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The decision to undergo pericardectomy for symptomatic pericardial constriction is usually dictated by an image of an abnormal pericardium. We report a case of symptomatic pericardial constriction despite radiographic and pathological evidence of a normal pericardium. The patient was successfully treated with a pericardectomy, with resolution of constrictive hemodynamics and symptoms. Our report suggests that a normal pericardium by computed tomography and biopsy should not preclude pericardectomy for patients who have refractory symptoms, physical findings, and intracardiac pressures diagnostic of constrictive pericarditis. [ABSTRACT FROM AUTHOR]

Experimental heart failure is associated with cardiac magnesium loss, causing increased beat-to-beat variability in the action potential. Unstable repolarization contributes to sudden death, but no therapy has been shown to reduce repolarization variability safely. We sought to test whether a prolonged infusion of magnesium sulfate (MgSO(4); 40 mmol/24 hours) would normalize QT interval variability in patients with compensated heart failure. Fifteen patients (New York Heart Association class II to III; mean age 63 years) were enrolled in a placebo-controlled, double-blind study. Surface electrocardiograms were recorded and digitized at entry and at 48 and 168 hours (drug washout). Repolarization stability was assessed using an automated method measuring each QT interval in a 5-minute epoch. The QT variability index was derived as the ratio of normalized QT-to-normalized heart rate variability. Seven of 15 patients received MgSO(4). Mean heart rate and QT did not change in either group. The QT variability index was stable in the placebo group (-0.69 +/- 0.15 at entry, -0.71 +/- 0.22 at 48 hours, -0.70 +/- 0.18 at 168 hours), but decreased significantly in the treated group at 48 hours (-0.95 +/- 0.19 to -1.36 +/- 0.13, p <0.05 repeated-measures analysis of variance), returning to baseline at 168 hours (-0.84 +/- 0.18). Regression analyses showed that administration of MgSO(4) resulted in a stronger correlation between the QT and RR interval (p <0.01). Thus, MgSO(4) stabilizes cardiac repolarization in patients with compensated heart failure due to ischemic heart disease. Magnesium therapy may be useful in altering the proarrhythmic substrate in heart failure. [ABSTRACT FROM AUTHOR]

Introduction: Loss-of-control (LOC) eating, or the subjective experience of being unable to stop eating, is a hallmark feature of binge-eating episodes, which are also characterized by consuming an unusually large amount of food. However, regardless of the size of eating episode, LOC-eating may be a risk factor for adverse health outcomes. This systematic review and meta-analysis comprehensively examine the relationship of LOC-eating with cardiometabolic health components and inflammatory markers., Methods: Search procedures were conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines in six electronic databases. Studies of adult or youth samples published in English from the year 2000 onward were included. Given heterogeneity in age groups and adjustment for body mass index across studies, these factors were included as meta-regression moderators., Results: Fifty-eight studies were identified through the literature search. Among individuals with (versus without) LOC-eating, relative risk ratios provided evidence of a greater relative risk for metabolic syndrome, hypertension, and dyslipidemia; standardized mean differences also provided evidence of higher waist circumference and impaired levels of fasting plasma glucose, high-density lipoprotein (HDL)-cholesterol, and triglycerides, but not blood pressure. Age group did not impact cardiometabolic health components. Body mass index differences moderated the effect on waist circumference. A narrative review of inflammatory markers revealed mixed findings linking inflammatory markers to LOC-eating., Discussion: Overall, evidence for the relationship between LOC-eating and impaired cardiometabolic health underscores LOC-eating as an important early intervention target for prevention of serious adverse health outcomes., (© 2024 The Author(s). Obesity Reviews published by John Wiley & Sons Ltd on behalf of World Obesity Federation.)

Background: Traumatic brain injury (TBI) is associated with a variety of adverse long-term outcomes and increases sympathetic nervous system activation, which could increase the risk of arrhythmias including atrial fibrillation or atrial flutter (AF/AFL)., Objective: We examined episodes of TBI and subsequent AF/AFL in a large cohort of post-9/11 servicemembers and veterans., Methods: The variable of interest was TBI, stratified by severity (mild, moderate/severe, and penetrating). The outcome was a subsequent diagnosis of AF/AFL. We used Fine-Gray competing risks models to evaluate the potential risk imparted by TBI on subsequent AF/AFL., Results: Of the 1,924,900 participants included in the analysis, 369,891 (19.2%) experienced an episode of documented TBI. Most were young (63% <35 years), male (81.7%), and non-Hispanic White (62.7%). AF/AFL was diagnosed in 22,087 patients. On univariate analysis, only penetrating TBI (hazard ratio [HR], 2.02; 95% confidence interval [CI], 1.84-2.23; P < .001) was associated with AF/AFL compared with veterans without TBI. After adjustment in the full multivariable model (adjusted for age, sex, race and ethnicity, service branch, rank, component, and comorbidities), mild (HR 1.27, 95% CI 1.22-1.32; P < .001), moderate/severe (HR, 1.34; 95% CI, 1.24-1.44; P < .001), and penetrating TBI (HR, 1.82; 95% CI, 1.65-2.02; P < .001) were significantly associated with AF/AFL compared with no TBI. Post hoc analyses demonstrated that the risk of AF/AFL was concentrated in female and younger patients., Conclusion: We found that an episode of TBI, particularly penetrating TBI, significantly increased the risk for AF/AFL. Further work is needed to delineate the long-term risk of arrhythmias after TBI., Competing Interests: Disclosures The authors have no conflicts of interest to disclose., (Published by Elsevier Inc.)

Food cravings during pregnancy are highly common, yet no measure of cravings has been validated among pregnant women. The current study evaluated the psychometric properties of the Food Craving Inventory (FCI) for use during pregnancy. U.S. military active-duty Service women (N = 192; 29.5 ± 3.8 years old; 44% Army, 36% Air Force, 15% Navy, and 4% Marine Corps) were recruited from the community at 12-27 weeks' gestation. Participants completed a modified version of the FCI validated for adults with binge-eating disorder, which included 13 additional items assessing cravings for foods that women commonly report experiencing during pregnancy (e.g., pickles, sour cream, hot or spicy wings). Additional measures also assessed disinhibited eating behaviors (i.e., loss of control eating and emotional eating). A series of confirmatory factor analyses were conducted to examine model fit for a four-factor structure of: (1) the FCI validated for binge-eating disorder (excluding the pregnancy-oriented food items) and (2) the FCI modified for pregnancy (with the pregnancy-oriented food items added). The previously validated four-factor structure of the FCI for binge-eating disorder demonstrated poor model fit in the current sample of pregnant women. After examining the structure of the FCI modified for pregnancy, several items were removed due to high cross-loading across multiple subscales. The resulting 16-item, four-factor (Fats, Sweets, Carbohydrates, Spicy/Strong foods) FCI for pregnancy (FCI-P) demonstrated generally good model fit (CFI = .95, TLI = .94, SRMR = .04, RMSEA = .09) and good-to-excellent internal consistency (Cronbach's alphas: .83-.96). Convergent validity was supported by significant correlations between the FCI-P scores and the disinhibited eating behavior scores (ps < .001). Results highlight the importance of psychometrically evaluating eating-related measures for use during pregnancy to appropriately capture the potentially unique experiences of the perinatal period., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Genetic counseling and genetic testing are important tools for diagnosis, screening, and employment of effective medical management strategies for hereditary cardiovascular diseases. Despite widespread recognition of the benefits of genetic counseling and testing in cardiovascular care, little is published regarding their use in large healthcare systems. We conducted a retrospective cross-sectional study using administrative claims data in the US Military Health System to assess the state of recommended genomic counseling in clinical cardiovascular care. Logistic regression models were used to examine associations of genetic counseling among beneficiaries with hereditary cardiovascular conditions. Approximately 0.44% of beneficiaries in fiscal year 2018 had a diagnosis of a hereditary cardiovascular condition. Among the 23,364 patients with a diagnosis of hereditary cardiovascular disease, only 175 (0.75%) had documented genetic counseling and 196 (0.84%) had documented genetic testing. Genetic counseling did not differ by race, sex, service, or diagnosis. Age group, Active Duty status, rank as a proxy for socioeconomic status, and geographic location contributed significantly to the likelihood of receiving genetic counseling. These findings suggest that genetic counseling is underutilized in clinical cardiovascular care in the Military Health System and may be more broadly, despite expert consensus recommendations for its use and potential life-saving benefits. Unlike previous studies in the US civilian health sector, there did not appear to be disparities in genetic counseling by race or sex in the Military Health System. Strategies to improve care for cardiovascular disease should address the underutilization of recommended genetics evaluations for heritable diagnoses and the challenges of assessing use in large health systems studies., (© 2023 National Society of Genetic Counselors. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Objective: Adolescent children of US service members (i.e., military-dependent youth) face unique stressors that increase risk for various forms of disinhibited eating, including emotional eating. Difficulties with adaptively responding to stress and aversive emotions may play an important role in emotional eating. This study examined emotion dysregulation as a potential moderator of the association between perceived stress and emotional eating in adolescent military dependents., Method: Participants were military-dependent youth (N = 163, 57.7% female, M age  = 14.5 ± 1.6, M BMI-z  = 1.9 ± 0.4) at risk for adult binge-eating disorder and high weight enrolled in a randomized controlled prevention trial. Prior to intervention, participants completed questionnaires assessing perceived stress and emotional eating. Parents completed a questionnaire assessing their adolescent's emotion dysregulation. Moderation analyses were conducted using the PROCESS macro in SPSS and adjusted for theoretically relevant sociodemographic covariates., Results: The interaction between adolescent perceived stress and emotion dysregulation (parent-reported about the adolescent) in relation to adolescent emotional eating was found to be significant, such that higher emotion dysregulation magnified the association between perceived stress and emotional eating (p = .010). Examination of simple slopes indicated that associations between perceived stress and emotional eating were strongest for youth with above-average emotion dysregulation, and non-significant for youth with average or below-average emotion dysregulation., Discussion: Findings suggest that greater emotion dysregulation may increase risk for emotional eating in response to stress among military-dependent youth at risk for binge-eating disorder or high weight. Improving emotion regulation skills may be a useful target for eating disorder prevention among youth who are at risk for emotional eating., Public Significance: Prior research has shown that adolescent military dependents are at increased risk for eating disorders and high weight. The current study found that emotion dysregulation moderated the relationship between perceived stress and emotional eating among military-dependent youth. There may be clinical utility in intervening on emotion regulation for adolescent dependents at particular risk for emotional eating and subsequent eating disorders., (© 2024 The Authors. International Journal of Eating Disorders published by Wiley Periodicals LLC.)

Introduction: Response to medications can differ widely among individual patients. Adverse drug reactions can lead to serious morbidity and mortality. Pharmacogenetic (PGx) testing can predict responses to medications and increased risks of adverse events where the genetic basis is understood. Several published manuscripts suggest positive impacts of systematic preemptive PGx testing. However, few studies have been conducted on PGx implementation in the Military Health System (MHS)., Material and Methods: A cross-sectional study of adult beneficiaries in a primary care clinic at a large military treatment facility was conducted in 2022. Participants underwent PGx genotyping of CYP2C19 and CYP2D6 genes at the Defense Health Agency Genetics Reference Laboratory. Participant medication lists were compared to the current Clinical Pharmacogenetic Implementation Consortium (CPIC) PGx gene-drug guidelines to assess potential actionability of these results., Results: Genotyping of CYP2C19 and CYP2D6 in 165 MHS beneficiaries (mean age: 65 years) revealed that 81.2% of participants had at least one abnormal PGx finding. Among those with an abnormal PGx result, 65% were taking a medication listed on the CPIC website with an association with the particular gene in which the finding was identified. In addition, 78% of all of the participants in the study were taking at least one medication that is metabolized by CYP2C19 or CYP2D6 with associated CPIC guidelines., Conclusions: Pharmacogenetic testing for CYP2C19 and CYP2D6 identified a substantial proportion of MHS patients at a single center who could benefit from evaluation of current medication regimens based on the CPIC guidelines. Individualized medical management may be warranted to a greater degree than previously recognized based on the findings given possible differences in medication metabolism. Many MHS beneficiaries already take medications metabolized by CYP2C19 and CYP2D6, and a substantial proportion may be at risk for preventable adverse events for medications metabolized by these enzymes. While preliminary, a large number of actionable polymorphisms among a relatively small set of individuals taking at-risk medications suggest that implementing PGx testing in clinical practice may be beneficial in the MHS with appropriate clinical infrastructure., (© The Association of Military Surgeons of the United States 2023. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Phaeochromocytomas and paragangliomas (PPGLs) release catecholamines leading to catecholamine-induced hypertensive (CIH) crises, with blood pressure greater than or equal to 180/120 mm Hg. CIH crises can be complicated by tachyarrhythmias, hypotension, or life-threatening target organ damage while treatment remains undefined, often requiring co-management between endocrinologists and cardiologists. Furthermore, biochemical diagnosis of a PPGL as a cause of a CIH crisis can be difficult to identify or confounded by comorbid conditions, potentially resulting in misdiagnosis. Here, we combine relevant evidence, 60 years of collective clinical experience, insights derived from assessing over 2600 patients with PPGL, and supplementary outcomes from 100 patients (treated at the National Institutes of Health) with a CIH crisis to inform diagnosis and treatment of CIH crises. Recognising that disparities exist between availability, cost, and familiarity of various agents, flexible approaches are delineated allowing for customisation, given institutional availability and provider preference. A CIH crisis and its complications are readily treatable with available drugs, with effective intervention defining an avenue for mitigating consequent morbidity and mortality in patients with PPGL., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Adolescent military-dependents are an understudied population who face unique stressors due to their parents' careers. Research suggests that adolescent military-dependents report more anxiety and disordered-eating than their civilian counterparts. While anxiety symptoms predict the onset and worsening of disordered-eating attitudes, the mechanisms underlying this relationship remain unclear. One factor that may underlie this relationship, and be particularly relevant for military-dependent youth, is coping. Therefore, we examined adolescent military-dependents ( N =136; 14.5±1.5 years; 59.6% female; BMI- z : 1.9±0.4) who were at-risk for adult obesity and binge-eating disorder due to an age- and sex-adjusted BMI ≥ 85 th percentile and loss-of-control eating and/or elevated anxiety. Participants completed an interview assessing disordered-eating attitudes and questionnaires on anxiety symptoms and coping strategies at a single time point. Bootstrapping models were conducted to examine the indirect paths between anxiety symptoms and disordered-eating attitudes through five coping subscales (aggression, distraction, endurance, self-distraction, and stress-recognition). Adjusting for relevant covariates, no significant indirect paths through the coping subscales ( p s > .05) were found in any models. General coping, non-specific to eating, may not be a pathway between anxiety symptoms and disordered-eating attitudes among adolescents. Future research should examine other potential mediators of this relationship., Competing Interests: Declarations of interest: None.

Purpose: Evidence suggests that difficulties identifying and describing one's feelings, core components of alexithymia, are associated with attitudinal and behavioral symptoms of disordered eating; depressive symptoms also may underlie these associations. Specifically, research indicates that alexithymia is positively related to depressive symptoms, which in turn may promote both disordered-eating attitudes and certain disinhibited-eating behaviors (e.g., emotional eating). Findings also suggest that military-dependent youth with high weight may exhibit elevated depressive symptoms and disordered eating. As such, understanding associations among alexithymia, depressive symptoms, and disordered eating is particularly relevant for this vulnerable population., Methods: We examined 149 adolescent military dependents (14.4 ± 1.6y; 55.0% female; 20.0% non-Hispanic Black; BMIz: 1.9 ± 0.4) at high risk for binge-eating disorder and obesity in adulthood. Participants completed questionnaires assessing two components of alexithymia (difficulty identifying feelings [DIF] and difficulty describing feelings [DDF]), depressive symptoms, emotional eating, and trait anxiety; disordered-eating attitudes were assessed via semi-structured interview., Results: A series of regression-based models examined indirect relationships of DIF and DDF with disordered-eating attitudes and emotional eating through depressive symptoms. Bootstrapped 95% confidence intervals revealed a significant indirect path from each of the alexithymia components to disordered-eating attitudes via depressive symptoms; indirect paths to emotional eating were non-significant., Conclusion: Results support the salience of depressive symptoms in the relationship between alexithymia and disordered-eating attitudes. Future research should utilize prospective designs and explore direct and indirect associations of alexithymia with other disordered-eating behaviors., Level of Evidence: Level III, evidence obtained from a well-designed cohort study., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Objectives: Adolescent military-dependents experience distinct risk and protective factors, which may necessitate additional clinical considerations. In civilian youth, overweight/obesity is associated with eating, internalizing, and externalizing difficulties, with some studies reporting more difficulties among non-Hispanic White (vs. non-Hispanic Black) youth. It is unknown if these disparities exist among adolescent military-dependents, or between civilian and military-dependent youth., Methods: Non-Hispanic Black (187 civilian, 38 military-dependent) and non-Hispanic White (205 civilian, 84 military-dependent) adolescents with overweight/obesity (14.7 ± 1.6 years; 73.9% girls; body mass index adjusted for age and sex 1.9 ± 0.5) completed a disordered-eating interview; parents completed a measure assessing their child's internalizing and externalizing difficulties. Multiple linear regressions examined parental military-status as a moderator of the relationship of participant race with eating, internalizing, and externalizing difficulties., Results: White civilian youth with overweight/obesity reported significantly greater disordered-eating than their Black peers (p < .001); there were no other significant racial differences. In all regressions, parental military-status significantly moderated the association between race and each dependent variable (ps < .047). Black military-dependents (vs. civilians) reported more disordered-eating and internalizing difficulties (ps = .01). White military-dependents (vs. civilians) reported fewer externalizing difficulties (p = .01)., Conclusions: Black adolescent military-dependents with overweight/obesity may experience more eating and internalizing difficulties (vs. civilians), a pattern not observed among White participants. Future work should examine if being a military-dependent and a historically marginalized racial group member accounts for these findings. Such data may inform providers of youth with intersecting minority identities., (Published by Oxford University Press on behalf of the Society of Pediatric Psychology 2022. This work is written by US Government employees and is in the public domain in the US.)

Background: Among adults, weight stigma is associated with markers of poor cardiometabolic health. Although weight-based teasing (WBT) is common among youth with high body weight, few studies have examined its associations with cardiometabolic markers. Owing to unique stressors ( e.g. , parental deployment and frequent moves), military-dependent youth may be at particularly high risk for obesity, WBT, and poor cardiometabolic health. We, therefore, assessed associations between WBT and cardiometabolic health markers among adolescent military dependents presenting for a weight gain prevention trial. Methods: Participants underwent fasting phlebotomy; had fasting weight, height, and waist circumference measured; and completed assessments of WBT, anxiety, and loss-of-control eating. Multivariate analysis of covariance, adjusting for relevant covariates including demographics and body composition, was used to examine differences in metabolic syndrome (MetS) components (waist circumference, systolic and diastolic blood pressure, high-density lipoprotein cholesterol, triglycerides, and glucose) between youth reporting WBT and youth reporting no WBT. Bootstrapped models examined whether WBT mediated the relationship between BMI z and MetS components. Results: Data from 142 youth (57.7% female; 14.4 ± 1.6 years; 51.2% non-Hispanic White, 20.9% non-Hispanic Black; BMI z : 1.9 ± 0.4) were analyzed. WBT was not significantly associated with any MetS component. Relationships were observed between BMI z and all MetS components (except systolic blood pressure and glucose), although WBT did not significantly mediate these relationships ( p' s > 0.05). Conclusions: This study did not find support for a relationship between WBT and MetS components in adolescent military dependents at risk for adult obesity. Prospective research is needed to determine whether associations between WBT and adverse cardiometabolic outcomes emerge primarily in adulthood.

Objective: Military-dependent youth appear to be at greater risk for disordered-eating than their civilian counterparts. Permanent change of station moves (PCS-moves), typically occurring every 2-3 years, are commonly experienced by adolescent military-dependents. However, the links between PCS-moves and disordered-eating in this population have not been explored. We hypothesized that stress arising from PCS-moves may contribute to the development and/or exacerbation of disordered-eating., Methods: One-hundred-forty-nine adolescent military-dependents with overweight or obesity (59.7% female; 46.3% non-Hispanic White; 14.4±1.5 years; BMI-z: 1.9±0.4) completed measures before commencing an adulthood obesity and binge-eating disorder prevention trial for adolescents at-risk for both conditions due to BMI percentile ≥85th and loss-of-control (LOC)-eating and/or elevated anxiety symptoms. Disordered-eating attitudes and LOC-eating were assessed by semi-structured interview, and emotional eating was self-reported. Adjusting for relevant covariates, multiple linear regressions examined the unique association of PCS-move frequency with disordered-eating attitudes and disinhibited-eating behaviors., Results: PCS-move frequency was not significantly associated with either LOC-eating frequency (β = 0.09, p = .27) or emotional eating (β = -0.04, p = .62). However, PCS-move frequency was positively associated with disordered-eating attitudes (β = 0.17, p = .04), which appeared to be primarily driven by shape concerns (β = 0.21, p = .01)., Discussion: Findings indicate that frequency of PCS-moves is related to disordered-eating attitudes, but not behaviors. Longitudinal research is needed to understand if PCS-moves prospectively relate to the onset and/or exacerbation of disordered-eating, and the relevance of disordered-eating attitudes as opposed to disinhibited-eating behaviors., (Copyright © 2020. Published by Elsevier Ltd.)

Techniques that enable longitudinal tracking of cell fate after myocardial delivery are imperative for optimizing the efficacy of cell-based cardiac therapies. However, these approaches have been underutilized in preclinical models and clinical trials, and there is considerable demand for site-specific strategies achieving long-term expression of reporter genes compatible with safe noninvasive imaging. In this study, the rhesus sodium/iodide symporter (NIS) gene was incorporated into rhesus macaque induced pluripotent stem cells (RhiPSCs) via CRISPR/Cas9. Cardiomyocytes derived from NIS-RhiPSCs (NIS-RhiPSC-CMs) exhibited overall similar morphological and electrophysiological characteristics compared to parental control RhiPSC-CMs at baseline and with exposure to physiological levels of sodium iodide. Mice were injected intramyocardially with 2 million NIS-RhiPSC-CMs immediately following myocardial infarction, and serial positron emission tomography/computed tomography was performed with 18 F-tetrafluoroborate to monitor transplanted cells in vivo. NIS-RhiPSC-CMs could be detected until study conclusion at 8 to 10 weeks postinjection. This NIS-based molecular imaging platform, with optimal safety and sensitivity characteristics, is primed for translation into large-animal preclinical models and clinical trials., (© 2020 The Authors. STEM CELLS Translational Medicine published by Wiley Periodicals LLC on behalf of AlphaMed Press.)

Background: Metabolic syndrome in adolescence has been associated with adverse cardiometabolic outcomes in adulthood. Preliminary data suggest that boys may have worsened metabolic syndrome components compared to girls. Yet, little is known about the physical health of military dependents, a potentially at-risk population., Objective: Examine sex differences in metabolic syndrome components in a sample of adolescent military dependents., Methods: Participants were adolescents (N = 139; 14.4 ± 1.6 years; 45.3% male; 41.0% non-Hispanic White, 19.4% non-Hispanic Black; BMI-z: 1.9 ± 0.4) at-risk for adult obesity and binge-eating disorder due to an age- and sex-adjusted BMI ≥85th percentile and loss-of-control eating and/or elevated anxiety. A multivariate analysis of covariance was conducted to compare objectively measured metabolic syndrome components across boys and girls. Covariates were age, race, loss-of-control eating status, anxiety symptoms, and BMI-z., Results: Metabolic syndrome components differed by sex (P = .01). Boys had higher systolic blood pressure (P = .049), lower high-density lipoprotein cholesterol (P = .01), and higher glucose (P = .001) than girls. Waist circumference, diastolic blood pressure, and triglycerides did not differ between boys and girls (P > .05)., Conclusions: Future research should prospectively examine these relationships into adulthood. If the current findings are supported, prevention programs should consider targeting cardiometabolic health particularly among male adolescent military dependents., (© 2020 World Obesity Federation.)

Binary expression systems like the LexA-LexAop system provide a powerful experimental tool kit to study gene and tissue function in developmental biology, neurobiology, and physiology. However, the number of well-defined LexA enhancer trap insertions remains limited. In this study, we present the molecular characterization and initial tissue expression analysis of nearly 100 novel StanEx LexA enhancer traps, derived from the StanEx 1 index line. This includes 76 insertions into novel, distinct gene loci not previously associated with enhancer traps or targeted LexA constructs. Additionally, our studies revealed evidence for selective transposase-dependent replacement of a previously-undetected KP element on chromosome III within the StanEx 1 genetic background during hybrid dysgenesis, suggesting a molecular basis for the over-representation of LexA insertions at the NK7.1 locus in our screen. Production and characterization of novel fly lines were performed by students and teachers in experiment-based genetics classes within a geographically diverse network of public and independent high schools. Thus, unique partnerships between secondary schools and university-based programs have produced and characterized novel genetic and molecular resources in Drosophila for open-source distribution, and provide paradigms for development of science education through experience-based pedagogy., (Copyright © 2019 Kockel et al.)

Background: Genomic sequencing has become a widely used tool in clinical and research settings in both civilian and military healthcare systems., Methods: In this paper, we consider potential military-specific implications of returning genomic sequencing secondary findings to ensure the proper protections, policies, and processes are in place for the use of this information., Results: We specifically use two examples to highlight potential military implications of the return of secondary findings., Conclusion: Clinicians and researchers are strongly encouraged to consider the military implications of the return of results for informed consent of service members or their families undergoing clinical or research genomic sequencing., (© 2018 The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)

Purpose: Obstructive sleep apnea (OSA) syndrome is a common condition that can impact clinical outcomes among patients with cardiovascular disease. Screening all subjects with heart disease via polysomnography (PSG) is costly and resource-limited. We sought to compare a Holter monitor-based algorithm to detect OSA to in-laboratory polysomnography (PSG)., Methods: Prospective cohort study of patients undergoing in-laboratory attended PSG for the evaluation of OSA. A standard 12-lead Holter monitor was attached to patients at the initiation of PSG. Holter-derived respiratory disturbance index (HDRDI) was extracted from the respiratory myogram, based on detecting skeletal muscle "noise" detected on the baseline. Apneic and hypopneic episodes were identified by comparing sudden changes in the myogram to abrupt increases in heart rate. The HDRDI was compared with the PSG-derived apnea-hypopnea index (PDAHI)., Results: Thirty patients underwent simultaneous Holter monitoring and overnight diagnostic PSG. An ROC curve for peak HDRDI was 0.79 (95% CI 0.61, 0.97) for OSA, with sensitivity of 94.4% and specificity of 54.5%. A cutoff value of HDRDI < 10 appeared to identify those individuals without clinically significant sleep-disordered breathing., Conclusion: Holter-derived respiration detected OSA comparable to PSG. Further study is warranted to determine its utility for screening and diagnosing OSA in appropriately selected patients.

Background: The failing heart exhibits an increased arrhythmia susceptibility that is often attributed to action potential (AP) prolongation due to significant ion channel remodeling. The inwardly rectifying K + current (I K1 ) has been reported to be reduced, but its contribution to shaping the AP waveform and cell excitability in the failing heart remains unclear., Objective: The purpose of this study was to define the effect of I K1 suppression on the cardiac AP and excitability in the normal and failing hearts., Methods: We used electrophysiological and pharmacological approaches to investigate I K1 function in a swine tachy-pacing model of heart failure (HF)., Results: Terminal repolarization of the AP (TRAP; the time constant of the exponential fit to terminal repolarization) was markedly prolonged in both myocytes and arterially perfused wedges from animals with HF. TRAP was increased by 54.1% in HF myocytes (P < .001) and 26.2% in HF wedges (P = .014). The increase in TRAP was recapitulated by the potent and specific I K1 inhibitor, PA-6 (pentamidine analog 6), indicating that I K1 is the primary determinant of the final phase of repolarization. Moreover, we find that I K1 suppression reduced the ratio of effective refractory period to AP duration at 90% of repolarization, permitting re-excitation before full repolarization, reduction of AP upstroke velocity, and likely promotion of slow conduction., Conclusion: Using an objective measure of terminal repolarization, we conclude that I K1 is the major determinant of the terminal repolarization time course. Moreover, suppression of I K1 prolongs repolarization and reduces postrepolarization refractoriness without marked effects on the overall AP duration. Collectively, these findings demonstrate how I K1 suppression may contribute to arrhythmogenesis in the failing heart., (Published by Elsevier Inc.)

Despite the rising rates of resistance to dihydroartemisinin-piperaquine (DP), DP remains a first-line therapy for uncomplicated malaria in many parts of Cambodia. While DP is generally well tolerated as a 3-day DP (3DP) regimen, compressed 2-day DP (2DP) regimens were associated with treatment-limiting cardiac repolarization effects in a recent clinical trial. To better estimate the risks of piperaquine on QT interval prolongation, we pooled data from three randomized clinical trials conducted between 2010 and 2014 in northern Cambodia. A population pharmacokinetic model was developed to compare exposure-response relationships between the 2DP and 3DP regimens while accounting for differences in regimen and sample collection times between studies. A 2-compartment model with first-order absorption and elimination without covariates best fit the data. The linear slope-intercept model predicted a 0.05-ms QT prolongation per ng/ml of piperaquine (5 ms per 100 ng/ml) in this largely male population. Though the plasma half-life was similar in both regimens, peak and total piperaquine exposures were higher in those treated with the 2DP regimen. Furthermore, the correlation between the plasma piperaquine concentration and the QT interval prolongation was stronger in the population receiving the 2DP regimen. Neither the time since the previous meal nor the baseline serum magnesium or potassium levels had additive effects on QT interval prolongation. As electrocardiographic monitoring is often nonexistent in areas where malaria is endemic, 2DP regimens should be avoided and the 3DP regimen should be carefully considered in settings where viable alternative therapies exist. When DP is employed, the risk of cardiotoxicity can be mitigated by combining a 3-day regimen, enforcing a 3-h fast before and after administration, and avoiding the concomitant use of QT interval-prolonging medications. (This study used data from three clinical trials that are registered at ClinicalTrials.gov under identifiers NCT01280162, NCT01624337, and NCT01849640.)., (Copyright © 2017 American Society for Microbiology.)

Cardiomyocytes can be differentiated from human pluripotent stem cells (hPSCs) in defined conditions, but efficient and consistent cardiomyocyte differentiation often requires expensive reagents such as B27 supplement or recombinant albumin. Using a chemically defined albumin-free (E8 basal) medium, we identified heparin as a novel factor that significantly promotes cardiomyocyte differentiation efficiency, and developed an efficient method to differentiate hPSCs into cardiomyocytes. The treatment with heparin helped cardiomyocyte differentiation consistently reach at least 80% purity (up to 95%) from more than 10 different hPSC lines in chemically defined Dulbecco's modified Eagle's medium/F-12-based medium on either Matrigel or defined matrices like vitronectin and Synthemax. One of heparin's main functions was to act as a Wnt modulator that helped promote robust and consistent cardiomyocyte production. Our study provides an efficient, reliable, and cost-effective method for cardiomyocyte derivation from hPSCs that can be used for potential large-scale drug screening, disease modeling, and future cellular therapies. Stem Cells Translational Medicine 2017;6:527-538., (© 2016 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.)

Objective: Studying physiologic underpinnings of loss-of-control (LOC) eating may inform its etiology and contribute to intervention efforts. We therefore examined temporal relationships between autonomic indices [heart rate (HR), heart rate variability (HRV)] and LOC-eating in the natural environment., Method: For two days, adolescents (n = 17, 14.77 ± 1.55 years, BMI-Z 2.17 ± 0.48) with LOC-eating reported on LOC using an electronic device while HR and HRV were assessed continuously using Holter monitoring., Results: Higher HR and lower HRV in the 30-minutes before eating were significantly associated with LOC-eating overall (p's < 0.001) and at the within-participants level (p's < 0.001), but not at the between-participants level (p's > 0.44). Examined categorically, HR was significantly higher, and HRV significantly lower, prior to high-LOC compared to low-LOC episodes (p's < 0.001)., Discussion: This pilot study suggests that LOC-eating may involve physiologic underpinnings. Additional research with larger samples is needed to further investigate this phenomenon., (© 2015 Wiley Periodicals, Inc.)

Cardiac-related clinical practice guidelines have become an integral part of the practice of cardiology. Unfortunately, these guidelines are often long, complex, and difficult for practicing cardiologists to use. Guidelines should be condensed and their format upgraded, so that the key messages are easier to comprehend and can be applied more readily by those involved in patient care. After presenting the historical background and describing the guideline structure, we make several recommendations to make clinical practice guidelines more user-friendly for clinical cardiologists. Our most important recommendations are that the clinical cardiology guidelines should focus exclusively on (1) class I recommendations with established benefits that are supported by randomized clinical trials and (2) class III recommendations for diagnostic or therapeutic approaches in which quality studies show no benefit or possible harm. Class II recommendations are not evidence based but reflect expert opinions related to published clinical studies, with potential for personal bias by members of the guideline committee. Class II recommendations should be published separately as "Expert Consensus Statements" or "Task Force Committee Opinions," so that both majority and minority expert opinions can be presented in a less dogmatic form than the way these recommendations currently appear in clinical practice guidelines., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Breathing is a critical component of cardiopulmonary function, but few tools exist to evaluate respiration in ambulatory patients. Holter monitoring allows accurate diagnosis of a host of cardiac issues, and several investigators have demonstrated the ability to detect respiratory effort on the electrocardiogram. In this study we introduce a myogram signal derived from 12-lead, high frequency Holter as a means of detecting respiratory effort. Using the combined myogram and ECG signal, four novel variables were created: total number of Cheyne-Stokes episodes; the BWRatio, the ratio of power (above baseline) measured one second after peak-to-peak respiratory power, an assessment of the "shape" of the respiratory effort; DRR, the change in RR interval centering around peak inspiration; and minutes of synchronized breathing, a fixed ratio of heart beats to respiratory cycles. These variables were assessed in 24-hour recordings from three cohorts: healthy volunteers (n=33), heart failure subjects from the GISSI HF trial (n=383), and subjects receiving implantable defibrillators with severely depressed left ventricular function enrolled in the M2Risk trial (n=470). We observed a statistically significant 6-fold increase in the number of Cheyne-Stokes episodes (p=0.01 by ANOVA), decreases in BWRatio (p<0.001), as well as decrease in DRR in heart failure subjects; only minutes of synchronized breathing was not significantly decreased in heart failure. This study provides "proof of concept" that novel variables incorporating Holter-derived respiration can distinguish healthy subjects from heart failure. The utility of these variables for predicting heart failure, arrhythmia, and death risk in prospective studies needs to be assessed., (Published by Elsevier Inc.)

Dihydroartemisinin-piperaquine, the current first-line drug for uncomplicated malaria caused by Plasmodium falciparum and Plasmodium vivax in Cambodia, was previously shown to be of benefit as malaria chemoprophylaxis when administered as a monthly 3-day regimen. We sought to evaluate the protective efficacy of a compressed monthly 2-day treatment course in the Royal Cambodian Armed Forces. The safety and efficacy of a monthly 2-day dosing regimen of dihydroartemisinin-piperaquine were evaluated in a two-arm, randomized, double-blind, placebo-controlled cohort study with 2:1 treatment allocation. Healthy military volunteers in areas along the Thai-Cambodian border where there is a high risk of malaria were administered two consecutive daily doses of 180 mg dihydroartemisinin and 1,440 mg piperaquine within 30 min to 3 h of a meal once per month for a planned 4-month period with periodic electrocardiographic and pharmacokinetic assessment. The study was halted after only 6 weeks (69 of 231 projected volunteers enrolled) when four volunteers met a prespecified cardiac safety endpoint of QTcF (Fridericia's formula for correct QT interval) prolongation of >500 ms. The pharmacodynamic effect on the surface electrocardiogram (ECG) peaked approximately 4 h after piperaquine dosing and lasted 4 to 8 h. Unblinded review by the data safety monitoring board revealed mean QTcF prolongation of 46 ms over placebo at the maximum concentration of drug in serum (Cmax) on day 2. Given that dihydroartemisinin-piperaquine is one of the few remaining effective antimalarial agents in Cambodia, compressed 2-day treatment courses of dihydroartemisinin-piperaquine are best avoided until the clinical significance of these findings are more thoroughly evaluated. Because ECG monitoring is often unavailable in areas where malaria is endemic, repolarization risk could be mitigated by using conventional 3-day regimens, fasting, and avoidance of repeated dosing or coadministration with other QT-prolonging medications. (This study has been registered at ClinicalTrials.gov under registration no. NCT01624337.)., (Copyright © 2014, American Society for Microbiology. All Rights Reserved.)

Tachycardia induced cardiomyopathy is a potentially lethal cause of heart failure generally because of atrial tachycardia and less frequently ventricular tachycardia. We present two cases of Marines with severe traumatic blast injuries secondary to improvised explosive device attacks whose hospital courses included amputation, massive blood transfusions, and multiple surgeries. Both patients had prolonged sinus tachycardia averaging >110 beats per minute and developed depressed left ventricular function, which recovered when treated with β blockers. Sinus tachycardia is often considered a physiological response to stress, and the purpose of this manuscript is to describe the cardiac injury apparently related to a prolonged stress response. In addition, the literature does not clearly recommend controlling heart rates in trauma patients with persistent sinus tachycardia, but it is a therapeutic option that should be considered by providers., (Reprint & Copyright © 2014 Association of Military Surgeons of the U.S.)

Background: Electrocardiogram (ECG) with preparticipation evaluation (PPE) for athletes remains controversial in the United States and diagnostic accuracy of clinician ECG interpretation is unclear. This study aimed to assess reliability and validity of clinician ECG interpretation using expert-validated ECGs according to the 2010 European Society of Cardiology (ESC) interpretation criteria., Methods: This is a blinded, prospective study of diagnostic accuracy of clinician ECG interpretation. Anonymized ECGs were validated for normal and abnormal patterns by blinded expert interpreters according to the ESC interpretation criteria from October 2011 through March 2012. Six pairs of clinician interpreters were recruited from relevant clinical specialties in an academic medical center in March 2012. Each clinician interpreted 85 ECGs according to the ESC interpretation guidelines. Cohen and Fleiss' kappa, sensitivity, and specificity were calculated within specialties and across primary care and cardiology specialty groups., Results: Experts interpreted 189 ECGs yielding a kappa of 0.63, demonstrating "substantial" inter-rater agreement. A total of 85 validated ECGs, including 26 abnormals, were selected for clinician interpretation. The kappa across cardiology specialists was "substantial" and "moderate" across primary care (0.69 vs 0.52, respectively, P < 0.001). Sensitivity and specificity to detect abnormal patterns were similar between cardiology and primary care groups (sensitivity 93.3% vs 81.3%, respectively, P = 0.31; specificity 88.8% vs 89.8%, respectively, P = 0.91)., Conclusions: Clinician ECG interpretation according to the ESC interpretation criteria appears to demonstrate limited reliability and validity. Before widespread adoption of ECG for PPE of U.S. athletes, further research of training focused on improved reliability and validity of clinician ECG interpretation is warranted., (© 2014 Wiley Periodicals, Inc.)

Aims: Hospitalization for worsening heart failure (HF) is known to increase mortality and morbidity risk and has been frequently used as an endpoint in randomized clinical trials. Whether outpatient management of HF exacerbation carries similar prognostic and therapeutic information is less well known, but could be important for the design of trials that use HF hospitalization as an endpoint., Methods and Results: MADIT-CRT randomized patients with mild HF symptoms to resynchronization therapy vs. control with an average follow-up of 3.3 years and a total of 191 deaths. HF events were centrally adjudicated for receiving i.v. decongestive therapy in an outpatient setting, or an augmented HF regimen during a hospital stay. Patients were compared according to whether their first HF was an out- or inpatient event. The first primary event was non-fatal outpatient HF, non-fatal inpatient HF, and death in 52, 331, and 78 patients, respectively. Patients with inpatient HF tended to be older and more likely to have HF of ischaemic aetiology than subjects who developed outpatient HF events. The risk of death following either type of non-fatal HF events was extremely high [hazard ratio (HR) 12.4, 95% confidence interval (CI) 9.1-16.9 for inpatient HF; HR 10.7, 95% CI 6.1-18.7 for outpatient HF] compared with subjects without non-fatal HF events. Allocation to CRT-D was associated with significant reduction in both types of HF., Conclusion: Outpatient management of worsening HF portends a high risk of death, similar to inpatient HF events, and may be equally sensitive to the effects of therapy. These findings suggest that outpatient HF events should be considered in publicly reported outcomes measures and future HF clinical trials., Trial Registration: NCT01294449., (© 2014 The Authors. European Journal of Heart Failure © 2014 European Society of Cardiology.)

Background: Identifying which patients might benefit the most from ICD therapy remains challenging. We hypothesize that increased T-wave alternans (TWA) and QT variability (QTV) provide complementary information for predicting appropriate ICD therapy in patients with previous myocardial infarction and reduced ejection fraction., Methods: We analyzed 10-min resting ECGs from MADIT-II patients with baseline heart rate >80 beats/min. TWA indices IAA and IAA90 were computed with the multilead Laplacian Likelihood ratio method. QTV indices QTVN and QTVI were measured using a standard approach. Cox proportional hazard models were adjusted considering appropriate ICD therapy and sudden cardiac death (SCD) as endpoints., Results: TWA and QTV were measured in 175 patients. Neither QTV nor TWA predicted SCD. Appropriate ICD therapy was predicted by combining IAA90 and QTVN after adjusting for relevant correlates., Conclusion: Increased TWA and QTV are independent predictors of appropriate ICD therapy in MADIT-II patients with elevated heart rate at baseline., (© 2013.)

The QT Variability Index (QTVI) is a non-invasive measure of repolarization lability that has been applied to a wide variety of subjects with cardiovascular disease. It is a ratio of normalized QT variability to normalized heart rate variability, and therefore includes an assessment of autonomic nervous system tone. The approach assesses beat-to-beat variability in the duration of the QT and U wave in conventional surface electrocardiographic recordings, as well as determines the heart rate variability (HRV) from the same recording. As opposed to T wave alternans, QTVI assesses variance in repolarization at all frequencies. Nineteen studies have published data on QTVI in healthy individuals, while 20 have evaluated its performance in cohorts with cardiovascular disease. Six studies have assessed the utility of QTVI in predicting VT/VF, cardiac arrest, or cardiovascular death. A prospective study utilizing QTVI to determine therapy allocation has not been performed, and therefore the final determination of the value of the metric awaits definitive exploration., (© 2013.)