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Objective To delineate the etiology, symptomatology, and treatment of sickle cell intrahepatic cholestasis (SCIC). Sickle cell disease (SCD) is the most frequently inherited hematologic disease, and SCIC is one rare and often fatal complication and comorbid disease. The literature contains only a small number of case reports involving SCIC and hence limited guidance can be obtained. Methods We reviewed the scientific literature to evaluate the science of SCIC to determine if there were consistencies in presentation, evaluation, treatment, and clinical outcomes. Results We reviewed 6 case reports and a limited number of clinical papers on SCIC. We reported consistencies in clinical presentation and treatment outcomes among cases as well as serological and hematological finding. Conclusions While there is some consistency in the symptom presentation of individuals with SCIC, reliable evaluation and clinical procedures were not demonstrated in what we reviewed. Further research is needed to delineate the attributes of this complicated disease that occurs within SCD.

International audience; Background In international trials, glucagon-like protein-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2Is) were effective in improving cardiovascular (CV) outcomes. Methods We assessed the effect of GLP-1RAs and SGLT2Is treatment effect on CV endpoints by geographical region in multiple international trials using random effects weighted least squares meta-regressions. Results The estimated effects of both SGLT2Is and GLP-1RAs on major adverse CV events (MACE) in North America (SGLT2Is n = 12,399, HR 0.90, 95% CI 0.81-1.01; GLP-1RAs n = 12,515, HR 0.95, 95% CI 0.83-1.09) and in Europe (SGLT2Is n = 19,435, HR 0.93, 95% CI 0.85-1.02; GLP-1RAs n = 22,812, HR 0.88, 95% CI 0.79-0.99) were numerically lower but not statistically different to the rest of the world (ROW) (SGLT2Is n = 15,127, HR 0.83, 95% CI 0.75-0.92, p-value for interaction 0.26; GLP-1RAs n = 17,494, HR 0.82, 95% CI 0.73-0.92, p-value for interaction 0.28). Effects of SGLT2Is on heart failure readmission or CV death varied significantly by region (P = 0.0094). The effect of SGLT2Is was significantly smaller in Europe (n = 18,653, HR 0.86, 95% CI 0.78-0.95) than in the ROW (n = 12,463, HR 0.68, 95% CI 0.61-0.76, P = 0.0024). The smaller effect in North America (n = 9776, HR 0.76, 95% CI 0.66-0.87) did not differ significantly from that in the ROW (P = 0.2370). Conclusion The effects of SGLT2Is on HF events are larger in the ROW. Further analyses and studies are needed to better elucidate the differential effects of SGLTIs and GLP-1RAs by geographical regions.

Background and Aim Liver histology changes are the current gold standard for evaluating non‐alcoholic steatohepatitis (NASH), but are limited by their invasiveness and variability for sampling and interpretation. We evaluated noninvasive biomarkers as an indication of histologic changes in NASH. Methods Associations between 12‐month biomarker and NASH Clinical Research Network histologic score changes in 339 patients with NASH in the EMMINENCE trial was examined with multivariable models and partial canonical correlation. A meta‐analysis of 17 NASH trials including 3717 patients examined associations between these same changes and histologic response within treatment groups, and treatment effects on biomarkers and on liver histology. Biopsy measures assessed were changes in ballooning, steatosis, inflammation, and fibrosis, NASH improvement without worsening of fibrosis, and fibrosis improvement without worsening of NASH. All analytic methods suggest that a combination of aspartate aminotransferase (AST), cytokeratin‐18 (CK‐18 [M30 or M65]), and hemoglobin A1C (HbA1c) changes best predicts overall liver biopsy changes in response to interventions. Results The weighted average of standardized mean changes (0.403 × AST, 0.314 × CK‐18, 0.283 × HbA1c) facilitated comparisons of within‐group responses and treatment effects among studies included in the meta‐analysis. This composite in EMMINENCE discriminated between patients with and without NASH resolution without worsening fibrosis with area under the receiver‐operator characteristic curve of 0.7880, and for fibrosis improvement without NASH worsening of 0.7553. Conclusion A composite score based on changes in AST, HbA1c, and CK‐18 could serve as a surrogate for liver histologic improvement and an effective objective, noninvasive tool for comparative assessment of treatment effects of novel interventions., Liver histology changes are the current gold standard for evaluating treatments for non‐alcoholic steatohepatitis (NASH), but are limited by their invasiveness and variability for sampling and interpretation. We evaluated noninvasive biomarkers as an indication of histologic changes in NASH. A composite score based on changes in AST, HbA1c, and CK‐18 could serve as a surrogate for liver histologic improvement and an effective objective, noninvasive tool for comparative assessment of treatment effects of novel interventions.

Background & Aims Liver biopsies are a critical component of pivotal studies in non-alcoholic steatohepatitis (NASH), constituting inclusion criteria, risk stratification factors and endpoints. We evaluated the reliability of NASH Clinical Research Network scoring of liver biopsies in a NASH clinical trial. Methods Digitized slides of 678 biopsies from 339 patients with paired biopsies randomized into the EMMINENCE study – examining a novel insulin sensitizer (MSDC-0602K) in NASH – were read independently by 3 hepatopathologists blinded to treatment code and scored using the NASH CRN histological scoring system. Various endpoints were computed from these scores. Results Inter-reader linearly weighted kappas were 0.609, 0.484, 0.328, and 0.517 for steatosis, fibrosis, lobular inflammation, and ballooning, respectively. Inter-reader unweighted kappas were 0.400 for the diagnosis of NASH, 0.396 for NASH resolution without worsening fibrosis, and 0.366 for fibrosis improvement without worsening NASH. In the current study, 46.3% of the patients included in the study based on 1 hepatopathologist's qualifying reading were deemed not to meet the study's histologic inclusion criteria by at least 1 of the 3 hepatopathologists. The MSDC-0602K treatment effect was lowest for those histologic features with lower inter-reader reliability. Simulations show that the lack of reliability of endpoints and inclusion criteria can drastically reduce study power – from >90% in a well-powered study to as low as 40%. Conclusions The reliability of hepatopathologists' liver biopsy evaluation using currently accepted criteria is suboptimal. This lack of reliability may affect NASH pivotal studies by introducing patients who do not meet NASH study entry criteria, misclassifying fibrosis subgroups, and attenuating apparent treatment effects. Lay summary Since liver biopsy analysis plays such an important role in clinical studies of non-alcoholic steatohepatitis, it is important to understand the reliability of hepato-pathologist readings. We examined both inter- and intra-reader variability in a large data set of paired liver biopsies from a clinical trial. We found very poor inter-reader and modest intra-reader variability. This result has important implications for entry criteria, fibrosis stratification, and the ability to measure a treatment effect in clinical trials.

Aims The relationship between N‐terminal pro‐brain natriuretic peptide (NT‐pro‐BNP) and galectin‐3 and outcomes has not been studied in African patients with acute heart failure (AHF). The current analysis sought to describe the association between plasma levels of NT‐pro‐BNP and galectin‐3 and cardiovascular (CV) death or heart failure (HF) hospitalization, as well as their associations with symptoms and echocardiography markers of left and right ventricular remodelling among AHF patientsv in sub‐Saharan Africa. Methods and results In a subset of 80 patients with complete data in a study assessing the effects of hydralazine and nitrates in patients with AHF (BAHEF trial; NCT01822808), NT‐pro‐BNP and galectin‐3 analyses were performed, and the association with various characteristics and outcome measures assessed. The mean age of the patients for whom the aforementioned biomarkers were measured was 52.6 years, with 52.5% women. Galectin‐3 at baseline predicted changes (Week 24 to baseline) in left ventricular ejection fraction, left ventricular end‐systolic diameter, left ventricular end‐diastolic diameter, and tricuspid annular plane systolic excursion. Biomarkers and their changes were not associated with changes in 6 min walk test at 24 weeks. Baseline galectin‐3 and change in NT‐pro‐BNP were associated with improvements in dyspnoea at 24 weeks. Nine patients had an HF readmission or died of CV causes through 24 weeks (11.6%). Both biomarkers at baseline predicted combined CV death or HF hospitalization through Week 24 (P‐values = 0.0328 and 0.0001, respectively). Conclusions In a cohort of patients with AHF from sub‐Saharan Africa, NT‐pro‐BNP and galectin‐3 at baseline and their changes were associated with some changes in dyspnoea, echocardiographic remodelling, and CV death or HF hospitalization through Week 24. These tests have potential of being used for risk stratification of AHF patients in sub‐Saharan Africa where resources are scarce.

International audience; Aims: Over the last 30 years, many medicine development programmes in acute and chronic heart failure (HF) with preserved ejection fraction (HFpEF) have failed, in contrast to those in HF with reduced ejection fraction (HFrEF). We explore how the neutral results in larger HF trials may be attributable to chance and/or the dilution of statistical power.Methods and results: Using simulations, we examined the probability that a positive finding in a Phase 2 trial would result in the study of a truly effective medicine in a Phase 3 trial. We assessed the similarity of clinical trial and registry patient populations. We conducted a meta-analysis of paired Phase 2 and 3 trials in HFrEF and acute HF examining the associations of trial phase and size with placebo event rates and treatment effects for HF events and death. We estimated loss in trial power attributable to dilution with increasing trial size. Appropriately powered Phase 3 trials should have yielded ∼35% positive results. Patient populations in Phase 3 trials are similar to those in Phase 2 trials but both differ substantially from the populations of 'real-life' registries. We observed decreasing placebo event rates and smaller treatment effects with increasing trial size, especially for HF events (and less so for mortality). This was more pronounced in trials in acute HF patients.Conclusions: The selection of more positive Phase 2 trials for further development does not explain the failure of HFpEF and acute HF medicine development. Increasing sample size may lead to reduced event rates and smaller treatment effects, resulting in a high rate of neutral Phase 3 trials.

Background & Aims MSDC-0602K is a novel insulin sensitizer designed to preferentially target the mitochondrial pyruvate carrier while minimizing direct binding to the transcriptional factor PPARγ. Herein, we aimed to assess the efficacy and safety of MSDC-0602K in patients with non-alcoholic steatohepatitis. Methods Patients with biopsy-confirmed NASH and fibrosis (F1-F3) were randomized to daily oral placebo, or 1 of 3 MSDC-0602K doses in a 52-week double-blind study. The primary efficacy endpoint was hepatic histological improvement of ≥2 points in non-alcoholic fatty liver disease activity score (NAS) with a ≥1-point reduction in either ballooning or lobular inflammation and no increase in fibrosis stage at 12 months. Secondary endpoints included NAS improvement without worsening fibrosis, NASH resolution, and fibrosis reduction. Exploratory endpoints included changes in insulin sensitivity, liver injury and liver fibrosis markers. Results Patients were randomly assigned to placebo (n = 94), or 62.5 mg (n = 99), 125 mg (n = 98), or 250 mg (n = 101) of MSDC-0602K. At baseline, glycated hemoglobin was 6.4 ± 1.0%, 61.5% of patients had fibrosis F2/F3 and the average NAS was 5.3. The primary endpoint was reached in 29.7%, 29.8%, 32.9% and 39.5% of patients in the placebo, 62.5 mg, 125 mg and 250 mg dose arms, respectively, with adjusted odds ratios relative to placebo of 0.89 (95% CI 0.44–1.81), 1.22 (95% CI 0.60–2.48), and 1.64 (95% CI 0.83–3.27). The 2 highest doses of MSDC-0602K led to significant reductions in glucose, glycated hemoglobin, insulin, liver enzymes and NAS compared to placebo. The incidence of hypoglycemia and PPARγ-agonist-associated events such as edema and fractures were similar in the placebo and MSDC-0602K groups. Conclusions MSDC-0602K did not demonstrate statistically significant effects on primary and secondary liver histology endpoints. However, effects on non-invasive measures of liver cell injury and glucose metabolism support further exploration of MSDC-0602K's safety and potential efficacy in patients with type 2 diabetes and liver injury. [ClinicalTrials.gov Identifier: NCT02784444]. Lay summary First-generation insulin sensitizers are used to treat type 2 diabetes, but are associated with side effects including edema, bone fractures, and hypoglycemia. MSDC-0602K is a second-generation insulin sensitizer designed to reduce these side effects. We hypothesized that insulin sensitization could improve non-alcoholic steatohepatitis. In the current study of patients with non-alcoholic steatohepatitis, MSDC-0602K did not demonstrate significant effects on liver histology with the biopsy techniques used. However, useful information was gained for the design of future studies and MSDC-0602K significantly decreased fasting glucose, insulin, glycated hemoglobin, and markers of liver injury without dose-limiting side effects.

BACKGROUND: Rheumatic heart disease (RHD) was found in the THESUS-HF registry to be the third most common cause of acute heart failure (AHF) in Sub-Saharan Africa. METHODS: One thousand six patients with AHF from 9 Sub-Saharan African countries were recruited in THESUS-HF, of which 143 (14.3%) had RHD-AHF. Clinical characteristics and outcomes in patients with RHD-AHF and non-RHD-AHF were compared. Kaplan-Meier plots for time to all-cause death and/or HF readmission according to the presence of RHD-AHF and non-RHD-AHF were performed and survival distributions compared using the log-rank test. Cox regression was used to determine the hazard ratio of death to day 180 and death or readmission to day 60 after adjusting for confounders. RESULTS: Patients with RHD-AHF were younger, more often females, had higher rates of atrial fibrillation, had less hypertension, hyperlipidemia and diabetes, had lower BP, and higher pulse rate and better kidney function and echocardiographic higher ejection fraction larger left atria and more diastolic dysfunction. Patients with RHD-AHF had a numerically longer mean stay in the hospital (10.5 vs. 8.8 days) and significantly higher initial hospitalization mortality (9.1% vs. 3.4%). CONCLUSIONS: In conclusion, patients with HF related to RHD were younger, have higher rate of atrial fibrillation and have a worse short-term outcome compared to HF related to other etiologies in Sub-Saharan Africa.

Throughout history there have been reports and claims that consideration of dreams can produce personal realizations and insight. We assessed Exploration-Insight scores associated with discussing Rapid Eye Movement (REM) and non-REM (NREM) dreams in connection with recent waking life experiences. Thirty-one participants were cued in the sleep laboratory for a daydream report and then awakened from REM and N2 sleep for dream reports. Participants subsequently discussed each of their dream and daydream reports for 30-40 minutes with two experimenters, following the structured Ullman (1996) dream group discussion procedure. Participants assessed the benefit of discussing the reports by completing the Gains from (Day)Dream Interpretation (G(D)DI) questionnaire. We found no difference in G(D)DI scores between discussing REM and N2 dream reports, and no difference between dream and daydream discussions in engagement and thoroughness of exploring the reports. However, discussing dream reports produced higher scores on the G(D)DI Exploration-Insight subscale compared with discussing daydream reports. Significant differences were evident in items reflecting the learning of what the report means in terms of waking life issues. Frontal theta prior to waking from N2 was significantly associated with Exploration-Insight score obtained after N2 dream discussion, but this relationship was not found for REM dreams. The findings of high ratings of Exploration-Insight after discussing dreams were evident even though participants did not select the dream, unlike what can occur for home recorded dreams, and even though discussion was brief. We suggest that insight might be produced by embodied and metaphorical thinking in dreams.

This paper presents a brief historical look at education for young African American men from the post-Civil War era to the present. It explores reasons why education for this group has become a less favorable aspiration than when education became available to them. Changing role models are strong factors that negatively influence school participation and excellence. Suggestions for ways to instill resilience in young African American men to excel academically are offered, as well as areas for further study

International audience; No abstract available

Aims: \ud This retrospective analysis sought to identify markers that might distinguish between acute heart failure (HF) and worsening HF in chronic outpatients.\ud \ud Methods and Results: \ud The BIOSTAT‐CHF index cohort included 2516 patients with new or worsening HF symptoms: 1694 enrolled as inpatients (acute HF) and 822 as outpatients (worsening HF in chronic outpatients). A validation cohort included 935 inpatients and 803 outpatients. Multivariable models were developed in the index cohort using clinical characteristics, routine laboratory values, and proteomics data to examine which factors predict adverse outcomes in both conditions and to determine which factors differ between acute HF and worsening HF in chronic outpatients, validated in the validation cohort.\ud \ud Patients with acute HF had substantially higher morbidity and mortality (6 months mortality was 12..3% for acute HF and 4..7% for worsening HF in chronic outpatients). Multivariable models predicting 180‐day mortality and 180‐day HF re‐admission differed substantially between acute HF and worsening HF in chronic outpatients. CA‐125 was the strongest single biomarker to distinguish acute HF from worsening HF in chronic outpatients, but only yielded a C‐index of 0..71. A model including multiple biomarkers and clinical variables achieved a high degree of discrimination with a C‐index of 0..913 in the index cohort and 0..901 in the validation cohort.\ud \ud Conclusion: \ud The study identifies different characteristics and predictors of outcome in acute HF patients as compared to outpatients with chronic HF developing worsening HF. The markers identified may be useful in better diagnosing acute HF and may become targets for treatment development.

The present study examined if high levels of religious attendance (ORG), private religious activity (NOR), or intrinsic religiosity (SUB) buffer cardiovascular responses to active speech and anger recall lab stressors alone and by John Henryism Active Coping (JHAC) and educational attainment. A sample of 74 healthy African American males, aged 23 to 47 years, completed psychosocial surveys and a lab reactivity protocol involving active speech and anger recall with a 5-minute baseline and ensuing recovery periods. Measures of religiosity, JHAC, and education were related to continuous measures of systolic and diastolic blood pressure (BP), for each task and rest period with repeated measures ANOVA tests. The period by education by JHAC interaction effect was significant for diastolic BP responses at low but not higher NOR. At low education and low NOR, diastolic BP levels increased significantly during anger recall and ensuing recovery for high but not low JHAC persons. Thus, being deprived of education and private religious activity may put these African American men in a vulnerable situation where higher effort coping may exacerbate their cardiovascular reactivity and recovery to anger induction.

This study investigates the time course of incorporation of waking life experiences into daydreams. Thirty-one participants kept a diary for 10 days, reporting major daily activities (MDAs), personally significant events (PSEs) and major concerns (MCs). They were then cued for daydream, Rapid Eye Movement (REM) and N2 dream reports in the sleep laboratory. There was a higher incorporation into daydreams of MCs from the previous two days (day-residue effect), but no day-residue effect for MDAs or PSEs, supporting a function for daydreams of processing current concerns. A day-residue effect for PSEs and the delayed incorporation of PSEs from 5 to 7 days before the dream (the dream-lag effect) have previously been found for REM dreams. Delayed incorporation was not found in this study for daydreams. Daydreams might thus differ in function from REM sleep dreams. However, the REM dream-lag effect was not replicated here, possibly due to design differences from previous studies.

Aims Changes in systolic blood pressure (SBP) during an admission for acute heart failure (AHF), especially those leading to hypotension, have been suggested to increase the risk for adverse outcomes. Methods and results We analysed associations of SBP decrease during the first 24 h from randomization with serum creatinine changes at the last time-point available (72 h), using linear regression, and with 30- and 180-day outcomes, using Cox regression, in 1257 patients in the VERITAS study. After multivariable adjustment for baseline SBP, greater SBP decrease at 24 h from randomization was associated with greater creatinine increase at 72 h and greater risk for 30-day all-cause death, worsening heart failure (HF) or HF readmission. The hazard ratio (HR) for each 1 mmHg decrease in SBP at 24 h for 30-day death, worsening HF or HF rehospitalization was 1.01 [95% confidence interval (CI) 1.00–1.02; P = 0.021]. Similarly, the HR for each 1 mmHg decrease in SBP at 24 h for 180-day all-cause mortality was 1.01 (95% CI 1.00–1.03; P = 0.038). The associations between SBP decrease and outcomes did not differ by tezosentan treatment group, although tezosentan treatment was associated with a greater SBP decrease at 24 h. Conclusions In the current post hoc analysis, SBP decrease during the first 24 h was associated with increased renal impairment and adverse outcomes at 30 and 180 days. Caution, with special attention to blood pressure monitoring, should be exercised when vasodilating agents are given to AHF patients.

Aims Left ventricular (LV) reverse remodelling is an important marker of improved outcomes in patients with advanced heart failure (HF). We examined the impact of the intramyocardial administration of bone-marrow-derived, lineage-directed, autologous cardiopoietic mesenchymal stem cells (C3BS-CQR-1) on LV remodelling in patients with advanced HF enrolled in the CHART-1 study. Methods and results Patients (n=351) with symptomatic advanced HF secondary to ischaemic heart disease, and reduced LV ejection fraction (LVEF

Background: The selective adenosine A1 receptor antagonist rolofylline showed a neutral overall result on clinical outcomes in the PROTECT trial. However, we hypothesized that response to rolofylline treatment could be influenced by underlying clinical risk.Methods: We performed a post-hoc analysis of the PROTECT trial -a large, double-blind, randomized, placebo-controlled trial that enrolled 2033 patients. Baseline risk of 180-day all-cause mortality was estimated using a previously published 8-item model. Evaluation of efficacy of rolofylline across subpopulations defined based on estimated risk of mortality was performed using subpopulation treatment effect pattern plot (STEPP) analysis. Findings were validated in an independent cohort of acute heart failure patients.Results: Median estimated risk of mortality was 13.0%, IQR [8.0%-23.0%] and was comparable between the rolofylline and placebo arms. In low to intermediate risk subgroups of patients, rolofylline was associated with a higher rate of 180-day all-cause mortality (11.9% in the rolofylline versus 8.4% in the placebo arms, p = 0.050). In the high risk subgroup of patients, particularly those with estimated risk of mortality between 20% and 30%, 180-day all-cause mortality rate was markedly lower in the rolofylline arm(18.4% in the rolofylline versus 34.0% in the placebo arms, p = 0.003). The trend towards potential harm with rolofylline treatment in the low to intermediate risk subpopulations and significant benefit in high risk patients was also observed in the validation cohort.Conclusion: Our findings suggest that selective adenosine A1 receptor antagonism could be harmful in low risk acute heart failure patients, while it might significantly benefit higher risk patients. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

Beauty ideals in the Caribbean are shifting with increased exposure to Western and European standards of appearance. Previous research has shown a consistent link between internalization of Western beauty ideals and depressive symptoms and other forms of psychological disturbance among diverse populations including Caribbeans. We examined the association between internalization of Western beauty ideals and depressive symptoms as well as the potential mediating role of self-esteem on this relation in N = 222 students (155 females, 79 males) attending a tertiary institution in Kingston, Jamaica. Internalization of Western ideals was inversely associated with self-esteem (r =− .35, p

Suppressing thoughts often leads to a “rebound” effect, both in waking cognition (thoughts) and in sleep cognition (dreams). Rebound may be influenced by the valence of the suppressed thought, but there is currently no research on the effects of valence on dream rebound. Further, the effects of dream rebound on subsequent emotional response to a suppressed thought have not been studied before. The present experiment aimed to investigate whether emotional valence of a suppressed thought affects dream rebound, and whether dream rebound subsequently influences subjective emotional response to the suppressed thought. Participants (N=77) were randomly assigned to a pleasant or unpleasant thought suppression condition, suppressed their target thought for five minutes pre-sleep every evening, reported the extent to they successfully suppressed the thought, and reported their dreams every morning, for seven days. It was found that unpleasant thoughts were more prone to dream rebound than pleasant thoughts. There was no effect of valence on the success or failure of suppression during wakefulness. Dream rebound and successful suppression were each found to have beneficial effects for subjective emotional response to both pleasant and unpleasant thoughts. The results may lend support for an emotion-processing theory of dream function.

Objective We evaluated the effects of menstrual types inclusive of PMS on reports of chronic pain intensity and psychopathology in twenty-eight women (mean age 38.93 ± 13.51) with Sickle Cell disease (SCD). Methods Using the Menstrual Symptoms Questionnaire, we compared women with PMS to those with less distressing spasmodic cycle types. Results Thirty-four percent of the sample used oral contraception; there were no significant effects of birth control use on reports of pain. Women with PMS characterized the sensory (p = .04) and affective (p = .04) experiences of their SCD-related chronic pain, including their current pain intensity (p = .03), as significantly greater than women with primary spasmodic menstrual type. Further, there was a trend towards significance for women with PMS to report greater levels of overall pain intensity (p = .07) and average pain intensity over the past month (p = .08). Conclusions The authors interpret these results to suggest that there may be a complex interaction of neurohormonal, biological, and psychological factors associated with PMS that influence manifestation and experience of chronic pain in patients with SCD.

AimsThe course of patients following admission for acute heart failure (AHF) is of major importance to patients and healthcare providers. We examined predictors and associations of length of stay (LOS), 30-day post-discharge readmission and 90-day post-discharge mortality in 1990 patients enrolled in the PROTECT study. Methods and resultsPROTECT was a randomized study that examined the effect of the adenosine blocker rolofylline in patients within 24h of admission for AHF with mild to moderate renal impairment. Geographic-region-adjusted multivariable models showed that LOS was only partly explained by the severity of heart failure (HF), comorbidities (diabetes mellitus, renal impairment, ischaemic heart disease) and degree of metabolic dysfunction (cholesterol and albumin) at baseline (adjusted R-2 0.27). Addition of in-hospital worsening heart failure (WHF) and changes in metabolic markers contributed significantly to prediction of LOS [R-2 difference 0.050, 95% confidence interval (CI) 0.0282-0.072]. Thirty-day HF readmission was associated with more severe HF and previous HF admission but not with LOS (odds ratios 1.00, 95% CI 0.97-1.04). Death within 90days after discharge was associated with older age, more severe HF, worse renal function, and lower sodium and bicarbonate at admission; LOS was a strong predictor of 90-day post-discharge mortality. ConclusionsIn patients admitted for AHF, LOS is not well-predicted by traditional markers of disease severity, but strongly associated with the occurrence of in-hospital WHF. Longer LOS is a strong predictor of early mortality after discharge but not of readmission. These findings may help focus efforts to reduce LOS and post-discharge outcomes on patients' subgroups at increased risk.

Summary Scale formation in downhole tubular-flow passages can cause partial to complete plugging that will affect production or injection rates adversely. In an intelligent-well completion in which the interval-control-valve (ICV) opening must be changed to control flow rate, the completion will become ineffective if plugging of clearances prevents valve actuation. To mitigate these problems, a method to predict the potential rate of scale formation under realistic conditions has been developed. This empirical method allows prediction of tool performance under scale-forming conditions for downhole applications, and uses chemical data and flow fields generated by computational-fluid-dynamics (CFD) models for downhole tools. Chemical data are obtained from laboratory tests on coupons by use of brines matching the chemistry of connate fluids. Tests were conducted in a high-pressure, corrosion-resistant vessel over a range of high pressures (100 to 10,000 psi) and high temperatures (75 to 150 °C) to simulate downhole well conditions. Two test sets were conducted, each with fluid at rest and with an impeller generating low velocity in the reaction vessel, ranging from 4 hours to 4 days, with scaling rates determined from coupon-weight gain. Concentrations in the range of 50 to 125% of the typical connate-fluid concentration were used. The weight-gain data obtained from the coupon tests and from a tube-plugging test were used to develop an empirical model for scale-growth rate at a given point on a solid surface with pressure, pressure gradient, temperature, fluid velocity, and brine concentration as independent variables. Artificial-intelligence methodology was used to develop this model, which can be used to predict the scale-growth rate for any arbitrary geometry. By use of the internal geometry of any tool to be modeled, a CFD model is prepared and the pressure, fluid velocity, and pressure-gradient data are generated for the entire internal solid surface of the tool for a given flow rate through the tool. These data are fed into the empirical model to calculate the scale-growth rate, which is integrated to obtain scale thickness at each point of the internal solid boundary. To verify accuracy, scale formation in a 4.5-in. ICV was predicted at high-pressure, high-temperature conditions at a low flow rate. Laboratory tests on the valve matched the model predictions well enough, which enabled Petrobras to design a better completion and fluid-handling system for a presalt well.

After the publication of the original article, the Editor was notified by Duke University that they have determined the authorship to be incomplete. Consequently, Dr Edward Suarez has been added as a co-author to represent his contribution to the conception and design of the work and acquisition of the data.

Pain, psychosocial issues and impaired activities of daily living (ADLs) are common in sickle cell disease (SCD). Improved longevity may be leading to increases in body mass index (BMI). We both describe an SCD clinic population and determine if BMI, psychosocial distress, and pain predict impairments in ADLs. Archival data from 252 adult African American SCD clinic patients were examined (ie gender, BMI, SCD type, psychosocial status via Symptom Checklist-90-Revised; pain via Short-form McGill Pain Questionnaire: Sensory Pain, Affective Pain (AP), Present Pain Intensity and ADLs. In total, 44% of the sample was overweight (BMI ≥ 25 kg/m2). Depression, anxiety, and Symptom Checklist-90-Revised Global Severity Index were in the clinical range. Patients with HbSβ+-thalassemia and hemoglobin SC disease had higher BMIs than those with HbSS (P < 0.001). AP and age-predicted impaired ADLs. In an OW/OB subsample, AP, age, and SCD severity predicted impaired ADLs. The consistent relationship of AP to ADL impairment suggests targeting AP via behavioral pain management may improve functioning.

Background: The importance of a serum creatinine increase, traditionally considered worsening renal function (WRF), during admission for acute heart failure has been recently debated, with data suggesting an interaction between congestion and creatinine changes. Methods and Results: In post hoc analyses, we analyzed the association of WRF with length of hospital stay, 30-day death or cardiovascular/renal readmission and 90-day mortality in the PROTECT study (Placebo-Controlled Randomized Study of the Selective A1 Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized With Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function). Daily creatinine changes from baseline were categorized as WRF (an increase of 0.3 mg/dL or more) or not. Daily congestion scores were computed by summing scores for orthopnea, edema, and jugular venous pressure. Of the 2033 total patients randomized, 1537 patients had both available at study day 14. Length of hospital stay was longer and 30-day cardiovascular/renal readmission or death more common in patients with WRF. However, these were driven by significant associations in patients with concomitant congestion at the time of assessment of renal function. The mean difference in length of hospital stay because of WRF was 3.51 (95% confidence interval, 1.29–5.73) more days ( P =0.0019), and the hazard ratio for WRF on 30-day death or heart failure hospitalization was 1.49 (95% confidence interval, 1.06–2.09) times higher ( P =0.0205), in significantly congested than nonsignificantly congested patients. A similar trend was observed with 90-day mortality although not statistically significant. Conclusions: In patients admitted for acute heart failure, WRF defined as a creatinine increase of ≥0.3 mg/dL was associated with longer length of hospital stay, and worse 30- and 90-day outcomes. However, effects were largely driven by patients who had residual congestion at the time of renal function assessment. Clinical Trial Registration : URL: https://www.clinicaltrials.gov . Unique identifiers: NCT00328692 and NCT00354458.

Objectives These studies conducted analyses to examine patient characteristics and outcomes associated with worsening heart failure (WHF). Background WHF during an admission for acute heart failure (AHF) represents treatment failure and is a potential therapeutic target for clinical trials of AHF. Methods Individual patient data from the PROTECT (Placebo-Controlled Randomized Study of the Selective A1 Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function) and RELAX-AHF (Relaxin in Acute Heart Failure) phase II and III studies were pooled for analysis. Results Of 3,691 patients, death or WHF through day 5 occurred in 12.4%, ranging from 9.5% to 14.5% among studies. A multivariable model provided modest discrimination between patients who did or did not develop WHF (C-index = 0.68). After multivariable adjustment, WHF was associated with a mean increase in length of stay of 5.2 days (95% confidence interval [CI]: 4.6 to 5.8 days) and increased risks of 60-day HF or renal failure readmission or cardiovascular death (hazard ratio [HR]: 1.64, 95% CI: 1.34 to 2.01) and 180-day mortality (HR: 1.93, 95% CI: 1.55 to 2.41) (all p Conclusions WHF during the first 5 days of admission for AHF occurred in approximately 10% to 15% of patients and was associated with longer length of stay and higher risk for readmission and death.

Cognitive-behavioral models for both insomnia and pain are well established. Few studies have addressed the cognitive-behavioral aspects of these conditions occurring together with a unified model. Worry, rumination, catastrophizing, monitoring, misperceptions, dysfunctional beliefs, and safety behaviors are reviewed. Sleep hygiene among those with co-occurring pain and insomnia is also discussed. It is proposed that more concerted efforts are needed to develop an integrated cognitive-behavioral model to address insomnia and pain as a complex integrated phenomenon.

Summary Background: The role of echocardiography in the risk stratification of acute heart failure (HF) is unknown. Some small studies and retrospective analyses have found little change in echocardiographic variables during admission for acute HF and some echocardiographic parameters were not found to be associated with outcomes. It is unknown which echocardiographic variables will predict outcomes in sub-Saharan African patients admitted with acute HF. Using echocardiograms, this study aimed to determine the predictors of death and re-admissions within 60 days and deaths up to 180 days in patients with acute heart failure. Methods: Out of the 1 006 patients in the THESUS-HF registry, 954 had had an echocardiogram performed within a few weeks of admission. Echocardiographic measurements were performed according to the American Society of Echocardiography guidelines. We examined the associations between each echocardiographic predictor and outcome using regression models. Results: Heart rate and left atrial size predicted death within 60 days or re-admission. Heart rate, left ventricular posterior wall thickness in diastole (PWTd), and presence of aortic stenosis were associated with the risk of death within 180 days. PTWd added to clinical variables in predicting 180-day mortality rates. Conclusions: Echocardiographic variables, especially those of left ventricular size and function, were not found to have additional predictive value in patients admitted for acute HF. Left atrial size, aortic stenosis, heart rate and measures of hypertrophy (LV PWTd) had some predictive value, suggesting the importance of early treatment of hypertension and severe valvular heart disease.

Co-occurring chronic pain and insomnia are common in a clinical setting. Cognitive–behavioral theoretical (CBT) frameworks exist for both conditions independently. The purpose of this study was to address the problem of co-occurring chronic pain and insomnia with an integrated CBT model based on empirical support. One-hundred eleven individuals (age range 21–65 years) meeting the general criteria for chronic pain and insomnia were included in this study. Participants completed a demographic form, the Dysfunctional Beliefs and Attitudes about Sleep—16-item version, Insomnia Severity Index, Sleep Hygiene Index, Sleep Associated Monitoring Index, Pain Catastrophizing Scale, Pain Disability Questionnaire, Modified Somatic Perceptions Questionnaire, Hospital Anxiety and Depression Scale, and Multidimensional Scale of Perceived Social Support. Significant positive bivariate relationships were observed for pain catastrophizing (PC) and dysfunctional beliefs and attitudes about sleep (DBAS), as well as somatic awareness and sleep-associated monitoring. Two backward stepwise regression models were utilized to determine a model for predicting insomnia severity and pain disability respectively using a combination of sleep and pain-associated measures. Insomnia severity was predicted by DBAS, PC, and somatic awareness. Pain disability was predicted by PC, DBAS, depression, and social support. Maladaptive thought patterns related to pain and insomnia and associated features appear to have a synergistic effect on both insomnia severity and pain disability and support a combined cognitive–behavioral model.

Aims In Western countries with typically elderly ischaemic acute heart failure patients, predictors and clinical outcome of renal dysfunction and worsening renal function are well described. However, the prevalence, predictors and clinical outcome of renal dysfunction in younger, mainly hypertensive acute heart failure patients from Africa, have not been described. Methods and results From 1006 patients enrolled in the sub-Saharan Africa Survey of Heart Failure (THESUS-HF), renal function was determined by the estimated glomerular filtration rate using the Modification of Diet in Renal Disease (MDRD) formula. Worsening renal function was defined as an increase in creatinine ≤0.3 mg/dL (26.5 µmol/L) from baseline to day 7/discharge. The mean (SD) age of the patients was 52.4 (18.2) years, 481 (50.8%) were women and the predominant race was black African [932 of 946 (98.5%)]. Heart failure was most commonly a result of hypertension (n = 363, 39.5%) and only 7.8% had ischaemic heart failure. At hospital admission, 289 patients (30.6%) had an estimated glomerular filtration rate ≤60 ml/min.1.73m2. Worsening renal function during hospitalization was detected in 53 (9.8 %) of 543 patients with a follow-up creatinine value, and was independently associated with the Western sub-Saharan region, body mass index, and the presence of rales. Worsening renal function was an independent predictor of death or readmission over 60 days [multivariable hazard ratio = 2.06 (1.10, 3.38); P = 0.023] and all-cause death over 180 days [multivariable hazard ratio =1.92 (1.08, 3.38); P = 0.025]. Conclusions Renal dysfunction is also prevalent in younger non-ischaemic acute heart failure patients in Africa, but worsening renal function is less prevalent and has different predictors compared with Western cohorts. Nevertheless, worsening renal function is strongly and independently related with clinical outcome.

Aims Contrary to elderly patients with ischaemic-related acute heart failure (AHF) typically enrolled in North American and European registries, patients enrolled in the sub-Saharan Africa Survey of Heart Failure (THESUS-HF) were middle-aged with AHF due primarily to non-ischaemic causes. We sought to describe factors prognostic of re-admission and death in this developing population. Methods and results Prognostic models were developed from data collected on 1006 patients enrolled in THESUS-HF, a prospective registry of AHF patients in 12 hospitals in nine sub-Saharan African countries, mostly in Nigeria, Uganda, and South Africa. The main predictors of 60-day re-admission or death in a model excluding the geographic region were a history of malignancy and severe lung disease, admission systolic blood pressure, heart rate and signs of congestion (rales), kidney function (BUN), and echocardiographic ejection fraction. In a model including region, the Southern region had a higher risk. Age and admission sodium levels were not prognostic. Predictors of 180-day mortality included malignancy, severe lung disease, smoking history, systolic blood pressure, heart rate, and symptoms and signs of congestion (orthopnoea, peripheral oedema and rales) at admission, kidney dysfunction (BUN), anaemia, and HIV positivity. Discrimination was low for all models, similar to models for European and North American patients, suggesting that the main factors contributing to adverse outcomes are still unknown. Conclusion Despite the differences in age and disease characteristics, the main predictors for 6 months mortality and combined 60 days re-admission and death are largely similar in sub-Saharan Africa as in the rest of the world, with some exceptions such as the association of the HIV status with mortality.

Objectives The aim of this study was to assess the effects of serelaxin on short-term changes in markers of organ damage and congestion and relate them to 180-day mortality in patients with acute heart failure. Background Hospitalization for acute heart failure is associated with high post-discharge mortality, and this may be related to organ damage. Methods The Pre-RELAX-AHF (Relaxin in Acute Heart Failure) phase II study and RELAX-AHF phase III study were international, multicenter, double-blind, placebo-controlled trials in which patients hospitalized for acute heart failure were randomized within 16 h to intravenous placebo or serelaxin. Each patient was followed daily to day 5 or discharge and at days 5, 14, and 60 after enrollment. Vital status was assessed through 180 days. In RELAX-AHF, laboratory evaluations were performed daily to day 5 and at day 14. Plasma levels of biomarkers were measured at baseline and days 2, 5, and 14. All-cause mortality was assessed as a safety endpoint in both studies. Results Serelaxin reduced 180-day mortality, with similar effects in the phase II and phase III studies (combined studies: N = 1,395; hazard ratio: 0.62; 95% confidence interval: 0.43 to 0.88; p = 0.0076). In RELAX-AHF, changes in markers of cardiac (high-sensitivity cardiac troponin T), renal (creatinine and cystatin-C), and hepatic (aspartate transaminase and alanine transaminase) damage and of decongestion (N-terminal pro–brain natriuretic peptide) at day 2 and worsening heart failure during admission were associated with 180-day mortality. Serelaxin administration improved these markers, consistent with the prevention of organ damage and faster decongestion. Conclusions Early administration of serelaxin was associated with a reduction of 180-day mortality, and this occurred with fewer signs of organ damage and more rapid relief of congestion during the first days after admission.

Improving clinical research participation among diverse populations continues to be a challenge, despite governmental policy which mandates the inclusion of women and minorities in clinical studies. Underrepresentation of these groups contributes to a literature that fails to serve all populations with equal effectiveness and lessens opportunities to eliminate health disparities. The lack of inclusion of Blacks, Hispanics, Native Americans, Asians, and Pacific Islanders, along with women, contributes to a scientific literature that neglects the lives of many who it was intended to serve. Investing in historically disenfranchised populations in a manner that yields a better understanding of their communities, cultures, morals, attitudes, values, and beliefs will require a facilitated shift in perspective and behaviors of researchers and participants. The effectiveness of science will be impaired, and health disparities will continue to increase without intentional and strategic efforts to engage diverse communities in research and clinical trials. In this chapter, the authors address the significance of minority inclusion in research, outline unique challenges to recruitment and retention, and offer important concepts and methodologies that address these challenges.

Background: \ud \ud The length of hospital stay (LOS) is important in patients admitted for acute heart failure (AHF) because it prolongs an unpleasant experience for the patients and adds substantially to health care costs.\ud \ud Methods and Results: \ud \ud We examined the association between LOS and baseline characteristics, 10-day post-discharge HF readmission, and 90-day post-discharge mortality in 1347 patients with AHF enrolled in the VERITAS program. Longer LOS was associated with greater HF severity and disease burden at baseline; however, most of the variability of LOS could not be explained by these factors. LOS was associated with a higher HF risk of both HF readmission (odds ratio for 1-day increase: 1.08; 95% confidence interval [CI] 1.01–1.16; P = .019) and 90-day mortality (hazard ratio for 1-day increase: 1.05; 95% CI 1.02–1.07; P

Introduction: Rheumatic heart disease (RHD) is the commonest cause of valvular heart disease and a common cause of heart failure in sub-Saharan Africa (SSA). Atrial fibrillation (AF) complicates RHD, precipitates and worsens heart failure and cause unfavourable outcomes. We set out to describe the prevalence, clinical characteristics and outcomes of valvular atrial fibrillation in a cohort of African patients with acute heart failure (AHF). Methods: The sub-Saharan Africa Survey of Heart Failure (THESUS-HF) was a prospective, observational survey of AHF in nine countries. We collected demographic data, medical history and signs and symptoms of HF. Electrocardiograms (ECGs) were done in a standard fashion. AF was defined as either a history of AF or AF on the admission ECG. Using Cox regression models, we examined the associations of AF with all-cause death over 180 days and a composite endpoint of all-cause death or readmission over 60 days. Results: There were 1 006 patients in the registry. The mean age was 52.3 years and 50.8% were women. AF was present in 209 (20.8%) cases. Those with AF were older (57.1 vs 51.1 years), more likely to be female (57.4 vs 49.1%), had significantly lower systolic (125 vs 132 mmHg) and diastolic (81 vs 85 mmHg) blood pressure (BP), and higher heart rates (109 vs 102 bpm). Ninety-two (44%) AF patients had valvular heart disease. The presence of AF was not associated with the primary endpoints, but having valvular AF predicted death within 180 days. Conclusion: AF was present in one-fifth of African patients with AHF. Almost half of the AF patients had valvular disease (RHD) and were significantly younger and at risk of dying within six months. It is important to identify these high-risk patients and prioritise their management, especially in SSA where resources are limited.

Aims Patients with acute heart failure in Africa are rarely being treated with a hydralazine/nitrates combination. Therefore the effect of this treatment was studied here Methods and results The study was planned to enrol 500 patients during an acute heart failure (HF) admission, from nine sub-Saharan African countries. Patients were randomized in a double-blind manner to receive 50 mg hydralazine/20 mg isosorbide dinitrate (HYIS) t.i.d. or matching placebo for 24 weeks followed by open label HYIS for all patients. The study was terminated after 147 patients were enrolled due mostly to issues with recruitment into a prospective, placebo-controlled study. Most patients were recruited from Mozambique, South Africa, Kenya, and Uganda. The primary endpoint of death or HF readmission through 24 weeks was neutral [hazard ratio (HR) 1.05, 95% confidence interval (CI) 0.48–2.27, P = 0.90] in the 133 randomized patients included in the analyses. There were non-signficant effects in favour of HYIS in secondary endpoints including change in dyspnoea severity at day 7 or discharge, decrease in systolic blood pressure, greater decrease in weight, and increase in 6-min walk test distance at week 24. There were also small changes in echocardiographic indices of cardiac size and function in favour or HYIS, but none was significant. Conclusion The BA-HEF trial demonstrated challenges in recruiting the expected number of patients with acute HF in a number of African countries, which highlights the need for strategic logistic support. Trial registration: NCT01822808.

Previous research suggests that demographic factors are important correlates of cognitive functioning in African Americans; however, less attention has been given to the influence of personality. The present study explored how dimensions and facets of personality predicted individual variability in cognition in a sample of older African Americans from the Baltimore Study of Black Aging. Cognition was assessed by verbal learning and attention/working memory measures. Personality was measured by the NEO Personality Inventory. Linear regressions controlling for demographic factors showed that Neuroticism, Openness, and Agreeableness were significant regression predictors of cognitive performance. Individual facets of all five personality dimensions were also associated with cognitive performance. These findings suggest personality is important in understanding variability in cognition among older African Americans.

Purpose: To determine the genetic and environmental influences exerted on arthritis by measuring the distribution of self-reported arthritis diagnoses among monozygotic (MZ) and dizygotic (DZ) African American twins. Methods: A cross-sectional study was conducted on 97 MZ and 113 DZ twin pairs recruited into the Carolina African American Twin Study of Aging (CAATSA). The sample had a mean age of 47 ± 13.9 years. A twin design was used to determine correlations in arthritis diagnosis for MZ and DZ twins and to estimate the contribution of genes and environment to the variation in an arthritis diagnosis. Results: The concordance rate for being diagnosed with arthritis was 42% for MZ twins, and 20% for DZ twins, resulting in a 2.1:1 ratio of MZ to DZ concordance. These results indicate a significant proportion of individual variability was due to genetic factors (43%) on an arthritis diagnosis as well as 57% of variance due to nonshared environmental influences. Conclusions: This research suggests that while there are genetic influences on arthritis diagnosis, environmental factors, such as infections, dietary factors, urbanization, and pollutants, also play a role in accounting for variability in the diagnosis and treatment of arthritis among diverse populations.

Healthcare disparities are a growing area of interest among scientists and clinicians. Articles identified from searches of the PubMed and PsycInfo databases, as well as the Google Scholar search engine including combinations of the key words and phrases: Black men, circadian rhythm, disease, ethnicity, gender, health disparities, illness, insomnia, race, sleep, sleep apnea, and sleep disorders were used for this review. This brief review addresses some of the limited work on sleep among Black men. Some information is available regarding expected sleep parameters, insomnia, sleep-disordered breathing, and sleep disturbances related to general medical conditions. Many areas are still in need of exploration and, although emphasizing aspects of sleep, the present work is intended as a foundation to encourage further exploration across many disciplines in the health sciences.