Bayesian transition models for ordinal longitudinal outcomes.

Ordinal longitudinal outcomes are becoming common in clinical research, particularly in the context of COVID-19 clinical trials. These outcomes are information-rich and can increase the statistical efficiency of a study when analyzed in a principled manner. We present Bayesian ordinal transition models as a flexible modeling framework to analyze ordinal longitudinal outcomes. We develop the theory from first principles and provide an application using data from the Adaptive COVID-19 Treatment Trial (ACTT-1) with code examples in R. We advocate that researchers use ordinal transition models to analyze ordinal longitudinal outcomes when appropriate alongside standard methods such as time-to-event modeling.

Development of a set of measurable outcome indicators for Flemish patients with inflammatory bowel disease.

OBJECTIVE: Uniform and standardised quality measurement allows care assessment and improvement. Following a pragmatic consensus method we aimed to agree on a selection of measurable quality indicators that can be used to assess, benchmark and gradually improve inflammatory bowel disease (IBD) care in Flanders. METHODS: Of 49 structures, 135 processes and 37 outcome indicators identified through literature, 58 were preselected and reformulated into measurable outcome indicators by four IBD physicians. A larger expert group scored the 58 indicators on a 10-point importance scale twice, endorsed by patient and expert perspectives in between rounds. Additional items could be suggested. A final selection and subset of indicators with room for improvement were agreed upon during a consensus meeting. RESULTS: Fifty indicators received an importance score of 7 or higher by ≥80% of the participants (seven IBD nurses, one abdominal surgeon, one chief medical officer and 31 IBD physicians including two paediatricians). Eight indicators scored highly important by 60-80%, two indicators reintroduced by patients and one newly suggested, were discussed during the consensus meeting. Among 26 participants, eight indicators were agreed to be added to the final selection. Of the 58 selected items, 19 were retained in the improvement subset, related to patient-reported outcomes, use of hospital services and survival, patient characteristics, monitoring of disease activity and remission, endoscopy guidelines, infection prevention, steroid and other medication use. CONCLUSION: Fifty-eight indicators were selected to assess IBD care in Flanders and a subset of 19 for use in clinical practice to steer quality improvement initiatives.

Defluorination of monofluorinated alkane by Rhodococcus sp. NJF-7 isolated from soil.

Microbial degradation of fluorinated compounds raised significant attention because of their widespread distribution and potential environmental impacts. Here, we report a bacterial isolate, Rhodococcus sp. NJF-7 capable of defluorinating monofluorinated medium-chain length alkanes. This isolate consumed 2.29 ± 0.13 mmol L- 1 of 1-fluorodecane (FD) during a 52 h incubation period, resulting in a significant release of inorganic fluoride amounting to 2.16 ± 0.03 mmol L- 1. The defluorination process was strongly affected by the initial FD concentration and pH conditions, with lower pH increasing fluoride toxicity to bacterial cells and inhibiting enzymatic defluorination activity. Stoichiometric conversion of FD to fluoride was observed at neutral pH with resting cells, while defluorination was significantly lower at reduced pH (6.5). The discovery of the metabolites decanoic acid and methyl decanoate suggests that the initial attack by monooxygenases may be responsible for the biological defluorination of FD. The findings here provide new insights into microbial defluorination processes, specifically aiding in understanding the environmental fate of organic semi-fluorinated alkane chemicals.

N-of-1 Trial of Angina Verification Before Percutaneous Coronary Intervention.

BACKGROUND: In stable coronary artery disease, 30% to 60% of patients remain symptomatic despite successful revascularization. Perhaps not all symptoms reported by a patient with myocardial ischemia are, in fact, angina. OBJECTIVES: This study sought to determine whether independent symptom verification using a placebo-controlled ischemic stimulus could distinguish which patients achieve greatest symptom relief from percutaneous coronary intervention (PCI). METHODS: ORBITA-STAR was a multicenter, n-of-1, placebo-controlled study in patients undergoing single-vessel PCI for stable symptoms. Participants underwent 4 episodes (60 seconds each) of low-pressure balloon occlusion across their coronary stenosis, randomly paired with 4 episodes of placebo inflation. Following each episode, patients reported the similarity of the induced symptom in comparison with their usual symptom. The similarity score ranged from -10 (placebo replicated the symptom more than balloon occlusion) to +10 (balloon occlusion exactly replicated the symptom). The primary endpoint was the ability of the similarity score to predict symptom relief with PCI. RESULTS: Fifty-one patients were recruited, aged 62.9 ± 8.6 years. The median fractional flow reserve was 0.68 (Q1-Q3: 0.57-0.79), and the instantaneous wave-free ratio was 0.80 (Q1-Q3: 0.48-0.89). The median similarity score was 3 (Q1-Q3: 0.875-5.25). The similarity score was a strong predictor of symptom improvement following PCI: a patient with an upper quartile similarity score of 5.25 was significantly more likely to have lower angina frequency at follow-up (OR: 8.01; 95% credible interval: 2.39-15.86) than a patient with a lower quartile similarity score of 0.875 (OR: 1.31; 95% credible interval: 0.71-1.99), Pr(difference) >99.9%. CONCLUSIONS: Similarity score powerfully predicted symptom improvement from PCI. These data lay the foundation for independent symptom mapping to target PCI to those patients most likely to benefit. (Systematic Trial of Angina Assessment Before Revascularization [ORBITA-STAR]; NCT04280575).

Symptoms as a Predictor of the Placebo-Controlled Efficacy of PCI in Stable Coronary Artery Disease.

BACKGROUND: Placebo-controlled evidence from ORBITA-2 (Objective Randomised Blinded Investigation with Optimal Medical Therapy of Angioplasty in Stable Angina-2) found that percutaneous coronary intervention (PCI) in stable coronary artery disease with little or no antianginal medication relieved angina, but residual symptoms persisted in many patients. The reason for this was unclear. OBJECTIVES: This ORBITA-2 secondary analysis investigates the relationship between presenting symptoms and disease severity (anatomic, noninvasive, and invasive ischemia) and the ability of symptoms to predict the placebo-controlled efficacy of PCI. METHODS: Prerandomization symptom severity and nature were assessed using the ORBITA smartphone application and symptom and quality of life questionnaires including the World Health Organization Rose angina questionnaire (Rose). Disease severity was assessed using quantitative coronary angiography, stress echocardiography, fractional flow reserve, and instantaneous wave-free ratio. Bayesian ordinal regression was used. RESULTS: At prerandomization, the median number of daily angina episodes was 0.8 (Q1-Q3: 0.4-1.6), 64% had Rose angina, quantitative coronary angiography diameter stenosis was 61% (Q1-Q3: 49%-74%), stress echocardiography score was 1.0 (Q1-Q3: 0.0-2.7), fractional flow reserve was 0.63 (Q1-Q3: 0.49-0.75), and instantaneous wave-free ratio was 0.78 (Q1-Q3: 0.55-0.87). There was little relationship between symptom severity and nature and disease severity: angina symptom score with quantitative coronary angiography ordinal correlation coefficient: 0.06 (95% credible interval [CrI]: 0.00-0.08); stress echocardiography: 0.09 (95% CrI: 0.02-0.10); fractional flow reserve: 0.04 (95% CrI: -0.03 to 0.07); and instantaneous wave-free ratio: 0.04 (95% CrI: -0.01 to 0.07). However, Rose angina and guideline-based typical angina were strong predictors of placebo-controlled PCI efficacy (angina symptom score: OR: 1.9; 95% CrI: 1.6-2.1; probability of interaction [PrInteraction] = 99.9%; and OR: 1.8; 95% CrI: 1.6-2.1; PrInteraction = 99.9%, respectively). CONCLUSIONS: Although symptom severity and nature were poorly associated with disease severity, the nature of symptoms powerfully predicted the placebo-controlled efficacy of PCI.

The LTAR cropland common experiment in the Lower Mississippi River Basin.

The Lower Mississippi River Basin-Long-Term Agroecosystem Research Site (LMRB-LTAR) encompasses six states from Missouri to the Gulf of Mexico and is coordinated by the USDA-ARS National Sedimentation Laboratory, Oxford, MS. The overarching goal of LTAR is to assess regionally diverse and geographically scalable farming practices for enhanced sustainability of agroecosystem goods and services under changing environment and resource-use conditions. The LMRB-LTAR overall goal is to assess sustainable row crop agricultural production systems that integrate regional environmental and socioeconomic needs. Primary row crops in the region include soybeans, corn, cotton, rice, and sugarcane with crop rotations influenced by commodity crop price and other factors. The field-scale common experiment (CE) includes four row crop farms (26-101 ha) established in 2021 and 2023. Three fields are managed with alternative practices, including reduced tillage, cover crops, and automated prescription irrigation, and three fields are managed with prevailing farming practices, consisting of conventional tillage, no cover crop, and nonprescription irrigation. Treatment effects on crop productivity, soil quality, water use efficiency, water quality, and carbon storage are assessed. Research from the LMRB CE will deliver outcomes linked to overarching LTAR network goals, including innovative agricultural systems, strengthened partnerships, data management technologies, and precision environmental tools.

pH selects for distinct N2O-reducing microbiomes in tropical soil microcosms.

Nitrous oxide (N2O), a greenhouse gas with ozone destruction potential, is mitigated by the microbial reduction to dinitrogen catalyzed by N2O reductase (NosZ). Bacteria with NosZ activity have been studied at circumneutral pH but the microbiology of low pH N2O reduction has remained elusive. Acidic (pH < 5) tropical forest soils were collected in the Luquillo Experimental Forest in Puerto Rico, and microcosms maintained with low (0.02 mM) and high (2 mM) N2O assessed N2O reduction at pH 4.5 and 7.3. All microcosms consumed N2O, with lag times of up to 7 months observed in microcosms with 2 mM N2O. Comparative metagenome analysis revealed that Rhodocyclaceae dominated in circumneutral microcosms under both N2O feeding regimes. At pH 4.5, Peptococcaceae dominated in high-N2O, and Hyphomicrobiaceae in low-N2O microcosms. Seventeen high-quality metagenome-assembled genomes (MAGs) recovered from the N2O-reducing microcosms harbored nos operons, with all eight MAGs derived from acidic microcosms carrying the Clade II type nosZ and lacking nitrite reductase genes (nirS/K). Five of the eight MAGs recovered from pH 4.5 microcosms represent novel taxa indicating an unexplored N2O-reducing diversity exists in acidic tropical soils. A survey of pH 3.5-5.7 soil metagenome datasets revealed that nosZ genes commonly occur, suggesting broad distribution of N2O reduction potential in acidic soils.

On the structural evolution of nanoporous optically transparent CuO photocathodes upon calcination for photoelectrochemical applications.

Copper oxides are promising photocathode materials for solar hydrogen production due to their narrow optical band gap energy allowing broad visible light absorption. However, they suffer from severe photocorrosion upon illumination, mainly due to copper reduction. Nanostructuring has been proven to enhance the photoresponse of CuO photocathodes; however, there is a lack of precise structural control on the nanoscale upon sol-gel synthesis and calcination for achieving optically transparent CuO thin film photoabsorbers. In this study, nanoporous and nanocrystalline CuO networks were prepared by a soft-templating and dip-coating method utilizing poly(ethylene oxide)-block-poly(propylene oxide)-block-poly(ethylene oxide) (Pluronic® F-127) as a structure-directing agent, resulting for the first-time in uniformly structured, crack-free, and optically transparent CuO thin films. The photoelectrochemical properties of the nanoporous CuO frameworks were investigated as a function of the calcination temperature and film thickness, revealing important information about the photocurrent, photostability, and photovoltage. Based on surface photovoltage spectroscopy (SPV), the films are p-type and generate up to 60 mV photovoltage at 2.0 eV (0.050 mW cm-2) irradiation for the film annealed at 750 °C. For these high annealing temperatures, the nanocrystalline domains in the thin film structure are more developed, resulting in improved electronic quality. In aqueous electrolytes with or without methyl viologen (as a fast electron acceptor), CuO films show cathodic photocurrents of up to -2.4 mA cm-2 at 0.32 V vs. RHE (air mass (AM) 1.5). However, the photocurrents were found to be entirely due to photocorrosion of the films and decay to near zero over the course of 20 min under AM 1.5 illumination. These fundamental results on the structural and morphological development upon calcination provide a direction and show the necessity for further (surface) treatment of sol-gel derived CuO photocathodes for photoelectrochemical applications. The study demonstrates how to control the size of nanopores starting from mesopore formation at 400 °C to the evolution of macroporous frameworks at 750 °C.

Matrix-based key to the click beetle genera of Canada and USA with a summary of habitat use (Coleoptera, Elateridae).

The Elateridae, or click beetles are abundant and diverse in most terrestrial ecosystems in North America, acting as plant pests and filling many other ecological roles. The 112 genera of Elateridae Leach, 1815, or click beetles, known from Canada and USA are included in a first comprehensive digital interactive key to adults. A link to an online peer-reviewed LUCID key to elaterid genera and downloadable LUCID files are provided. Diagnostic morphological summaries using information from the 61 characters and 158 character states of the matrix key are presented for all genera. A table summarizes current understanding of habitat use by all elaterid genera in Canada and USA from literature, collections, citizen science, and our own observations. Diversity of elaterid genera was high throughout warm and cool temperate regions, especially in mountainous areas and mesic woodlands. Larvae of most genera were associated with soil, litter and decaying wood.

Sustained bacterial N2O reduction at acidic pH.

Nitrous oxide (N2O) is a climate-active gas with emissions predicted to increase due to agricultural intensification. Microbial reduction of N2O to dinitrogen (N2) is the major consumption process but microbial N2O reduction under acidic conditions is considered negligible, albeit strongly acidic soils harbor nosZ genes encoding N2O reductase. Here, we study a co-culture derived from acidic tropical forest soil that reduces N2O at pH 4.5. The co-culture exhibits bimodal growth with a Serratia sp. fermenting pyruvate followed by hydrogenotrophic N2O reduction by a Desulfosporosinus sp. Integrated omics and physiological characterization revealed interspecies nutritional interactions, with the pyruvate fermenting Serratia sp. supplying amino acids as essential growth factors to the N2O-reducing Desulfosporosinus sp. Thus, we demonstrate growth-linked N2O reduction between pH 4.5 and 6, highlighting microbial N2O reduction potential in acidic soils.

Metabolite cross-feeding enables concomitant catabolism of chlorinated methanes and chlorinated ethenes in synthetic microbial assemblies.

Isolate studies have been a cornerstone for unraveling metabolic pathways and phenotypical (functional) features. Biogeochemical processes in natural and engineered ecosystems are generally performed by more than a single microbe and often rely on mutualistic interactions. We demonstrate the rational bottom-up design of synthetic, interdependent co-cultures to achieve concomitant utilization of chlorinated methanes as electron donors and organohalogens as electron acceptors. Specialized anaerobes conserve energy from the catabolic conversion of chloromethane or dichloromethane to formate, H2, and acetate, compounds that the organohalide-respiring bacterium Dehalogenimonas etheniformans strain GP requires to utilize cis-1,2-dichloroethenene and vinyl chloride as electron acceptors. Organism-specific qPCR enumeration matched the growth of individual dechlorinators to the respective functional (i.e. dechlorination) traits. The metabolite cross-feeding in the synthetic (co-)cultures enables concomitant utilization of chlorinated methanes (i.e. chloromethane and dichloromethane) and chlorinated ethenes (i.e. cis-1,2-dichloroethenene and vinyl chloride) without the addition of an external electron donor (i.e. formate and H2). The findings illustrate that naturally occurring chlorinated C1 compounds can sustain anaerobic food webs, an observation with implications for the development of interdependent, mutualistic communities, the sustenance of microbial life in oligotrophic and energy-deprived environments, and the fate of chloromethane/dichloromethane and chlorinated electron acceptors (e.g. chlorinated ethenes) in pristine environments and commingled contaminant plumes.

Population structure in Mixornis tit-babblers across Sunda Shelf matches interfluvia of paleo-rivers.

Rivers constitute an important biogeographic divide in vast areas of tropical rainforest, such as the Amazon and Congo Basins. Southeast Asia's rainforests are currently fragmented across islands divided by sea, which has long obscured their extensive history of terrestrial connectivity as part of a vast (but now submerged) subcontinent - Sundaland - during most of the Quaternary. The role of paleo-rivers in determining population structure in Sundaic rainforests at a time when these forests were connected remains little understood. We examined the coloration of museum skins and used the genomic DNA of museum samples and freshly-collected blood tissue of a pair of Sundaic songbird species, the pin-striped and bold-striped tit-babblers (Mixornis gularis and M. bornensis, respectively), to assess the genetic affinity of populations on small Sundaic islands that have largely been ignored by modern research. Our genomic and morphological results place the populations from the Anambas and Natuna Islands firmly within M. gularis from the Malay Peninsula in western Sundaland, even though some of these islands are geographically much closer to Borneo, where M. bornensis resides. Our results reveal genetic structure consistent with the course of Sundaic paleo-rivers and the location of the interfluvia they formed, and add to a small but growing body of evidence that rivers would have been of equal biogeographic importance in Sundaland's former connected forest landscape as they are in Amazonia and the Congo Basin today.

Solving the 250-year-old mystery of the origin and global spread of the German cockroach, Blattella germanica.

The origin of the German cockroach, Blattella germanica, is enigmatic, in part because it is ubiquitous worldwide in human-built structures but absent from any natural habitats. The first historical records of this species are from ca. 250 years ago (ya) from central Europe (hence its name). However, recent research suggests that the center of diversity of the genus is Asian, where its closest relatives are found. To solve this paradox, we sampled genome-wide markers of 281 cockroaches from 17 countries across six continents. We confirm that B. germanica evolved from the Asian cockroach Blattella asahinai approximately 2,100 ya, probably by adapting to human settlements in India or Myanmar. Our genomic analyses reconstructed two primary global spread routes, one older, westward route to the Middle East coinciding with various Islamic dynasties (~1,200 ya), and another younger eastward route coinciding with the European colonial period (~390 ya). While Europe was not central to the early domestication and spread of the German cockroach, European advances in long-distance transportation and temperature-controlled housing were likely important for the more recent global spread, increasing chances of successful dispersal to and establishment in new regions. The global genetic structure of German cockroaches further supports our model, as it generally aligns with geopolitical boundaries, suggesting regional bridgehead populations established following the advent of international commerce.

Unraveling the evolutionary origin of the complex Nuclear Receptor Element (cNRE), a cis-regulatory module required for preferential expression in the atrial chamber.

Cardiac function requires appropriate proteins in each chamber. Atria requires slow myosin to act as reservoirs, while ventricles demand fast myosin for swift pumping. Myosins are thus under chamber-biased cis-regulation, with myosin gene expression imbalances leading to congenital heart dysfunction. To identify regulatory inputs leading to cardiac chamber-biased expression, we computationally and molecularly dissected the quail Slow Myosin Heavy Chain III (SMyHC III) promoter that drives preferential expression to the atria. We show that SMyHC III gene states are orchestrated by a complex Nuclear Receptor Element (cNRE) of 32 base pairs. Using transgenesis in zebrafish and mice, we demonstrate that preferential atrial expression is achieved by a combinatorial regulatory input composed of atrial activation motifs and ventricular repression motifs. Using comparative genomics, we show that the cNRE might have emerged from an endogenous viral element through infection of an ancestral host germline, revealing an evolutionary pathway to cardiac chamber-specific expression.

Coronary sinus reducer for the treatment of refractory angina (ORBITA-COSMIC): a randomised, placebo-controlled trial.

BACKGROUND: The coronary sinus reducer (CSR) is proposed to reduce angina in patients with stable coronary artery disease by improving myocardial perfusion. We aimed to measure its efficacy, compared with placebo, on myocardial ischaemia reduction and symptom improvement. METHODS: ORBITA-COSMIC was a double-blind, randomised, placebo-controlled trial conducted at six UK hospitals. Patients aged 18 years or older with angina, stable coronary artery disease, ischaemia, and no further options for treatment were eligible. All patients completed a quantitative adenosine-stress perfusion cardiac magnetic resonance scan, symptom and quality-of-life questionnaires, and a treadmill exercise test before entering a 2-week symptom assessment phase, in which patients reported their angina symptoms using a smartphone application (ORBITA-app). Patients were randomly assigned (1:1) to receive either CSR or placebo. Both participants and investigators were masked to study assignment. After the CSR implantation or placebo procedure, patients entered a 6-month blinded follow-up phase in which they reported their daily symptoms in the ORBITA-app. At 6 months, all assessments were repeated. The primary outcome was myocardial blood flow in segments designated ischaemic at enrolment during the adenosine-stress perfusion cardiac magnetic resonance scan. The primary symptom outcome was the number of daily angina episodes. Analysis was done by intention-to-treat and followed Bayesian methodology. The study is registered with ClinicalTrials.gov, NCT04892537, and completed. FINDINGS: Between May 26, 2021, and June 28, 2023, 61 patients were enrolled, of whom 51 (44 [86%] male; seven [14%] female) were randomly assigned to either the CSR group (n=25) or the placebo group (n=26). Of these, 50 patients were included in the intention-to-treat analysis (24 in the CSR group and 26 in the placebo group). 454 (57%) of 800 imaged cardiac segments were ischaemic at enrolment, with a median stress myocardial blood flow of 1·08 mL/min per g (IQR 0·77-1·41). Myocardial blood flow in ischaemic segments did not improve with CSR compared with placebo (difference 0·06 mL/min per g [95% CrI -0·09 to 0·20]; Pr(Benefit)=78·8%). The number of daily angina episodes was reduced with CSR compared with placebo (OR 1·40 [95% CrI 1·08 to 1·83]; Pr(Benefit)=99·4%). There were two CSR embolisation events in the CSR group, and no acute coronary syndrome events or deaths in either group. INTERPRETATION: ORBITA-COSMIC found no evidence that the CSR improved transmural myocardial perfusion, but the CSR did improve angina compared with placebo. These findings provide evidence for the use of CSR as a further antianginal option for patients with stable coronary artery disease. FUNDING: Medical Research Council, Imperial College Healthcare Charity, National Institute for Health and Care Research Imperial Biomedical Research Centre, St Mary's Coronary Flow Trust, British Heart Foundation.

Atrial Shunt Device Effects on Cardiac Structure and Function in Heart Failure With Preserved Ejection Fraction: The REDUCE LAP-HF II Randomized Clinical Trial.

Importance: Although the results of A Study to Evaluate the Corvia Medical Inc IASD System II to Reduce Elevated Left Atrial Pressure in Patients with Heart Failure (REDUCE LAP-HF II) trial were neutral overall, atrial shunt therapy demonstrated potential efficacy in responders (no latent pulmonary vascular disease and no cardiac rhythm management device). Post hoc analyses were conducted to evaluate the effect of shunt vs sham stratified by responder status. Objective: To evaluate the effect of atrial shunt vs sham control on cardiac structure/function in the overall study and stratified by responder status. Design, Setting, and Participants: This was a sham-controlled randomized clinical trial of an atrial shunt device in heart failure with preserved ejection fraction (HFpEF)/HF with mildly reduced EF (HFmrEF). Trial participants with evaluable echocardiography scans were recruited from 89 international medical centers. Data were analyzed from April 2023 to January 2024. Interventions: Atrial shunt device or sham control. Main Outcome Measures: Changes in echocardiographic measures from baseline to 1, 6, 12, and 24 months after index procedure. Results: The modified intention-to-treat analysis of the REDUCE LAP-HF II trial included 621 randomized patients (median [IQR] age, 72.0 [66.0-77.0] years; 382 female [61.5%]; shunt arm, 309 [49.8%]; sham control arm, 312 [50.2%]). Through 24 months, 212 of 217 patients (98%) in the shunt arm with evaluable echocardiograms had patent shunts. In the overall trial population, the shunt reduced left ventricular (LV) end-diastolic volume (mean difference, -5.65 mL; P <.001), left atrial (LA) minimal volume (mean difference, -2.8 mL; P =.01), and improved LV systolic tissue Doppler velocity (mean difference, 0.69 cm/s; P <.001) and LA emptying fraction (mean difference, 1.88 percentage units; P =.02) compared with sham. Shunt treatment also increased right ventricular (RV; mean difference, 9.58 mL; P <.001) and right atrial (RA; mean difference, 9.71 mL; P <.001) volumes but had no effect on RV systolic function, pulmonary artery pressure, or RA pressure compared with sham. In the shunt arm, responders had smaller increases in RV end-diastolic volume (mean difference, 5.71 mL vs 15.18 mL; interaction P =.01), RV end-systolic volume (mean difference, 1.58 mL vs 7.89 mL; interaction P =.002), and RV/LV ratio (mean difference, 0.07 vs 0.20; interaction P <.001) and larger increases in transmitral A wave velocity (mean difference, 5.08 cm/s vs -1.97 cm/s; interaction P =.02) compared with nonresponders randomized to the shunt, suggesting greater ability to accommodate shunted blood through the pulmonary circulation enabling LA unloading. Conclusions and Relevance: In this post hoc analysis of the REDUCE LAP-HF II trial, over 2 years of follow-up, atrial shunting led to reverse remodeling of left-sided chambers and increases in volume of right-sided chambers consistent with the shunt flow but no change in RV systolic function compared with sham. Changes in cardiac structure/function were more favorable in responders compared with nonresponders treated with the shunt, supporting the previously identified responder group hypothesis and mechanism, although further evaluation with longer follow-up is needed. Trial Registration: ClinicalTrials.gov Identifier: NCT03088033.

Impact of Insurance Status and Region on Angiotensin Receptor-Neprilysin Inhibitor Prescription During Heart Failure Hospitalizations.

BACKGROUND: An angiotensin receptor-neprilysin inhibitor (ARNI) is the preferred renin-angiotensin system (RAS) inhibitor for heart failure with reduced ejection fraction (HFrEF). Among eligible patients, insurance status and prescriber concern regarding out-of-pocket costs may constrain early initiation of ARNI and other new therapies. OBJECTIVES: In this study, the authors sought to evaluate the association of insurance and other social determinants of health with ARNI initiation at discharge from HFrEF hospitalization. METHODS: The authors analyzed ARNI initiation from January 2017 to June 2020 among patients with HFrEF eligible to receive RAS inhibitor at discharge from hospitals in the Get With The Guidelines-Heart Failure registry. The primary outcome was the proportion of ARNI prescription at discharge among those prescribed RAS inhibitor who were not on ARNI on admission. A logistic regression model was used to determine the association of insurance status, U.S. region, and their interaction, as well as self-reported race, with ARNI initiation at discharge. RESULTS: From 42,766 admissions, 24,904 were excluded for absolute or relative contraindications to RAS inhibitors. RAS inhibitors were prescribed for 16,817 (94.2%) of remaining discharges, for which ARNI was prescribed in 1,640 (9.8%). Self-reported Black patients were less likely to be initiated on ARNI compared to self-reported White patients (OR: 0.64; 95% CI: 0.50-0.81). Compared to Medicare beneficiaries, patients with third-party insurance, Medicaid, or no insurance were less likely to be initiated on ARNI (OR: 0.47 [95% CI: 0.31-0.72], OR: 0.41 [95% CI: 0.25-0.67], and OR: 0.20 [95% CI: 0.08-0.47], respectively). ARNI therapy varied by hospital region, with lowest utilization in the Mountain region. An interaction was demonstrated between the impact of insurance disparities and hospital region. CONCLUSIONS: Among patients hospitalized between 2017 and 2020 for HFrEF who were prescribed RAS inhibitor therapy at discharge, insurance status, geographic region, and self-reported race were associated with ARNI initiation.

Efficacy and Safety of Dapagliflozin in Patients With Acute Heart Failure.

BACKGROUND: The primary goals during acute heart failure (AHF) hospitalization are decongestion and guideline-directed medical therapy (GDMT) optimization. Unlike diuretics or other GDMT, early dapagliflozin initiation could achieve both AHF goals. OBJECTIVES: The authors aimed to assess the diuretic efficacy and safety of early dapagliflozin initiation in AHF. METHODS: In a multicenter, open-label study, 240 patients were randomized within 24 hours of hospital presentation for hypervolemic AHF to dapagliflozin 10 mg once daily or structured usual care with protocolized diuretic titration until day 5 or hospital discharge. The primary outcome, diuretic efficiency expressed as cumulative weight change per cumulative loop diuretic dose, was compared across treatment assignment using a proportional odds model adjusted for baseline weight. Secondary and safety outcomes were adjudicated by a blinded committee. RESULTS: For diuretic efficiency, there was no difference between dapagliflozin and usual care (OR: 0.65; 95% CI: 0.41-1.02; P = 0.06). Dapagliflozin was associated with reduced loop diuretic doses (560 mg [Q1-Q3: 260-1,150 mg] vs 800 mg [Q1-Q3: 380-1,715 mg]; P = 0.006) and fewer intravenous diuretic up-titrations (P ≤ 0.05) to achieve equivalent weight loss as usual care. Early dapagliflozin initiation did not increase diabetic, renal, or cardiovascular safety events. Dapagliflozin was associated with improved median 24-hour natriuresis (P = 0.03) and urine output (P = 0.005), expediting hospital discharge over the study period. CONCLUSIONS: Early dapagliflozin during AHF hospitalization is safe and fulfills a component of GDMT optimization. Dapagliflozin was not associated with a statistically significant reduction in weight-based diuretic efficiency but was associated with evidence for enhanced diuresis among patients with AHF. (Efficacy and Safety of Dapagliflozin in Acute Heart Failure [DICTATE-AHF]; NCT04298229).