Hypokalaemia in patients with type 2 diabetes and chronic kidney disease: the effect of finerenone - a FIDELITY analysis.

AIMS: Hypokalaemia is associated with cardiovascular events and mortality in patients with chronic kidney disease (CKD). This exploratory FIDELITY analysis, a prespecified pooled patient-dataset from FIDELIO-DKD and FIGARO-DKD, investigated the incidence and effect of hypokalaemia in patients with CKD and type 2 diabetes (T2D) treated with finerenone vs. placebo. METHODS: Outcomes include the incidence of treatment-emergent hypokalaemia (serum potassium < 4.0 or < 3.5 mmol/L) and the effect of finerenone on cardiovascular composite outcome (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for heart failure) and arrhythmia composite outcome (new diagnosis of atrial fibrillation/atrial flutter, hospitalization due to arrhythmia, or sudden cardiac death) by baseline serum potassium subgroups. RESULTS: In the FIDELITY population, treatment-emergent hypokalaemia with serum potassium < 4.0 and < 3.5 mmol/L occurred in 41.1% and 7.5%, respectively. Hazards of cardiovascular and arrhythmia composite outcomes were higher in patients with baseline serum potassium < 4.0 vs. 4.0-4.5 mmol/L (hazard ratio [HR] 1.16; 95% confidence interval [CI] 1.02-1.32, P = 0.022 and HR 1.20; 95% CI 1.00-1.44, P = 0.055, respectively). Finerenone reduced the incidence of hypokalaemia with serum potassium < 4.0 mmol/L (HR 0.63; 95% CI 0.60-0.66) and < 3.5 mmol/L (HR 0.46; 95% CI 0.40-0.53) vs. placebo. Finerenone lessened the hazard of cardiovascular and arrhythmia events vs. placebo, irrespective of baseline serum potassium. CONCLUSION: A substantial proportion of patients with CKD and T2D experienced hypokalaemia, which was associated with an increased hazard of adverse cardiovascular outcomes. Finerenone reduced the incidence of hypokalaemia. Finerenone reduced the hazard of cardiovascular and arrhythmia outcomes irrespective of serum potassium subgroups. Clinical trials registration: FIDELIO-DKD and FIGARO-DKD are registered with ClinicalTrials.gov, numbers NCT02540993 and NCT02545049, respectively (funded by Bayer AG).

The potential of preregistration in psychology: Assessing preregistration producibility and preregistration-study consistency.

Study preregistration has become increasingly popular in psychology, but its potential to restrict researcher degrees of freedom has not yet been empirically verified. We used an extensive protocol to assess the producibility (i.e., the degree to which a study can be properly conducted based on the available information) of preregistrations and the consistency between preregistrations and their corresponding papers for 300 psychology studies. We found that preregistrations often lack methodological details and that undisclosed deviations from preregistered plans are frequent. These results highlight that biases due to researcher degrees of freedom remain possible in many preregistered studies. More comprehensive registration templates typically yielded more producible preregistrations. We did not find that the producibility and consistency of preregistrations differed over time or between original and replication studies. Furthermore, we found that operationalizations of variables were generally preregistered more producible and consistently than other study parts. Inconsistencies between preregistrations and published studies were mainly encountered for data collection procedures, statistical models, and exclusion criteria. Our results indicate that, to unlock the full potential of preregistration, researchers in psychology should aim to write more producible preregistrations, adhere to these preregistrations more faithfully, and more transparently report any deviations from their preregistrations. This could be facilitated by training and education to improve preregistration skills, as well as the development of more comprehensive templates. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Pharmacological effects of small molecule BCR-ABL tyrosine kinase inhibitors on platelet function.

Tyrosine kinase inhibitors (TKIs) targeting the BCR-ABL fusion protein, such as imatinib (Gleevec), have revolutionized targeted cancer therapies. However, drug resistance and side effects, particularly those affecting hemostasis, continue to pose significant challenges for TKI therapies. As tyrosine kinases serve pivotal roles in platelet hemostatic function, we investigated the potential impact of both established and emerging ABL TKIs on human platelet activities ex vivo Our study included standard-of-care agents (e.g., imatinib and nilotinib), and second-generation ABL inhibitors including ponatinib and bosutinib designed to mitigate drug resistance. Additionally, we explored the effects of allosteric inhibitors targeting the myristoyl pocket of ABL (e.g., asciminib and GNF-2), and novel agents in preclinical development, including ELVN-919, which uniquely exhibits high specificity for the ABL kinase active site. Our findings reveal that while ABL inhibitors such as ponatinib and bosutinib impede platelet activity, highly specific new-generation ABL inhibitors, including first-in-class therapeutics, do not impact platelet function ex vivo Overall, these new insights around the effects of ABL TKIs on platelet function could inform the development of targeted therapies with reduced hematologic toxicities. Significance Statement This study examines the effects of clinically relevant small molecule BCR-ABL tyrosine kinase inhibitors (TKIs) on platelet activity. This analysis includes first-time assessments of agents such as asciminib and ELVN-919 on human platelet function ex vivo, alongside established therapies (e.g., imatinib, ponatinib) with well-characterized effects on platelet function, to discern potential anti-platelet and other effects of BCR-ABL TKIs and inform clinical safety.

Heart failure in Europe: Guideline-directed medical therapy use and decision making in chronic and acute, pre-existing and de novo, heart failure with reduced, mildly reduced, and preserved ejection fraction - the ESC EORP Heart Failure III Registry.

AIMS: We analysed baseline characteristics and guideline-directed medical therapy (GDMT) use and decisions in the European Society of Cardiology (ESC) Heart Failure (HF) III Registry. METHODS AND RESULTS: Between 1 November 2018 and 31 December 2020, 10 162 patients with acute HF (AHF, 39%, age 70 [62-79], 36% women) or outpatient visit for HF (61%, age 66 [58-75], 33% women), with HF with reduced (HFrEF, 57%), mildly reduced (HFmrEF, 17%) or preserved (HFpEF, 26%) ejection fraction were enrolled from 220 centres in 41 European or ESC-affiliated countries. With AHF, 97% were hospitalized, 2.2% received intravenous treatment in the emergency department, and 0.9% received intravenous treatment in an outpatient clinic. AHF was seen by most by a general cardiologist (51%) and outpatient HF most by a HF specialist (48%). A majority had been hospitalized for HF before, but 26% of AHF and 6.1% of outpatient HF had de novo HF. Baseline use, initiation and discontinuation of GDMT varied according to AHF versus outpatient HF, de novo versus pre-existing HF, and by ejection fraction. After the AHF event or outpatient HF visit, use of any renin-angiotensin system inhibitor, angiotensin receptor-neprilysin inhibitor, beta-blocker, mineralocorticoid receptor antagonist and loop diuretics was 89%, 29%, 92%, 78%, and 85% in HFrEF; 89%, 9.7%, 90%, 64%, and 81% in HFmrEF; and 77%, 3.1%, 80%, 48%, and 80% in HFpEF. CONCLUSION: Use and initiation of GDMT was high in cardiology centres in Europe, compared to previous reports from cohorts and registries including more primary care and general medicine and regions more local or outside of Europe and ESC-affiliated countries.

Toward Expanded Access to Cancer Care With Cost Awareness: An Optimization Modeling Analysis of Rwanda.

PURPOSE: Cancers are a growing cause of mortality especially in low- and middle-income countries in Africa. Rwanda is no exception. Two cancer centers currently provide care to the public, but there are both political and human interest in expanding access to tertiary cancer care. Improved geographic access could lead to both better patient outcomes and a better understanding of the existing cancer burden across Rwanda. METHODS: To identify cost-aware ways of expanding geographic access, we adopt an optimization approach and identify expansion plans that minimize the average travel time to a cancer center across the country while remaining under a given monetary budget. RESULTS: Three additional hospitals could reduce average travel times by 40%, with the largest decrease in travel times observed in populations with long travel times. However, such an expansion would require a 50% increase in the number of in-country oncologists. We find that oncologist scarcity, as opposed to monetary constraints, is likely to be a limiting factor for improved access to cancer care. CONCLUSION: We present an array of expansion plans and suggest that further modeling approaches that incorporate oncologist scarcity can help deliver better policy recommendations.

Competing Risks in Clinical Trials: Do They Matter and How Should We Account for Them?

During patient follow-up in a randomized trial, some deaths may occur. Where death (or noncardiovascular death) is not part of an outcome of interest it is termed a competing risk. Conventional analyses (eg, Cox proportional hazards model) handle death similarly to other censored follow-up. Patients still alive are unrealistically assumed to be representative of those who died. The Fine and Gray model has been used to handle competing risks, but is often used inappropriately and can be misleading. We propose an alternative multiple imputation approach that plausibly accounts for the fact that patients who die tend also to be at high risk for the (unobserved) outcome of interest. This provides a logical framework for exploring the impact of a competing risk, recognizing that there is no unique solution. We illustrate these issues in 3 cardiovascular trials and in simulation studies. We conclude with practical recommendations for handling competing risks in future trials.

The Interplay of Chronic Hepatitis C and COVID-19: Implications for Prognosis and Treatment.

Introduction Chronic hepatitis C (CHC) remains a significant public health concern due to both hepatic and extrahepatic manifestations associated with substantial morbidity and mortality. The emergence of SARS-CoV-2 has raised concerns about the outcomes of COVID-19 in CHC patients. Method We conducted a retrospective analysis of patients with CHC and SARS-CoV-2 infection admitted to a tertiary care hospital between 2020 and 2023. We performed a global analysis of the entire batch of patients and, later, we evaluated the patients according to the severity of the SARS-CoV-2 infection Results The cohort included 89 patients (63 females, 26 males) with a median age of 65 years. Most patients were hospitalized in 2021. Common clinical manifestations included fever, cough, digestive symptoms, and headache. The most frequent comorbidities were renal disease, thyroid disorders, and cancer. Univariate logistic regression analysis identified older age, hospitalization in 2021, and respiratory failure as risk factors for severe COVID-19. Elevated lactate dehydrogenase levels were also associated with an increased risk of severe COVID-19. Regarding CHC, detectable hepatitis C virus viremia was associated with more severe liver disease (p<0.01). Conclusion Patients with CHC and SARS-CoV-2 infection have a substantial risk of severe outcomes. Early identification and management of these patients are crucial to improve their prognosis.

Interatrial Shunt Treatment for Heart Failure: The Randomized RELIEVE-HF Trial.

BACKGROUND: An interatrial shunt may provide an autoregulatory mechanism to decrease left atrial pressure and improve heart failure (HF) symptoms and prognosis. METHODS: Patients with symptomatic HF with any left ventricular ejection fraction (LVEF) were randomized 1:1 to transcatheter shunt implantation versus a placebo procedure, stratified by reduced (≤40%) versus preserved (>40%) LVEF. The primary safety outcome was a composite of device-related or procedure-related major adverse cardiovascular or neurological events at 30 days compared with a prespecified performance goal of 11%. The primary effectiveness outcome was the hierarchical composite ranking of all-cause death, cardiac transplantation or left ventricular assist device implantation, HF hospitalization, outpatient worsening HF events, and change in quality of life from baseline measured by the Kansas City Cardiomyopathy Questionnaire overall summary score through maximum 2-year follow-up, assessed when the last enrolled patient reached 1-year follow-up, expressed as the win ratio. Prespecified hypothesis-generating analyses were performed on patients with reduced and preserved LVEF. RESULTS: Between October 24, 2018, and October 19, 2022, 508 patients were randomized at 94 sites in 11 countries to interatrial shunt treatment (n=250) or a placebo procedure (n=258). Median (25th and 75th percentiles) age was 73.0 years (66.0, 79.0), and 189 patients (37.2%) were women. Median LVEF was reduced (≤40%) in 206 patients (40.6%) and preserved (>40%) in 302 patients (59.4%). No primary safety events occurred after shunt implantation (upper 97.5% confidence limit, 1.5%; P<0.0001). There was no difference in the 2-year primary effectiveness outcome between the shunt and placebo procedure groups (win ratio, 0.86 [95% CI, 0.61-1.22]; P=0.20). However, patients with reduced LVEF had fewer adverse cardiovascular events with shunt treatment versus placebo (annualized rate 49.0% versus 88.6%; relative risk, 0.55 [95% CI, 0.42-0.73]; P<0.0001), whereas patients with preserved LVEF had more cardiovascular events with shunt treatment (annualized rate 60.2% versus 35.9%; relative risk, 1.68 [95% CI, 1.29-2.19]; P=0.0001; Pinteraction<0.0001). There were no between-group differences in change in Kansas City Cardiomyopathy Questionnaire overall summary score during follow-up in all patients or in those with reduced or preserved LVEF. CONCLUSIONS: Transcatheter interatrial shunt implantation was safe but did not improve outcomes in patients with HF. However, the results from a prespecified exploratory analysis in stratified randomized groups suggest that shunt implantation is beneficial in patients with reduced LVEF and harmful in patients with preserved LVEF. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03499236.

Reaffirmation of Mechanistic Proteomic Signatures Accompanying SGLT2 Inhibition in Patients With Heart Failure: A Validation Cohort of the EMPEROR Program.

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors exert a distinctive pattern of direct biological effects on the heart and kidney under experimental conditions, but the meaningfulness of these signatures for patients with heart failure has not been fully defined. OBJECTIVES: We performed the first mechanistic validation study of large-scale proteomics in a double-blind randomized trial of any treatment in patients with heart failure. METHODS: In a discovery cohort from the EMPEROR (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure and Reduced Ejection Fraction) program, we studied the effect of randomized treatment with placebo or empagliflozin on 1,283 circulating proteins in 1,134 patients with heart failure with a reduced or preserved ejection fraction. In a validation cohort, we expanded the number to 2,155 assessed proteins, which were measured in 1,120 EMPEROR participants who had not been studied previously. RESULTS: In the validation cohort, 25 proteins were the most differentially enriched by empagliflozin (ie, ≥15% between-group difference and false discovery rate <1% at 12 weeks with known effects on the heart or kidney): 1) 13 proteins promote autophagy and other cellular quality-control functions (IGFBP1, OTUB1, DNAJB1, DNAJC9, RBP2, IST1, HSPA8, H-FABP, FABP6, ATPIFI, TfR1, EPO, IGBP1); 2) 12 proteins enhance mitochondrial health and ATP production (UMtCK, TBCA, L-FABP, H-FABP, FABP5, FABP6, RBP2, IST1, HSPA8, ATPIFI, TfR1, EPO); 3) 7 proteins augment cellular iron mobilization or erythropoiesis (TfR1, EPO, IGBP1, ERMAP, UROD, ATPIF1, SNCA); 4) 3 proteins influence renal tubular sodium handling; and 5) 9 proteins have restorative effects in the heart or kidneys, with many proteins exerting effects in >1 domain. These biological signatures replicated those observed in our discovery cohort. When the threshold for a meaningful between-group difference was lowered to ≥10%, there were 58 additional differentially enriched proteins with actions on the heart and kidney, but the biological signatures remained the same. CONCLUSIONS: The replication of mechanistic signatures across discovery and validation cohorts closely aligns with the experimental effects of SGLT2 inhibitors. Thus, the actions of SGLT2 inhibitors-to promote autophagy, restore mitochondrial health and production of ATP, promote iron mobilization and erythropoiesis, influence renal tubular ion reabsorption, and normalize cardiac and renal structure and function-are likely to be relevant to patients with heart failure. (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Preserved Ejection Fraction [EMPEROR-Preserved], NCT03057951; EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction [EMPEROR-Reduced], NCT03057977).

Finerenone and left ventricular hypertrophy in chronic kidney disease and type 2 diabetes.

AIMS: Left ventricular hypertrophy (LVH) has been associated with an increased risk of cardiovascular (CV) disease and linked to increased morbidity and mortality. In patients with chronic kidney disease (CKD) and type 2 diabetes (T2D), hypertension is common, and patients with these co-morbidities additionally have a high prevalence of LVH. This analysis of the prespecified pooled FIDELITY analysis comprising the randomized, double-blind, placebo-controlled, multicentre FIDELIO-DKD and FIGARO-DKD phase III studies aimed to explore the CV and kidney effects of finerenone, a nonsteroidal mineralocorticoid receptor antagonist, in patients with CKD and T2D stratified by a diagnosis of LVH at baseline. METHODS AND RESULTS: A diagnosis of LVH in the FIDELITY patient population was determined at baseline using investigator-reported electrocardiogram (ECG) findings. The two efficacy outcomes, assessed by baseline LVH, were the composite CV outcome of time to CV death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for heart failure (HHF), and a composite kidney outcome of time to onset of kidney failure, a sustained decrease in estimated glomerular filtration rate (eGFR) ≥57% from baseline over ≥4 weeks, or kidney-related death. Safety outcomes by baseline LVH were reported as treatment-emergent adverse events. At baseline out of 13 026 patients in FIDELITY, 96.5% had hypertension and 9.6% had investigator-reported LVH. The relative risk reduction for the composite CV and kidney outcomes with finerenone versus placebo was lower in the LVH subgroup; however, the treatment effect of finerenone was not modified by baseline LVH for either outcome (Pinteraction = 0.1075 for composite CV outcome and Pinteraction = 0.1782 for composite kidney outcome). Analysis of the composite CV outcome components showed a greater reduction in the risk of HHF versus placebo for patients with baseline LVH compared with those without (Pinteraction = 0.0024). Overall safety events were comparable between the LVH subgroups and treatment arms. Treatment-emergent hyperkalaemia was observed more frequently with finerenone versus placebo, but discontinuation rates were low in both treatment arms and between LVH subgroups. CONCLUSIONS: In conclusion, the overall CV and kidney benefits of finerenone versus placebo were not modified by the presence of LVH at baseline, with overall safety findings being similar between LVH subgroups. A greater benefit was observed for HHF in patients with versus without LVH, suggesting that LVH may be a predictor of the treatment effect of finerenone on HHF.

Patiromer Facilitates Angiotensin Inhibitor and Mineralocorticoid Antagonist Therapies in Patients With Heart Failure and Hyperkalemia.

BACKGROUND: Hyperkalemia (HK) is associated with suboptimal renin-angiotensin system (RAS) inhibitor and mineralocorticoid receptor antagonist (MRA) use in heart failure with reduced ejection fraction (HFrEF). OBJECTIVES: This study sought to assess characteristics and RAS inhibitor/MRA use in patients receiving patiromer during the DIAMOND (Patiromer for the Management of Hyperkalemia in Subjects Receiving RAASi Medications for the Treatment of Heart Failure) run-in phase. METHODS: Patients with HFrEF and HK or past HK entered a run-in phase of ≤12 weeks with patiromer-facilitated RAS inhibitor/MRA optimization to achieve ≥50% recommended RAS inhibitor dose, 50 mg/d MRA, and normokalemia. Patients achieving these criteria (randomized group) were compared with the run-in failure group (patients not meeting the randomization criteria). RESULTS: Of 1,038 patients completing the run-in, 878 (84.6%) were randomized and 160 (15.4%) were run-in failures. Overall, 422 (40.7%) had HK entering run-in with a similar frequency in the randomized and run-in failure groups (40.3% vs 42.5%; P = 0.605). From start to the end of run-in, in the randomized group, an increase was observed in target RAS inhibitor and MRA use in patients with HK (RAS inhibitor: 76.8% to 98.6%; MRA: 35.9% to 98.6%) and past HK (RAS inhibitor: 60.5% to 98.1%; MRA: 15.6% to 98.7%). Despite not meeting the randomization criteria, an increase after run-in was observed in the run-in failure group in target RAS inhibitor (52.5% to 70.6%) and MRA use (15.0% to 48.1%). This increase was observed in patients with HK (RAS inhibitor: 51.5% to 64.7%; MRA: 19.1% to 39.7%) and past HK (RAS inhibitor: 53.3% to 75.0%; MRA: 12.0% to 54.3%). CONCLUSIONS: In patients with HFrEF and HK or past HK receiving suboptimal RAS inhibitor/MRA therapy, RAS inhibitor/MRA optimization increased during patiromer-facilitated run-in.

The rate of ileostomy site incisional hernias: more common than we think?

PURPOSE: Incisional hernias (IH) rates after diverting loop ileostomy reversal (DLI-R) have been reported up to 24%. We aimed to characterize the incidence rate and risk factors associated with DLI-R site IH formation within 1-year in a large patient cohort. METHODS: A retrospective review at a single quaternary referral center hospital of adult patients who underwent DLI-R over a 5-year period and abdominal computerized tomography (CT) imaging performed within 1-year for any indication postoperatively was conducted. All CTs scans were independently reviewed by staff surgeons to determine the presence of a fascial defect at the DLI-R site. RESULTS: 2,196 patients underwent DLI-R; of these, 569 (25.9%) underwent CT imaging for any indication. Mean patient age, 54.8 (± 14.9), BMI 27.6 kg/m2. 87 (15%) patients had a parastomal hernia at time of DLI-R. After median follow-up of 10 months, 203 patients (35.7%) had IH at the DLI-R site. Age (p = 0.14), sex (p = 0.39), race (p = 0.75), and smoking status (p = 0.82) weren't associated with IH after DLI-R. Comorbidities weren't significantly associated with IH following DLI-R. In univariate analysis, increased BMI (p < 0.001), presence of a parastomal hernia (p = 0.008), and suture type (p = 0.01) were associated with IH development. On multivariate analysis, BMI remained significant, and polyglyconate compared to polydioxanone suture were associated with higher rates of IH (p < 0.001). CONCLUSION: We observed that the rate of incisional hernias within 1-year of diverting ileostomy reversal was indeed common at 36%. Granted, a high percentage of the population was excluded due to heterogeneity in radiographic evaluation that could be mitigated in future prospective studies. Our study suggests that IH preventative strategies include weight loss for overweight and obese patients prior to DLI-R and that the optimal suture for DLI-R is polydioxanone.

Single-stapled colorectal anastomotic techniques: Do not cross the line.

The double-stapled technique is the most common method of colorectal anastomosis. Despite its widespread use, emerging data suggests that this technique may be a risk factor for anastomotic complications, as it is believed that crossing staple lines and resultant dog-ears are potentially weak points that are prone to ischemia and anastomotic leak. Herein, we describe technical variations of single-stapled colorectal anastomoses which surgeons can readily adopt and integrate into their armamentarium of anastomotic techniques.

PrEP discontinuation, cycling, and risk: Understanding the dynamic nature of PrEP use among female sex workers in South Africa.

PrEP cycling among women is thought to be safe when there are distinct "seasons of risk." However, cyclical PrEP use over short periods may be associated with increased risk of HIV acquisition. We aimed to characterize key social ecological factors contributing toward PrEP cycling among female sex workers (FSW) in the context of high HIV risk. Semi-structured, in-depth interviews were conducted with 36 FSW at risk for HIV acquisition and 12 key informant (KI) service providers in eThekwini (Durban), South Africa from January-October 2020. FSW identified key factors driving temporary discontinuation of PrEP including relocation, lack of information on or difficulty coping with side effects, and delays in accessing PrEP. In many cases, FSW were motivated to restart PrEP once barriers were overcome. In contrast, KIs emphasized the importance of individual adherence to PrEP and reliance on personal risk assessments when counselling FSW on cycling decisions. FSW and KI perspectives highlight a disconnect between providers' recommendations on the potential for cyclical use of PrEP during periods of minimal risk and actual drivers among FSW causing temporary PrEP discontinuation. Further interventions supporting safe PrEP cycling are needed to ensure decisions around cycling are deliberate and guided by changes in HIV risk rather than external factors.

Patiromer for Heart Failure Medication Optimization in Patients With Current or Past Hyperkalemia: DIAMOND Subanalysis.

BACKGROUND: For heart failure with reduced ejection fraction (HFrEF), suboptimal use of renin-angiotensin-aldosterone system inhibitors (RAASis), including mineralocorticoid receptor antagonists (MRAs), due to hyperkalemia, may be improved by potassium binders. OBJECTIVES: This prespecified analysis of the phase 3 DIAMOND (Patiromer for the Management of Hyperkalemia in Subjects Receiving RAASi Medications for the Treatment of Heart Failure) trial assessed the effect of patiromer in patients with HFrEF and either current or past hyperkalemia. METHODS: Patients with HFrEF and current or past (within 1 year before enrollment) hyperkalemia (serum potassium [sK+] >5.0 mmol/L) entered a single-blind, run-in phase to optimize RAASis while receiving patiromer. They were subsequently randomized, double-blind, to continue patiromer or change to placebo. RESULTS: Of the 1,038 patients who completed run-in, 354 (83.9%) of 422 with current hyperkalemia and 524 (85.1%) of 616 with past hyperkalemia achieved RAASi optimization and were randomized to treatment. During the double-blind phase, patiromer lowered sK+ levels compared with placebo in both the current and past hyperkalemia subgroups: difference in adjusted mean change from baseline: -0.12 (95% CI: -0.17 to -0.07) and -0.08 (95% CI: -0.12 to -0.05), respectively; Pinteraction = 0.166. Patiromer was more effective than placebo in maintaining MRA at target dose in patients with current vs past hyperkalemia (HR: 0.45 [95% CI: 0.26-0.76] vs HR: 0.85 [95% CI: 0.54-1.32]; Pinteraction = 0.031). Adverse events were similar between subgroups. CONCLUSIONS: The use of patiromer facilitates achieving target doses of RAASis in patients with HFrEF with either current or past hyperkalemia. For those with current hyperkalemia before RAASi optimization, use of patiromer may be more beneficial in helping to maintain sK+ control and achieve MRA target dose. (Patiromer for the Management of Hyperkalemia in Subjects Receiving RAASi Medications for the Treatment of Heart Failure [DIAMOND]; NCT03888066).

Taxonomic variation, plastic degradation, and antibiotic resistance traits of plastisphere communities in the maturation pond of a wastewater treatment plant.

Wastewater treatment facilities can filter out some plastics before they reach the open environment, yet microplastics often persist throughout these systems. As they age, microplastics in wastewater may both leach and sorb pollutants and fragment to provide an increased surface area for bacterial attachment and conjugation, possibly impacting antimicrobial resistance (AMR) traits. Despite this, little is known about the effects of persistent plastic pollution on microbial functioning. To address this knowledge gap, we deployed five different artificially weathered plastic types and a glass control into the final maturation pond of a municipal wastewater treatment plant in Otautahi-Christchurch, Aotearoa/New Zealand. We sampled the plastic-associated biofilms (plastisphere) at 2, 6, 26, and 52 weeks, along with the ambient pond water, at three different depths (20, 40, and 60 cm from the pond water surface). We investigated the changes in plastisphere microbial diversity and functional potential through metagenomic sequencing. Bacterial 16S ribosomal RNA genes composition did not vary among plastic types and glass controls (P = 0.997) but varied among sampling times [permutational multivariate analysis of variance (PERMANOVA), P = 0.001] and depths (PERMANOVA, P = 0.011). Overall, there was no polymer-substrate specificity evident in the total composition of genes (PERMANOVA, P = 0.67), but sampling time (PERMANOVA, P = 0.002) and depth were significant factors (PERMANOVA, P = 0.001). The plastisphere housed diverse AMR gene families, potentially influenced by biofilm-meditated conjugation. The plastisphere also harbored an increased abundance of genes associated with the biodegradation of nylon, or nylon-associated substances, including nylon oligomer-degrading enzymes and hydrolases.IMPORTANCEPlastic pollution is pervasive and ubiquitous. Occurrences of plastics causing entanglement or ingestion, the leaching of toxic additives and persistent organic pollutants from environmental plastics, and their consequences for marine macrofauna are widely reported. However, little is known about the effects of persistent plastic pollution on microbial functioning. Shotgun metagenomics sequencing provides us with the necessary tools to examine broad-scale community functioning to further investigate how plastics influence microbial communities. This study provides insight into the functional consequence of continued exposure to waste plastic by comparing the prokaryotic functional potential of biofilms on five types of plastic [linear low-density polyethylene (LLDPE), nylon-6, polyethylene terephthalate, polylactic acid, and oxygen-degradable LLDPE], glass, and ambient pond water over 12 months and at different depths (20, 40, and 60 cm) within a tertiary maturation pond of a municipal wastewater treatment plant.

Sexual behavior stigma and HIV/STI biospecimen self-collection among cisgender gay, bisexual, and other sexually minoritized men in the United States.

INTRODUCTION: Disparities in HIV and other sexually transmitted infections (STIs) persist among cisgender sexually minoritized men in the United States, driven in part by sexual behavior stigma, which is a barrier to clinic-based HIV/STI testing. HIV/STI biospecimen self-collection (HSBS) is a novel testing approach that mitigates stigma by allowing for some testing-related procedures to be conducted by oneself in one's home or any private location rather than a facility that requires interpersonal interactions and exposure to other members of the public. HSBS has demonstrated acceptability, feasibility, and effectiveness in testing uptake, but the extent to which stigma persists in HSBS and the quantification of stigma's role in HSBS is limited. METHODS: From 2019-2020, a nationwide sample of sexually minoritized men completed an online biobehavioral survey. Those who agreed to be recontacted (N = 4147) were invited to participate in HSBS; consented participants received self-collection kits that were laboratory-tested if completed. Sexual behavior stigma and HSBS associations were assessed with logistic regression. RESULTS: Mean age of participants was 35 years, 58% (2421/4147) were non-Hispanic white, 82% (3391/4147) were gay-identifying, 47% (1967/4147) had at least a college degree, and 56% (2342/4147) earned ≥ $40,000 annually; 27% (1112/4147) expressed HSBS interest, and 67% (689/1034) completed HSBS. HSBS interest and completion were less common among non-Hispanic Black sexually minoritized men and sexually minoritized men of lower socioeconomic status. Stigma from family and friends was significantly, negatively associated with HSBS interest (aOR = 0.72, 95% CI = 0.56, 0.93). Among those who had not tested for HIV/STIs in the past year, anticipated healthcare stigma was marginally, negatively associated with HSBS completion (aOR = 0.40, 95% CI = 0.15, 1.07). Among those who had never previously tested for HIV/STIs, anticipated healthcare stigma was significantly, negatively associated with HSBS interest (aOR = 0.32, 95% CI = 0.14, 0.72). CONCLUSIONS: Sexual behavior stigma persists as an HIV/STI testing barrier, even in the case of HSBS, limiting its utilization. Increasing HSBS among sexually minoritized men in the US necessitates stigma mitigation efforts that directly address equity in implementation.

Finerenone in heart failure and chronic kidney disease with type 2 diabetes: FINE-HEART pooled analysis of cardiovascular, kidney and mortality outcomes.

Cardiovascular-kidney-metabolic syndrome is an emerging entity that connects cardiovascular diseases, chronic kidney disease and diabetes. The non-steroidal mineralocorticoid receptor antagonist finerenone has been studied in three prospective randomized clinical trials of patients with cardiovascular-kidney-metabolic syndrome: FIDELIO-DKD, FIGARO-DKD and FINEARTS-HF. In light of the strong epidemiological overlap and shared mechanistic drivers of clinical outcomes across cardiovascular-kidney-metabolic syndrome, we summarize the efficacy and safety of finerenone on cardiovascular, kidney and mortality outcomes in this pre-specified participant-level pooled analysis. The three trials included 18,991 participants (mean age 67 ± 10 years; 35% women). During 2.9 years of median follow-up, the primary outcome of cardiovascular death occurred in 421 (4.4%) participants assigned to finerenone and 471 (5.0%) participants assigned to placebo (hazard ratio (HR): 0.89; 95% confidence interval (CI): 0.78-1.01; P = 0.076). Death from any cause occurred in 1,042 (11.0%) participants in the finerenone arm and in 1,136 (12.0%) participants in the placebo arm (HR: 0.91; 95% CI: 0.84-0.99; P = 0.027). Finerenone further reduced the risk of hospitalization from heart failure (HR: 0.83; 95% CI: 0.75-0.92; P < 0.001) and the composite kidney outcome (HR: 0.80; 95% CI: 0.72-0.90; P < 0.001). While in this pooled analysis the reduction in cardiovascular death was not statistically significant, finerenone reduced the risks for deaths of any cause, cardiovascular events and kidney outcomes. PROSPERO identifier: CRD42024570467 .

Cardiovascular and Renal Treatment in Heart Failure Patients With Hyperkalemia or High Risk of Hyperkalemia: Rationale and Design of the CARE-HK in HF Registry.

BACKGROUND: Despite guideline recommendations, many patients with heart failure (HF) do not receive target dosages of renin-angiotensin-aldosterone system inhibitors (RAASis) in clinical practice due, in part, to concerns about hyperkalemia (HK). METHODS AND RESULTS: This noninterventional, multinational, multicenter registry (NCT04864795; 111 sites in Europe and the USA) enrolled 2558 eligible adults with chronic HF (mostly with reduced ejection fraction [HFrEF]). Eligibility criteria included use of angiotensin-converting-enzyme inhibitor/angiotensin-II receptor blocker/angiotensin-receptor-neprilysin inhibitor, being a candidate for or treatment with a mineralocorticoid receptor antagonist, and increased risk of HK (eg, current serum potassium > 5.0 mmol/L), history of HK in the previous 24 months, or estimated glomerular filtration rate < 45 mL/min/1.73 m2). Information on RAASi and other guideline-recommended therapies was collected retrospectively and prospectively (≥ 6 months). Patients were followed according to local clinical practice, without study-specific visits or interventions. The main objectives were to characterize RAASi treatment patterns compared with guideline recommendations, describe RAASi modifications following episodes of HK, and describe RAASi treatment in patients treated with patiromer. Baseline characteristics for the first 1000 patients are presented. CONCLUSIONS: CARE-HK is a multinational prospective HF registry designed to report on the management and outcomes of patients with HF at high risk for HK in routine clinical practice.