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Abstract Interpreting the clinical significance of putative splice-altering variants outside canonical splice sites remains difficult without time-intensive experimental studies. To address this, we introduce Parallel Splice Effect Sequencing (ParSE-seq), a multiplexed assay to quantify variant effects on RNA splicing. We first apply this technique to study hundreds of variants in the arrhythmia-associated gene SCN5A. Variants are studied in ‘minigene’ plasmids with molecular barcodes to allow pooled variant effect quantification. We perform experiments in two cell types, including disease-relevant induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). The assay strongly separates known control variants from ClinVar, enabling quantitative calibration of the ParSE-seq assay. Using these evidence strengths and experimental data, we reclassify 29 of 34 variants with conflicting interpretations and 11 of 42 variants of uncertain significance. In addition to intronic variants, we show that many synonymous and missense variants disrupted RNA splicing. Two splice-altering variants in the assay also disrupt splicing and sodium current when introduced into iPSC-CMs by CRISPR-Cas9 editing. ParSE-seq provides high-throughput experimental data for RNA-splicing to support precision medicine efforts and can be readily adopted to study other loss-of-function genotype-phenotype relationships.

Abstract Rare genetic diseases are typically studied in referral populations, resulting in underdiagnosis and biased assessment of penetrance and phenotype. To address this, we develop a generalizable method of genotype inference based on distant relatedness and deploy this to identify undiagnosed Type 5 Long QT Syndrome (LQT5) rare variant carriers in a non-referral population. We identify 9 LQT5 families referred to a single specialty clinic, each carrying p.Asp76Asn, the most common LQT5 variant. We uncover recent common ancestry and a single shared haplotype among probands. Application to a non-referral population of 69,819 BioVU biobank subjects identifies 22 additional subjects sharing this haplotype, which we confirm to carry p.Asp76Asn. Referral and non-referral carriers have prolonged QT interval corrected for heart rate (QTc) compared to controls, and, among carriers, the QTc polygenic score is independently associated with QTc prolongation. Thus, our innovative analysis of shared chromosomal segments identifies undiagnosed cases of genetic disease and refines the understanding of LQT5 penetrance and phenotype.

Abstract Large‐scale design optimisation techniques enable the design of high‐performance electric machines. Electromagnetic 3D finite element analysis (FEA) is typically employed in optimisation studies for accurate analysis of axial flux permanent magnet (AFPM) machines, which require extensive computational resources. To reduce the computational burden, a FEA‐based mathematical method relying on the geometric and magnetic symmetry of coreless AFPM machines is proposed to estimate the machine performance indicators using the least number of FEA solutions, thereby significantly lowering the running time. This method is generally applicable to AFPM machines with low saturation effects and cogging torque as exemplified for a printed circuit board (PCB) stator coreless AFPM machine. To further reduce the computation time, a systematically simplified equivalent 3D FEA model for planar PCB coils integrated with this machine is also proposed. The practical implementation of the introduced method is elaborated based on an example optimisation study, and an analytical method for fast design scaling is also discussed. The results of the proposed approach are compared with detailed transient FEA results, and a prototype 26‐pole PCB stator coreless AFPM machine was also used to validate the results experimentally.

Abstract The Scanning Habitable Environments with Raman and Luminescence for Organics and Chemicals (SHERLOC) instrument onboard the Mars 2020 Perseverance rover detected so far some of the most intense fluorescence signals in association with sulfates analyzing abraded patches of rocks at Jezero crater, Mars. To assess the plausibility of an organic origin of these signals, it is key to understand if organics can survive exposure to ambient Martian UV after exposure by the Perseverance abrasion tool and prior to analysis by SHERLOC. In this work, we investigated the stability of organo-sulfate assemblages under Martian-like UV irradiation and we observed that the spectroscopic features of phthalic and mellitic acid embedded into hydrated magnesium sulfate do not change for UV exposures corresponding to at least 48 Martian sols and, thus, should still be detectable in fluorescence when the SHERLOC analysis takes place, thanks to the photoprotective properties of magnesium sulfate. In addition, different photoproduct bands diagnostic of the parent carboxylic acid molecules could be observed. The photoprotective behavior of hydrated magnesium sulfate corroborates the hypothesis that sulfates might have played a key role in the preservation of organics on Mars, and that the fluorescence signals detected by SHERLOC in association with sulfates could potentially arise from organic compounds.

Abstract Background Computational variant effect predictors offer a scalable and increasingly reliable means of interpreting human genetic variation, but concerns of circularity and bias have limited previous methods for evaluating and comparing predictors. Population-level cohorts of genotyped and phenotyped participants that have not been used in predictor training can facilitate an unbiased benchmarking of available methods. Using a curated set of human gene-trait associations with a reported rare-variant burden association, we evaluate the correlations of 24 computational variant effect predictors with associated human traits in the UK Biobank and All of Us cohorts. Results AlphaMissense outperformed all other predictors in inferring human traits based on rare missense variants in UK Biobank and All of Us participants. The overall rankings of computational variant effect predictors in these two cohorts showed a significant positive correlation. Conclusion We describe a method to assess computational variant effect predictors that sidesteps the limitations of previous evaluations. This approach is generalizable to future predictors and could continue to inform predictor choice for personal and clinical genetics.

Abstract Photonic lantern (PL) spatial multiplexers show great promise for a range of applications, such as future high-capacity mode division multiplexing (MDM) optical communication networks and free-space optical communication. They enable efficient conversion between multiple single-mode (SM) sources and a multimode (MM) waveguide of the same dimension. PL multiplexers operate by facilitating adiabatic transitions between the SM arrayed space and the single MM space. However, current fabrication methods are forcing the size of these devices to multi-millimeters, making integration with micro-scale photonic systems quite challenging. The advent of 3D micro and nano printing techniques enables the fabrication of freestanding photonic structures with a high refractive index contrast (photopolymer-air). In this work we present the design, fabrication, and characterization of a 6-mode mixing, 375 µm long PL that enables the conversion between six single-mode inputs and a single six-mode waveguide. The PL was designed using a genetic algorithm based inverse design approach and fabricated directly on a 7-core fiber using a commercial two-photon polymerization-based 3D printer and a photopolymer. Although the waveguides exhibit high index contrast, low insertion loss (−2.6 dB), polarization dependent (−0.2 dB) and mode dependent loss (−4.4 dB) were measured.

Abstract Background KCNE1 encodes a 129-residue cardiac potassium channel (I Ks) subunit. KCNE1 variants are associated with long QT syndrome and atrial fibrillation. However, most variants have insufficient evidence of clinical consequences and thus limited clinical utility. Methods In this study, we leveraged the power of variant effect mapping, which couples saturation mutagenesis with high-throughput sequencing, to ascertain the function of thousands of protein-coding KCNE1 variants. Results We comprehensively assayed KCNE1 variant cell surface expression (2554/2709 possible single-amino-acid variants) and function (2534 variants). Our study identified 470 loss- or partial loss-of-surface expression and 574 loss- or partial loss-of-function variants. Of the 574 loss- or partial loss-of-function variants, 152 (26.5%) had reduced cell surface expression, indicating that most functionally deleterious variants affect channel gating. Nonsense variants at residues 56–104 generally had WT-like trafficking scores but decreased functional scores, indicating that the latter half of the protein is dispensable for protein trafficking but essential for channel function. 22 of the 30 KCNE1 residues (73%) highly intolerant of variation (with > 70% loss-of-function variants) were in predicted close contact with binding partners KCNQ1 or calmodulin. Our functional assay data were consistent with gold standard electrophysiological data (ρ = − 0.64), population and patient cohorts (32/38 presumed benign or pathogenic variants with consistent scores), and computational predictors (ρ = − 0.62). Our data provide moderate-strength evidence for the American College of Medical Genetics/Association of Molecular Pathology functional criteria for benign and pathogenic variants. Conclusions Comprehensive variant effect maps of KCNE1 can both provide insight into I Ks channel biology and help reclassify variants of uncertain significance.

Abstract Cerebrovascular and α-synuclein pathologies are frequently observed alongside Alzheimer disease (AD). The heterogeneity of AD necessitates comprehensive approaches to postmortem studies, including the representation of historically underrepresented ethnic groups. In this cohort study, we evaluated small vessel disease pathologies and α-synuclein deposits among Hispanic decedents (HD, n = 92) and non-Hispanic White decedents (NHWD, n = 184) from three Alzheimer’s Disease Research Centers: Columbia University, University of California San Diego, and University of California Davis. The study included cases with a pathological diagnosis of Intermediate/High AD based on the National Institute on Aging– Alzheimer’s Association (NIA-AA) and/or NIA-Reagan criteria. A 2:1 random comparison sample of NHWD was frequency-balanced and matched with HD by age and sex. An expert blinded to demographics and center origin evaluated arteriolosclerosis, cerebral amyloid angiopathy (CAA), and Lewy bodies/Lewy neurites (LBs/LNs) with a semi-quantitative approach using established criteria. There were many similarities and a few differences among groups. HD showed more severe Vonsattel grading of CAA in the cerebellum (p = 0.04), higher CAA density in the posterior hippocampus and cerebellum (ps = 0.01), and increased LBs/LNs density in the frontal (p = 0.01) and temporal cortices (p = 0.03), as determined by Wilcoxon’s test. Ordinal logistic regression adjusting for age, sex, and center confirmed these findings except for LBs/LNs in the temporal cortex. Results indicate HD with AD exhibit greater CAA and α-synuclein burdens in select neuroanatomic regions when compared to age- and sex-matched NHWD with AD. These findings aid in the generalizability of concurrent arteriolosclerosis, CAA, and LBs/LNs topography and severity within the setting of pathologically confirmed AD, particularly in persons of Hispanic descent, showing many similarities and a few differences to those of NHW descent and providing insights into precision medicine approaches.

Abstract Clonal hematopoiesis (CH) is characterized by the acquisition of a somatic mutation in a hematopoietic stem cell that results in a clonal expansion. These driver mutations can be single nucleotide variants in cancer driver genes or larger structural rearrangements called mosaic chromosomal alterations (mCAs). The factors that influence the variations in mCA fitness and ultimately result in different clonal expansion rates are not well understood. We used the Passenger-Approximated Clonal Expansion Rate (PACER) method to estimate clonal expansion rate as PACER scores for 6,381 individuals in the NHLBI TOPMed cohort with gain, loss, and copy-neutral loss of heterozygosity mCAs. Our mCA fitness estimates, derived by aggregating per-individual PACER scores, were correlated (R2 = 0.49) with an alternative approach that estimated fitness of mCAs in the UK Biobank using population-level distributions of clonal fraction. Among individuals with JAK2 V617F clonal hematopoiesis of indeterminate potential or mCAs affecting the JAK2 gene on chromosome 9, PACER score was strongly correlated with erythrocyte count. In a cross-sectional analysis, genome-wide association study of estimates of mCA expansion rate identified a TCL1A locus variant associated with mCA clonal expansion rate, with suggestive variants in NRIP1 and TERT.

Abstract Standard cardiopulmonary exercise testing (CPET) produces a rich dataset but its current analysis is often limited to a few derived variables such as maximal or peak oxygen uptake (V̇O2). We tested whether breath‐by‐breath CPET data could be used to determine sample entropy (SampEn) in 81 healthy children and adolescents (age 7–18 years old, equal sex distribution). To overcome challenges of the relatively small time‐series CPET data size and its nonstationarity, we developed a Python algorithm for short‐duration physiological signals. Comparing pre‐ and post‐ventilatory threshold (VT1) CPET phases, we found: (1) SampEn decreased by 9.46% for V̇O2 and 5.01% for V̇CO2 (p

BackgroundBrain arteriovenous malformations (AVMs) are challenging vascular lesions. Extensive follow-up studies are necessary to refine the therapeutic algorithm, and to improve long-term survival in these patients. The aim of the study was to assess surgical outcomes, and to evaluate overall long-term mortality in patients treated for brain AVMs.MethodsThis retrospective single-center study included 191 patients with brain AVMs, admitted between 2012 and 2022. Clinical and angiographical particularities have been analyzed, to identify factors that might influence early outcome and overall long-term mortality.ResultsOut of 79 patients undergoing surgery, 51 had ruptured AVMs with total resection achieved in 68 cases (86.1%). Deep venous drainage was associated with incomplete resection. Female sex, admission modified Rankin Scale (mRS) > 2, and eloquent location were independent predictors of poor outcomes. Multiple venous drainage was associated with a higher risk of worsened early outcome. Eloquent brain region involvement, conservative treatment, increasing age, admission mRS > 2, and comorbidities significantly decrease survival in brain AVM patients. Patients treated with interventional treatments had significantly better survival than the conservatively managed ones, when adjusting for age and admission mRS.ConclusionThe study identified female sex, poor neurologic status on admission and eloquence as independent prognostic factors for a negative outcome after surgery. Patients who received interventional treatment had significantly better survival than patients managed conservatively. We recommend employing tailored, proactive management strategies as they significantly enhance long-term survival in brain AVM patients.

Abstract Polygenic variation unrelated to disease contributes to interindividual variation in baseline white blood cell (WBC) counts, but its clinical significance is uncharacterized. We investigated the clinical consequences of a genetic predisposition toward lower WBC counts among 89,559 biobank participants from tertiary care centers using a polygenic score for WBC count (PGSWBC) comprising single nucleotide polymorphisms not associated with disease. A predisposition to lower WBC counts was associated with a decreased risk of identifying pathology on a bone marrow biopsy performed for a low WBC count (odds-ratio = 0.55 per standard deviation increase in PGSWBC [95%CI, 0.30−0.94], p = 0.04), an increased risk of leukopenia (a low WBC count) when treated with a chemotherapeutic (n = 1724, hazard ratio [HR] = 0.78 [0.69−0.88], p = 4.0 × 10−5) or immunosuppressant (n = 354, HR = 0.61 [0.38–0.99], p = 0.04). A predisposition to benign lower WBC counts was associated with an increased risk of discontinuing azathioprine treatment (n = 1,466, HR = 0.62 [0.44−0.87], p = 0.006). Collectively, these findings suggest that there are genetically predisposed individuals who are susceptible to escalations or alterations in clinical care that may be harmful or of little benefit.

Abstract NASA uses a continuous risk management process to seek out new knowledge of spaceflight-induced risk to human health and performance. The evidence base that informs the risk assessments in this domain is constantly changing as more information is gleaned from a continuous human presence in space and from ongoing research. However, the limitations of this evidence are difficult to characterize because fewer than 700 humans have ever flown in space, and information comes from a variety of sources that span disciplines, including engineering, medicine, food and nutrition, and many other life sciences. The Human System Risk Board (HSRB) at NASA is responsible for assessing risk to astronauts and communicating this risk to agency decision-makers. A critical part of that communication is conveying the uncertainty regarding the understanding of the changes that spaceflight induces in human processes and the complex interactions between humans and the spacecraft. Although the strength of evidence grades is common in the academic literature, these scores are often not useful for the problems of human spaceflight. The HSRB continues to update the processes used to report the levels of evidence. This paper describes recent updates to the methods used to assign the level of evidence scores to the official risk postures and to the causal diagrams used by the HSRB.

Abstract Drug repurposing represents an attractive alternative to the costly and time-consuming process of new drug development, particularly for serious, widespread conditions with limited effective treatments, such as Alzheimer’s disease (AD). Emerging generative artificial intelligence (GAI) technologies like ChatGPT offer the promise of expediting the review and summary of scientific knowledge. To examine the feasibility of using GAI for identifying drug repurposing candidates, we iteratively tasked ChatGPT with proposing the twenty most promising drugs for repurposing in AD, and tested the top ten for risk of incident AD in exposed and unexposed individuals over age 65 in two large clinical datasets: (1) Vanderbilt University Medical Center and (2) the All of Us Research Program. Among the candidates suggested by ChatGPT, metformin, simvastatin, and losartan were associated with lower AD risk in meta-analysis. These findings suggest GAI technologies can assimilate scientific insights from an extensive Internet-based search space, helping to prioritize drug repurposing candidates and facilitate the treatment of diseases.

Abstract Lions (Panthera leo) are declining across their range, mainly due to human‐induced habitat fragmentation and prey depletion. However, the South African lion population continues to grow. Unlike other range states, South Africa actively manages wild lions across a continuum of landscapes and ecological constraints. Many of these lions are in small, fenced reserves where managers seek to mimic ecological processes in small landscapes. However, the effectiveness of this management approach has not been evaluated against meta‐population criteria. Given that meta‐population dynamics allows species living in fragmented habitats to persist, we evaluated how South Africa's lion population complies with meta‐population criteria using national audit data between 2010 and 2019 from 49 fenced, wild lion reserves. The small, fenced reserves holding wild lions fulfil the criteria for meta‐population functionality. However, this functionality was achieved through haphazard and uncoordinated management actions and not through a coordinated approach. Our main recommendation is to consider implementing a more coordinated meta‐population management approach. At the very least, meta‐population management guidelines should be reviewed and updated on a regular basis, regular audits should be conducted and periodic genetic evaluation of the meta‐population (every 10 years) should be instituted. We recommend incentivising lion managers to enhance the conservation of lions in South Africa within a meta‐population framework. We also recommend a focus on improving decision making and policy procedures that facilitates compliance with relevant legislation aimed at achieving high levels of lion conservation‐governance efficiency. South Africa's meta‐population approach to wild lion management in small, fenced reserves is effective at conserving lions and contributing to lion conservation more broadly. In an increasingly fragmented landscape, the need for human management actions to ensure persistence of large carnivores is likely to increase. A managed meta‐population approach of fenced (or unfenced, but geographically isolated) populations is a useful tool for conservationists to consider worldwide.

This paper introduces a new motor design for traction applications that achieves high power density and meets the power density target of 50kW/L target set by the US Department of Energy. The proposed motor has a doubly salient structure with concentrated toroidal 3-phase windings and permanent magnets (PMs) in the stator and a reluctance rotor, improves torque capability and operating speed compared to traditional designs. A design optimization process was conducted to balance efficiency, power density, and power factor. An equivalent circuit in the DQ reference frame is introduced to enable vector control for the proposed special double salient machine. The resulting design was validated through the creation of an open frame lab prototype (OFLP) and an experimental dyno test bench was developed. The prototype was tested through open circuit tests, static torque tests, and unity power factor tests. This paper also discusses the use of synchronous reference frame theory and per-phase diagrams to calculate electric machine parameters. In addition to experimentation, 3D and 2D electromagnetic FEA simulations have been performed for unity power factor operation as a generator to numerically separate the power loss components.

Abstract Background Sudden unexpected death in children is a tragic event. Understanding the genetics of sudden death in the young (SDY) enables family counseling and cascade screening. The objective of this study was to characterize genetic variation in an SDY cohort using whole genome sequencing. Methods The SDY Case Registry is a National Institutes of Health/Centers for Disease Control and Prevention surveillance effort to discern the prevalence, causes, and risk factors for SDY. The SDY Case Registry prospectively collected clinical data and DNA biospecimens from SDY cases

Humankind has entered a new era wherein a main characteristic is the convergence of various technologies providing services and exerting a major impact upon all aspects of human activity, be it social interactions with the natural environment. Fixed networks are about to play a major role in this convergence, since they form, along with mobile networks, the backbone that provides access to a broad gamut of services, accessible from any point of the globe. It is for this reason that we introduce a forward-looking approach for fixed networks, particularly focused on Fixed 6th Generation (F6G) networks. First, we adopt a novel classification scheme for the main F6G services, comprising six categories. This classification is based on the key service requirements, namely latency, capacity, and connectivity. F6G networks differ from those of previous generations (F1G–F5G) in that they concurrently support multiple key requirements. We then propose concrete steps towards transforming the main elements of fixed networks, such as optical transceivers, optical switches, etc., such that they satisfy the new F6G service requirements. Our study categorizes the main networking paradigm of optical switching into two categories, namely ultra-fast and ultra-high capacity switching, tailored to different service categories. With regard to the transceiver physical layer, we propose (a) the use of all-optical processing to mitigate performance barriers of analog-to-digital and digital-to-analog converters (ADC/DAC) and (b) the exploitation of optical multi-band transmission, space division-multiplexing, and the adoption of more efficient modulation formats.

Background Recurrence after atrial fibrillation (AF) ablation remains common. We evaluated the association between recurrence and levels of biomarkers of cardiac remodeling, and their ability to improve recurrence prediction when added to a clinical prediction model. Methods and Results Blood samples collected before de novo catheter ablation were analyzed. Levels of bone morphogenetic protein‐10, angiopoietin‐2, fibroblast growth factor‐23, insulin‐like growth factor‐binding protein‐7, myosin‐binding protein C3, growth differentiation factor‐15, interleukin‐6, N‐terminal pro‐brain natriuretic peptide, and high‐sensitivity troponin T were measured. Recurrence was defined as ≥30 seconds of an atrial arrhythmia 3 to 12 months postablation. Multivariable logistic regression was performed using biomarker levels along with clinical covariates: APPLE score (Age >65 years, Persistent AF, imPaired eGFR [

Abstract Influenza A Virus (IAV) is a recurring respiratory virus with limited availability of antiviral therapies. Understanding host proteins essential for IAV infection can identify targets for alternative host-directed therapies (HDTs). Using affinity purification-mass spectrometry and global phosphoproteomic and protein abundance analyses using three IAV strains (pH1N1, H3N2, H5N1) in three human cell types (A549, NHBE, THP-1), we map 332 IAV-human protein-protein interactions and identify 13 IAV-modulated kinases. Whole exome sequencing of patients who experienced severe influenza reveals several genes, including scaffold protein AHNAK, with predicted loss-of-function variants that are also identified in our proteomic analyses. Of our identified host factors, 54 significantly alter IAV infection upon siRNA knockdown, and two factors, AHNAK and coatomer subunit COPB1, are also essential for productive infection by SARS-CoV-2. Finally, 16 compounds targeting our identified host factors suppress IAV replication, with two targeting CDK2 and FLT3 showing pan-antiviral activity across influenza and coronavirus families. This study provides a comprehensive network model of IAV infection in human cells, identifying functional host targets for pan-viral HDT.

Abstract Recently, large scale genomic projects such as All of Us and the UK Biobank have introduced a new research paradigm where data are stored centrally in cloud-based Trusted Research Environments (TREs). To characterize the advantages and drawbacks of different TRE attributes in facilitating cross-cohort analysis, we conduct a Genome-Wide Association Study of standard lipid measures using two approaches: meta-analysis and pooled analysis. Comparison of full summary data from both approaches with an external study shows strong correlation of known loci with lipid levels (R2 ~ 83–97%). Importantly, 90 variants meet the significance threshold only in the meta-analysis and 64 variants are significant only in pooled analysis, with approximately 20% of variants in each of those groups being most prevalent in non-European, non-Asian ancestry individuals. These findings have important implications, as technical and policy choices lead to cross-cohort analyses generating similar, but not identical results, particularly for non-European ancestral populations.

Using the MIRI medium-resolution spectrometer on JWST, we have detected pure rotational, suprathermal OH emissions from the vicinity of the intermediate-mass protostar HOPS 370 (OMC2/FIR3). These emissions are observed from shocked knots in a jet/outflow and originate in states of rotational quantum number as high as 46 that possess excitation energies as large as E _U / k = 4.65 × 10 ^4 K. The relative strengths of the observed OH lines provide a powerful diagnostic of the ultraviolet radiation field in a heavily extinguished region ( A _V ∼ 10–20) where direct UV observations are impossible. To high precision, the OH line strengths are consistent with a picture in which the suprathermal OH states are populated following the photodissociation of water in its $\tilde{B}-X$ band by ultraviolet radiation produced by fast (∼80 km s ^−1 ) shocks along the jet. The observed dominance of emission from symmetric ( $A^{\prime} $ ) OH states over that from antisymmetric ( A ″) states provides a distinctive signature of this particular population mechanism. Moreover, the variation of intensity with rotational quantum number suggests specifically that Ly α radiation is responsible for the photodissociation of water, an alternative model with photodissociation by a 10 ^4 K blackbody being disfavored at a high level of significance. Using measurements of the Br α flux to estimate the Ly α production rate, we find that ∼4% of the Ly α photons are absorbed by water. Combined with direct measurements of water emissions in the ν _2 = 1 − 0 band, the OH observations promise to provide key constraints on future models for the diffusion of Ly α photons in the vicinity of a shock front.

Investigating Protostellar Accretion (IPA) is a JWST Cycle 1 GO program that uses NIRSpec integral field units and MIRI Medium Resolution Spectrograph to obtain 2.9–28 μ m spectral cubes of young, deeply embedded protostars with luminosities of 0.2–10,000 L _⊙ and central masses of 0.15–12 M _⊙ . In this Letter, we report the discovery of a highly collimated atomic jet from the Class 0 protostar IRAS 16253−2429, the lowest-luminosity source ( L _bol = 0.2 L _⊙ ) in the IPA program. The collimated jet is detected in multiple [Fe ii ] lines and [Ne ii ], [Ni ii ], and H i lines but not in molecular emission. The atomic jet has a velocity of about 169 ± 15 km s ^−1 , after correcting for inclination. The width of the jet increases with distance from the central protostar from 23 to 60 au, corresponding to an opening angle of 2.°6 ± 0.°5. By comparing the measured flux ratios of various fine-structure lines to those predicted by simple shock models, we derive a shock speed of 54 km s ^−1 and a preshock density of 2.0 × 10 ^3 cm ^−3 at the base of the jet. From these quantities and using a suite of jet models and extinction laws, we compute a mass-loss rate between 0.4 and 1.1 ×10 ^−10 M _⊙ yr ^−1 . The low mass-loss rate is consistent with simultaneous measurements of low mass accretion rate (2.4 ± 0.8 × 10 ^−9 M _⊙ yr ^−1 ) for IRAS 16253−2429 from JWST observations, indicating that the protostar is in a quiescent accretion phase. Our results demonstrate that very low-mass protostars can drive highly collimated, atomic jets, even during the quiescent phase.

Background: The combination of ropivacaine and dexmedetomidine has been used as an epidural analgesic for inducing labor. However, there is limited data regarding the administration of epidural analgesia for labor maintenance, hence, this study aimed to determine the optimum concentration through dose-response curves of ropivacaine plus dexmedetomidine, which could be used along with the Programmed Intermittent Epidural Bolus (PIEB) technique.Methods: One hundred parturients were randomized into 4 groups who were administered four different doses of ropivacaine (dexmedetomidine at 0.4 μg mL−1): 0.04%, 0.06%, 0.08%, and 0.1%. The primary outcome that was determined included the proportion of patients experiencing breakthrough pain during their 1st stage of labor. Breakthrough pain was described as a visual analog scale [VAS] score of >30 mm, requiring supplemental epidural analgesia after the administration of at least one patient-controlled bolus. The effective concentration of analgesia that was used for labor maintenance in 50% (EC50) and 90% (EC90) of patients were calculated with the help of probit regression. Secondary outcomes included epidural block characteristics, side effects, neonatal outcomes, and patient satisfaction.Results: The results indicated that the proportion of patients without breakthrough pain was 45% (10/22), 55% (12/22), 67% (16/24), and 87% (20/23) for 0.04%, 0.06%, 0.08%, and 0.10% doses of the analgesic that were administered, respectively. The EC50 value was 0.051% (95% confidence interval [CI], 0.011%–0.065%) while the EC90 value was recorded to be 0.117% (95% CI, 0.094%–0.212%). Side effects were similar among groups.Conclusion: A ropivacaine dose of 0.117% can be used as epidural analgesia for maintaining the 1st stage of labor when it was combined with dexmedetomidine (0.4 μg mL−1) and the PIEB technique.Clinical Trial Register:https://www.chictr.org.cn/index.aspx, identifier ChiCTR2200059557

Significant opportunity for savings in energy and investment through improved performance of power distribution systems exists in the optimal placement and rating of capacitors, a conventionally cost-effective and popular reactive power compensating technology. A novel optimal capacitor planning (OCP) procedure is proposed for large-scale utility power distribution systems, which is exemplified on an existing utility circuit of approximately 4,000 buses. An initial sensitivity analysis is employed to intelligently reduce OCP computation time and maintain quality of optimal configurations. Three optimization objectives are considered, including the minimization of total system active power losses, standard deviation of node voltages, and investment in total capacitor power rating. Eight multi-objective optimization methods that employ the non-dominated sorting algorithm III (NSGA-III) concept are compared to determine individual merits. Differences between the methods include the incorporation of a penalty constraint for voltage violations and the automatic readjustment of load-tap-changing (LTC) transformer tap settings for proposed capacitor re-configurations concurrently within the optimizer, which ensures peak system performance and fair comparison to the reference case. A multi-step model conversion process was developed with OpenDSS to enable the OCP procedure to be generally applicable to real large-scale utility circuits. OCP is performed for three example sub-circuits served by a substation with a 48MW, 9Mvar peak load, which represents the most extreme case and offers the best opportunity for savings. Example configurations from the resulting Pareto sets through a pseudo-weight vector approach are also analyzed through a systematic procedure of comparison between the most extreme configuration types to inform configuration selection.

The authors demonstrate a multi-dimensional communication scheme that combines wavelength- and mode- multiplexing on photonic integrated circuits using foundry-compatible photonic inverse design and spectrally flattened microcombs

Rare variants in TTN are the most common monogenic cause of early-onset atrial fibrillation and dilated cardiomyopathy. Whereas cardiac sarcoidosis is very underdiagnosed, a common presentation can be ventricular arrhythmias. This report presents a patient with a likely pathogenic TTN variant and cardiac sarcoidosis. (Level of Difficulty: Intermediate.)

We investigate the bright CO fundamental emission in the central regions of five protostars in their primary mass assembly phase using new observations from JWST’s Near-Infrared Spectrograph and Mid-Infrared Instrument. CO line emission images and fluxes are extracted for a forest of ∼150 rovibrational transitions from two vibrational bands, v = 1−0 and v = 2−1. However, ^13 CO is undetected, indicating that ^12 CO emission is optically thin. We use H _2 emission lines to correct fluxes for extinction and then construct rotation diagrams for the CO lines with the highest spectral resolution and sensitivity to estimate rotational temperatures and numbers of CO molecules. Two distinct rotational temperature components are required for v = 1 (∼600 to 1000 K and 2000 to ∼10 ^4 K), while one hotter component is required for v = 2 (≳3500 K). ^13 CO is depleted compared to the abundances found in the interstellar medium, indicating selective UV photodissociation of ^13 CO; therefore, UV radiative pumping may explain the higher rotational temperatures in v = 2. The average vibrational temperature is ∼1000 K for our sources and is similar to the lowest rotational temperature components. Using the measured rotational and vibrational temperatures to infer a total number of CO molecules, we find that the total gas masses range from lower limits of ∼10 ^22 g for the lowest mass protostars to ∼10 ^26 g for the highest mass protostars. Our gas mass lower limits are compatible with those in more evolved systems, which suggest the lowest rotational temperature component comes from the inner disk, scattered into our line of sight, but we also cannot exclude the contribution to the CO emission from disk winds for higher mass targets.

We present a combined Stratospheric Observatory for Infrared Astronomy (SOFIA) and two-epoch Hubble Space Telescope (HST) study of the region NGC 2071 IR containing the outflow from the protostar HOPS 361-A (NGC 2071 IRS 1). New [O i ] 63 μ m spectra, taken with the German REciever for Astronomy at Terahertz frequencies (GREAT) instrument aboard SOFIA, trace the outflow, spectrally resolve line profiles, and give radial velocities of the far-IR emission to yield 3D kinematics, shock properties, and feedback properties. Proper motions and extinction values from HST give a more complete quasi-3D picture that we use to model shock speeds and densities. We identify 14 distinct features that show proper motions. Combined with the GREAT data, we estimate that HOPS 361-A has a mass outflow rate of 3.16 × 10 ^−6 M _⊙ yr ^−1 with shock speeds up to 51 km s ^−1 . The outflow force summed over all knots per area is measured to be 1.45 × 10 ^−4 M _⊙ km ^−1 s ^−1 yr ^−1 and a power summed over all knotsper area of 2.37 × 10 ^−2 M _⊙ s ^−3 dissipated assuming constant $\dot{M}$ , with large uncertainties on the feedback values. The total [O i ] luminosity using all SOFIA apertures encompassing the HOPS 361 clump is 0.7 L _⊙ , corresponding to a mass outflow rate of 7 × 10 ^−5 M _⊙ yr ^−1 . This is the second 3D kinematic study of an outflow in NGC 2071 IR in the near- and far-IR regimes following Rubinstein et al. ( 2023 ). The SOFIA [O i ] spectra add unique focus to the entrained gas connecting the recent episode of outflows from HOPS 361-A to the outflow cavity and the surrounding NGC 2071 IR star-forming environment.

Modeling observations of the archetypal debris disk around β Pic, obtained in 2023 January with the MIRI Medium Resolution Spectrograph on board JWST, reveals significant differences compared with that obtained with the Infrared Spectrograph on board Spitzer. The bright 5–15 μ m continuum excess modeled using a ∼600 K black body has disappeared. The previously prominent 18 and 23 μ m crystalline forsterite emission features, arising from cold dust (∼100 K) in the Rayleigh limit, have disappeared and been replaced by very weak features arising from the hotter 500 K dust population. Finally, the shape of the 10 μ m silicate feature has changed, consistent with a shift in the temperature of the warm dust population from ∼300 to ∼500 K and an increase in the crystalline fraction of the warm, silicate dust. Stellar radiation pressure may have blown both the hot and the cold crystalline dust particles observed in the Spitzer spectra out of the planetary system during the intervening 20 yr between the Spitzer and JWST observations. These results indicate that the β Pic system has a dynamic circumstellar environment, and that periods of enhanced collisions can create large clouds of dust that sweep through the planetary system.

We present deep 1.4–4.8 μ m JWST-NIRCam imaging of the Serpens Main star-forming region and identify 20 candidate protostellar outflows, most with bipolar structure and identified driving sources. The outflow position angles (PAs) are strongly correlated, and they are aligned within ±24° of the major axis of the Serpens filament. These orientations are further aligned with the angular momentum vectors of the two disk shadows in this region. We estimate that the probability of this number of young stars being coaligned if sampled from a uniform PA distribution is 10 ^−4 . This in turn suggests that the aligned protostars, which seem to be at similar evolutionary stages based on their outflow dynamics, formed at similar times with a similar spin inherited from a local cloud filament. Further, there is tentative evidence for a systematic change in average PA between the northwestern and southeastern cluster, as well as increased scatter in the PAs of the southeastern protostars. SOFIA-HAWC+ archival dust polarization observations of Serpens Main at 154 and 214 μ m are perpendicular to the dominant jet orientation in the northwestern region in particular. We measure and locate shock knots and edges for all of the outflows and provide an identifying catalog. We suggest that Serpens main is a cluster that formed from an isolated filament and due to its youth retains its primordial outflow alignment.

Investigating Protostellar Accretion is a Cycle 1 JWST program using the NIRSpec+MIRI integral field units to obtain 2.9–28 μ m spectral cubes of five young protostars with luminosities of 0.2–10,000 L _⊙ in their primary accretion phase. This paper introduces the NIRSpec 2.9–5.3 μ m data of the inner 840–9000 au with spatial resolutions from 28 to 300 au. The spectra show rising continuum emission; deep ice absorption; emission from H _2 , H i , and [Fe ii ]; and the CO fundamental series in emission and absorption. Maps of the continuum emission show scattered light cavities for all five protostars. In the cavities, collimated jets are detected in [Fe ii ] for the four

We present JWST MIRI Medium Resolution Spectrograph (MRS) observations of the β Pictoris system. We detect an infrared excess from the central unresolved point source from 5 to 7.5 μ m which is indicative of dust within the inner ∼7 au of the system. We perform point-spread function (PSF) subtraction on the MRS data cubes and detect a spatially resolved dust population emitting at 5 μ m. This spatially resolved hot dust population is best explained if the dust grains are in the small grain limit (2 π a ≪ λ ). The combination of unresolved and resolved dust at 5 μ m could suggest that dust grains are being produced in the inner few astronomical units of the system and are then radiatively driven outwards, where the particles could accrete onto the known planets in the system, β Pictoris b and c. We also report the detection of an emission line at 6.986 μ m that we attribute to [Ar ii ]. We find that the [Ar ii ] emission is spatially resolved with JWST and appears to be aligned with the dust disk. Through PSF-subtraction techniques, we detect β Pictoris b at the 5 σ level in our MRS data cubes and present the first mid-infrared spectrum of the planet from 5 to 7 μ m. The planet’s spectrum is consistent with having absorption from water vapor between 5 and 6.5 μ m. We perform atmosphere model grid fitting of the spectra and photometry of β Pictoris b and find that the planet’s atmosphere likely has a substellar C/O ratio.

Background: Aversive conditioning weakens the gratifying value of a comfort meal. The aim was to determine the effect of a cognitive intervention to reverse aversive conditioning and restore hedonic postprandial response. Methods: This was a randomized, sham-controlled, single-blind, parallel study that was conducted on 12 healthy women (n = 6 in each group). The reward value of a comfort meal was measured on different days: at initial exposure, after aversive conditioning (administration of the same meal with a masked fat overload on the previous day) and after a cognitive intervention (disclosing the aversive conditioning paradigm in the test group vs. no explanation in the control group). The primary outcome, digestive wellbeing, was determined using graded scales at regular intervals before and after ingestion. Results: At initial exposure, the comfort meal produced a rewarding experience that was impaired using aversive conditioning; upon re-exposure to the original meal, the cognitive intervention increased meal wanting and liking; improved digestive wellbeing and mood; tended to reduce postprandial satiety, bloating/fullness; and abolished discomfort/pain, thereby restoring the hedonic value of the comfort meal. By contrast, sham intervention had no effects, and the postprandial sensations remained like the responses to the offending meal. Conclusion: In this proof-of-concept study, we demonstrate that in healthy women, a mild, short-term acquired aversion to a comfort meal can be reversed using a cognitive intervention. ClinicalTrials.gov ID: NCT05897411.

Background Acute facial nerve iatrogenic or traumatic injury warrants rapid management with the goal of reestablishing nerve continuity within 72 hours. However, reconstructive efforts should be performed up to 12 months from the time of injury since facial musculature may still be viable and thus facial tone and function may be salvaged.

Here, Li et al. integrate population genetic and protein structural perspectives to map the landscape of 3D constraint on 80% of human proteins. They show that 3D mutational constraint is pervasive and strongly associated with functional relevance.

Risk assessment and mitigation programs have been carried out over the last decades in the attempt to reduce transportation infrastructure downtime and post-disaster recovery costs. Recently, the concept of resilience gained increasing importance in design, assessment, maintenance, and rehabilitation structures and infrastructure systems, particularly bridges and transportation networks, exposed to natural and man-made hazards. In the field of disaster mitigation, frameworks have been proposed to provide a basis for development of qualitative and quantitative models quantifying the functionality and resilience at various scales, including components, groups and systems within infrastructure networks and communities. In these frameworks, the effects of aging and environmental aggressiveness must be explicitly considered, affecting the structural performance and functionality of civil infrastructure systems. Significant efforts have been made to incorporate risk and resilience assessment frameworks into informed decision making to decide how to best use resources to minimize the impact of hazards on civil infrastructure systems. This review paper is part of these efforts. It presents an overview of the main principles and concepts, methods and strategies, advances and accomplishments in the field of life-cycle reliability, risk and resilience of structures and infrastructure systems, with emphasis on seismic resilience of bridges and road networks.

Background and study aims Pancreatic necrosis is an independent predictor of morbidity and mortality among patients with acute pancreatitis. We compared the safety and outcomes of three techniques including endoscopic necrosectomy, fluoroscopy-guided percutaneous necrosectomy by an interventional radiologist, and surgical necrosectomy. Patients and methods Using the Nationwide Readmissions Database, we identified hospitalized patients who underwent pancreatic necrosectomy from 2016 to 2019. They were identified using the International Classification of Diseases, 10th Revision, Procedure Coding System. Results: Of the 2,281 patients meeting the selection criteria, the method of pancreatic necrosectomy was as follows: endoscopy (n = 672), percutaneous (n = 1,338), and surgery (n = 271). Compared to surgery, the rate of mortality was lowest for endoscopy (hazard ratio (HR) 0.27; 95 % CI 0.08–0.90; P = 0.033) followed by percutaneous (HR 0.44; 95 % CI, 0.20–0.98; P = 0.045). Endoscopy was associated with less post-procedure bleeding compared to percutaneous and surgical necrosectomy (P

Abstract Habitat heterogeneity is a key driver of the diversity and distribution of species. African savannas are experiencing changes in their vegetation structure causing shifts towards increased woody plant cover, which results in vegetation structure homogenization. Given the impact that increasing woody plant cover has on patterns of animal use, resource managers across Africa are implementing habitat management practices that are intended to reduce woody plant cover. To understand the ecological implications of various habitat management practices on arthropod and bird communities, we leveraged large‐scale tree clearing and subsequent mowing in an African savanna to understand how changes in both the herbaceous layer and woody plant cover (i.e., structural heterogeneity) may shape arthropod and bird communities at the local scale. We focused on four replicated treatments: (1) annual summer mow, (2) annual winter mow, (3) >5 years since last mow (rest), and (4) an adjacent unmanipulated savanna to act as a control. We found that the mowing treatments significantly influenced vegetation structure both with respect to tree density and herbaceous layer. Both arthropod and bird community composition varied across treatments. Grass biomass was the best predictor of arthropod richness and abundance, with arthropods selecting for areas with high biomass. Insectivorous bird richness and abundance was driven by tree density (i.e., perching locations) and not arthropod abundance. Our results suggest that vegetation management practices contribute to habitat heterogeneity at the landscape scale and increase bird species richness through species turnover. However, we caution that if a single vegetation management practice dominates the landscape, it is plausible that it could lead to the simplification of the avian community.

Background: Visualizing fibrosis on cardiac magnetic resonance (CMR) imaging with contrast enhancement (late gadolinium enhancement; LGE) is paramount in characterizing disease progression and identifying arrhythmia substrates. Segmentation and fibrosis quantification from LGE-CMR is intensive, manual, and prone to interobserver variability. There is an unmet need for automated LGE-CMR image segmentation that ensures anatomical accuracy and seamless extraction of clinical features. Objective: This study aimed to develop a novel deep learning solution for analysis of contrast-enhanced CMR images that produces anatomically accurate myocardium and scar/fibrosis segmentations and uses these to calculate features of clinical interest. Methods: Data sources were 155 2-dimensional LGE-CMR patient scans (1124 slices) and 246 synthetic “LGE-like” scans (1360 slices) obtained from cine CMR using a novel style-transfer algorithm. We trained and tested a 3-stage neural network that identified the left ventricle (LV) region of interest (ROI), segmented ROI into viable myocardium and regions of enhancement, and postprocessed the segmentation results to enforce conforming to anatomical constraints. The segmentations were used to directly compute clinical features, such as LV volume and scar burden. Results: Predicted LV and scar segmentations achieved 96% and 75% balanced accuracy, respectively, and 0.93 and 0.57 Dice coefficient when compared to trained expert segmentations. The mean scar burden difference between manual and predicted segmentations was 2%. Conclusion: We developed and validated a deep neural network for automatic, anatomically accurate expert-level LGE- CMR myocardium and scar/fibrosis segmentation, allowing direct calculation of clinical measures. Given the training set heterogeneity, our approach could be extended to multiple imaging modalities and patient pathologies.

Prioritizing drug repurposing candidates for downstream studies remains challenging. Here, the authors present a high-throughput approach to identify and validate drug repurposing candidates, integrating human gene expression, drug perturbation, and clinical data from publicly available resources.

Biochar, as a soil amendment, has been reported to improve plant growth by increasing soil moisture and retaining nutrients. In a previous 12-week greenhouse study with highbush blueberry (Vaccinium hybrid), we found that amending soil with biochar alone or in combination with bokashi (fermented wheat bran) increased plant growth relative to unamended soil. The biochar was produced from mixed conifer species during conversion of wood to energy. In the current study, we aimed to validate the greenhouse findings under field conditions in western Oregon. The specific objectives of this 2-year study were to determine the effect of amending soil with biochar or a combination of biochar and bokashi on growth and early fruit production during establishment of northern highbush blueberry (Vaccinium corymbosum L.). To achieve these objectives, we transplanted ‘Duke’ blueberry plants into soil that was either unamended or amended with biochar or 4:1 (v/v) mixtures of biochar and bokashi or biochar and douglas fir [Pseudotsuga menziesii (Mirb.) Franco] sawdust. Each amendment was either applied in the planting hole or incorporated into the row. A treatment with douglas fir sawdust incorporated into the row was also included and represented the industry standard for the region. Plants grown in soil amended with biochar (in the planting hole or row) had 40% to 74% greater total dry weight at the end of the first growing season and 70% to 82% greater fruit yield in the second season than those grown with no amendments or in soil amended with sawdust. However, leaf Mg concentrations were lower with biochar, suggesting it could limit Mg uptake in blueberry. Soil amended with sawdust, on the other hand, was higher in organic matter, microbial activity, and wet stable aggregates than the other soil treatments but resulted in lower leaf N concentrations during the second year after planting. Unlike in the greenhouse study, biochar had no effect on root colonization by mycorrhizal fungi, and there was no benefit to using biochar with bokashi. Adding 4 L of biochar to the planting hole was considerably more economical than applying it to the row and cost $1320/ha less than the industry standard of incorporating sawdust in the row. These findings indicate that biochar is a promising soil amendment for commercial production of highbush blueberry.

[This corrects the article DOI: 10.1371/journal.pone.0208645.].

BackgroundAs diagnostic tests for COVID-19 were broadly deployed under Emergency Use Authorization, there emerged a need to understand the real-world utilization and performance of serological testing across the United States.MethodsSix health systems contributed electronic health records and/or claims data, jointly developed a master protocol, and used it to execute the analysis in parallel. We used descriptive statistics to examine demographic, clinical, and geographic characteristics of serology testing among patients with RNA positive for SARS-CoV-2.ResultsAcross datasets, we observed 930,669 individuals with positive RNA for SARS-CoV-2. Of these, 35,806 (4%) were serotested within 90 days; 15% of which occurred 30%) in some datasets-limiting our ability to examine differences in serological testing by race. In datasets where race/ethnicity information was available, we observed a greater distribution of White individuals among those serotested; however, the time between RNA and serology tests appeared shorter in Black compared to White individuals. Test manufacturer data was available in half of the datasets contributing to the analysis.ConclusionOur results inform the underlying context of serotesting during the first year of the COVID-19 pandemic and differences observed between claims and EHR data sources-a critical first step to understanding the real-world accuracy of serological tests. Incomplete reporting of race/ethnicity data and a limited ability to link test manufacturer data, lab results, and clinical data challenge the ability to assess the real-world performance of SARS-CoV-2 tests in different contexts and the overall U.S. response to current and future disease pandemics.

BackgroundReal-world performance of COVID-19 diagnostic tests under Emergency Use Authorization (EUA) must be assessed. We describe overall trends in the performance of serology tests in the context of real-world implementation.MethodsSix health systems estimated the odds of seropositivity and positive percent agreement (PPA) of serology test among people with confirmed SARS-CoV-2 infection by molecular test. In each dataset, we present the odds ratio and PPA, overall and by key clinical, demographic, and practice parameters.ResultsA total of 15,615 people were observed to have at least one serology test 14-90 days after a positive molecular test for SARS-CoV-2. We observed higher PPA in Hispanic (PPA range: 79-96%) compared to non-Hispanic (60-89%) patients; in those presenting with at least one COVID-19 related symptom (69-93%) as compared to no such symptoms (63-91%); and in inpatient (70-97%) and emergency department (93-99%) compared to outpatient (63-92%) settings across datasets. PPA was highest in those with diabetes (75-94%) and kidney disease (83-95%); and lowest in those with auto-immune conditions or who are immunocompromised (56-93%). The odds ratios (OR) for seropositivity were higher in Hispanics compared to non-Hispanics (OR range: 2.59-3.86), patients with diabetes (1.49-1.56), and obesity (1.63-2.23); and lower in those with immunocompromised or autoimmune conditions (0.25-0.70), as compared to those without those comorbidities. In a subset of three datasets with robust information on serology test name, seven tests were used, two of which were used in multiple settings and met the EUA requirement of PPA ≥87%. Tests performed similarly across datasets.ConclusionAlthough the EUA requirement was not consistently met, more investigation is needed to understand how serology and molecular tests are used, including indication and protocol fidelity. Improved data interoperability of test and clinical/demographic data are needed to enable rapid assessment of the real-world performance of in vitro diagnostic tests.

Abstract Heart failure (HF) has no cure and, for HF with preserved ejection fraction (HFpEF), no life-extending treatments. Defining the clinical epidemiology of HF could facilitate earlier identification of high-risk individuals. We define the clinical epidemiology of HF subtypes (HFpEF and HF with reduced ejection fraction [HFrEF]), identified among 2.7 million individuals receiving routine clinical care. Differences in patterns and rates of accumulation of comorbidities, frequency of hospitalization, use of specialty care, were defined for each HF subtype. Among 28,156 HF cases, 8322 (30%) were HFpEF and 11,677 (42%) were HFrEF. HFpEF was the more prevalent subtype among older women. 177 Phenotypes differentially associated with HFpEF versus HFrEF. HFrEF was more frequently associated with diagnoses related to ischemic cardiac injury while HFpEF was associated more with non-cardiac comorbidities and HF symptoms. These comorbidity patterns were frequently present 3 years prior to a HFpEF diagnosis. HF subtypes demonstrated distinct patterns of clinical co-morbidities and disease progression. For HFpEF, these comorbidities were often non-cardiac and manifested prior to the onset of a HF diagnosis. Recognizing these comorbidity patterns, along the care continuum, may present a window of opportunity to identify individuals at risk for developing incident HFpEF.