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Copyright of Developmental Medicine & Child Neurology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Developmental Medicine & Child Neurology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background and Purpose: The major drug-metabolizing enzymes for the oxidation of oxycodone are CYP2D6 and CYP3A. A high interindividual variability in the activity of these enzymes because of genetic polymorphisms and/or drug-drug interactions is well established. The possible role of an active metabolite in the pharmacodynamics of oxycodone has been questioned and the importance of CYP3A-mediated effects on the pharmacokinetics and pharmacodynamics of oxycodone has been poorly explored.Experimental Approach: We conducted a randomized crossover (five arms) double-blind placebo-controlled study in 10 healthy volunteers genotyped for CYP2D6. Oral oxycodone (0.2 mg x kg(-1)) was given alone or after inhibition of CYP2D6 (with quinidine) and/or of CYP3A (with ketoconazole). Experimental pain (cold pressor test, electrical stimulation, thermode), pupil size, psychomotor effects and toxicity were assessed.Key Results: CYP2D6 activity was correlated with oxycodone experimental pain assessment. CYP2D6 ultra-rapid metabolizers experienced increased pharmacodynamic effects, whereas cold pressor test and pupil size were unchanged in CYP2D6 poor metabolizers, relative to extensive metabolizers. CYP2D6 blockade reduced subjective pain threshold (SPT) for oxycodone by 30% and the response was similar to placebo. CYP3A4 blockade had a major effect on all pharmacodynamic assessments and SPT increased by 15%. Oxymorphone C(max) was correlated with SPT assessment (rho(S)= 0.7) and the only independent positive predictor of SPT. Side-effects were observed after CYP3A4 blockade and/or in CYP2D6 ultra-rapid metabolizers.Conclusions and Implications: The modulation of CYP2D6 and CYP3A activities had clear effects on oxycodone pharmacodynamics and these effects were dependent on CYP2D6 genetic polymorphism. [ABSTRACT FROM AUTHOR]

Abstract: Small‐quantity lipid‐based nutrient supplements (SQ‐LNS) have been studied in efficacy and effectiveness trials, but little is known about how parents perceive the products and their effects. In a randomised trial in Ghana, efficacy of SQ‐LNS provided to women during pregnancy and the first 6 months postpartum and to their children from 6 to 18 months of age was assessed by comparison with iron‐folic acid (IFA) capsules and multiple micronutrient (MMN) capsules provided to women. In a follow‐up study conducted when the index children from the original trial were between 4 and 6 years of age, we used survey‐based methods to assess retrospective and current parental perceptions of nutrient supplements generally and of SQ‐LNS and their effects compared with perceptions IFA and MMN capsules. Most parents perceived that the assigned supplements (SQ‐LNS, IFA, or MMN) positively impacted the mother during pregnancy (approximately 89% of both mothers and fathers) and during lactation (84% of mothers and 86% of fathers). Almost all (≥90%) of mothers and fathers perceived that the assigned supplement positively impacted the index child and expected continued positive impacts on the child's health and human capital into the future. A smaller percentage of parents perceived negative impacts of the supplements (7%–17% of mothers and 4%–12% of fathers). Perceptions of positive impacts and of negative impacts did not differ by intervention group. The results suggest that similar populations would likely be receptive to programs to deliver SQ‐LNS or micronutrient capsules. [ABSTRACT FROM AUTHOR]

Aims: A network meta-analysis (NMA) of all recommended drug groups for the treatment of heart failure with reduced ejection fraction (HFrEF), including their combinations, was performed to assess the relative efficacy and incremental benefit.Methods and Results: A search was made in biomedical databases for randomized controlled trials published between 1987 and 2017 on angiotensin-converting enzyme inhibitors (ACEIs), beta-blockers (BBs), angiotensin receptor blockers (ARBs), mineralocorticoid receptor antagonists (MRAs), ivabradine (IVA), or angiotensin receptor-neprilysin inhibitors (ARNI). A total of 58 relevant trials were identified. The relative efficacy of each treatment group (or combination) in terms of all-cause mortality, cardiovascular mortality, all-cause hospitalizations and hospitalizations for heart failure, per patient-year of follow-up, were combined in a random-effects Bayesian NMA. The pairwise comparison between each regimen and for each outcome was estimated. The NMA was dominated by 15 large-scale trials with between 1984 and 18 898 patient-years of follow-up. Combinations of drug groups showed incremental benefits on outcomes over single groups. The most effective combinations were ARNI+BB + MRA and ACEI+BB + MRA + IVA, showing reductions in all-cause mortality (vs. placebo) of 62% and 59%, respectively; hazard ratios were 0.38 [credible interval (CrI) 0.20-0.65] and 0.41 (CrI 0.21-0.70); and in all-cause hospitalizations with reductions of 42% for both. These two combinations were also the most effective for the other outcomes studied.Conclusion: Our analysis shows that the incremental use of combinations of disease-modifying therapies has resulted in the progressive improvement in mortality and hospitalization outcomes in HFrEF. Our findings support the current guideline recommendations. [ABSTRACT FROM AUTHOR]

We report the rationale and design of a community PHARMacy-based prospective randomized controlled interdisciplinary study for ambulatory patients with Chronic Heart Failure (PHARM-CHF) and results of its pilot study. The pilot study randomized 50 patients to a pharmacy-based intervention or usual care for 12 months. It demonstrated the feasibility of the design and showed reduced systolic blood pressure in the intervention group as indicator for improved medication adherence. The main study will randomize patients ≥60 years on stable pharmacotherapy including at least one diuretic and a history of heart failure hospitalization within 12 months. The intervention group will receive a medication review at baseline followed by regular dose dispensing of the medication, counselling regarding medication use and symptoms of heart failure. The control patients are unknown to the pharmacy and receive usual care. The primary efficacy endpoint is medication adherence, pre-specified as a significant difference of the proportion of days covered between the intervention and control group within 365 days following randomization using pharmacy claims data for three CHF medications (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, beta-blockers, and mineralocorticoid receptor antagonists). The primary composite safety endpoint is days lost due to blindly adjudicated unplanned cardiovascular hospitalizations or death. Overall, 248 patients shall be randomized. The minimum follow-up is 12 months with an expected mean of 24 months. Based on the feasibility demonstrated in the pilot study, the randomized PHARM-CHF trial will test whether an interdisciplinary pharmacy-based intervention can safely improve medication adherence and will estimate the potential impact on clinical endpoints. ClinicalTrials.gov Identifier: NCT01692119. [ABSTRACT FROM AUTHOR]

Objective: The ketones d-β-hydroxybutyrate (BHB) and acetoacetate are elevated during prolonged fasting or during a "ketogenic" diet. Although weight loss on a ketogenic diet may be associated with decreased appetite and altered gut hormone levels, it is unknown whether such changes are caused by elevated blood ketones. This study investigated the effects of an exogenous ketone ester (KE) on appetite.Methods: Following an overnight fast, subjects with normal weight (n = 15) consumed 1.9 kcal/kg of KE, or isocaloric dextrose (DEXT), in drinks matched for volume, taste, tonicity, and color. Blood samples were analyzed for BHB, glucose, insulin, ghrelin, glucagon-like peptide 1 (GLP-1), and peptide tyrosine tyrosine (PYY), and a three-measure visual analogue scale was used to measure hunger, fullness, and desire to eat.Results: KE consumption increased blood BHB levels from 0.2 to 3.3 mM after 60 minutes. DEXT consumption increased plasma glucose levels between 30 and 60 minutes. Postprandial plasma insulin, ghrelin, GLP-1, and PYY levels were significantly lower 2 to 4 hours after KE consumption, compared with DEXT consumption. Temporally related to the observed suppression of ghrelin, reported hunger and desire to eat were also significantly suppressed 1.5 hours after consumption of KE, compared with consumption of DEXT.Conclusions: Increased blood ketone levels may directly suppress appetite, as KE drinks lowered plasma ghrelin levels, perceived hunger, and desire to eat. [ABSTRACT FROM AUTHOR]

Objective: The objective of this study was to test whether behavioral weight loss (BWL) intervention decreases headaches in women with comorbid migraine and overweight or obesity.Methods: This randomized, single-blind trial allocated women 18 to 50 years old with 4 to 20 migraine days per month and a BMI = 25.0-49.9 kg/m2 to 16 weeks of BWL (n = 54), which targeted exercise and eating behaviors for weight loss, or to migraine education control (ME, n = 56), which delivered didactic instruction on migraine and treatments. Participants completed a 4-week smartphone headache diary at baseline, posttreatment (16-20 wk), and follow-up (32-36 wk). The primary outcome was posttreatment change in migraine days per month, analyzed via linear mixed effects models.Results: Of 110 participants randomly assigned, 85 (78%) and 80 (73%) completed posttreatment and follow-up. Although the BWL group achieved greater weight loss (mean [95% CI] in kilograms) than the ME group at posttreatment (-3.8 [-2.5 to -5.0] vs. + 0.9 [-0.4 to 2.2], P < 0.001) and follow-up (-3.2 [-2.0 to -4.5] vs. + 1.1 [-0.2 to 2.4], P < 0.001), there were no significant group (BWL vs. ME) differences (mean [95% CI]) in migraine days per month at posttreatment (-3.0 [-2.0 to -4.0] vs. -4.0 [-2.9 to -5.0], P = 0.185) or follow-up (-3.8 [-2.7 to -4.8] vs. -4.4 [-3.4 to -5.5], P = 0.378).Conclusions: Contrary to hypotheses, BWL and ME yielded similar, sustained reductions in migraine headaches. Future research should evaluate whether adding BWL to standard pharmacological and/or nonpharmacological migraine treatment approaches yields greater benefits. [ABSTRACT FROM AUTHOR]

Background and Purpose: Our initial aim was to generate cannabinoid agents that control spasticity, occurring as a consequence of multiple sclerosis (MS), whilst avoiding the sedative side effects associated with cannabis. VSN16R was synthesized as an anandamide (endocannabinoid) analogue in an anti-metabolite approach to identify drugs that target spasticity.Experimental Approach: Following the initial chemistry, a variety of biochemical, pharmacological and electrophysiological approaches, using isolated cells, tissue-based assays and in vivo animal models, were used to demonstrate the activity, efficacy, pharmacokinetics and mechanism of action of VSN16R. Toxicological and safety studies were performed in animals and humans.Key Results: VSN16R had nanomolar activity in tissue-based, functional assays and dose-dependently inhibited spasticity in a mouse experimental encephalomyelitis model of MS. This effect occurred with over 1000-fold therapeutic window, without affecting normal muscle tone. Efficacy was achieved at plasma levels that are feasible and safe in humans. VSN16R did not bind to known CB1 /CB2 /GPPR55 cannabinoid-related receptors in receptor-based assays but acted on a vascular cannabinoid target. This was identified as the major neuronal form of the big conductance, calcium-activated potassium (BKCa ) channel. Drug-induced opening of neuronal BKCa channels induced membrane hyperpolarization, limiting excessive neural-excitability and controlling spasticity.Conclusions and Implications: We identified the neuronal form of the BKCa channel as the target for VSN16R and demonstrated that its activation alleviates neuronal excitability and spasticity in an experimental model of MS, revealing a novel mechanism to control spasticity. VSN16R is a potential, safe and selective ligand for controlling neural hyper-excitability in spasticity. [ABSTRACT FROM AUTHOR]

Copyright of Tropical Medicine & International Health is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Objective: To assess the short-term tolerability of lorcaserin alone or with two dose regimens of phentermine.Methods: This was a 12-week, randomized, double-blind, pilot safety study of N = 238 nondiabetic patients with obesity or overweight with ≥1 comorbidity randomized to lorcaserin 10 mg twice daily (BID; LOR BID) alone or with phentermine 15 mg once daily (QD; LOR BID+PHEN QD) or 15 mg twice daily (LOR BID+PHEN BID). Patients reporting ≥ 1 of 9 potentially serotonergic adverse events (AEs), mean weight loss (WL), and ≥5% WL are reported.Results: N = 238 were randomized, and N = 235 were treated. N = 94 reported potentially serotonergic AEs: 37.2% LOR BID, 42.3% LOR BID+PHEN QD, and 40.5% LOR BID+PHEN BID. AEs leading to discontinuation were reported approximately twice as often in the LOR BID+PHEN BID group versus the LOR BID group. Mean WL was 3.5 kg/3.3%, 7.0 kg/6.7%, and 7.6 kg/7.2% for LOR BID, LOR BID+PHEN QD, and LOR BID+PHEN BID, respectively. At least 5% WL was achieved by 28.2% LOR BID, 59.0% LOR BID+PHEN QD (P = 0.0002 vs. LOR BID), and 70.9% LOR BID+PHEN BID (P < 0.0001 vs. LOR BID) patients.Conclusions: Phentermine added to lorcaserin enhanced short-term weight loss but did not increase incidence of potentially serotonergic AEs; however, phentermine twice daily increased discontinuation compared to both lorcaserin alone and lorcaserin plus phentermine once daily. [ABSTRACT FROM AUTHOR]

Objective: In-person lifestyle interventions for obesity treatment yield significant improvements in depression. These improvements may be attributed to the excellent weight losses produced by in-person interventions. In contrast, Internet programs yield more modest weight losses, and their effect on depression is unknown. This study is the first to examine whether Internet-delivered obesity treatment impacts depressive symptoms.Methods: Participants (N = 136) were randomized to either a community campaign plus Internet behavioral weight loss (IBWL) or community campaign alone (Control). IBWL did not include online social support components. A measure of depressive symptoms was administered, and weight was objectively assessed.Results: Of the total sample, 24% met the clinical cutoff for elevated depression risk at baseline. IBWL participants lost more weight during treatment (P = 0.005) and experienced significantly greater improvements in depressive symptoms (P = 0.02). Among participants who met the clinical cutoff for elevated risk for depression at baseline, those assigned to IBWL had greater improvements in depressive symptoms during treatment compared to Control (P = 0.033). Consequently, at post-treatment, a smaller percentage of IBWL participants were at elevated risk for depression.Conclusions: This study is the first to show that Internet-delivered obesity treatment improves depression risk and depressive symptoms in individuals with overweight or obesity. [ABSTRACT FROM AUTHOR]

Objective: To determine the effect of prebiotic supplementation on metabolic endotoxemia and systemic inflammation in adults with overweight and obesity.Methods: Samples from a previously conducted randomized, double-blind, placebo-controlled trial were used for analysis. Participants were randomized to 21 g of oligofructose (n = 20; BMI 30.4 kg/m2 ) or a maltodextrin placebo (n = 17; BMI 29.5 kg/m2 ) for 12 weeks. A total of 37 participants had samples available for the current analysis. Resistin, adiponectin, plasminogen activator inhibitor-1 (PAI-1), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and macrophage chemoattractant protein-1 (MCP-1) were quantified using MILLIPLEX® assays. Lipopolysaccharide (LPS) was measured using PyroGene™ Recombinant Factor C Assay.Results: Plasma LPS concentrations were reduced by 40% in the oligofructose group over 12 weeks compared to a 48% increase in the placebo group (P = 0.04). PAI-1, a risk factor for thrombosis, was reduced to a greater extent in the oligofructose group (-17.3 ± 2.6 ng/ml) compared to the placebo group (-9.7 ± 1.8 ng/ml; P = 0.03). Oligofructose did not affect IL-6, TNF-α, MCP-1, adiponectin, or resistin.Conclusions: Oligofructose reduces metabolic endotoxemia and PAI-1. Incorporating prebiotics into the diet through supplements or functional foods may help mitigate some markers of obesity-associated inflammation. [ABSTRACT FROM AUTHOR]

Aim: Adolescents with intellectual disability experience poorer heath than their peers in the general population, partially due to communication barriers and knowledge gaps in their health history. This study aimed to test a health intervention package against usual care for a range of health promotion and disease detection outcomes.Method: A parallel-group cluster randomized controlled trial was conducted with Australian adolescents with intellectual disability living in the community. Randomization occurred at school level. The intervention package consisted of classroom-based health education, a hand-held personalized health record, and a health check. Evidence of health promotion, disease prevention, and case-finding activities were extracted from general practitioners' records for 12 months post-intervention.Results: Clinical data was available for 435 of 592 (73.5%) participants from 85 schools. Adolescents allocated to receive the health intervention were more likely to have their vision (odds ratio [OR] 3.3; 95% confidence interval [CI] 1.8-6.1) and hearing (OR 2.7; 95% CI 1.0-7.3) tested, their blood pressure checked (OR 2.4; 95% CI 1.6-3.7), and weight recorded (OR 4.8; 95% CI 3.1-7.6). There was no difference between health intervention and usual care for identification of new diseases.Interpretation: The school-based intervention package increased healthcare activity in adolescents with intellectual disability living in the community. [ABSTRACT FROM AUTHOR]

Aims: In the ENGAGE AF-TIMI 48 trial, edoxaban, a factor Xa inhibitor, was not found to be inferior to warfarin for the prevention of stroke or systemic embolic events (SEE) in patients with atrial fibrillation (AF) and was associated with significantly less bleeding. The higher-dose edoxaban regimen (HDER; 60 mg dose-reduced to 30 mg once daily) has been approved in various countries in Europe, the USA, and Japan. Among patients treated with vitamin K antagonists (VKAs), symptomatic heart failure (HF) is an independent risk factor for lower time-in-therapeutic range, which reduces the efficacy and safety of VKA therapy. We evaluated the efficacy and safety of edoxaban compared with warfarin across the spectrum of HF severity in the ENGAGE AF-TIMI 48 trial.Methods and Results: Of 14 071 patients randomized to well-controlled warfarin or the HDER, 5926 (42%) had no history of HF, 6344 (45%) were in New York Heart Association (NYHA) class I-II, and 1801 (13%) were in NYHA class III-IV. The efficacy of edoxaban compared with warfarin in preventing stroke/SEE was similar in patients without and with HF regardless of the severity of HF; [HDER vs. warfarin: No-HF: hazard ratio (HR) 0.87, 95% confidence interval (CI) 0.69-1.11; NYHA class I-II: HR 0.88, 95% CI 0.69-1.12; NYHA class III-IV: HR 0.83, 95% CI 0.55-1.25; Pinteraction = 0.97]. Compared with warfarin, HDER was consistently associated with lower risk of major bleeding (No-HF: HR 0.82, 95% CI 0.68-0.99; NYHA class I-II: HR 0.79, 95% CI 0.65-0.96; NYHA class III-IV: HR 0.79, 95% CI 0.54-1.17; Pinteraction = 0.96).Conclusion: The relative efficacy and safety of HDER compared with well-managed warfarin in AF patients with HF were similar to those without HF. [ABSTRACT FROM AUTHOR]

Aim: We compared two botulinum toxin A (BoNT-A) injection frequency regimens, 12-monthly versus 4-monthly, for spastic equinus in a randomized clinical trial. The primary outcome measure was passive ankle dorsiflexion.Method: Forty-two ambulant children with spastic equinus, secondary to cerebral palsy (23 males and 19 females; mean age 3y 6mo, SD 13mo; GMFCS levels I [n=20], II [n=19], III [n=3]) were randomized to receive either 12-monthly or 4-monthly BoNT-A injections to the calf, over a 26-month period. Twenty-one children had spastic hemiplegia, 21 children had spastic diplegia. A fixed 6U/kg dose of Botox was injected into the gastrocnemius muscle of both limbs in children with diplegia and the gastrocsoleus of the affected limb in children with hemiplegia, under mask anaesthesia.Results: Forty-two children entered the trial with 21 participants randomized to each group. There were three withdrawals and two children received serial casting midway through the trial. There was no significant difference in passive dorsiflexion between 12-monthly and 4-monthly regimens (p=0.41). There were also no significant between group differences on secondary outcome measures. There were no serious adverse events - the rate was 1.2 adverse events per child per year in the 12-monthly group and 2.2 adverse events per child per year in the 4-monthly group. Subgroup analysis revealed a significant difference in passive dorsiflexion between children with hemiplegia and diplegia (p=0.01).Interpretation: There was no significant difference between 12-monthly and 4-monthly injection regimens on passive dorsiflexion or secondary outcome measures. BoNT-A injections for spastic equinus may be recommended on a 12-monthly basis. [ABSTRACT FROM AUTHOR]

Background and Purpose: Exposure-response (ER) modelling (concentration-QTc analysis) is gaining as much acceptance as the traditional by-time analysis of the placebo-adjusted change from baseline in the QTc interval (ΔΔQTcF). It has been postulated that intensive ECG analysis and ER modelling during early-phase drug development could be a cost-effective approach of estimating QT liability of a new drug, in a small number of subjects.Experimental Approach: We used a highly automated analysis of ECGs from 46 subjects from a crossover thorough QT/QTc study to detect ΔΔQTcF with moxifloxacin. Using these data, we also simulated (bootstrapped) 1000 datasets of a parallel study with eight subjects receiving moxifloxacin and eight others receiving placebo.Key Results: The slope from the concentration-QTc analysis for moxifloxacin in 46 subjects was 4.12 ms of ΔΔQTcF per μg(-1) mL(-1) ; at mean Cmax of 2.95 μg·mL(-1) , estimated ΔΔQTcF was 13.4 ms (90% confidence interval 11.3, 15.4 ms). In the 1000 simulated datasets, in 996 datasets, ER modelling showed that the upper bound of the 90% confidence interval for ΔΔQTcF at geometric mean Cmax exceeded 10 ms. In 895 of these 996 datasets, the slope of the ER relationship was statistically significantly positive. Thus, with a small sample size (eight subjects on active drug and eight on placebo), moxifloxacin-induced QTc prolongation was demonstrated using ER analysis with statistical power of >80%.Conclusions and Implications: Our study adds to the growing body of data supporting intensive ECG collection and analysis in early-phase studies to estimate QT liability. [ABSTRACT FROM AUTHOR]

Objective: Aim is to predict successful weight loss by metabolic signatures at baseline and to identify which differences in metabolic status may underlie variations in weight loss success.Methods: In DiOGenes, a randomized, controlled trial, weight loss was induced using a low-calorie diet (800 kcal) for 8 weeks. Men (N = 236) and women (N = 431) as well as groups with overweight/obesity and morbid obesity were studied separately. The relation between the metabolic status before weight loss and weight loss was assessed by stepwise regression on multiple data sets, including anthropometric parameters, NMR-based plasma metabolites, and LC-MS-based plasma lipid species.Results: Maximally, 57% of the variation in weight loss success can be predicted by baseline parameters. The most powerful predictive models were obtained in subjects with morbid obesity. In these models, the metabolites most predictive for weight loss were acetoacetate, triacylglycerols, phosphatidylcholines, specific amino acids, and creatine and creatinine. This metabolic profile suggests that high energy metabolism activity results in higher amounts of weight loss.Conclusions: Possible predictive (pre-diet) markers were found for amount of weight loss for specific subgroups. [ABSTRACT FROM AUTHOR]

Aim: Neurofibromatosis type 1 (NF1) is a genetic disorder with a cognitive profile that includes visual-spatial perception deficits and a high incidence of reading disability. There is a paucity of information about how this cognitively complex population responds to mainstream reading interventions. The clinical trial goals were to determine whether children and adolescents with NF1 and reading deficits (NF+RD) benefit from mainstream remedial reading programs and whether responsiveness varies with differences in program-related visual-spatial demands.Method: Forty-nine participants (28 males, 21 females; aged 8-14y) with either NF+RD (n=17, 11 males, six females) or idiopathic reading deficit (IRD) (n=32, 17 males, 15 females) were randomly assigned to intensive remedial teaching using one of two multisensory reading programs: one with greater kinesthetic demands and the other with greater visual-spatial demands. Two control groups - wait-list IRD (n=14, 11 males, three females) and typically developing readers (n=26, 13 males, 13 females) - received no treatment. Repeated measures and multivariate ANOVA analyses compared each group's growth in reading achievement from pre- to post-testing.Results: Treated groups showed significant growth whereas untreated groups did not. Comparing treated groups, the IRD group responded equally well to both interventions, whereas the NF+RD group showed a better response to the more kinesthetic approach.Interpretation: Results suggest that multisensory remedial reading teaching that emphasizes kinesthetic demands more than visual-spatial demands is suitable for students with NF+RD. [ABSTRACT FROM AUTHOR]

Data on the potential beneficial effects of combining diet and exercise on blood pressure (BP) are still scarce. A 4-week randomized controlled clinical trial was undertaken in 40 hypertensive patients with type 2 diabetes with uncontrolled blood pressure (BP) in office and daytime ambulatory BP monitoring (ABPM). Patients were assigned to follow a Dietary Approaches to Stop Hypertension (DASH) diet associated with advice to increase walking using a pedometer (intervention group) or a diet based on the American Diabetes Association recommendations (control group). The lifestyle intervention caused a greater ABPM (mm Hg) reduction in systolic 24-hour, diastolic 24-hour, nighttime systolic, daytime systolic, and daytime diastolic measurements than observed in the control group. In the intervention group there was a decrease in urinary sodium and an increase in urinary potassium, plasma aldosterone, and the number of steps per day (P<.05). The DASH diet and increased walking were associated with clinically significant reductions in ABPM values in hypertensive patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Aims and Methods: To: (i) describe the baseline characteristics of patients in ATMOSPHERE and the changes in the planned analysis of ATMOSPHERE resulting from the mandated discontinuation of study treatment in patients with diabetes; (ii) compare the baseline characteristics of patients in ATMOSPHERE with those in the Prospective comparison of Angiotensin Receptor neprilysin inhibitors with Angiotensin converting enzyme inhibitors to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF); and (iii) compare the characteristics of patients with and without diabetes at baseline in ATMOSPHERE.Results: A total of 7063 patients were randomized into ATMOSPHERE April 2009-April 2014 at 755 sites in 43 countries. Their average age was 63 years and 78% were men. ATMOSPHERE patients were generally similar to those in PARADIGM-HF although fewer had diabetes, renal dysfunction, and were treated with a mineralocorticoid receptor antagonist. In ATMOSPHERE, patients with diabetes differed in numerous ways from those without. Patients with diabetes were older and had worse heart failure status but a similar left ventricular ejection fraction (mean 28%); they had a higher body mass index and more co-morbidity, especially hypertension and coronary heart disease. Mean estimated glomerular filtration rate was slightly lower in those with diabetes compared with those without.Conclusion: ATMOSPHERE will determine whether patients with HF and reduced ejection fraction (particularly those without diabetes) benefit from the addition of a direct renin inhibitor to standard background therapy, including an angiotensin-converting enzyme inhibitor, beta-blocker, and a mineralocorticoid receptor antagonist. ATMOSPHERE will also determine whether aliskiren alone is superior to, or at least non-inferior to, enalapril. [ABSTRACT FROM AUTHOR]

Aims: Hyperkalaemia in heart failure patients limits use of cardioprotective renin-angiotensin-aldosterone system inhibitors (RAASi). Sodium zirconium cyclosilicate (ZS-9) is a selective potassium ion trap, whose mechanism of action may allow for potassium binding in the upper gastrointestinal tract as early as the duodenum following oral administration. ZS-9 previously demonstrated the ability to reduce elevated potassium levels into the normal range, with a median time of normalization of 2.2 h and sustain normal potassium levels for 28 days in HARMONIZE--a Phase 3, double-blind, randomized, placebo-controlled trial. In the present study we evaluated management of serum potassium with daily ZS-9 over 28 days in heart failure patients from HARMONIZE, including those receiving RAASi therapies.Methods and Results: Heart failure patients with evidence of hyperkalaemia (serum potassium ≥5.1 mmol/L, n = 94) were treated with open-label ZS-9 for 48 h. Patients (n = 87; 60 receiving RAASi) who achieved normokalaemia (potassium 3.5-5.0 mmol/L) were randomized to daily ZS-9 (5, 10, or 15 g) or placebo for 28 days. Mean potassium and proportion of patients maintaining normokalaemia during days 8-29 post-randomization were evaluated. Despite RAASi doses being kept constant, patients on 5 g, 10 g, and 15 g ZS-9 maintained a lower potassium level (4.7 mmol/L, 4.5 mmol/L, and 4.4 mmol/L, respectively) than the placebo group (5.2 mmol/L; P<0.01 vs. each ZS-9 group); greater proportions of ZS-9 patients (83%, 89%, and 92%, respectively) maintained normokalaemia than placebo (40%; P < 0.01 vs. each ZS-9 group). The safety profile was consistent with previously reported overall study population.Conclusion: Compared with placebo, all three ZS-9 doses lowered potassium and effectively maintained normokalaemia for 28 days in heart failure patients without adjusting concomitant RAASi, while maintaining a safety profile consistent with the overall study population. [ABSTRACT FROM AUTHOR]

Background: Patients with heart failure and preserved ejection fraction (HFpEF) have a poor prognosis, and no therapies have been proven to improve outcomes. It has been proposed that heart failure, including HFpEF, represents overlapping syndromes that may have different prognoses. We present an exploratory study of patients enrolled in the Irbesartan in Heart Failure with Preserved Ejection Fraction Study (I-PRESERVE) using latent class analysis (LCA) with validation using the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM)-Preserved study to identify HFpEF subgroups.Methods and Results: In total, 4113 HFpEF patients randomized to irbesartan or placebo were characterized according to 11 clinical features. The HFpEF subgroups were identified using LCA. Event-free survival and effect of irbesartan on the composite of all-cause mortality and cardiovascular hospitalization were determined for each subgroup. Subgroup definitions were applied to 3203 patients enrolled in CHARM-Preserved to validate observations regarding prognosis and treatment response. Six subgroups were identified with significant differences in event-free survival (P < 0.001). Clinical profiles and prognoses of the six subgroups were similar in CHARM-Preserved. The two subgroups with the worst event-free survival in both studies were characterized by a high prevalence of obesity, hyperlipidaemia, diabetes mellitus, anaemia, and renal insufficiency (Subgroup C) and by female predominance, advanced age, lower body mass index, and high rates of atrial fibrillation, valvular disease, renal insufficiency, and anaemia (Subgroup F).Conclusion: Using a data-driven approach, we identified HFpEF subgroups with significantly different prognoses. Further development of this approach for characterizing HFpEF subgroups is warranted. [ABSTRACT FROM AUTHOR]

Background: The association between sympathetic activation and mortality in chronic heart failure and the favorable effect of beta blocking drugs has raised the possibility of therapeutic efficacy for central sympathetic inhibition with sustained-release (SR) moxonidine, an imidazoline receptor agonist. Methods: A randomized double-blind, placebo-controlled trial was initiated in 425 centers in 17 countries with a plan to enter 4533 patients with New York Heart Association class II–IV heart failure and a reduced ejection fraction. Moxonidine SR or matching placebo was titrated to a target dose of 1.5 mg BID. The trial was powered to detect a 20% reduction in mortality, which required a total of 724 deaths. Findings: An early increase in death rate and adverse events in the moxonidine SR group led to premature termination of the trial because of safety concerns after 1934 patients were entered. Final analysis revealed 54 deaths (5.5%) in the moxonidine SR group and 32 deaths (3.4%) in the placebo group during the active treatment phase. Survival curves revealed a significantly (P=0.012) worse outcome in the moxonidine SR group. Hospitalization for heart failure, acute myocardial infarction and adverse events were also more frequent in the moxonidine SR group. Plasma norepinephrine was significantly decreased by moxonidine SR (−18.8% from baseline) vs. placebo (+6.9%). Interpretation: Early termination of the trial limited conclusions regarding the long-term effects of central sympathetic inhibition. Nonetheless, the excess early mortality and morbidity suggest the likelihood of an adverse effect of moxonidine SR and raise concerns regarding the efficacy of generalized sympathetic inhibition in heart failure. [Copyright &y& Elsevier]

Aims: Drug-induced changes in QT dispersion may be a way of detecting harmful repolarisation abnormalities for patients receiving antiarrhythmic drugs affecting ventricular repolarisation. Methods and results: In 463 congestive heart failure (CHF) patients enrolled in the Danish Investigations Of Arrhythmia and Mortality On Dofetilide-CHF (DIAMOND-CHF) study, both pre-treatment and on-treatment day 2–6 QT dispersion was available from standard 12-lead ECGs. Patients were randomised in a double-blind manner to receive either placebo or dofetilide, a new class III antiarrhythmic drug. During a median follow-up of 19 months (minimum 1 year), 179 patients (39%) died (135 patients from cardiac causes). Changes in QT dispersion did not predict all-cause or cardiac mortality for patients treated with dofetilide in multivariate survival analysis (Risk ratio: 1.02, 95% confidence interval: 0.97–1.08, P>0.4). This finding was independent of pre-treatment QT dispersion. Dofetilide caused a small QT dispersion increment of 8 ms, not different from the changes seen in the placebo group (3 ms). Conclusion: For patients with CHF and reduced left ventricular systolic function, changes in QT dispersion following treatment with dofetilide do not predict all-cause or cardiac mortality. The dofetilide-induced QT dispersion changes are small and comparable to those seen in placebo treated patients. [Copyright &y& Elsevier]

Chemotherapy with praziquantel is the cornerstone of schistosomiasis control. In view of recent concern about tolerance or resistance to praziquantel, monitoring its efficacy in different epidemiological settings is required. We report a study among 253 schoolchildren in an area highly endemic for Schistosoma mansoni in western Côte d'Ivoire. After examining four consecutive stool specimens from each child, the first praziquantel treatment at 60 mg/kg divided into two doses was administered. Four weeks later, stool specimens were again screened over 4 consecutive days and revealed a cure rate of 71.6% and an egg reduction rate of 79.9%. There was a significant association between cure rate and intensity of infection prior to treatment with highest cure rates observed in light infections (P < 0.01). Praziquantel, at a single dose of 40 mg/kg, was again administered 35 days after the first treatment. The overall cure and egg reduction rates increased considerably. The association between cure rate and intensity of infection prior to the second treatment was significant but less pronounced. Twenty-two children remained S. mansoni positive after the two chemotherapy campaigns, and interestingly, many of these were only identified after repeated stool examinations. We argue that pre-patent infections may account for some of these 'treatment failures'. However, further studies in other endemic settings are needed, with parasitological diagnoses having a high sensitivity. [ABSTRACT FROM AUTHOR]