A Bayesian Analysis to Determine the Prevalence of Barth Syndrome in the Pediatric Population.

OBJECTIVE: To determine the prevalence of Barth syndrome in the pediatric population. STUDY DESIGN: Data were collected from the Barth Syndrome Foundation Registry and relevant literature. With the advent of genetic testing and whole-exome sequencing, a multipronged Bayesian analysis was used to estimate the prevalence of Barth syndrome based on published data on the incidence and prevalence of cardiomyopathy and neutropenia, and the respective subpopulations of patients with Barth syndrome indicated in these publications. RESULTS: Based on 7 published studies of cardiomyopathy and 2 published studies of neutropenia, the estimated prevalence of Barth syndrome is approximately 1 case per million male population. This contrasts with 99 cases in the Barth Syndrome Foundation Registry, 58 of which indicate a US location, and only 230-250 cases known worldwide. CONCLUSIONS: It appears that Barth syndrome is greatly underdiagnosed. There is a need for better education and awareness of this rare disease to move toward early diagnosis and treatment.

Gender Differences in Hospital CEO Compensation: A National Investigation of Not-for-Profit Hospitals.

Gender pay equity is a desirable social value and an important strategy to fill every organizational stratum with gender-diverse talent to fulfill an organization's goals and mission. This study used national, large-sample data to examine gender difference in CEO compensation among not-for-profit hospitals. Results showed the average unadjusted annual compensation for female CEOs in 2009 was $425,085 compared with $581,121 for male CEOs. With few exceptions, the difference existed across all types of not-for-profit hospitals. After controlling for hospital- and area-level characteristics, female CEOs of not-for-profit hospitals earned 22.6% less than male CEOs of not-for-profit hospitals. This translates into an earnings differential of $132,652 associated with gender. Explanations and implications of the results are discussed.

Impact of Postdischarge Follow-Up Care on Medicare Expenditures: Does Rural Make a Difference?

Reducing postdischarge Medicare expenditures is a key focus for hospitals. Early follow-up care is an important piece of this focus, but it is unclear whether there are rural-urban differences in the impact of follow-up care on Medicare expenditures. To assess this difference, we use the Medicare Current Beneficiary Survey, Cost and Use Files, 2000-2010. We conduct a retrospective analysis of 30-day postdischarge Medicare expenditures using two-stage residual inclusion with a quantile regression, where the receipt of 7-day follow-up care was the main independent variable. Postdischarge follow-up care increased the 25th percentile of 30-day expenditures, decreased the 75th percentile, and there were no rural-urban differences. Partial effects show postdischarge follow-up care resulted in higher 30-day expenditures among low-cost rural beneficiaries. Ensuring early follow-up care for high-cost beneficiaries may be advantageous to both rural and urban providers in helping reduce postdischarge Medicare expenditures.

What's new in ankle fractures.

The diagnosis and treatment of ankle fractures has evolved considerably over the past two decades. Recent topics of interest have included indications for operative treatment of isolated lateral malleolus fractures, need for fixation of the posterior malleolus, utilization of the posterolateral approach, treatment of the syndesmosis, and the potential role of fibular nailing. In this update, we concisely review these topics and what to expect in the future literature.

Rural-Urban Differences in the Effect of Follow-Up Care on Postdischarge Outcomes.

OBJECTIVE: To assess rural-urban differences in quality of postdischarge care among Medicare beneficiaries, controlling for selection bias of postdischarge services. DATA SOURCES: The Medicare Current Beneficiary Survey (MCBS), Cost and Use Files from 2000 to 2010, the Area Resource File, Provider of Services File, and the Dartmouth Atlas of Health Care. STUDY DESIGN: Retrospective analysis of 30- and 60-day hospital readmission, emergency department (ED) use, and mortality using two-stage residual inclusion; receipt of 14-day follow-up care was the main independent variable. DATA EXTRACTION METHOD: We defined index admission from the MCBS as any admission without a previous admission within 60 days. PRINCIPAL FINDINGS: Noninstrumental variables estimation was the preferred estimation strategy. Fourteen-day follow-up care reduced the risk of readmission, ED use, and mortality. There were no rural- urban differences in the effect of 14-day follow-up care on readmission and mortality. Rural beneficiaries experienced a greater effect of 14-day follow-up care on reducing 30-day ED use compared to urban beneficiaries. CONCLUSIONS: Follow-up care reduces 30- and 60-day readmission, ED use, and mortality. Rural and urban Medicare beneficiaries experience similar beneficial effects of follow-up care on the outcomes. Policies that improve follow-up care in rural settings may be beneficial.

Rural Medicare Beneficiaries Have Fewer Follow-up Visits and Greater Emergency Department Use Postdischarge.

BACKGROUND: Hospitals are focused on improving postdischarge services for older adults, such as early follow-up care after hospitalization to reduce readmissions and unnecessary emergency department (ED) use. Rural Medicare beneficiaries face many barriers to receiving quality care, but little is known about their postdischarge care and outcomes. We hypothesize that rural Medicare beneficiaries compared with urban beneficiaries, will have fewer follow-up visits, and a greater likelihood of readmission and ED use. METHODS: We conducted a retrospective analysis of elderly Medicare beneficiaries discharged home using the Medicare Current Beneficiary Survey, Cost and Use files, 2000-2010. Multivariate Cox proportional hazard models were used to assess the risk of rural residency on readmission, ED use, and follow-up care up to 30 days' postdischarge. Covariates include demographic, health, and hospital-level characteristics. RESULTS: Compared with urban beneficiaries, Medicare beneficiaries living in isolated rural settings had a lower rate of follow-up care [hazard ratio (HR)=0.81, P<0.001]. Beneficiaries in large and small rural settings had a greater risk of an ED visit compared with urban beneficiaries (HR=1.44, P<0.001; HR=1.52, P<0.01). Rural beneficiaries did not have a greater risk of readmission, though risk of readmission was higher for beneficiaries discharged from hospitals in large and small rural settings (HR=1.33, P<0.05; HR=1.42, P<0.05). CONCLUSIONS: This study provides evidence of lower quality postdischarge care for Medicare beneficiaries in rural settings. As readmission penalties expand, hospitals serving rural beneficiaries may be disproportionately affected. This suggests a need for policies that increase follow-up care in rural settings.

The pharmacological chaperone AT2220 increases the specific activity and lysosomal delivery of mutant acid alpha-glucosidase, and promotes glycogen reduction in a transgenic mouse model of Pompe disease.

Pompe disease is an inherited lysosomal storage disorder that results from a deficiency in acid α-glucosidase (GAA) activity due to mutations in the GAA gene. Pompe disease is characterized by accumulation of lysosomal glycogen primarily in heart and skeletal muscles, which leads to progressive muscle weakness. We have shown previously that the small molecule pharmacological chaperone AT2220 (1-deoxynojirimycin hydrochloride, duvoglustat hydrochloride) binds and stabilizes wild-type as well as multiple mutant forms of GAA, and can lead to higher cellular levels of GAA. In this study, we examined the effect of AT2220 on mutant GAA, in vitro and in vivo, with a primary focus on the endoplasmic reticulum (ER)-retained P545L mutant form of human GAA (P545L GAA). AT2220 increased the specific activity of P545L GAA toward both natural (glycogen) and artificial substrates in vitro. Incubation with AT2220 also increased the ER export, lysosomal delivery, proteolytic processing, and stability of P545L GAA. In a new transgenic mouse model of Pompe disease that expresses human P545L on a Gaa knockout background (Tg/KO) and is characterized by reduced GAA activity and elevated glycogen levels in disease-relevant tissues, daily oral administration of AT2220 for 4 weeks resulted in significant and dose-dependent increases in mature lysosomal GAA isoforms and GAA activity in heart and skeletal muscles. Importantly, oral administration of AT2220 also resulted in significant glycogen reduction in disease-relevant tissues. Compared to daily administration, less-frequent AT2220 administration, including repeated cycles of 4 or 5 days with AT2220 followed by 3 or 2 days without drug, respectively, resulted in even greater glycogen reductions. Collectively, these data indicate that AT2220 increases the specific activity, trafficking, and lysosomal stability of P545L GAA, leads to increased levels of mature GAA in lysosomes, and promotes glycogen reduction in situ. As such, AT2220 may warrant further evaluation as a treatment for Pompe disease.

Closeness to God among those doing God's work: a spiritual well-being measure for clergy.

Measuring spiritual well-being among clergy is particularly important given the high relevance of God to their lives, and yet its measurement is prone to problems such as ceiling effects and conflating religious behaviors with spiritual well-being. To create a measure of closeness to God for Christian clergy, we tested survey items at two time points with 1,513 United Methodist Church clergy. The confirmatory factor analysis indicated support for two, six-item factors: Presence and Power of God in Daily Life, and Presence and Power of God in Ministry. The data supported the predictive and concurrent validity of the two factors and evidenced high reliabilities without ceiling effects. This Clergy Spiritual Well-being Scale may be useful to elucidate the relationship among dimensions of health and well-being in clergy populations.

Barriers to HIV care for women of color living in the Southeastern US are associated with physical symptoms, social environment, and self-determination.

HIV-infected women of color (WOC) face particular barriers to accessing HIV medical care. To understand the impact of physical symptoms, social support, and self-determination on barriers to care, we interviewed HIV-infected women of color. HIV-infected WOC (N=141), attending an academic infectious disease clinic for HIV care in North Carolina, completed the Barriers to Care scale and were categorized as reporting a history of low (less than four of eleven barriers) or high (five or more) barriers to care. Binomial regression was used to estimate prevalence ratios and risk differences of reported barriers to care and its correlates such as depression, anxiety, illness-severity, psychological abuse, social support, treatment-specific social support, and self-determination (autonomy, relatedness, competency). A lower risk of reporting five or more barriers to care was associated with higher levels of autonomy (PR=0.93, 95% CI: 0.89, 0.96), relatedness (PR=0.92, 95% CI: 0.89, 0.94), competency (PR=0.93, 95% CI: 0.87, 0.98), and social support (PR=0.24, 95% CI: 0.81, 0.81). Depression, illness severity, and psychological abuse were associated with a greater risk of having five or more barriers to care. There are multiple social and psychological factors that contribute to perceived barriers to HIV care among WOC in the southeastern USA. Interventions that promote social support and increase individual self-determination have the potential to improve access to HIV care for WOC.

Using effort-reward imbalance theory to understand high rates of depression and anxiety among clergy.

The clergy occupation is unique in its combination of role strains and higher calling, putting clergy mental health at risk. We surveyed all United Methodist clergy in North Carolina, and 95% (n = 1,726) responded, with 38% responding via phone interview. We compared clergy phone interview depression rates, assessed using the Patient Health Questionnaire (PHQ-9), to those of in-person interviews in a representative United States sample that also used the PHQ-9. The clergy depression prevalence was 8.7%, significantly higher than the 5.5% rate of the national sample. We used logistic regression to explain depression, and also anxiety, assessed using the Hospital Anxiety and Depression Scale. As hypothesized by effort-reward imbalance theory, several extrinsic demands (job stress, life unpredictability) and intrinsic demands (guilt about not doing enough work, doubting one's call to ministry) significantly predicted depression and anxiety, as did rewards such as ministry satisfaction and lack of financial stress. The high rate of clergy depression signals the need for preventive policies and programs for clergy. The extrinsic and intrinsic demands and rewards suggest specific actions to improve clergy mental health.

Barth syndrome.

First described in 1983, Barth syndrome (BTHS) is widely regarded as a rare X-linked genetic disease characterised by cardiomyopathy (CM), skeletal myopathy, growth delay, neutropenia and increased urinary excretion of 3-methylglutaconic acid (3-MGCA). Fewer than 200 living males are known worldwide, but evidence is accumulating that the disorder is substantially under-diagnosed. Clinical features include variable combinations of the following wide spectrum: dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), endocardial fibroelastosis (EFE), left ventricular non-compaction (LVNC), ventricular arrhythmia, sudden cardiac death, prolonged QTc interval, delayed motor milestones, proximal myopathy, lethargy and fatigue, neutropenia (absent to severe; persistent, intermittent or perfectly cyclical), compensatory monocytosis, recurrent bacterial infection, hypoglycaemia, lactic acidosis, growth and pubertal delay, feeding problems, failure to thrive, episodic diarrhoea, characteristic facies, and X-linked family history. Historically regarded as a cardiac disease, BTHS is now considered a multi-system disorder which may be first seen by many different specialists or generalists. Phenotypic breadth and variability present a major challenge to the diagnostician: some children with BTHS have never been neutropenic, whereas others lack increased 3-MGCA and a minority has occult or absent CM. Furthermore, BTHS was first described in 2010 as an unrecognised cause of fetal death. Disabling mutations or deletions of the tafazzin (TAZ) gene, located at Xq28, cause the disorder by reducing remodeling of cardiolipin, a principal phospholipid of the inner mitochondrial membrane. A definitive biochemical test, based on detecting abnormal ratios of different cardiolipin species, was first described in 2008. Key areas of differential diagnosis include metabolic and viral cardiomyopathies, mitochondrial diseases, and many causes of neutropenia and recurrent male miscarriage and stillbirth. Cardiolipin testing and TAZ sequencing now provide relatively rapid diagnostic testing, both prospectively and retrospectively, from a range of fresh or stored tissues, blood or neonatal bloodspots. TAZ sequencing also allows female carrier detection and antenatal screening. Management of BTHS includes medical therapy of CM, cardiac transplantation (in 14% of patients), antibiotic prophylaxis and granulocyte colony-stimulating factor (G-CSF) therapy. Multidisciplinary teams/clinics are essential for minimising hospital attendances and allowing many more individuals with BTHS to live into adulthood.

Relationship between trauma and high-risk behavior among HIV-positive men who do not have sex with men (MDSM).

The incidence of heterosexual HIV transmission continues to increase in the USA. However, little is known about factors that influence high-risk behavior among men who do not have sex with men (MDSM). This study examines the association of childhood sexual abuse and high-risk behaviors among MDSM. The Coping with HIV/AIDS in the Southeast (CHASE) study included 611 HIV-positive individuals in the Southeastern US Bivariate statistics were used to examine the influence of childhood sexual abuse among MDSM, men who have sex with men (MSM), and women. Study findings indicated that among MDSM with HIV, childhood sexual abuse predicted a higher number of sexual partners, alcohol and drug use problems, depression, post-traumatic stress disorder (PTSD), and less trust in medical providers. Similar statistically significant relationships between childhood sexual abuse and negative outcomes were not found for MSM and women with the exception of childhood sexual abuse predicting PTSD and alcohol use in women. Study findings indicate a need for more in-depth research to examine the role of childhood sexual abuse in shaping adult risk behaviors among MDSM as well as a need to assess for and address childhood sexual abuse in this population.

Cardiac and skeletal muscle defects in a mouse model of human Barth syndrome.

Barth syndrome is an X-linked genetic disorder caused by mutations in the tafazzin (taz) gene and characterized by dilated cardiomyopathy, exercise intolerance, chronic fatigue, delayed growth, and neutropenia. Tafazzin is a mitochondrial transacylase required for cardiolipin remodeling. Although tafazzin function has been studied in non-mammalian model organisms, mammalian genetic loss of function approaches have not been used. We examined the consequences of tafazzin knockdown on sarcomeric mitochondria and cardiac function in mice. Tafazzin knockdown resulted in a dramatic decrease of tetralinoleoyl cardiolipin in cardiac and skeletal muscles and accumulation of monolysocardiolipins and cardiolipin molecular species with aberrant acyl groups. Electron microscopy revealed pathological changes in mitochondria, myofibrils, and mitochondrion-associated membranes in skeletal and cardiac muscles. Echocardiography and magnetic resonance imaging revealed severe cardiac abnormalities, including left ventricular dilation, left ventricular mass reduction, and depression of fractional shortening and ejection fraction in tafazzin-deficient mice. Tafazzin knockdown mice provide the first mammalian model system for Barth syndrome in which the pathophysiological relationships between altered content of mitochondrial phospholipids, ultrastructural abnormalities, myocardial and mitochondrial dysfunction, and clinical outcome can be completely investigated.

Characterization of a transgenic short hairpin RNA-induced murine model of Tafazzin deficiency.

Barth's syndrome (BTHS) is an X-linked mitochondrial disease that is due to a mutation in the Tafazzin (TAZ) gene. Based on sequence homology, TAZ has been characterized as an acyltransferase involved in the metabolism of cardiolipin (CL), a unique phospholipid almost exclusively located in the mitochondrial inner membrane. Yeast, Drosophila, and zebrafish models have been invaluable in elucidating the role of TAZ in BTHS, but until recently a mammalian model to study the disease has been lacking. Based on in vitro evidence of RNA-mediated TAZ depletion, an inducible short hairpin RNA (shRNA)-mediated TAZ knockdown (TAZKD) mouse model has been developed (TaconicArtemis GmbH, Cologne, Germany), and herein we describe the assessment of this mouse line as a model of BTHS. Upon induction of the TAZ-specific shRNA in vivo, transgenic mouse TAZ mRNA levels were reduced by >89% in cardiac and skeletal muscle. TAZ deficiency led to the absence of tetralineoyl-CL and accumulation of monolyso-CL in cardiac muscle. Furthermore, mitochondrial morphology from cardiac and skeletal muscle was altered. Skeletal muscle mitochondria demonstrated disrupted cristae, and cardiac mitochondria were significantly enlarged and displace neighboring myofibrils. Physiological measurements demonstrated a reduction in isometric contractile strength of the soleus and a reduction in cardiac left ventricular ejection fraction of TAZKD mice compared with control animals. Therefore, the inducible TAZ-deficient model exhibits some of the molecular and clinical characteristics of BTHS patients and may ultimately help to improve our understanding of BTHS-related cardioskeletal myopathy as well as serve as an important tool in developing therapeutic strategies for BTHS.

Loss of intestinal fatty acid binding protein increases the susceptibility of male mice to high fat diet-induced fatty liver.

Mice lacking I-FABP (encoded by the Fabp2 gene) exhibit a gender dimorphic response to a high fat/cholesterol diet challenge characterized by hepatomegaly in male I-FABP-deficient mice. In this study, we determined if this gender-specific modification of liver mass in mice lacking I-FABP is attributable to the high fat content of the diet alone and whether hepatic Fabp1 gene (encodes L-FABP) expression contributes to this difference. Wild-type and Fabp2-/- mice of both genders were fed a diet enriched with either polyunsaturated or saturated fatty acids (PUFA or SFA, respectively) in the absence of cholesterol. Male Fabp2-/- mice, but not female Fabp2-/- mice, exhibited increased liver mass and hepatic triacylglycerol (TG) deposition as compared to corresponding wild-type mice. In wild-type mice that were fed the standard chow diet, there was no difference in the concentration of hepatic L-FABP protein between males and females although the loss of I-FABP did cause a slight reduction of hepatic L-FABP abundance in both genders. The hepatic L-FABP mRNA abundance in both male and female wild-type and Fabp2-/- mice was higher in the PUFA-fed group than in the SFA-fed group, and was correlated with L-FABP protein abundance. No correlation between hepatic L-FABP protein abundance and hepatic TG concentration was found. The results obtained demonstrate that loss of I-FABP renders male mice sensitive to high fat diet-induced fatty liver, and this effect is independent of hepatic L-FABP.

Intracellular lipid binding proteins of the small intestine.

The small intestine contains three distinct proteins belonging to the intracellular lipid binding protein family: the liver-type fatty acid binding protein (L-FABP), the intestinal fatty acid binding protein (I-FABP) and the ileal lipid binding protein (ilbp). The function of these proteins in the small intestine has remained enigmatic. Targeted gene disruption studies may shed insights into the physiological importance of these proteins. In the case of I-FABP, this approach has demonstrated that the complete elimination of this protein in murine intestine does not compromise dietary fat absorption in vivo but is associated with the development of insulin resistance.