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In the PARAGLIDE-HF trial, treatment with sacubitril/valsartan (Sac/Val) was associated with greater reduction in NT-proBNP than valsartan (Val) alone in patients stabilized after an episode of worsening heart failure (HF) with left ventricular ejection fraction (LVEF) >40%. Treatment effects were most apparent in the subgroup with LVEF below normal (≤60%). This prespecified analysis sought to compare the detailed treatment effects and adverse event profiles of Sac/Val vs Val in patients with LVEF ≤60% vs >60%. Baseline demographics and clinical characteristics were compared between patients with baseline LVEF ≤60% vs >60%. Rates of recurrent composite events (adjudicated CV death, HF hospitalizations, and urgent HF visits) were compared between groups using a semi-parametric proportional rates model. These recurrent composite events were also analyzed across the continuous LVEF spectrum using restricted cubic splines. Incidence of adverse events were analyzed using a logistic regression model with LVEF ≤60% vs >60%, treatment arm, and in-hospital/out-of-hospital randomization as covariates. The interaction of LVEF category and treatment arm was assessed for all models Compared to those with LVEF >60%, patients with LVEF ≤60% were younger with lower NYHA class, but similar NT-proBNP values at baseline and similar co-morbidity burden. Among patients with LVEF ≤60%, those treated with Sac/Val experienced fewer recurrent composite events compared to those treated with Val (rate ratio 0.60 [95% CI: 0.37-0.99], P = .046); predominantly driven by HF hospitalizations. Patients with LVEF >60% treated with Sac/Val vs Val demonstrated similar rates of recurrent composite events (RR 1.46 [0.77-2.79], P = .24) (interaction P-value = .032). This was consistent with the continuous analysis in which patients treated with Sac/Val were significantly less likely to have events compared with patients with Val at LVEF values below 58%. Patients with LVEF >60% treated with Sac/Val experienced more symptomatic hypotension (OR 3.55 [95% CI: 1.35-9.37], P = .01) compared to those treated with Val, whereas rates of symptomatic hypotension were comparable across treatment groups in patients with LVEF ≤60% (OR 1.36 [0.79-2.32], P = .27, interaction P-value .09). Compared to treatment with Val in patients with worsening HF and LVEF >40%, treatment with Sac/Val is associated with greater clinical benefit in those with LVEF ≤60% than in those with LVEF >60%. Clinicaltrials.gov identifier, NCT03988634.

The win ratio (WR) is an emerging alternative for reporting composite outcomes, prioritizing clinically significant events such as mortality while incorporating surrogate measures. However, its benefits should be weighed against limitations, particularly the influence of lower hierarchical outcomes. This secondary analysis of the PARAGLIDE-HF trial performed a WR sensitivity analysis using a modified hierarchical composite outcome to assess the utility of WR sensitivity analysis and the efficacy of sacubitril/valsartan versus valsartan. PARAGLIDE-HF compared sacubitril/valsartan with valsartan in heart failure (HF) patients with ejection fraction >40% (N = 466). A hierarchical outcome in the primary analysis included cardiovascular death, HF hospitalizations, urgent HF visits, and change in N-terminal pro–B-type natriuretic peptide (NT-proBNP), with a 25% decrease considered a win. In the prespecified subgroup with ejection fraction ≤60% (N = 357), sacubitril/valsartan showed a treatment effect on the hierarchical outcome (WR, 1.46; 95% CI, 1.08-1.97). Sensitivity analyses for this subgroup included: (1) excluding NT-proBNP change, (2) substituting the 25% proportion change of NT-proBNP with 10% or 50%, and (3) including renal outcomes within the hierarchical outcome. In addition to the WR, the win odds (WO), in which 50% of the ties are allocated to both the numerator and denominator of the WR—a potentially more suitable modification of the WR that accounts for the presence of ties—were presented. Excluding NT-proBNP (WR, 1.49; 95% CI, 1.00-2.22; WO, 1.12; 95% CI, 1.00-1.26), adjusting the NT-proBNP threshold from 25% to 10% or 50% (WR, 1.41; 95% CI, 1.06-1.89; WO, 1.27; 95% CI, 1.04-1.56 for 10%; and WR, 1.54; 95% CI, 1.11-2.12; WO, 1.25; 95% CI, 1.06-1.48 for 50%), and incorporating renal outcomes (WR, 1.44; 95% CI, 1.07-1.94; WO, 1.28; 95% CI, 1.05-1.56) consistently favored sacubitril/valsartan. Multiple WR sensitivity analyses support a consistent treatment benefit of sacubitril/valsartan versus valsartan in patients with ejection fraction >40% to 60%. Future studies could consider prespecifying WR sensitivity analysis for comprehensive assessment of treatment effects. PARAGLIDE-HF; ClinicalTrials.gov ID, NCT03988634 (https://clinicaltrials.gov/study/NCT03988634).

Botulinum neurotoxins are a varied group of protein toxins that share similar structures and modes of activity. They include at least seven serotypes and over forty subtypes that are produced by seven different clostridial species. These bacterial species are not limited strictly to BoNT-producers as neuro-toxigenic and non-neuro-toxigenic members have been identified within each species. The nomenclature surrounding these toxins and associated bacteria has been evolving as new isolations and discoveries have arisen, resulting in challenges in diagnostic reporting, epidemiology and food safety studies, and in the application of therapeutic products. An understanding of the intricacies regarding the nomenclature of BoNTs and BoNT-producing clostridia is crucial for communication that allows for accurate reporting of information that is pertinent to each situation.

The outcome of infection is dependent on the ability of viruses to manipulate the infected cell to evade immunity, and the ability of the immune response to overcome this evasion. Understanding this process is key to understanding pathogenesis, genetic risk factors, and both natural and vaccine-induced immunity. SARS-CoV-2 antagonises the innate interferon response, but whether it manipulates innate cellular immunity is unclear. An unbiased proteomic analysis determined how cell surface protein expression is altered on SARS-CoV-2-infected lung epithelial cells, showing downregulation of activating NK ligands B7-H6, MICA, ULBP2, and Nectin1, with minimal effects on MHC-I. This occurred at the level of protein synthesis, could be mediated by Nsp1 and Nsp14, and correlated with a reduction in NK cell activation. This identifies a novel mechanism by which SARS-CoV-2 host-shutoff antagonises innate immunity. Later in the disease process, strong antibody-dependent NK cell activation (ADNKA) developed. These responses were sustained for at least 6 months in most patients, and led to high levels of pro-inflammatory cytokine production. Depletion of spike-specific antibodies confirmed their dominant role in neutralisation, but these antibodies played only a minor role in ADNKA compared to antibodies to other proteins, including ORF3a, Membrane, and Nucleocapsid. In contrast, ADNKA induced following vaccination was focussed solely on spike, was weaker than ADNKA following natural infection, and was not boosted by the second dose. These insights have important implications for understanding disease progression, vaccine efficacy, and vaccine design.

Globally, lake surface water temperatures have warmed rapidly relative to air temperatures, but changes in deepwater temperatures and vertical thermal structure are still largely unknown. We have compiled the most comprehensive data set to date of long-term (1970-2009) summertime vertical temperature profiles in lakes across the world to examine trends and drivers of whole-lake vertical thermal structure. We found significant increases in surface water temperatures across lakes at an average rate of+0.37 degrees C decade(-1), comparable to changes reported previously for other lakes, and similarly consistent trends of increasing water column stability (+0.08 kg m(-3) decade(-1)). In contrast, however, deepwater temperature trends showed little change on average (+0.06 degrees C decade(-1)), but had high variability across lakes, with trends in individual lakes ranging from -0.68 degrees C decade(-1) to+0.65 degrees C decade(-1). The variability in deepwater temperature trends was not explained by trends in either surface water temperatures or thermal stability within lakes, and only 8.4% was explained by lake thermal region or local lake characteristics in a random forest analysis. These findings suggest that external drivers beyond our tested lake characteristics are important in explaining long-term trends in thermal structure, such as local to regional climate patterns or additional external anthropogenic influences.

At least 40 toxin subtypes of botulinum neurotoxins (BoNTs), a heterogenous group of bacterial proteins, are produced by seven different clostridial species. A key factor that drives the diversity of neurotoxigenic clostridia is the association of bont gene clusters with various genomic locations including plasmids, phages and the chromosome. Analysis of Clostridium sporogenes BoNT/B1 strain CDC 1632, C. argentinense BoNT/G strain CDC 2741, and Clostridium parabotulinum BoNT/B1 strain DFPST0006 genomes revealed bont gene clusters within plasmid-like sequences within the chromosome or nested in large contigs, with no evidence of extrachromosomal elements. A nucleotide sequence (255,474 bp) identified in CDC 1632 shared 99.5% identity (88% coverage) with bont/B1-containing plasmid pNPD7 of C. sporogenes CDC 67071; CDC 2741 contig AYSO01000020 (1.1 MB) contained a ~140 kb region which shared 99.99% identity (100% coverage) with plasmid pRSJ17_1 of C. argentinense BoNT/G strain 89G; and DFPST0006 contig JACBDK0100002 (573 kb) contained a region that shared 100% identity (99%) coverage with the bont/B1-containing plasmid pCLD of C. parabotulinum Okra. This is the first report of full-length plasmid DNA-carrying complete neurotoxin gene clusters integrated in three distinct neurotoxigenic species: C. parabotulinum, C. sporogenes and C. argentinense.

We examine the first three BepiColombo Mercury flybys Using data from the Miniature Ion Precipitation Analyzer (MIPA), an ion mass analyzer in the Search for Exospheric Refilling and Natural Abundances package on the Mercury Planetary Orbiter designed to study magnetospheric dynamics. These flybys all passed from dusk to dawn through the nightside equatorial region but were noticeably different from each other. In the first flyby, we observe a low latitude boundary layer and ∼${\\sim} $ 1 keV ions near closest approach. For flybys 2 and 3 we see ions up to 14 keV in the same location, including freshly injected precipitating ions inside the loss cone. High time resolution data from flyby 3 show variations consistent with bursty bulk flows 10s long and occurring over ∼30${\\sim} 30$ s periods, the first such observation in this region. MIPA data demonstrate that high‐energy injection processes are an important source of precipitation ions at Mercury.

Lake surface water temperatures are warming worldwide, raising concerns about the future integrity of valuable lake ecosystem services. In contrast to surface water temperatures, we know far less about what is happening to water temperature beneath the surface, where most organisms live. Moreover, we know little about which characteristics make lakes more or less sensitive to climate change and other environmental stressors. We examined changes in lake thermal structure for 231 lakes across northeastern North America (NENA), a region with an exceptionally high density of lakes. We determined how lake thermal structure has changed in recent decades (1975–2012) and assessed which lake characteristics are related to changes in lake thermal structure. In general, NENA lakes had increasing near-surface temperatures and thermal stratification strength. On average, changes in deepwater temperatures for the 231 lakes were not significantly different than zero, but individually, half of the lakes experienced warming and half cooling deepwater temperature through time. More transparent lakes (Secchi transparency >5 m) tended to have higher near-surface warming and greater increases in strength of thermal stratification than less transparent lakes. Whole-lake warming was greatest in polymictic lakes, where frequent summer mixing distributed heat throughout the water column. Lakes often function as important sentinels of climate change, but lake characteristics within and across regions modify the magnitude of the signal with important implications for lake biology, ecology and chemistry.

Background A lack of clear trial evidence often hampers clinical decision-making during support of the preterm lung at birth. Protein biomarkers have been used to define acute lung injury phenotypes and improve patient selection for specific interventions in adult respiratory distress syndrome. The objective of the study was to use proteomics to provide a deeper biological understanding of acute lung injury phenotypes resulting from different aeration strategies at birth in the preterm lung. Methods Changes in protein abundance against an unventilated group (n = 7) were identified via mass spectrometry in a biobank of gravity dependent and non-dependent lung tissue from preterm lambs managed with either a Sustained Inflation (SI, n = 20), Dynamic PEEP (DynPEEP, n = 19) or static PEEP (StatPEEP, n = 11). Ventilation strategy-specific pathways and functions were identified (PANTHER and WebGestalt Tool) and phenotypes defined using integrated analysis of proteome, physiological and clinical datasets (MixOmics package). Results 2372 proteins were identified. More altered proteins were identified in the non-dependent lung, and in SI group than StatPEEP and DynPEEP. Different inflammation, immune system, apoptosis and cytokine pathway enrichment were identified for each strategy and lung region. Specific integration maps of clinical and physiological outcomes to specific proteins could be generated for each strategy. Conclusions Proteomics mapped the molecular events initiating acute lung injury and identified detailed strategy-specific phenotypes. This study demonstrates the potential to characterise preterm lung injury by the direct aetiology and response to lung injury; the first step towards true precision medicine in neonatology.

INTRODUCTION Pragmatic research studies that include diverse dyads of persons living with dementia (PLWD) and their family caregivers are rare. METHODS Community‐dwelling dyads were recruited for a pragmatic clinical trial evaluating three approaches to dementia care. Four clinical trial sites used shared and site‐specific recruitment strategies to enroll health system patients. RESULTS Electronic health record (EHR) queries of patients with a diagnosis of dementia and engagement of their clinicians were the main recruitment strategies. A total of 2176 dyads were enrolled, with 80% recruited after the onset of the pandemic. PLWD had a mean age of 80.6 years (SD 8.5), 58.4% were women, and 8.8% were Hispanic/Latino, and 11.9% were Black/African American. Caregivers were mostly children of the PLWD (46.5%) or spouses/partners (45.2%), 75.8% were women, 9.4% were Hispanic/Latino, and 11.6% were Black/African American. DISCUSSION Health systems can successfully enroll diverse dyads in a pragmatic clinical trial.