Finally, a SNP in GAB2 (rs948662) was associated with increased risk for GCT (OR [95% CI]: 1.56 [1.20, 2.03]). Nominal associations (P 0.05) were noted for eight additional loci. A maternal effect was observed for KITLG SNP rs4474514 (OR [95% CI]: 1.66 [1.21, 2.28]) and a paternal parent-of-origin effect was observed for rs7221274 (P = 0.00007), near TEX14, RAD51C, and PPM1E. We observed associations between SNPs in SPRY4, BAK1, and GAB2 and GCTs. This analysis suggests there may be common genetic risk factors for GCT in all age groups.

Background: The efficacy of tranexamic acid (TXA) in reducing blood loss and transfusion requirements in total hip and knee arthroplasty has been well established in small controlled clinical trials and meta-analyses. The purpose of the current study was to determine the risks and benefits of TXA use in routine orthopaedic surgical practice on the basis of data from a large, statewide arthroplasty registry. Methods: From April 18, 2013, to September 30, 2014, there were 23,236 primary total knee arthroplasty cases and 11,489 primary total hip arthroplasty cases completed and registered in the Michigan Arthroplasty Registry Collaborative Quality Initiative (MARCQI). We evaluated the association between TXA use and hemoglobin drop, transfusion, length of stay (LOS), venous thromboembolism (VTE), readmission, and cardiovascular events by fitting mixed-effects generalized linear and mixed-effects Cox models. We used inverse probability of treatment weighting to enhance causal inference. Results: For total hip arthroplasty, TXA use was associated with a smaller drop in hemoglobin (mean difference = −0.65 g/dL; 95% confidence interval [CI] = −0.60 to −0.71 g/dL), decreased odds of blood transfusion (odds ratio [OR] = 0.72; 95% CI = 0.60 to 0.86), and decreased readmissions (OR = 0.77; 95% CI = 0.64 to 0.93) compared with no TXA use. There was no effect on VTE (hazard ratio [HR] = 0.91; 95% CI = 0.62 to 1.33), LOS (incident rate ratio [IRR] = 1.00; 95% CI = 0.97 to 1.03), or cardiovascular events (OR = 0.85; 95% CI = 0.47 to 1.52). For total knee arthroplasty, TXA was associated with a smaller drop in hemoglobin (mean difference = −0.68 g/dL; 95% CI = −0.64 to −0.71 g/dL) and one-fourth the odds of blood transfusion (OR = 0.26; 95% CI = 0.21 to 0.31). There was an association with decreased risk of VTE within 90 days after surgery (HR = 0.56; 95% CI = 0.42 to 0.73), slightly decreased LOS (IRR = 0.93; 95% CI = 0.92 to 0.95), and no association with readmissions (OR = 0.90; 95% CI = 0.79 to 1.04) or cardiovascular events (OR = 1.12; 95% CI = 0.74 to 1.71). Conclusions: In routine orthopaedic surgery practice, TXA use was associated with decreased blood loss and transfusion risk for both total knee and total hip arthroplasty, without evidence of increased risk of complications. TXA use was also associated with reduced risk of readmission among total hip arthroplasty patients and reduced risk of VTE among total knee arthroplasty patients, and did not have an adverse effect on cardiovascular complications in either group. Level of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

In an effort to reduce episode payment variation for joint replacement at US hospitals, the Centers for Medicare and Medicaid Services (CMS) recently implemented the Comprehensive Care for Joint Replacement bundled payment program. Some stakeholders are concerned that the program may unintentionally penalize hospitals because it lacks a mechanism (such as risk adjustment) to sufficiently account for patients' medical complexity. Using Medicare claims for patients in Michigan who underwent lower extremity joint replacement in the period 2011-13, we applied payment methods analogous to those CMS intends to use in determining annual bonuses or penalties (reconciliation payments) to hospitals. We calculated the net difference in reconciliation payments with and without risk adjustment. We found that reconciliation payments were reduced by $827 per episode for each standard-deviation increase in a hospital's patient complexity. Moreover, we found that risk adjustment could increase reconciliation payments to some hospitals by as much as $114,184 annually. Our findings suggest that CMS should include risk adjustment in the Comprehensive Care for Joint Replacement program and in future bundled payment programs.

Objective To compare the effectiveness of levetiracetam (LEV) with extended-release sodium valproate (VPA-ER) and controlled-release carbamazepine (CBZ-CR) as monotherapy in patients with newly diagnosed epilepsy. Methods This unblinded, randomised, 52-week superiority trial (NCT00175903) recruited patients (≥16 years of age) with ≥2 unprovoked seizures in the previous 2 years and ≥1 in the previous 6 months. The physician chose VPA or CBZ as preferred standard treatment; each patient was randomised to standard treatment or LEV. The primary outcome was time to treatment withdrawal (LEV vs standard antiepileptic drugs (AEDs)). Analyses also compared LEV with VPA-ER, and LEV with CBZ-CR. Findings 1688 patients (mean age 41 years; 44% female) were randomised to LEV (n=841) or standard AEDs (n=847). Time to treatment withdrawal was not significantly different between LEV and standard AEDs: HR (95% CI) 0.90 (0.74 to 1.08). Time to treatment withdrawal (HR (95% CI)) was 1.02 (0.74 to 1.41) for LEV/VPA-ER and 0.84 (0.66 to 1.07) for LEV/CBZ-CR. Time to first seizure (HR, 95% CI) was significantly longer for standard AEDs, 1.20 (1.03 to 1.39), being 1.19 (0.93 to 1.54) for LEV/VPA-ER and 1.20 (0.99 to 1.46) for LEV/CBZ-CR. Estimated 12-month seizure freedom rates from randomisation: 58.7% LEV versus 64.5% VPA-ER; 50.5% LEV versus 56.7% CBZ-CR. Similar proportions of patients within each stratum reported at least one adverse event: 66.1% LEV versus 62.0% VPA-ER; 73.4% LEV versus 72.5% CBZ-CR. Conclusions LEV monotherapy was not superior to standard AEDs for the global outcome, namely time to treatment withdrawal, in patients with newly diagnosed focal or generalised seizures.

The impedance threshold device (ITD) is designed to enhance venous return and cardiac output during cardiopulmonary resuscitation (CPR) by increasing the degree of negative intrathoracic pressure. Previous studies have suggested that the use of an ITD during CPR may improve survival rates after cardiac arrest.We compared the use of an active ITD with that of a sham ITD in patients with out-of-hospital cardiac arrest who underwent standard CPR at 10 sites in the United States and Canada. Patients, investigators, study coordinators, and all care providers were unaware of the treatment assignments. The primary outcome was survival to hospital discharge with satisfactory function (i.e., a score of ≤3 on the modified Rankin scale, which ranges from 0 to 6, with higher scores indicating greater disability).Of 8718 patients included in the analysis, 4345 were randomly assigned to treatment with a sham ITD and 4373 to treatment with an active device. A total of 260 patients (6.0%) in the sham-ITD group and 254 patients (5.8%) in the active-ITD group met the primary outcome (risk difference adjusted for sequential monitoring, -0.1 percentage points; 95% confidence interval, -1.1 to 0.8; P=0.71). There were also no significant differences in the secondary outcomes, including rates of return of spontaneous circulation on arrival at the emergency department, survival to hospital admission, and survival to hospital discharge.Use of the ITD did not significantly improve survival with satisfactory function among patients with out-of-hospital cardiac arrest receiving standard CPR. (Funded by the National Heart, Lung, and Blood Institute and others; ROC PRIMED ClinicalTrials.gov number, NCT00394706.).

Background In a departure from the previous strategy of immediate defibrillation, the 2005 resuscitation guidelines from the American Heart Association–International Liaison Com mittee on Resuscitation suggested that emergency medical service (EMS) personnel could provide 2 minutes of cardiopulmonary resuscitation (CPR) before the first analysis of cardiac rhythm. We compared the strategy of a brief period of CPR with early analysis of rhythm with the strategy of a longer period of CPR with delayed analysis of rhythm. Methods We conducted a cluster-randomized trial involving adults with out-of-hospital cardiac arrest at 10 Resuscitation Outcomes Consortium sites in the United States and Canada. Patients in the early-analysis group were assigned to receive 30 to 60 seconds of EMS-administered CPR and those in the later-analysis group were assigned to receive 180 seconds of CPR, before the initial electrocardiographic analysis. The primary outcome was survival to hospital discharge with satisfactory functional status (a modified Rankin scale score of ≤3, on a scale of 0 to 6, with higher scores indicating greater disability). Results We included 9933 patients, of whom 5290 were assigned to early analysis of cardiac rhythm and 4643 to later analysis. A total of 273 patients (5.9%) in the later-analysis group and 310 patients (5.9%) in the early-analysis group met the criteria for the primary outcome, with a cluster-adjusted difference of −0.2 percentage points (95% confidence interval, −1.1 to 0.7; P = 0.59). Analyses of the data with adjustment for confounding factors, as well as subgroup analyses, also showed no survival benefit for either study group. Conclusions Among patients who had an out-of-hospital cardiac arrest, we found no difference in the outcomes with a brief period, as compared with a longer period, of EMS-administered CPR before the first analysis of cardiac rhythm. (Funded by the National Heart, Lung, and Blood Institute and others; ROC PRIMED ClinicalTrials.gov number, NCT00394706.)

This report summarizes the treatments and outcomes of a large series of patients with pediatric head injuries (PHIs), who were admitted to a tertiary pediatric trauma center at the University of Mississippi Medical Center from January 1, 2003 through December 31, 2006.Data were retrieved from the Department of Neurosurgery's Brain Trauma Registry (BTR) on patients who are ≤16 years old. Data include Glasgow Coma Scale (GCS) and injury severity scores (ISS) on admission and Glasgow Outcome Scale (GOS) scores at 6 months follow-up.The BTR registered 554 patients with accidental and nonaccidental PHIs. Follow-up was complete in 98.2%. Aggressive first-tier management with ventricular drainage was used to lower intracranial pressure. Vasopressors were used only to correct hypotension. Second-tier therapies were used infrequently. Craniectomies (14 patients) were associated with good outcomes (GOS 4-5) in nine patients; hypothermia (six patients) and barbiturate (four patients) therapies were ineffective. All 439 patients with ISS25 showed good outcomes. Fifteen of 16 patients with GCS8 and ISS ≥25 had good outcomes. In 134 patients with severe PHIs (GCS ≤8), all 45 with ISS25 and 46 with ISS ≥25 showed good outcomes. Forty-three patients with GCS ≤8 and ISS ≥25 had poor outcomes. Of these patients, 38 died; 22 died within 3 days of admission.This study indicated that poor outcomes occurred only in PHIs with severe generalized trauma. While 28.4% of patients with GSC ≤8 died, more than half of these sustained nonsurvivable injuries. Aggressive medical management with ventricular drainage was the mainstay of therapy.

Background The direct anterior approach (DAA) for total hip arthroplasty (THA) has rapidly become popular, but there is little consensus regarding the risks and benefits of this approach in comparison with a modern posterior approach (PA). Methods A total of 2147 patients who underwent DAA THA were propensity score matched with patients undergoing PA THA on the basis of age, gender, body mass index, and American Society of Anesthesia classification using data from a state joint replacement registry. Mean age of the matched cohort was 64.8 years, mean body mass index was 29.1 kg/m 2 , and 53% were female. Multilevel logistic regression models using generalized estimating equations to control for grouping at the hospital level were used to identify differences in various outcomes. Results There was no difference in the dislocation rate between patients undergoing DAA (0.84%) and PA (0.79%) THA. Trends indicating a slightly longer length of stay with the PA and a slightly greater risk of fracture, increased blood loss, and hematoma with the DAA are consistent with previous studies. Conclusion On the basis of short-term outcome and complication data, neither approach has a compelling advantage over each other, including no difference in the dislocation risk.

Background Randomized trials of prehospital cooling after cardiac arrest have shown that neither prehospital cooling nor targeted temperature management differentially affected short‐term survival or neurological function. In this follow‐up study, we assess the association of prehospital hypothermia with neurological function at least 3 months after cardiac arrest and survival 1 year after cardiac arrest. Methods and Results There were 508 individuals who were discharged alive from hospitals in King County, Washington; 373 (73%) were interviewed by telephone 123±43 days after the initial event. Overall, 59% of the treatment group and 58% of the control group had Cerebral Performance Category ( CPC ) 1 or 2 ( P =0.70), and 50% of the treatment group and 49% of the control group had slight disability or better by the Modified Rankin Scale ( MRS ; ( P =0.35). One‐year survival was 87% in the treatment group and 84% in the control group ( P =0.42). Of those with CPC 1 at hospital discharge, 68% had CPC 1 or 2 at follow‐up, and 59% had MRS of slight disability or better. Of 41 patients with CPC 3 or 4 at discharge, only 12% had CPC 2 at follow‐up, and just 5% had MRS of slight disability or better. One‐year survival was 92% for CPC 1 at discharge, but only 40% for CPC 4. Conclusion In addition to excellent survival, patients who had good neurological function at discharge continued to have good function at least 3 months after the event. Clinical Trial Registration URL: Clinicaltrials.gov. Unique identifier: NCT00391469

We compared 2 studies of implantable cardiac defibrillators (ICDs) to determine the effects of device mode on outcomes. The Antiarrhythmics Versus Implantable Defibrillators (AVID) trial (1993 to 1997) demonstrated improved survival with the ICD compared with antiarrhythmic drug therapy. The Dual-chamber And VVI Implantable Defibrillator (DAVID) trial (2000 to 2002) showed that VVI pacing at 40 beats/min in patients with ICDs reduced the combined end point of death and hospitalization for congestive heart failure compared with DDDR pacing at 70 beats/min. Patients in the AVID trial (631 of 1,016) and the DAVID trial (221 of 506) meeting common inclusion and all exclusion criteria were studied. The major end points were the time to death, and the composite end point of time to death or hospitalization for congestive heart failure. Patients in the AVID and DAVID trials were similar, but more AVID patients had coronary artery disease (p = 0.04), history of myocardial infarction (p = 0.005), and previous ventricular arrhythmias (p = 0.03). DAVID patients underwent more previous revascularization procedures (coronary artery bypass surgery, p = 0.03; percutaneous coronary intervention, p = 0.001), and were more often taking beta-blocking drugs at hospital discharge (p0.001). The backup VVI ICD groups in both studies had similar outcomes (p = 0.4), even when corrected for the previous demographic differences. The time-to- composite end point was similar in AVID patients treated with antiarrhythmic drugs and DAVID patients treated with DDDR ICDs (p = 0.6). Despite improved pharmacologic therapy and revascularization, outcomes have not improved with backup VVI pacing ICDs. If DDDR ICDs had been used in the AVID trial, benefit from ICDs for patients with serious ventricular arrhythmias could have been missed.

BACKGROUND The rate of survival after out-of-hospital cardiac arrest is low. It is not known whether this rate will increase if laypersons are trained to attempt defibrillation with the use of automated external defibrillators (AEDs). METHODS We conducted a prospective, community-based, multicenter clinical trial in which we randomly assigned community units (e.g., shopping malls and apartment complexes) to a structured and monitored emergency-response system involving lay volunteers trained in cardiopulmonary resuscitation (CPR) alone or in CPR and the use of AEDs. The primary outcome was survival to hospital discharge. RESULTS More than 19,000 volunteer responders from 993 community units in 24 North American regions participated. The two study groups had similar unit and volunteer characteristics. Patients with treated out-of-hospital cardiac arrest in the two groups were similar in age (mean, 69.8 years), proportion of men (67 percent), rate of cardiac arrest in a public location (70 percent), and rate of witnessed cardiac arrest (72 percent). No inappropriate shocks were delivered. There were more survivors to hospital discharge in the units assigned to have volunteers trained in CPR plus the use of AEDs (30 survivors among 128 arrests) than there were in the units assigned to have volunteers trained only in CPR (15 among 107; P=0.03; relative risk, 2.0; 95 percent confidence interval, 1.07 to 3.77); there were only 2 survivors in residential complexes. Functional status at hospital discharge did not differ between the two groups. CONCLUSIONS Training and equipping volunteers to attempt early defibrillation within a structured response system can increase the number of survivors to hospital discharge after out-of-hospital cardiac arrest in public locations. Trained laypersons can use AEDs safely and effectively.

Introduction: The implantable cardioverter defibrillator (ICD) is commonly used to treat patients with documented sustained ventricular tachycardia (VT) or ventricular fibrillation (VF). Arrhythmia recurrence rates in these patients are high, but which patients will receive a therapy and the forms of arrhythmia recurrence (VT or VF) are poorly understood. Methods and Results: The therapy delivered by the ICD was examined in 449 patients randomized to ICD therapy in the Antiarrhythmics Versus Implantable Defibrillators (AVID) Trial. Events triggering ICD shocks or antitachycardia pacing (ATP) were reviewed for arrhythmia diagnosis, clinical symptoms, activity at the onset of the arrhythmia, and appropriateness and results of therapy. Both shock and ATP therapies were frequent by 2 years, with 68% of patients receiving some therapy or having an arrhythmic death. An appropriate shock was delivered in 53% of patients, and ATP was delivered in 68% of patients who had ATP activated. The first arrhythmia treated in follow-up was diagnosed as VT (63%), VF (13%), supraventricular tachycardia (18%), unknown arrhythmia (3%), or due to ICD malfunction or inappropriate sensing (3%). Acceleration of an arrhythmia by the ICD occurred in 8% of patients who received any therapy. No physical activity consistently preceded arrhythmias, nor did any single clinical factor predict the symptoms of the arrhythmia. Conclusion: Delivery of ICD therapy in AVID patients was common, primarily due to VT. Inappropriate ICD therapy occurred frequently. Use of ICD therapy as a surrogate endpoint for death in clinical trials should be avoided. (J Cardiovasc Electrophysiol, Vol. 14, pp. 940-948, September 2003)

Objectives We sought to determine the value of electrophysiology (EP) testing in patients with ventricular fibrillation (VF), ventricular tachycardia (VT) with syncope, or sustained VT in the setting of left ventricular dysfunction. Background Traditionally, EP testing is part of the workup of patients with sustained VT or VF. Recently, some have suggested that EP testing is unnecessary in these patients, many of whom are likely to receive an implantable cardioverter-defibrillator (ICD). Methods Within a multicenter trial (Antiarrhythmics Versus Implantable Defibrillators) designed to evaluate whether drugs or ICD resulted in a better outcome, data were analyzed regarding EP testing. Although this testing was not required, it was performed in >50% of patients. Information regarding the results of EP testing was correlated to baseline clinical characteristics and outcome. Results Of 572 patients subjected to an EP test, 384 (67%) had inducible sustained VT or VF. Inducible patients were more likely to have coronary artery disease, previous infarction, and VT as their index arrhythmic event. Inducibility of VT or VF did not predict death or recurrent VT or VF. Conclusions Information derived from EP testing in this patient population, particularly those with VF, is of limited value and may not be worth the risks and costs of the procedure, particularly in those patients likely to receive an ICD. (Am Heart J 2002;144:478-84.)

Background Patients at high risk of sudden cardiac death, yet at low risk of nonsudden death, might be ideal candidates for antiarrhythmic drugs or devices. Most previous studies of prognostic markers for sudden cardiac death have ignored the competitive risk of nonsudden cardiac death. The goal of the present study was to evaluate the ability of clinical factors to distinguish the risks of sudden and nonsudden cardiac death. Methods We identified all deaths during a 3.3-year follow-up of 30,680 patients discharged alive after admission to the cardiac care unit of a Seattle hospital. Detailed chart reviews were conducted on 1093 subsequent out-of-hospital sudden deaths, 973 nonsudden cardiac deaths, and 442 randomly selected control patients. Results Patients who died in follow-up (suddenly or nonsuddenly) were significantly different for many clinical factors from control patients. In contrast, patients with sudden cardiac death were insignificantly different for most clinical characteristics from patients with nonsudden cardiac death. The mode of death was 20% to 30% less likely to be sudden in women, patients who had angioplasty or bypass surgery, and patients prescribed β-blockers. The mode of death was 20% to 30% more likely to be sudden in patients with heart failure, frequent ventricular ectopy, or a discharge diagnosis of acute myocardial infarction. A multivariable model had only modest predictive capacity for mode of death (c-index of 0.62). Conclusion Standard clinical evaluation is much better at predicting overall risk of death than at predicting the mode of death as sudden or nonsudden. (Am Heart J 2002;144:390-6.)

ICD Utilization.Introduction: Implantable cardioverter defibrillators (ICDs) have become an accepted therapy for patients at high risk of sudden cardiac death. To assess the current utilization of this therapy, we estimated the number of patients at risk of sudden death using an historical claims-based study and compared these results to current ICD usage volumes. Methods and Results: Managed care and Medicare databases (claims related to 4.6 million covered U.S. lives during a 12-month period) were analyzed to identify patients who had either a primary or secondary diagnosis of ventricular tachycardia, ventricular fibrillation, ventricular flutter, or cardiac arrest. These patients were further required to have a diagnosis code indicating a previous myocardial infarction or congestive heart failure. Patients who died during the study period or did not have medical insurance were excluded. In the base case scenario, 1,226 patients per million population were identified as potential ICD candidates. Sensitivity analyses reduced that value to a range from 736 to 1,140 ICD candidates per million population. Sensitivity factors considered included acute myocardial infarction, comorbidities, age, secondary ventricular tachycardia/ventricular fibrillation diagnosis, and varying degrees of left ventricular dysfunction. These results contrast with an ICD usage rate of 416 per million population in the United States and lower rates in other countries. Conclusion: This study suggests that, based on discharge diagnoses, many patients who could benefit from ICDs are not receiving this therapy. Diverse reasons for this underutilization should be addressed to improve access to, and appropriate use of, this therapy.

Background— The 2010 American Heart Association guidelines suggested an increase in cardiopulmonary resuscitation compression depth with a target >50 mm and no upper limit. This target is based on limited evidence, and we sought to determine the optimal compression depth range. Methods and Results— We studied emergency medical services–treated out-of-hospital cardiac arrest patients from the Resuscitation Outcomes Consortium Prehospital Resuscitation Impedance Valve and Early Versus Delayed Analysis clinical trial and the Epistry-Cardiac Arrest database. We calculated adjusted odds ratios for survival to hospital discharge, 1-day survival, and any return of circulation. We included 9136 adult patients from 9 US and Canadian cities with a mean age of 67.5 years, mean compression depth of 41.9 mm, and a return of circulation of 31.3%, 1-day survival of 22.8%, and survival to hospital discharge of 7.3%. For survival to discharge, the adjusted odds ratios were 1.04 (95% CI, 1.00–1.08) for each 5-mm increment in compression depth, 1.45 (95% CI, 1.20–1.76) for cases within 2005 depth range (>38 mm), and 1.05 (95% CI, 1.03–1.08) for percentage of minutes in depth range (10% change). Covariate-adjusted spline curves revealed that the maximum survival is at a depth of 45.6 mm (15-mm interval with highest survival between 40.3 and 55.3 mm) with no differences between men and women. Conclusions— This large study of out-of-hospital cardiac arrest patients demonstrated that increased cardiopulmonary resuscitation compression depth is strongly associated with better survival. Our adjusted analyses, however, found that maximum survival was in the depth interval of 40.3 to 55.3 mm (peak, 45.6 mm), suggesting that the 2010 American Heart Association cardiopulmonary resuscitation guideline target may be too high. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00394706.

Introduction Caring for a person with advanced disease can have a detrimental impact on the quality of life of family caregivers. This is further compounded in rural areas that have few or no palliative care services. Hope has a positive influence on the quality of life of family caregivers of persons with advanced cancer but factors influencing hope specifically in rural women caregivers of persons with advanced cancer have not been examined. Purpose The purpose of this study was to determine factors influencing the hope of rural women caring for persons with advanced cancer, by examining the relationship of hope with demographic variables, self-efficacy, guilt, and caregiver physical and mental health. Methods A cross-sectional prospective correlational design was used. Inclusion criteria for the study were: (a) female, (b) 18 years of age or older, (c) caring for a person diagnosed with advanced cancer, (d) home address with a rural postal code, and (e) English-speaking. Using a modified Dillman technique, surveys and an invitation to participate were mailed to 780 persons with advanced cancer living in rural areas using two western Canadian provincial cancer registries. A reminder card was sent 4 weeks later. The persons with advanced cancer were asked to give the survey to their primary caregiver to complete. Surveys included measures of hope (Herth Hope Index (HHI)), general self-efficacy (General Self-Efficacy Scale (GSES)), grief (Non Death Version Revised Grief Experience Inventory (NDRGEI)), mental and physical health (Short Form Health Survey Version 2 (SF-12v2)), and demographic data such as their relationship to the person for whom the caregiver was caring. Data were entered into the Statistical Package for the Social Sciences v19 (SPSS) and analyzed using generalized linear modeling. Results Significant factors (p ≤ 0.05) influencing HHI scores were GSES ( p ≤ 0.0001), NDRGEI subscale (p=0.001), and SF-12v2 mental health summary scores (p=0.002). Participants with higher GSES, lower NDRGEI, and higher SF-12v2 mental health summary scores had higher HHI scores. The SF-12v2 physical health summary mean score of 43.30 (standard deviation (SD)=4.63) was below the 25th percentile (46.53) of US population norms. The SF-12v2 mental health summary mean score of 45.24 (SD=5.98) was just above the 25th percentile of US population norms (45.13). Conclusion Participants with higher hope scores had higher mental health scores, lower perceptions of loss and grief scores, and higher scores in their confidence in their ability to deal with difficult situations (self-efficacy). The significant relationships found between hope and mental health, general self-efficacy, and perceptions of guilt provide a foundation for future research and underscore the importance of hope to rural women caregivers. The low physical and mental health scores of rural women caregivers are of concern and highlight the need to support this population.

Background —Electrical storm, multiple temporally related episodes of ventricular tachycardia (VT) or ventricular fibrillation (VF), is a frequent problem among recipients of implantable cardioverter defibrillators (ICDs). However, insufficient data exist regarding its prognostic significance. Methods and Results —This analysis includes 457 patients who received an ICD in the Antiarrhythmics Versus Implantable Defibrillators (AVID) trial and who were followed for 31±13 months. Electrical storm was defined as ≥3 separate episodes of VT/VF within 24 hours. Characteristics and survival of patients surviving electrical storm (n=90), those with VT/VF unrelated to electrical storm (n=184), and the remaining patients (n=183) were compared. The 3 groups differed in terms of ejection fraction, index arrhythmia, revascularization status, and baseline medication use. Survival was evaluated using time-dependent Cox modeling. Electrical storm occurred 9.2±11.5 months after ICD implantation, and most episodes (86%) were due to VT. Electrical storm was a significant risk factor for subsequent death, independent of ejection fraction and other prognostic variables (relative risk [RR], 2.4; 95% confidence interval [CI], 1.3 to 4.2; P =0.003), but VT/VF unrelated to electrical storm was not (RR, 1.0; 95% CI, 0.6 to 1.7; P =0.9). The risk of death was greatest 3 months after electrical storm (RR, 5.4; 95% CI, 2.4 to 12.3; P =0.0001) and diminished beyond this time (RR, 1.9; 95% CI, 1.0 to 3.6; P =0.04). Conclusions —Electrical storm is an important, independent marker for subsequent death among ICD recipients, particularly in the first 3 months after its occurrence. However, the development of VT/VF unrelated to electrical storm does not seem to be associated with an increased risk of subsequent death.

Background —Sustained ventricular tachycardia (VT) can be unstable, can be associated with serious symptoms, or can be stable and relatively free of symptoms. Patients with unstable VT are at high risk for sudden death and are best treated with an implantable defibrillator. The prognosis of patients with stable VT is controversial, and it is unknown whether implantable cardioverter-defibrillator therapy is beneficial. Methods and Results —Screening for the Antiarrhythmics Versus Implantable Defibrillators (AVID) trial identified patients with both stable and unstable VT. Both groups were included in a registry, and their clinical characteristics and discharge treatments were recorded. Mortality data were obtained through the National Death Index. The mortality in 440 patients with stable VT tended to be greater than that observed in 1029 patients presenting with unstable VT (33.6% versus 27.6% at 3 years; relative risk [RR]=1.22; P =0.07). After adjustment for baseline and treatment differences, the RR was little changed (RR=1.25, P =0.06). Conclusions —Sustained VT without serious symptoms or hemodynamic compromise is associated with a high mortality rate and may be a marker for a substrate capable of producing a more malignant arrhythmia. Implantable cardioverter-defibrillator therapy may be indicated in patients presenting with stable VT.

Despite extensive training of citizens of Seattle in cardiopulmonary resuscitation (CPR), bystanders do not perform CPR in almost half of witnessed cardiac arrests. Instructions in chest compression plus mouth-to-mouth ventilation given by dispatchers over the telephone can require 2.4 minutes. In experimental studies, chest compression alone is associated with survival rates similar to those with chest compression plus mouth-to-mouth ventilation. We conducted a randomized study to compare CPR by chest compression alone with CPR by chest compression plus mouth-to-mouth ventilation.The setting of the trial was an urban, fire-department-based, emergency-medical-care system with central dispatching. In a randomized manner, telephone dispatchers gave bystanders at the scene of apparent cardiac arrest instructions in either chest compression alone or chest compression plus mouth-to-mouth ventilation. The primary end point was survival to hospital discharge.Data were analyzed for 241 patients randomly assigned to receive chest compression alone and 279 assigned to chest compression plus mouth-to-mouth ventilation. Complete instructions were delivered in 62 percent of episodes for the group receiving chest compression plus mouth-to-mouth ventilation and 81 percent of episodes for the group receiving chest compression alone (P=0.005). Instructions for compression required 1.4 minutes less to complete than instructions for compression plus mouth-to-mouth ventilation. Survival to hospital discharge was better among patients assigned to chest compression alone than among those assigned to chest compression plus mouth-to-mouth ventilation (14.6 percent vs. 10.4 percent), but the difference was not statistically significant (P=0.18).The outcome after CPR with chest compression alone is similar to that after chest compression with mouth-to-mouth ventilation, and chest compression alone may be the preferred approach for bystanders inexperienced in CPR.

The aim of this study was to determine if the benefit of implantable cardioverter-defibrillators (ICDs) is modulated by medical comorbidity.Primary prevention ICDs improve survival in patients at risk for sudden cardiac death. Their benefit in patients with significant comorbid illness has not been demonstrated.Original, patient-level datasets from MADIT I (Multicenter Automatic Defibrillator Implantation Trial I), MADIT II, DEFINITE (Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation), and SCD-HeFT (Sudden Cardiac Death in Heart Failure Trial) were combined. Patients in the combined population (N = 3,348) were assessed with respect to the following comorbidities: smoking, pulmonary disease, diabetes, peripheral vascular disease, atrial fibrillation, ischemic heart disease, and chronic kidney disease. The primary outcome was overall mortality, using the hazard ratio (HR) of time to death for patients receiving an ICD versus no ICD by extent of medical comorbidity, and adjusted for age, sex, race, left ventricular ejection fraction, use of antiarrhythmic drugs, beta-blockers, and angiotensin-converting enzyme inhibitors.Overall, 25% of patients (n = 830) had2 comorbid conditions versus 75% (n = 2,518) with significant comorbidity (≥2). The unadjusted hazard of death for patients with an ICD versus no ICD was significantly lower, but this effect was less for patients with ≥2 comorbidities (unadjusted HR: 0.71; 95% confidence interval: 0.61 to 0.84) compared with those with2 comorbidities (unadjusted HR: 0.59; 95% confidence interval: 0.40 to 0.87). After adjustment, the benefit of an ICD decreased with increasing number of comorbidities (p = 0.004).Patients with extensive comorbid medical illnesses may experience less benefit from primary prevention ICDs than those with less comorbidity; implantation should be carefully considered in sick patients. Further study of ICDs in medically complex patients is warranted.

In the Antiarrhythmics Vs Implantable Defibrillators (AVID) trial, all patients who meet the study entry criteria are followed in a registry. During the period between June 1993 and June 1995, of 1,117 patients who were enrolled in the registry and met the study entry criteria, 476 were randomized to receive either implantable cardioverter-defibrillators (ICDs) or drug therapy (amiodarone or sotalol), and 641 patients were not randomized for a variety of reasons including: patient refusal (42%); physician refusal (43%); concerns about ability to maintain follow-up over several years (10%), and others (6%). There were no significant differences between the 476 randomized and 641 nonrandomized patients with regard to clinical characteristics, left ventricular function, history of congestive heart failure, medical history, and previous cardiac procedures performed before the index event, except that randomized patients were slightly older (65 vs 62 years) and had a slightly higher prevalence of coronary artery disease and previous myocardial infarction. The index event and location of the index event were not significantly different between the 2 groups. Although 14% of registry patients received neither ICD nor antiarrhythmic drug therapy, ICDs were no more frequently used in the registry patient than antiarrhythmic drugs (45% for ICD vs 42% for drugs). Thus, randomized AVID patients have very similar clinical characteristics, cardiac history, and presenting arrhythmias as to nonrandomized eligible patients. Therefore, the results of the AVID trial may be generalized for all patients with AVID-eligible arrhythmias.

This research examined the influences of social circumstances, coping and level and length of drug intake on dependence and withdrawal from benzodiazepine use. A sample of long-term benzodiazepine users were followed up over a period of six months. At first interview the participants' drug intake and anxiety and depression levels were established and the Life Events and Difficulties Schedule (LEDS) was administered. At follow up these measures were repeated and individuals' coping strategies for dealing with dependence were also assessed. By the time of the follow-up interview slightly more than half of the participants (57 per cent) had either withdrawn completely from benzodiazepine medication or had reduced their daily dose. Analyses showed that reduction was unrelated to factors associated with the drugs themselves, to the severity of life-events and difficulties, to lessening of difficulties or to the occurrence of positive life-events. Significant associations, however, were found between participants' coping responses in relation to long-term benzodiazepine use and the individuals' reduction or cessation of benzodiazepine use in the six month study period. The study showed that in the absence of positive life-events and in spite of ongoing difficulties actively confronting the problems of benzodiazepine use can have a positive effect on outcome. The findings suggest that interventions which encourage cognitive, behavioural and affective aspects of coping are those which would appear to be most likely to succeed.

To identify those food groups best discriminating individuals at high/low cardiovascular disease (CVD) risk and to investigate the relationship between dairy consumption and CVD risk factors (individual and scores) in adolescents (12.5-17.5 years) from eight European cities participating in the cross-sectional (2006-2007) HELENA (Healthy Lifestyle in Europe by Nutrition in Adolescence) project.Diet, waist circumference, skin-folds thickness, systolic blood pressure, insulin resistance, triglycerides, total cholesterol/high-density lipoprotein ratio and cardiorespiratory fitness (CRF) were assessed in 511 (49.9% boys) adolescents. Individual z-scores of CVD risk factors were summed to compute sex-specific clustered CVD risk scores.Dairy emerged as the food group best discriminating adolescents at low/high CVD risk. In both genders, waist circumference and sum of skin-folds were inversely associated with consumption of milk and yogurt, and milk- and yogurt-based beverages, whereas a positive association was observed with CRF. Moreover, CVD risk score (β = -0.230, P = 0.001) was also inversely associated with overall dairy consumption only in girls.Dairy consumption is associated with lower adiposity and higher CRF in these adolescents. An inverse association between CVD risk score and dairy consumption is also depicted in girls. The study adds further evidence to the scarce literature on the influence of milk and dairy products on adolescents' cardiovascular health.

The enzyme Cytochrome P450 2W1 (CYP2W1) is found in fetal colon tissue and is also detected in colorectal cancer but not in non-transformed tissue. In a pilot study, we reported that the immunohistochemically-detected expression of CYP2W1 might be of prognostic value since high expression of CYP2W1 was indicative of a worse prognosis. The aim of this study was to validate the pilot study's results using a larger, independent group of patients with colon cancer.Immunohistochemical detection of CYP2W1 in 235 malignant colon tumors of stage II and III, was carried out using a polyclonal antibody. Grading of staining was carried out by two independent readers. The highest grade that involved more than 5% of the tumor area on each slide was used for the classification of CYP2W1 expression.CYP2W1 was expressed at high levels in 30% of the tumors. In the entire colon cancer group it was an independent prognostic factor in multivariate analysis (p=0.04), where high expression (grade 3) correlated with worse outcome. CYP2W1 expression was an independent prognostic factor in the subgroup of patients with colon cancer stage III (p=0.003), but not for those with stage II. In 107 cases, two slices from different areas of the same tumor were available, and no significant difference in CYP2W1 expression between the slices was observed (r=0.53, p0.001).The results of the current study were in agreement with those of the previous pilot study and show that higher expression of CYP2W1 seems to be of prognostic value in colon cancer. Furthermore, we found equal expression in slices from two different areas of the same tumor. Since the CYP2W1 enzyme has been shown to catalytically activate compounds to cytotoxic products, the enzyme might be used as a novel drug target for the treatment of colon cancer.

BACKGROUND The Cardiac Arrhythmia Suppression Trial (CAST) was designed to test the hypothesis that suppression of ventricular ectopy with antiarrhythmic drugs after a myocardial infarction reduces the incidence of sudden arrhythmic death. Patients in whom ventricular ectopy could be suppressed with encainide, flecainide, or moricizine were randomly assigned to receive either active drug or placebo. The encainide and flecainide arms of the study were discontinued in 1989 (CAST-I) and the moricizine arm in 1991 (CAST-II) because of excess mortality. To explore the mechanisms of these adverse outcomes, we examined the interaction of baseline characteristics with the hazard of therapy with encainide, flecainide, or moricizine compared with their respective placebos. METHODS AND RESULTS CAST-I comprised 755 patients assigned to flecainide or encainide and 743 patients assigned to placebo, whereas in CAST-II, 502 patients received moricizine and 491 patients received placebo. Clinical and laboratory baseline variables of patients receiving active drug and those receiving placebo were similar. In CAST-I patients, there was a significant interaction of active therapy with both all-cause death/cardiac arrest and arrhythmic death/cardiac arrest for non-Q-wave myocardial infarction (total mortality hazard ratios, 1.8 versus 7.9 for Q-wave versus non-Q-wave infarction, P = .03). Ventricular premature depolarization (VPD) frequency > or = 50/h and heart rate > or = 74 beats per minute each interacted significantly with total mortality/cardiac arrest only. In the sicker CAST-II patients (ejection fraction < or = 40%), only diuretic use at baseline interacted significantly with moricizine use for both all-cause death/cardiac arrest and arrhythmic death/cardiac arrest (total mortality hazard ratios, 1.9 versus 0.7 for diuretic use versus no use, P = .01). CONCLUSIONS Although active treatment in CAST-I was associated with greater mortality than placebo with respect to almost all baseline variables, the therapeutic hazard was more than expected in patients with non-Q-wave myocardial infarction and (for total mortality) frequent premature VPDs and higher heart rates, suggesting that the adverse effect of encainide or flecainide therapy is greater when ischemic and electrical instability are present. The relative hazard of therapy with moricizine in the sicker CAST-II population was greater in those using diuretics. Thus, although these drugs have the common ability to suppress ventricular ectopy after myocardial infarction, their detrimental effects on survival may be mediated by different mechanisms in different populations, emphasizing the complex, poorly understood hazards associated with antiarrhythmic drug treatment.

To determine whether out-of-hospital administration of hypertonic fluids would improve survival after severe injury with hemorrhagic shock.Hypertonic fluids have potential benefit in the resuscitation of severely injured patients because of rapid restoration of tissue perfusion, with a smaller volume, and modulation of the inflammatory response, to reduce subsequent organ injury.Multicenter, randomized, blinded clinical trial, May 2006 to August 2008, 114 emergency medical services agencies in North America within the Resuscitation Outcomes Consortium.injured patients, age ≥ 15 years with hypovolemic shock (systolic blood pressure ≤ 70 mm Hg or systolic blood pressure 71-90 mm Hg with heart rate ≥ 108 beats per minute). Initial resuscitation fluid, 250 mL of either 7.5% saline per 6% dextran 70 (hypertonic saline/dextran, HSD), 7.5% saline (hypertonic saline, HS), or 0.9% saline (normal saline, NS) administered by out-of-hospital providers. Primary outcome was 28-day survival. On the recommendation of the data and safety monitoring board, the study was stopped early (23% of proposed sample size) for futility and potential safety concern. : A total of 853 treated patients were enrolled, among whom 62% were with blunt trauma, 38% with penetrating. There was no difference in 28-day survival-HSD: 74.5% (0.1; 95% confidence interval [CI], -7.5 to 7.8); HS: 73.0% (-1.4; 95% CI, -8.7-6.0); and NS: 74.4%, P = 0.91. There was a higher mortality for the postrandomization subgroup of patients who did not receive blood transfusions in the first 24 hours, who received hypertonic fluids compared to NS [28-day mortality-HSD: 10% (5.2; 95% CI, 0.4-10.1); HS: 12.2% (7.4; 95% CI, 2.5-12.2); and NS: 4.8%, P0.01].Among injured patients with hypovolemic shock, initial resuscitation fluid treatment with either HS or HSD compared with NS, did not result in superior 28-day survival. However, interpretation of these findings is limited by the early stopping of the trial.Clinical Trials.gov, NCT00316017.

Two simple questions have been used to classify neurologic outcome in patients with stroke. Could they be similarly applied to patients with cardiac arrest?As part of a randomized trial, study personnel interviewed by telephone survivors of out-of-hospital cardiac arrest to assess their outcomes 3 months after discharge. They asked two simple questions: (1) In the last 2 weeks, did you require help from another person for your everyday activities? and (2) Do you feel that you have made a complete mental recovery form your heart arrest? Next they administered the Mini-Mental State Examination (MMSE) from the Adult Lifestyles and Function Interview (ALFI) to assess cognition on a scale from 0 to 22 and the Health Utilities Index Mark 3 (HUI3) to assess quality of life on a scale from 0 (death) to 1 (perfect health).Based on responses to the two simple questions, 32 survivors were classified as dependent (n=5, 16%), independent (n=3, 9%) and full recovery (n=24, 75%). The mean ALFI-MMSE score was 19.1 (standard deviation 5.1), and the mean HUI3 score was 0.76 (standard deviation 0.28). The classification based on the two simple questions was significantly correlated with ALFI-MMSE (p=0.002) and HUI3 (p=0.001). Scores for the HUI3 were missing in eight survivors.Neurologic outcomes based on the two simple questions after cardiac arrest can be easily determined, sensibly applied, and readily interpreted. These preliminary findings justify further evaluation of this simple and practical approach to classify neurologic outcome in survivors of cardiac arrest.

Since 1988, 641 black and 11,892 white patients with chest pain of presumed cardiac origin have been admitted to coronary care units in 19 hospitals in metropolitan Seattle. Black men and women were younger (58 vs 66, p less than 0.0001), more often admitted to central city hospitals (p less than 0.0001), and developed evidence of acute myocardial infarction (AMI) less often (19 vs 23%, p = 0.01). In the subset of 2,870 AMI patients, blacks (n = 121) were younger (59 vs 67, p less than 0.0001) and had less prior coronary artery bypass graft surgery (2 vs 10%, p = 0.005) and more prior hypertension (67 vs 46%, p less than 0.0001). During hospitalization, whites (n = 2,749) had higher rates of coronary angioplasty (18 vs 10%, p = 0.03) and coronary artery bypass graft surgery (10 vs 4%, p = 0.04), although thrombolytic therapy and cardiac catheterization were used equally in the 2 groups. Hospital mortality was 7.4% for black and 13.1% for white patients (p = 0.07). However, after adjustment for key demographic and clinical variables by logistic regression, this difference was not as apparent (p = 0.38). Questions about the premature onset of coronary artery disease, excess systemic hypertension, and the differential use of interventions in black persons have been raised by other investigators. Despite differences in age, referral patterns and the use of coronary angioplasty and bypass surgery, black and white patients with AMI in metropolitan Seattle had similar outcomes.

This article reviews the medical conditions that are associated with adverse pregnancy outcomes for women and their offspring. We also present the degree to which specific preconception interventions and treatments can impact the effects of the condition on birth outcomes. Because avoiding, delaying, or achieving optimal timing of a pregnancy is often an important component of the preconception care of women with medical conditions, contraceptive considerations particular to the medical conditions are also presented.

Background Quality-of-life (QoL) instruments evaluate various aspects of physical, mental, and emotional health, but how these psychosocial characteristics impact long-term outcome after cardiac arrest and ventricular tachycardia (VT) is unknown. Objective The purpose of this study was to evaluate the relationship of baseline QoL scores with long-term survival of patients enrolled in the Antiarrhythmics Versus Implantable Defibrillators (AVID) trial. Methods Formal QoL measures included SF-36 mental and physical components, Patient Concerns Checklist, and Ferrans and Powers Quality-of-Life Index–Cardiac Version. Multivariate Cox regression was used to assess the association of survival and these measures, adjusting for index arrhythmia type, gender, race, age, ejection fraction, history of congestive heart failure, antiarrhythmic therapy, and beta-blocker use. Results During mean follow-up of 546 ± 356 days, 129 deaths occurred among 740 patients. Higher baseline SF-36 physical summary scores ( P P = .015), and lower baseline Patient Concerns Checklist summary scores ( P = .047) were associated with longer survival, even after adjustment for clinical variables. When QoL measures were examined simultaneously, only the SF-36 physical summary score remained significant ( P = .002). Conclusion During recovery after sustained VT or cardiac arrest, formal baseline QoL assessment provides important prognostic information independent of traditional clinical data.