Sodium zirconium cyclosilicate increases serum bicarbonate concentrations among patients with hyperkalaemia: exploratory analyses from three randomized, multi-dose, placebo-controlled trials.

BACKGROUND: Sodium zirconium cyclosilicate (SZC) binds potassium and ammonium in the gastrointestinal tract. In addition to serum potassium reduction, Phase 2 trial data have shown increased serum bicarbonate with SZC, which may be clinically beneficial because maintaining serum bicarbonate ≥22 mmol/L preserves kidney function. This exploratory analysis examined serum bicarbonate and urea, and urine pH data from three SZC randomized, placebo-controlled Phase 3 studies among patients with hyperkalaemia [ZS-003 (n = 753), HARMONIZE (n = 258) and HARMONIZE-Global (n = 267)]. METHODS: In all studies, patients received ≤10 g SZC 3 times daily (TID) for 48 h to correct hyperkalaemia, followed by randomization to maintenance therapy with SZC once daily (QD) versus placebo for ≤29 days among those achieving normokalaemia. RESULTS: Significant dose-dependent mean serum bicarbonate increases from baseline of 0.3 to 1.5 mmol/L occurred within 48 h of SZC TID in ZS-003 (all P < 0.05), which occurred regardless of chronic kidney disease (CKD) stage. Similar acute increases in HARMONIZE and HARMONIZE-Global were maintained over 29 days. With highest SZC maintenance doses, patient proportions with serum bicarbonate <22 mmol/L fell from 39.4% at baseline to 4.9% at 29 days (P = 0.005) in HARMONIZE and from 87.9% to 70.1%, (P = 0.006) in HARMONIZE-Global. Path analyses demonstrated that serum urea decreases (but not serum potassium or urine pH changes) were associated with SZC effects on serum bicarbonate. CONCLUSIONS: SZC increased serum bicarbonate concentrations and reduced patient proportions with serum bicarbonate <22 mmol/L, likely due to SZC-binding of gastrointestinal ammonium. These SZC-induced serum bicarbonate increases occurred regardless of CKD stage and were sustained during ongoing maintenance therapy.

The Role of Transparency, Trust, and Social Influence on Uncertainty Reduction in Times of Pandemics: Empirical Study on the Adoption of COVID-19 Tracing Apps.

BACKGROUND: Contact tracing apps are an essential component of an effective COVID-19 testing strategy to counteract the spread of the pandemic and thereby avoid overburdening the health care system. As the adoption rates in several regions are undesirable, governments must increase the acceptance of COVID-19 tracing apps in these times of uncertainty. OBJECTIVE: Building on the Uncertainty Reduction Theory (URT), this study aims to investigate how uncertainty reduction measures foster the adoption of COVID-19 tracing apps and how their use affects the perception of different risks. METHODS: Representative survey data were gathered at two measurement points (before and after the app's release) and analyzed by performing covariance-based structural equation modeling (n=1003). RESULTS: We found that uncertainty reduction measures in the form of the transparency dimensions disclosure and accuracy, as well as social influence and trust in government, foster the adoption process. The use of the COVID-19 tracing app in turn reduced the perceived privacy and performance risks but did not reduce social risks and health-related COVID-19 concerns. CONCLUSIONS: This study contributes to the mass adoption of health care technology and URT research by integrating interactive communication measures and transparency as a multidimensional concept to reduce different types of uncertainty over time. Furthermore, our results help to derive communication strategies to promote the mass adoption of COVID-19 tracing apps, thus detecting infection chains and allowing intelligent COVID-19 testing.

Effect of ferric citrate on serum phosphate and fibroblast growth factor 23 among patients with nondialysis-dependent chronic kidney disease: path analyses.

BACKGROUND: Among patients with nondialysis-dependent chronic kidney disease (NDD-CKD) and iron-deficiency anemia (IDA), ferric citrate increases hemoglobin and iron parameters and reduces serum phosphate and fibroblast growth factor 23 (FGF23), a key phosphate-regulating hormone. We conducted post hoc analyses of a phase 3 trial to explore associations between iron replacement, serum phosphate changes and FGF23 regulation. METHODS: We employed multivariable regression and longitudinal mixed-effects models to identify and confirm, respectively, whether baseline demographic and laboratory variables were associated with ferric citrate-induced changes in serum phosphate or FGF23 concentrations. We employed path analyses to determine whether changes in FGF23 concentrations were mediated via changes in serum phosphate and/or transferrin saturation (TSAT). RESULTS: We analyzed a total of 117 and 115 ferric citrate-treated and placebo-treated patients, respectively. At 16 weeks, ferric citrate significantly reduced serum phosphate versus placebo (P = 0.006) only among patients with elevated baseline serum phosphate (≥4.5 mg/dL) and did not reduce serum phosphate among patients with baseline serum phosphate within the population reference range. Ferric citrate reduced intact FGF23 and C-terminal FGF23 partially via changes in TSAT (for C-terminal FGF23) and serum phosphate (for intact FGF23) and partially via unknown/unmeasured mechanisms. CONCLUSIONS: Ferric citrate reduced serum FGF23 concentrations (partially via effects on serum phosphate and iron balance) and did not reduce serum phosphate among patients with baseline serum phosphate concentrations within the population reference range.

EPA but not DHA appears to be responsible for the efficacy of omega-3 long chain polyunsaturated fatty acid supplementation in depression: evidence from a meta-analysis of randomized controlled trials.

BACKGROUND: Epidemiologic and case-control data suggest that increased dietary intake of omega-3 long-chain polyunsaturated fatty acids (omega3 LC-PUFAs) may be of benefit in depression. However, the results of randomized controlled trials are mixed and controversy exists as to whether either eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) or both are responsible for the reported benefits. OBJECTIVE: The aim of the current study was to provide an updated meta-analysis of all double-blind, placebo-controlled, randomized controlled trials examining the effect of omega3 LC-PUFA supplementation in which depressive symptoms were a reported outcome. The study also aimed to specifically test the differential effectiveness of EPA versus DHA through meta-regression and subgroup analyses. DESIGN: Studies were selected using the PubMed database on the basis of the following criteria: (1) randomized design; (2) placebo controlled; (3) use of an omega3 LC-PUFA preparation containing DHA, EPA, or both where the relative amounts of each fatty acid could be quantified; and (4) reporting sufficient statistics on scores of a recognizable measure of depressive symptoms. RESULTS: Two hundred forty-one studies were identified, of which 28 met the above inclusion criteria and were therefore included in the subsequent meta-analysis. Using a random effects model, overall standardized mean depression scores were reduced in response to omega3 LC-PUFA supplementation as compared with placebo (standardized mean difference = -0.291, 95% CI = -0.463 to -0.120, z = -3.327, p = 0.001). However, significant heterogeneity and evidence of publication bias were present. Meta-regression studies showed a significant effect of higher levels of baseline depression and lower supplement DHAEPA ratio on therapeutic efficacy. Subgroup analyses showed significant effects for: (1) diagnostic category (bipolar disorder and major depression showing significant improvement with omega3 LC-PUFA supplementation versus mild-to-moderate depression, chronic fatigue and non-clinical populations not showing significant improvement); (2) therapeutic as opposed to preventive intervention; (3) adjunctive treatment as opposed to monotherapy; and (4) supplement type. Symptoms of depression were not significantly reduced in 3 studies using pure DHA (standardized mean difference 0.001, 95% CI -0.330 to 0.332, z = 0.004, p = 0.997) or in 4 studies using supplements containing greater than 50% DHA (standardized mean difference = 0.141, 95% CI = -0.195 to 0.477, z = 0.821, p = 0.417). In contrast, symptoms of depression were significantly reduced in 13 studies using supplements containing greater than 50% EPA (standardized mean difference = -0.446, 95% CI = -0.753 to -0.138, z = -2.843, p = 0.005) and in 8 studies using pure ethyl-EPA (standardized mean difference = -0.396, 95% CI = -0.650 to -0.141, z = -3.051, p = 0.002). However, further meta-regression studies showed significant inverse associations between efficacy and study methodological quality, study sample size, and duration, thus limiting the confidence of these findings. CONCLUSIONS: The current meta-analysis provides evidence that EPA may be more efficacious than DHA in treating depression. However, owing to the identified limitations of the included studies, larger, well-designed, randomized controlled trials of sufficient duration are needed to confirm these findings.

An evaluation of the use and handling errors of currently available recombinant human follicle-stimulating hormone pen injectors by women with infertility and fertility nurses.

Background: This study compared preference ratings of women with infertility and nurses before and after simulated injection, and handling errors, with the GONAL-f®, Bemfola®, Ovaleap® and Rekovelle® pen injectors. Research design and methods: Injector-naïve women and injector-experienced fertility nurses tested injectors with masked labels in a randomized testing order. Injections were made into a foam pad and injectors were rated before and after use. Handling errors were recorded during the study. Ratings and errors were compared between pen injectors using ordinal or Poisson linear mixed models adjusted for testing order. Results: 120 women and 60 nurses participated. All participants tested GONAL-f and Bemfola injectors. Because of their similarity, participants tested either Rekovelle (71 women; 30 nurses) or Ovaleap (49 women; 30 nurses) injectors. The ratings from women were higher for GONAL-f vs other injectors after simulated use (p < 0.001 for all comparisons). Fertility nurses rated GONAL-f injector higher than other injectors both before and after use (p < 0.01 for all comparisons). Adjusted rates of total handling errors were lower with the GONAL-f vs other injectors (p < 0.001 for all comparisons) for both groups. Conclusions: GONAL-f injector was rated significantly higher than other injectors, which may be related to less handling errors observed with the GONAL-f injector.

A Randomized Controlled Trial of Dapagliflozin Plus Once-Weekly Exenatide Versus Placebo in Individuals with Obesity and Without Diabetes: Metabolic Effects and Markers Associated with Bodyweight Loss.

INTRODUCTION: The sodium-glucose cotransporter 2 inhibitor dapagliflozin and the glucagon-like peptide-1 (GLP-1) receptor agonist exenatide reduce bodyweight via differing and complementary mechanisms. This post hoc analysis investigated the metabolic effects and baseline associations with bodyweight loss on coadministration of dapagliflozin and exenatide once weekly (QW) among adults with obesity and without diabetes. METHODS: In the primary trial, adults with obesity and without diabetes [n = 50; 18-70 years; body mass index (BMI) 30-45 kg/m2] were randomized to double-blind oral dapagliflozin 10 mg (DAPA) once daily plus subcutaneous long-acting exenatide 2 mg QW (ExQW) or placebo over 24 weeks, followed by an open-label extension from 24-52 weeks during which all participants received active treatment. Primary results have been published previously. This analysis evaluated: (1) the effects of DAPA + ExQW on changes in substrates [free fatty acids (FFAs), glycerol, beta-OH-butyrate, and glucose], hormones (glucagon and insulin), and insulin secretion [insulinogenic index (IGI)] via an oral glucose tolerance test (OGTT) and (2) associations between bodyweight loss and baseline characteristics (e.g., BMI), single-nucleotide polymorphisms (SNPs) associated with the GLP-1 pathway, and markers of glucose regulation. RESULTS: Compared with placebo at 24 weeks, 2-h FFAs post-OGTT increased (mean difference, +20.4 µmol/l; P < 0.05), and fasting glucose, 2-h glucose post-OGTT, and glucose area under the concentration-time curve (AUC) decreased with DAPA + ExQW [mean differences, -0.68 mmol/l [P < 0.001], -2.20 mmol/l (P < 0.01), and -306 mmol/l min (P < 0.001), respectively]. Glucagon, glycerol, beta-OH-butyrate, and IGI did not differ by treatment group at 24 weeks. Over 52 weeks, DAPA + ExQW decreased fasting insulin, 2-h post-OGTT insulin, and insulin AUC. Among DAPA + ExQW-treated participants, for each copy of the SNP variant rs10010131 A allele (gene WFS1), bodyweight decreased by 2.4 kg (P < 0.05). Lower BMI and a lower IGI were also associated with greater bodyweight loss with DAPA + ExQW. CONCLUSIONS: Metabolic effects with DAPA + ExQW included less FFA suppression versus placebo during the OGTT, suggesting compensatory lipid mobilization for energy production when glucose availability was reduced because of glucosuria. The expected increase in glucagon with DAPA did not occur with DAPA + ExQW coadministration. Bodyweight loss with DAPA + ExQW was associated with the SNP variant rs10010131 A allele, lower baseline adiposity (BMI), and lower baseline insulin secretion (IGI). These findings require further validation. FUNDING: AstraZeneca.

Which polyunsaturated fatty acids are active in children with attention-deficit hyperactivity disorder receiving PUFA supplementation? A fatty acid validated meta-regression analysis of randomized controlled trials.

Concerns about growth retardation and unknown effects on long-term brain development with stimulants have prompted interest in polyunsaturated fatty acid supplementation (PUFA) as an alternative treatment. However, randomized controlled trials (RCTs) and meta-analyses of PUFA supplementation in ADHD have shown marginal benefit, and uncertainty exists as to which, if any, PUFA might be effective in alleviating symptoms of ADHD. We conducted an updated meta-analysis of RCTs in ADHD together with multivariable meta-regression analyses using data on PUFA content obtained from independent fatty acid methyl ester analyses of each study PUFA regimen. The PubMed, Embase and PsycINFO databases were searched with no start date and up to 28th July 2013. Study inclusion criteria were: randomized design, placebo controlled, PUFA preparation as active intervention, reporting change scores on ADHD rating-scale measures. Rating-scale measures of inattention and hyperactive-impulsive symptoms were extracted, study authors were contacted to obtain missing data, studies not reporting negative findings had these data imputed, and study quality was assessed using the Jadad system plus other indicators. Random-effects models were used for pooled effects and for meta-regression analyses. Standardized mean differences (SMD) in inattention, hyperactive-impulsive and combined symptoms were assessed as rated by parents, teachers or all raters. The influence of study characteristics and PUFA regimen content was explored in multivariable meta-regression analyses. The overall pooled estimate from 18 studies showed that combined ADHD symptoms rated by all raters decreased with PUFA supplementation; SMD -0.192 (95% CI: -0.297, -0.086; P<0.001). However, when analyzed by rater, only parent-rated symptoms decreased significantly. Multivariable meta-regression showed that longer study duration, γ-linolenic acid (GLA), and the interaction between GLA and eicosapentaenoic acid (EPA) were associated with significant decreases in inattention; however, PUFA regimen content was unrelated to changes in hyperactive-impulsive symptoms. Certain fatty acids present in placebo preparations may potentially have been psychoactive. This meta-analysis provides modest evidence of PUFA effectiveness in ADHD, especially GLA and EPA for inattention symptoms; however, evidence of reporting bias, publication bias, variable methodological quality, and use of potentially psychoactive placebos limit the generalizability of these findings.