bluuebunny/crossref_metadata_2025_split huggingface dataset:
Progression of Frailty and Cardiovascular Outcomes Among Medicare Beneficiaries
Authors: Gong Yusi , Song Yang , Xu Jiaman , Dong Huaying , Orkaby Ariela R. , Kramer Daniel B. , Dodson John A. , Strom Jordan B. 
Published: February 2024

ABSTRACTBackgroundFrailty is associated with adverse cardiovascular outcomes independent of age and comorbidities, yet the independent influence of frailty progression remains uncertain.MethodsMedicare Fee-for-service beneficiaries ≥ 65 years at cohort inception with continuous enrollment from 2003-2015 were included. Frailty trajectory was measured by annualized change in a validated claims-based frailty index (CFI) over a 5-year period. Linear mixed effects models, adjusting for baseline frailty, were used to estimate CFI change over a 5-year period. Survival analysis was used to evaluate associations of frailty progression and future health outcomes (major adverse cardiovascular and cerebrovascular events [MACCE], all-cause death, heart failure, myocardial infarction, ischemic stroke, and days alive at home [DAH] within the following calendar year).Results26.4 million unique beneficiaries were included (mean age 75.4 ± 7.0 years, 57% female, 13% non-White). In total, 20% had frailty progression, 66% had no change in frailty, and 14% frailty regression over median follow-up of 2.4 years. Compared to those without a change in CFI, when adjusting for baseline frailty, those with frailty progression had significantly greater risk of incident MACCE (hazard ratio [HR] 2.30, 95% confidence interval [CI] 2.30-2.31), all-cause mortality (HR 1.59, 95% CI 1.58-1.59), acute myocardial infarction (HR 1.78, 95% CI 1.77-1.79), heart failure (HR 2.78, 95% CI 2.77-2.79), and stroke (HR 1.78, 95% CI 1.77-1.79). There was also a graded increase in risk of each outcome with more rapid progression and significantly fewer DAH with the most rapid vs. the slowest progression group (270.4 ± 112.3 vs. 308.6 ± 93.0 days, rate ratio 0.88, 95% CI 0.87-0.88, p < 0.001).ConclusionsIn this large, nationwide sample of Medicare beneficiaries, frailty progression, independent of baseline frailty, was associated with fewer DAH and a graded risk of MACCE, all-cause mortality, myocardial infarction, heart failure, and stroke compared to those without progression.NON-STANDARD ABBREVIATIONS AND ACRONYMSClaims-based frailty index (CFI)Major adverse cardiovascular and cerebrovascular events (MACCE)Number of days alive at home within the following calendar year (DAH)Medicare Fee-for-Service (FFS)
Human cytomegalovirus glycoprotein variants governing viral tropism and syncytium formation in epithelial cells and macrophages
Authors: Cimato Giorgia , Zhou Xuan , Brune Wolfram , Frascaroli Giada 
Published: February 2024

AbstractHuman cytomegalovirus (HCMV) displays a broad cell tropism, and the infection of biologically relevant cells such as epithelial, endothelial, and hematopoietic cells supports viral transmission, systemic spread, and pathogenesis in the human host. HCMV strains differ in their ability to infect and replicate in these cell types, but the genetic basis of these differences has remained incompletely understood. In this study, we investigated HCMV strain VR1814, which is highly infectious for epithelial cells and macrophages and induces cell-cell fusion in both cell types. A VR1814-derived bacterial artificial chromosome (BAC) clone, FIX-BAC, was generated many years ago but has fallen out of favor because of its modest infectivity. By sequence comparison and genetic engineering of FIX, we demonstrate that the high infectivity of VR1814 and its ability to induce syncytium formation in epithelial cells and macrophages depends on VR1814-specific variants of the envelope glycoproteins gB, UL128, and UL130. We also show that UL130-neutralizing antibodies inhibit syncytium formation, and a FIX-specific mutation in UL130 is responsible for its low infectivity by reducing the amount of the pentameric glycoprotein complex in viral particles. Moreover, we found that a VR1814-specific mutation in US28 further increases viral infectivity in macrophages, possibly by promoting lytic rather than latent infection of these cells. Our findings show that variants of gB and the pentameric complex are major determinants of infectivity and syncytium formation in epithelial cells and macrophages. Furthermore, the VR1814-adjusted FIX strains can serve as valuable tools to study HCMV infection of myeloid cells.ImportanceHCMV is a major cause of morbidity and mortality in transplant patients and the leading cause of congenital infections. HCMV infects various cell types, including epithelial cells and macrophages, and some strains induce the fusion of neighboring cells, leading to the formation of large multinucleated cells called syncytia. This process may limit the exposure of the virus to host immune factors and facilitate its spread. However, the reason why some HCMV strains exhibit a broader cell tropism and why some induce cell fusion more than others is not well understood. We compared two closely related HCMV strains and provided evidence that small differences in viral envelope glycoproteins can massively increase or decrease the virus infectivity and its ability to induce syncytium formation. The results of the study suggest that natural strain variations may influence HCMV infection and pathogenesis in humans.
Tackling inequalities in preconception health and care: barriers, facilitators and recommendations for action from the 2023 UK Preconception EMCR Network conference
Authors: Schoenaker Danielle , Hall Jennifer , Stewart Catherine , Hanley Stephanie J. , Cassinelli Emma H. , Benton Madeleine , Wynn-Jones Alexandra Azzari , Chawla Mehar , Currie Sinéad ,   2023 UK Preconception EMCR Network conference workshop participants
Published: February 2024

AbstractReducing inequalities in preconception health and care is critical to improving the health and life chances of current and future generations. A hybrid workshop was held at the 2023 UK Preconception Early and Mid-Career Researchers (EMCR) Network conference to co-develop recommendations on ways to address inequalities in preconception health and care. The workshop engaged multi-disciplinary professionals across diverse career stages and people with lived experience (total n=69). Interactive discussions explored barriers to achieving optimal preconception health, driving influences of inequalities, and recommendations. The Socio-Ecological Model framed the identified themes, with recommendations structured at interpersonal (e.g. community engagement), institutional (e.g. integration of preconception care within existing services) and environmental/societal levels (e.g. education in schools). The co-developed recommendations provide a framework for addressing inequalities in preconception health, emphasising the importance of a whole-systems approach. Further research and evidence-based interventions are now needed to advance the advocacy and implementation of our recommendations.
COVID-19 vaccination was a rare potential etiology for cause of death after medicolegal autopsy. A Finnish nationwide study
Authors: Pakanen Lasse , Nieminen Tuomo , Kuvaja Paula , Nohynek Hanna , Goebeler Sirkka , Artama Miia , Hovi Petteri 
Published: February 2024

ABSTRACTCOVID-19 vaccinations began globally at the end of 2020. By the end of 2021, 9.8 million doses were given in Finland. Regarding safety, most vaccine-related adverse reactions have been mild, but serious and lethal ones have also occurred. Autopsies in post vaccination deaths may give insight to the extent of fatal health conditions with potential COVID-19 vaccine etiology and provide new hypotheses of possible causalities between vaccination and severe health conditions. We searched the complete documentation on all medicolegal autopsies in Finland between December 2020 and December 2021 to assess how often the basis for autopsy was a suspected fatal adverse reaction to COVID-19 vaccination, and whether vaccination remained a potential etiology for any health condition determined as a cause of death after the autopsy. We linked register-based data on individual COVID-19 vaccination course and pre-existing health conditions.We found 428 autopsy cases with a mention of COVID-19 vaccination, and prior to autopsy, vaccination was suspected to play a part in 76 deaths. Post autopsy, a forensic pathologist considered vaccination as a potential etiology in five underlying and seven contributory causes of death. These included seven thromboembolisms, two diabetic ketoacidoses, one myocarditis, one acute pancreatitis, and one eosinophilic granulomatosis with polyangiitis. In relation to the number of vaccinations within Finland, a suspicion of vaccine-related serious adverse reaction was rarely an indication for medicolegal autopsy. Even less frequently was vaccination considered to play a part in the process leading to death, although considerable doubt remains in the accuracy of individual considerations, and autopsy cannot definitively confirm causality between vaccination and death. Regarding vaccination safety, continuing evaluation of suspected vaccine-related deaths is essential, and an autopsy should be part of the investigation when such a suspicion arises.
Was CED the Right Choice? A Decision-Theoretic Evaluation of CMS’s ‘Cover with Evidence Development’ Policy for Aducanumab
Authors: Popp Jonah , Jutkowitz Eric , Trikalinos Thomas 
Published: February 2024

BackgroundIn 2022, the Centers for Medicare & Medicaid Services (CMS) issued its final national coverage policy for aducanumab, a novel FDA-approved treatment for Alzheimer’s disease, deciding to ‘Cover with Evidence Development’ (CED). CMS will thus only pay for the treatment of AD patients enrolled in an approved randomized controlled trial (RCT). We sought to understand whether, given current evidence, CED was best from a societal perspective.MethodsWe conducted a modeling-based expected value of sample information analysis to estimate the expected net decision-theoretic value of a further RCT to evaluate the clinical efficacy of high-dose (10 mg/kg) aducanumab and to determine what sized trial, if any, is optimal conditional on an initial decision to cover or not. We also evaluated the expected net benefit of the manufacturer’s proposed RCT (‘ENVISION’). We considered two post-trial decision criteria: cost-effectiveness given updated evidence (‘efficiency’) and does the new trial demonstrate a statistical significant (p<0.05) clinical benefit. Results were used to calculate the expected population net monetary benefit (NMB) of four decision alternatives (including CED) depending on an initial coverage and trial decision. We ranked alternatives and calculated the expected opportunity loss of a suboptimal decision. We used a societal perspective and focused on willingness-to-pay (WTP) values for a quality-adjusted life year (QALY) between $50K-$200K. We conducted scenario analyses using different assumptions about population size, efficacy, and drug cost.FindingsCMS’s decision to not cover aducanumab avoids an expected societal loss (NMB) of $15B-$110B. Even an optimally designed RCT would confer no or negative decision-theoretic value for WTP≤$100K or with statistical significance as a post-trial decision criterion, respectively, and thus denying coverage without a trial (rather than CED) is clearly preferable. For WTP=$150K (WTP=$200K) and assuming an efficiency criterion, CED with ENVISION or a similar trial is reasonable (decidedly optimal). The case for future research would become less ambiguous if the manufacturer again voluntarily dropped the price ≥50%.InterpretationThe societal net value of a future trial (and thus CED) depends on how CMS would use the trial results to update its coverage decision and the WTP per QALY. Assuming CMS policymakers can avoid the pitfalls of a legal framework that limits their ability to consider costs in coverage decisions, the CED decision is at least reasonable, if not optimal, if a QALY is valued ≥$150K.
Unbiased characterization of atrial fibrillation phenotypic architecture provides insight to genetic liability and clinically relevant outcomes
Authors: Davogustto Giovanni , Zhao Shilin , Li Yajing , Farber-Eger Eric , Lowery Brandon D. , Shaffer Lauren Lee , Mosley Jonathan D. , Shoemaker M. Benjamin , Xu Yaomin , Roden Dan M. , Wells Quinn S. 
Published: February 2024

ABSTRACTBackgroundAtrial Fibrillation (AF) is a common and clinically heterogeneous arrythmia. Machine learning (ML) algorithms can define data-driven disease subtypes in an unbiased fashion, but whether the AF subgroups defined in this way align with underlying mechanisms, such as high polygenic liability to AF or inflammation, and associate with clinical outcomes is unclear.MethodsWe identified individuals with AF in a large biobank linked to electronic health records (EHR) and genome-wide genotyping. The phenotypic architecture in the AF cohort was defined using principal component analysis of 35 expertly curated and uncorrelated clinical features. We applied an unsupervised co-clustering machine learning algorithm to the 35 features to identify distinct phenotypic AF clusters. The clinical inflammatory status of the clusters was defined using measured biomarkers (CRP, ESR, WBC, Neutrophil %, Platelet count, RDW) within 6 months of first AF mention in the EHR. Polygenic risk scores (PRS) for AF and cytokine levels were used to assess genetic liability of clusters to AF and inflammation, respectively. Clinical outcomes were collected from EHR up to the last medical contact.ResultsThe analysis included 23,271 subjects with AF, of which 6,023 had available genome-wide genotyping. The machine learning algorithm identified 3 phenotypic clusters that were distinguished by increasing prevalence of comorbidities, particularly renal dysfunction, and coronary artery disease. Polygenic liability to AF across clusters was highest in the low comorbidity cluster. Clinically measured inflammatory biomarkers were highest in the high comorbid cluster, while there was no difference between groups in genetically predicted levels of inflammatory biomarkers. Subgroup assignment was associated with multiple clinical outcomes including mortality, stroke, bleeding, and use of cardiac implantable electronic devices after AF diagnosis.ConclusionPatient subgroups identified by unsupervised clustering were distinguished by comorbidity burden and associated with risk of clinically important outcomes. Polygenic liability to AF across clusters was greatest in the low comorbidity subgroup. Clinical inflammation, as reflected by measured biomarkers, was lowest in the subgroup with lowest comorbidities. However, there were no differences in genetically predicted levels of inflammatory biomarkers, suggesting associations between AF and inflammation is driven by acquired comorbidities rather than genetic predisposition.
Interference of mid-level sound statistics underlie human speech recognition sensitivity in natural noise
Authors: Clonan Alex C. , Zhai Xiu , Stevenson Ian H. , Escabí Monty A. 
Published: February 2024

AbstractRecognizing speech in noise, such as in a busy restaurant, is an essential cognitive skill where the task difficulty varies across environments and noise levels. Although there is growing evidence that the auditory system relies on statistical representations for perceiving1-5and coding4,6-9natural sounds, it’s less clear how statistical cues and neural representations contribute to segregating speech in natural auditory scenes. We demonstrate that human listeners rely on mid-level statistics to segregate and recognize speech in environmental noise. Using natural backgrounds and variants with perturbed spectro-temporal statistics, we show that speech recognition accuracy at a fixed noise level varies extensively across natural backgrounds (0% to 100%). Furthermore, for each background the unique interference created by summary statistics can mask or unmask speech, thus hindering or improving speech recognition. To identify the neural coding strategy and statistical cues that influence accuracy, we developedgeneralized perceptual regression, a framework that links summary statistics from a neural model to word recognition accuracy. Whereas a peripheral cochlear model accounts for only 60% of perceptual variance, summary statistics from a mid-level auditory midbrain model accurately predicts single trial sensory judgments, accounting for more than 90% of the perceptual variance. Furthermore, perceptual weights from the regression framework identify which statistics and tuned neural filters are influential and how they impact recognition. Thus, perception of speech in natural backgrounds relies on a mid-level auditory representation involving interference of multiple summary statistics that impact recognition beneficially or detrimentally across natural background sounds.Significance StatementRecognizing speech in natural auditory scenes with competing talkers and environmental noise is a critical cognitive skill. Although normal listeners effortlessly perform this task, for instance in a crowded restaurant, it challenges individuals with hearing loss and our most sophisticated machine systems. We tested human participants listening to speech in natural noises with varied statistical characteristics and demonstrate that they rely on a statistical representation of sounds to segregate speech from environmental noise. Using a model of the auditory system, we then demonstrate that a brain inspired statistical representation of natural sounds accurately predicts human perceptual trends across wide range of natural backgrounds and noise levels and reveals key statistical features and neural computations underlying human abilities for this task.
A haplotype-resolved reference genome ofQuercus albasheds light on the evolutionary history of oaks
Authors: Larson Drew A. , Staton Margaret E. , Kapoor Beant , Islam-Faridi Nurul , Zhebentyayeva Tetyana , Fan Shenghua , Stork Jozsef , Thomas Austin , Ahmed Alaa S. , Stanton Elizabeth C. , Houston Allan , Schlarbaum Scott E. , Hahn Matthew W. , Carlson John E. , Abbott Albert G. , DeBolt Seth , Dana Nelson C. 
Published: February 2024

SummaryWhite oak (Quercus alba) is an abundant forest tree species across eastern North America that is ecologically, culturally, and economically important.We report the first haplotype-resolved chromosome-scale genome assembly ofQ. albaand conduct comparative analyses of genome structure and gene content against other published Fagaceae genomes. In addition, we probe the genetic diversity of this widespread species and investigate its phylogenetic relationships with other oaks using whole-genome data.Our genome assembly comprises two haplotypes each consisting of 12 chromosomes. We found that the species has high genetic diversity, much of which predates the divergence ofQ. albafrom other oak species and likely impacts divergence time estimation inQuercus. Our phylogenetic results highlight phylogenetic discordance across the genus and suggest different relationships among North American oaks than have been reported previously. Despite a high preservation of chromosome synteny and genome size across theQuercusphylogeny, certain gene families have undergone rapid changes in size including resistance genes (R genes).The white oak genome represents a major new resource for studying genome diversity and evolution inQuercusand forest trees more generally. Future research will continue to reveal the full scope of genomic diversity across the white oak clade.
A selection of Golden Gate vectors to simplify recombinant protein production inEscherichia coli
Authors: Fairhead Michael , Koekemoer Lizbe , Williams Eleanor , von Delft Frank 
Published: February 2024

SummaryIn this work multiple plasmids have been created to allow the simple Golden Gate cloning of a target gene for recombinant protein production inEscherichia coli. To simplify as much as possible the generation of different target gene vector combinations, the 22 plasmids contain the same Golden Gate cloning sites (BsaI), antibiotic resistance (kanamycin) and promoter (T7) for expression in the standard protein production strain ofE. coliBL21[DE3]. The plasmid set includes commonly used tags for purification and assays (his, twin-strep and avi tag) as well as fusion protein partners that may aid target protein solubility and yield, SUMO, MBP, GST and sfGFP. Also included are plasmids with secretion peptide signals for transport of the target protein to theE. coliperiplasmviavarious pathways (SEC, SRP, TatA).We have evaluated the 4 of the vectors using a test super folder GFP insert and found that using the Golden Gate process allows cloning efficiencies of greater than 90% to be routinely obtained. Vectors were further evaluated by expressing and purifying the target insert. The plasmid vector set described herein should prove useful to any investigator who has to routinely evaluate numerous protein expression constructs and are freely available through Addgene.
Pseudotyped virus infection of multiplexed ACE2 libraries reveals SARS-CoV-2 variant shifts in receptor usage
Authors: Shukla Nidhi , Roelle Sarah M. , Snell John C. , DelSignore Olivia , Bruchez Anna M. , Matreyek Kenneth A. 
Published: February 2024

AbstractPairwise compatibility between virus and host proteins can dictate the outcome of infection. During transmission, both inter- and intraspecies variabilities in receptor protein sequences can impact cell susceptibility. Many viruses possess mutable viral entry proteins and the patterns of host compatibility can shift as the viral protein sequence changes. This combinatorial sequence space between virus and host is poorly understood, as traditional experimental approaches lack the throughput to simultaneously test all possible combinations of protein sequences. Here, we created a pseudotyped virus infection assay where a multiplexed target-cell library of host receptor variants can be assayed simultaneously using a DNA barcode sequencing readout. We applied this assay to test a panel of 30 ACE2 orthologs or human sequence mutants for infectability by the original SARS-CoV-2 spike protein or the Alpha, Beta, Gamma, Delta, and Omicron BA1 variant spikes. We compared these results to an analysis of the structural shifts that occurred for each variant spike’s interface with human ACE2. Mutated residues were directly involved in the largest shifts, although there were also widespread indirect effects altering interface structure. The N501Y substitution in spike conferred a large structural shift for interaction with ACE2, which was partially recreated by indirect distal substitutions in Delta, which does not harbor N501Y. The structural shifts from N501Y greatly influenced the set of animal orthologs the variant spike was capable of interacting with. Out of the thirteen non-human orthologs, ten exhibited unique patterns of variant-specific compatibility, demonstrating that spike sequence changes during human transmission can toggle ACE2 compatibility and potential susceptibility of other animal species, and cumulatively increase overall compatibilities as new variants emerge. These experiments provide a blueprint for similar large-scale assessments of protein compatibility during entry by diverse viruses. This dataset demonstrates the complex compatibility relationships that occur between variable interacting host and virus proteins.