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Abstract Aims Proteomic profiling offers an expansive approach to biomarker discovery and mechanistic hypothesis generation for LV remodelling, a critical component of heart failure (HF). We sought to identify plasma proteins cross‐sectionally associated with left ventricular (LV) size and geometry in a diverse population‐based cohort without known cardiovascular disease (CVD). Methods and results Among participants of the Multi‐Ethnic Study of Atherosclerosis (MESA), we quantified plasma abundances of 1305 proteins using an aptamer‐based platform at exam 1 (2000–2002) and exam 5 (2010–2011) and assessed LV structure by cardiac magnetic resonance (CMR) at the same time points. We used multivariable linear regression with robust variance to assess cross‐sectional associations between plasma protein abundances and LV structural characteristics at exam 1, reproduced findings in later‐life at exam 5, and explored relationships of associated proteins using annotated enrichment analysis. We studied 763 participants (mean age 60 ± 10 years at exam 1; 53% female; 19% Black race; 31% Hispanic ethnicity). Following adjustment for renal function and traditional CVD risk factors, plasma levels of 3 proteins were associated with LV mass index at both time points with the same directionality (FDR

Abstract Aims Intercellular adhesion molecule‐1 (ICAM‐1) facilitates inflammation via leucocyte recruitment and has been implicated in heart failure with preserved ejection fraction (HFpEF). Approximately 35% of African American individuals carry a copy of an ICAM1 missense variant (rs5491; p.K56M), which is associated with an increased risk of HFpEF. The pathways by which rs5491 increases HFpEF risk are not well defined. We evaluated the circulating immune cell profile of rs5491. Methods Among African American individuals in the Multi‐Ethnic Study of Atherosclerosis, we evaluated the associations of rs5491 with 29 circulating peripheral blood mononuclear cell subsets. The top immune cells were then related to echocardiographic measures of structure and function. Results Among 502 individuals with immune cell profiling (mean age 63 years, 51% female), 191 individuals (38%) had at least one copy of rs5491. Each additional rs5491 allele was significantly associated with higher proportions of Tc17 CD8+ cytotoxic T cells (β = 1.34, SE = 0.45, P = 9.5 × 10−5) and Tc2 CD8+ cytotoxic T cells (β = 1.19, SE = 0.44, P = 0.00012). There were no other associations noted between rs5491 and the remaining immune cells. A higher proportion of Tc17 cells was significantly associated with a higher left ventricular ejection fraction, E/e′ average and right ventricular systolic pressure (RVSP), while a higher proportion of Tc2 cells was significantly associated with a higher RVSP. Conclusions The ICAM1 p.K56M variant (rs5491) carries a distinct and inflammatory T‐cell subset profile. These cytotoxic T cells are in turn associated with alterations in cardiac function and adverse haemodynamics later in life, thus providing insight into pathways by which rs5491 may increase the risk of HFpEF.

Abstract The role of rare non-coding variation in complex human phenotypes is still largely unknown. To elucidate the impact of rare variants in regulatory elements, we performed a whole-genome sequencing association analysis for height using 333,100 individuals from three datasets: UK Biobank (N = 200,003), TOPMed (N = 87,652) and All of Us (N = 45,445). We performed rare (

Abstract Whole genome sequences (WGS) enable discovery of rare variants which may contribute to missing heritability of coronary artery disease (CAD). To measure their contribution, we apply the GREML-LDMS-I approach to WGS of 4949 cases and 17,494 controls of European ancestry from the NHLBI TOPMed program. We estimate CAD heritability at 34.3% assuming a prevalence of 8.2%. Ultra-rare (minor allele frequency ≤ 0.1%) variants with low linkage disequilibrium (LD) score contribute ~50% of the heritability. We also investigate CAD heritability enrichment using a diverse set of functional annotations: i) constraint; ii) predicted protein-altering impact; iii) cis-regulatory elements from a cell-specific chromatin atlas of the human coronary; and iv) annotation principal components representing a wide range of functional processes. We observe marked enrichment of CAD heritability for most functional annotations. These results reveal the predominant role of ultra-rare variants in low LD on the heritability of CAD. Moreover, they highlight several functional processes including cell type-specific regulatory mechanisms as key drivers of CAD genetic risk.

Abstract In the electron Born self-energy (eBse) model, free electrons are of finite-size and possess both a rest mass, m e , as well as, a Born mass, m e B = 74,000 m e . The Born mass, which originates from the energy contained within the electric field that surrounds a finite-sized electron, serves as a Dark Matter (DM) particle in this theory (designated eBDM, electron Born Dark Matter). The equation of state for m e B is w = -1, which implies that two Born masses experience a repulsive gravitational interaction. This repulsive gravitational interaction stabilizes the formation of a DM halo of m e B particles, of typical halo size ~ 100 kpc, around a central mass M (e.g. a galaxy), where this gravitational stability arises from the competing attractive M - m e B and repulsive m e B - m e B interactions. A solution of the linearized Poisson-Boltzmann equation, for this system, allows one to derive an expression for the rotational velocity V eBDM (R), as a function of radius R from the galactic center. A composite model composed of rotational velocity contributions from the galactic bulge, galactic disk, as well as, V eBDM (R) is found to provide a good description of the Grand Rotation Curves for the Milky Way and M31 galaxies.

Abstract Emergency physicians are well‐positioned to take a leadership role in telehealth, particularly in emerging categories such as triage, direct acute unscheduled care, and virtual observation. However, the growth of telehealth has outpaced curricular development in emergency medicine (EM) residency programs. This manuscript presents a model longitudinal telehealth curriculum, developed by the consensus of education experts, including representatives from the telehealth interest groups from EM's two primary specialty societies: the American College of Emergency Physicians and the Society for Academic Emergency Medicine. The curriculum describes overarching goals and components that may serve as a foundation for individual institutions seeking to train future operational and academic leaders in telehealth.

Background Available evidence supports the importance of inflammation in atrial fibrillation (AF) pathogenesis, yet general anti‐inflammatory therapies have failed to show benefit for prevention of the arrhythmia. Better understanding of the specific inflammatory pathways involved is necessary to advance therapeutics. Methods and Results We evaluated 9 circulating markers of inflammation measured by immunoassays and incidence of AF in a population‐based older cohort. Biomarkers included measures of general inflammation and the NLR (nucleotide‐binding oligomerization domain‐like receptor) family pyrin domain containing 3 inflammasome, TNF‐α (tumor necrosis factor α), monocyte activation markers, and sIL‐2 (soluble interleukin‐2). Among 5726 participants (median age 72 years), 1836 developed AF over median follow‐up of 11.5 years. After adjustment for conventional risk factors, 5 biomarkers were positively associated with incident AF: IL‐6 (interleukin‐6), hazard ratio (HR), 1.14 (95% CI, 1.07–1.21); hs‐CRP (high‐sensitivity C‐reactive protein), HR, 1.05 (95% CI, 1.01–1.09); white blood cell count, HR, 1.18 (95% CI, 1.04–1.35); sTNFR1 (soluble TNF receptor 1), HR, 1.21 (95% CI, 1.05–1.39); and sIL‐2Rα (sIL‐2 receptor α), HR, 1.16 (95% CI, 1.05–1.29) (all per doubling of biomarker). sCD14, sCD163, IL‐18, and IL‐1 receptor antagonist showed no association with AF. Upon concurrent adjustment for all biomarkers, only IL‐6 remained significantly associated with the arrhythmia, HR, 1.17 (95% CI, 1.07–1.26). Conclusions Among older adults, IL‐6, hs‐CRP, white blood cell count, sTNFR1, and sIL‐2Rα were positively associated with incident AF, but only IL‐6 retained significance on concurrent adjustment. These findings newly document associations for sTNFR1 and sIL‐2Rα and lend support to a preeminent role for IL‐6 in development of this arrhythmia. The efficacy of IL‐6 blockade for AF prevention awaits completion of appropriate clinical trials.

Abstract Introduction Antimicrobial resistance (AMR) is a global public health challenge. Global efforts to decrease AMR through antimicrobial stewardship (AMS) initiatives include education and optimising the use of diagnostic technologies and antibiotics. Despite this, economic and societal challenges hinder AMS efforts. The objective of this study was to obtain insights from healthcare professionals (HCPs) on current challenges and identify opportunities for optimising diagnostic test utilisation and AMS efforts. Methods Three hundred HCPs from six countries (representing varied gross national incomes per capita, healthcare system structure, and AMR rates) were surveyed between November 2022 through January 2023. A targeted literature review and expert interviews were conducted to inform survey development. Descriptive statistics were used to summarise survey responses. Results These findings suggest that the greatest challenges to diagnostic test utilisation were economic in nature; many HCPs reported that AMS initiatives were lacking investment (32.3%) and resourcing (40.3%). High resistance rates were considered the greatest barriers to appropriate antimicrobial use (52.0%). Most HCPs found local and national guidelines to be very useful (≥ 51.0%), but areas for improvement were noted. The importance of AMS initiatives was confirmed; diagnostic practices were acknowledged to have a positive impact on decreasing AMR (70.3%) and improving patient outcomes (81.0%). Conclusion AMS initiatives, including diagnostic technology utilisation, are pivotal to decreasing AMR rates. Interpretation of these survey results suggests that while HCPs consider diagnostic practices to be important in AMS efforts, several barriers to successful implementation still exist including patient/institutional costs, turnaround time of test results, resourcing, AMR burden, and education. While some barriers differ by country, these survey results highlight areas of opportunities in all countries for improved use of diagnostic technologies and broader AMS efforts, as perceived by HCPs. Greater investment, resourcing, education, and updated guidelines offer opportunities to further strengthen global AMS efforts.

Case Presentation: A 33-year-old female with a history of antiphospholipid syndrome presented with exertional chest pain and ST-elevation in aVR with diffuse ST-segment depression. An emergent catheterization was performed, which showed an isolated 99% stenosis in the left main coronary artery. The remaining coronary arteries were without any stenosis. Successful stent placement was performed, and the patient was discharged without complications. Discussion: Previous guidelines have suggested that ST-segment elevation with diffuse ST-segment depression should be treated as a ST-elevation myocardial infarction equivalent involving either the left-main or proximal left anterior descending coronary artery. However, recent data suggests that most of these cases may not involve that region. Regardless, this electrocardiogram finding should still be a concern for acute coronary syndrome, with the need for urgent catheterization.

This study evaluated the in vitro effectiveness of anti-cryptosporidial agents nitazoxanide, halofuginone, the pyrazolopyridine analog KDU731, and paromomycin (PMC) in combating the significant zoonotic pathogen Cryptosporidium parvum. The study utilized HCT-8 host cells to culture C. parvum and fluorescent microscopy/quantitative PCR (qPCR) for detecting parasitic growth. The efficacy of the compounds was assessed by calculating their inhibitory concentrations (IC) against the total growth of C. parvum at 48 h post-infection. The study further investigated the impact of these compounds on early parasitophorous vacuole (PV) formation, merozoite egress, host cell viability, and cell growth cycle. KDU731 displayed the most promising profile, with low nanomolar (102 nM ± 2.28) activity and negligible host cell toxicity. This study offers new insights into the relative efficacy and safety of various anti-cryptosporidial compounds, highlighting their stage-specific effects on C. parvum and the consequential impacts on host cells. Identifying safe and effective anti-cryptosporidial agents contributes significantly to the One Health approach, which emphasizes the importance of integrated strategies in controlling zoonotic diseases.

Introduction Surgery is a cost-effective public health intervention. Access to safe surgery is a basic human right. However, there are still significant disparities in the access to and safety of surgical and anaesthesia care between low-income and middle-income countries and high-income countries. The Latin American Surgical Outcomes Study in Paediatrics (LASOS-Peds) is an international, observational, 14-day cohort study to investigate the incidence of 30-day in-hospital complications following elective or emergency paediatric surgery in Latin American countries.Methods and analysis LASOS-Peds is a prospective, international, multicentre observational study of paediatric patients undergoing both elective and non-elective surgeries and procedures, inpatient and outpatient, including those performed outside the operating room. The primary outcome is the incidence of in-hospital postoperative complications up to 30 days after surgery. Secondary outcomes include intraoperative complications and the need for intensive care unit admission.Ethics and dissemination This study received approval from the Institutional Review Board of the coordinating centre (Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo) as well as from all the participating centres. The study results are expected to be published in peer-reviewed journals and disseminated at international conferences.Trial registration number NCT05934682.

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 We construct non-linear machine learning (ML) prediction models for systolic and diastolic blood pressure (SBP, DBP) using demographic and clinical variables and polygenic risk scores (PRSs). We developed a two-model ensemble, consisting of a baseline model, where prediction is based on demographic and clinical variables only, and a genetic model, where we also include PRSs. We evaluate the use of a linear versus a non-linear model at both the baseline and the genetic model levels and assess the improvement in performance when incorporating multiple PRSs. We report the ensemble model’s performance as percentage variance explained (PVE) on a held-out test dataset. A non-linear baseline model improved the PVEs from 28.1 to 30.1% (SBP) and 14.3% to 17.4% (DBP) compared with a linear baseline model. Including seven PRSs in the genetic model computed based on the largest available GWAS of SBP/DBP improved the genetic model PVE from 4.8 to 5.1% (SBP) and 4.7 to 5% (DBP) compared to using a single PRS. Adding additional 14 PRSs computed based on two independent GWASs further increased the genetic model PVE to 6.3% (SBP) and 5.7% (DBP). PVE differed across self-reported race/ethnicity groups, with primarily all non-White groups benefitting from the inclusion of additional PRSs. In summary, non-linear ML models improves BP prediction in models incorporating diverse populations.

Background: Posterior cervical fusion (PCF) with lateral mass screws is a favorable treatment option to revise a symptomatic pseudarthrosis due to reliable rates of arthrodesis; however, this technique introduces elevated risk for wound infection and hospital readmission. A tissue-sparing PCF approach involving facet fixation instrumentation reduces the rates of postoperative complications while stabilizing the symptomatic level to achieve arthrodesis; however, these outcomes have been limited to small study cohorts from individual surgeons commonly with mixed indications for treatment. Materials and Methods: One hundred and fifty cases were identified from a retrospective chart review performed by seven surgeons across six sites in the United States. All cases involved PCF revision for a pseudarthrosis at one or more levels from C3 to C7 following anterior cervical discectomy and fusion (ACDF). PCF was performed using a tissue-sparing technique with facet instrumentation. Cases involving additional supplemental fixation such as lateral mass screws, rods, wires, or other hardware were excluded. Demographics, operative notes, postoperative complications, hospital readmission, and subsequent surgical interventions were summarized as an entire cohort and according to the following risk factors: age, sex, number of levels revised, body mass index (BMI), and history of nicotine use. Results: The average age of patients at the time of PCF revision was 55 ± 11 years and 63% were female. The average BMI was 29 ± 6 kg/m2 and 19% reported a history of nicotine use. Postoperative follow-up visits were available with a median of 68 days (interquartile range = 41–209 days) from revision PCF. There were 91 1-level, 49 2-level, 8 3-level, and 2 4±-level PCF revision cases. The mean operative duration was 52 ± 3 min with an estimated blood loss of 14 ± 1.5cc. Participants were discharged an average of 1 ± 0.05 days following surgery. Multilevel treatment resulted in longer procedure times (single = 45 min, multi = 59 min, P = 0.01) but did not impact estimated blood loss (P = 0.94). Total nights in the hospital increased by 0.2 nights with multilevel treatment (P = 0.01). Sex, age, nicotine history, and BMI had no effect on recorded perioperative outcomes. There was one instance of rehospitalization due to deep-vein thrombosis, one instance of persistent pseudarthrosis at the revised level treated with ACDF, and four instances of adjacent segment disease. In patients initially treated with multilevel ACDF, revisions occurred most commonly on the caudal level (48% of revised levels), followed by the cranial (43%), and least often in the middle level (9%). Conclusions: This chart review of perioperative and safety outcomes provides evidence in support of tissue-sparing PCF with facet instrumentation as a treatment for symptomatic pseudarthrosis after ACDF. The most common locations requiring revision were the caudal and cranial levels. Operative duration and estimated blood loss were favorable when compared to open alternatives. There were no instances of postoperative wound infection, and the majority of patients were discharged the day following surgery.

Abstract Aims Heart failure (HF) has shared genetic architecture with its risk factors: atrial fibrillation (AF), body mass index (BMI), coronary heart disease (CHD), systolic blood pressure (SBP), and type 2 diabetes (T2D). We aim to assess the association and risk prediction performance of risk‐factor polygenic risk scores (PRSs) for incident HF and its subtypes in bi‐racial populations. Methods and results Five PRSs were constructed for AF, BMI, CHD, SBP, and T2D in White participants of the Atherosclerosis Risk in Communities (ARIC) study. The associations between PRSs and incident HF and its subtypes were assessed using Cox models, and the risk prediction performance of PRSs was assessed using C statistics. Replication was performed in the ARIC study Black and Cardiovascular Health Study (CHS) White participants. In 8624 ARIC study Whites, 1922 (31% cumulative incidence) HF cases developed over 30 years of follow‐up. PRSs of AF, BMI, and CHD were associated with incident HF (P

Abstract Introduction Long-acting lipoglycopeptides such as dalbavancin may have utility in patients with Gram-positive bloodstream infections (BSI), particularly in those with barriers to discharge or who require prolonged parenteral antibiotic courses. A retrospective cohort study was performed to provide further multicenter real-world evidence on dalbavancin use as a sequential therapy for Gram-positive BSI. Methods One hundred fifteen patients received dalbavancin with Gram-positive BSI, defined as any positive blood culture or diagnosed with infective endocarditis, from 13 centers geographically spread across the United States between July 2015 and July 2021. Results Patients had a mean (SD) age of 48.5 (17.5) years, the majority were male (54%), with many who injected drugs (40%). The most common infection sources (non-exclusive) were primary BSI (89%), skin and soft tissue infection (SSTI) (25%), infective endocarditis (19%), and bone and joint infection (17%). Staphylococcus aureus accounted for 72% of index cultures, coagulase-negative Staphylococcus accounted for 18%, and Streptococcus species in 16%. Dalbavancin started a median (Q1–Q3) of 10 (6–19) days after index culture collection. The most common regimen administered was dalbavancin 1500 mg as one dose for 50% of cases. The primary outcome of composite clinical failure occurred at 12.2%, with 90-day mortality at 7.0% and 90-day BSI recurrence at 3.5%. Conclusions Dalbavancin may serve as a useful tool in facilitating hospital discharge in patients with Gram-positive BSI. Randomized controlled trials are anticipated to validate dalbavancin as a surrogate to current treatment standards.

Introduction: In the 2023 National Resident Matching Program (NRMP) match, there were 554 unfilled emergency medicine (EM) positions before the Supplemental Offer and Acceptance Program (SOAP). We sought to describe features of EM programs that participated in the match and the association between select program characteristics and unfilled positions. Methods: The primary outcome measures included the proportion of positions filled in relation to state and population density, hospital ownership type, and physician employment model. Secondary outcome measures included comparing program-specific attributes between filled and unfilled programs, including original accreditation type, year of original accreditation, the total number of approved training positions, length of training, urban-rural designation, hospital size by number of beds, resident-to-bed ratio, and the percentage of disproportionate share patients seen. Results: The NRMP Match had 276 unique participating EM programs with 554 unfilled positions. Six states offered 52% of the total NRMP positions available. Five states were associated with two-thirds of the unfilled positions. Public hospitals had a statistically significant higher match rate (88%) when compared to non-profit and for-profit hospitals, which had match rates of 80% and 75%, respectively (P

Summary: Most cases of Alzheimer's disease (AD) are late-onset dementias (LOAD). However, research on AD is predominantly of early-onset disease (EOAD). The determinants of EOAD, gene variants of APP and presenilin proteins, are not the basic precursors of LOAD. Rather, multiple other genes and associated cellular processes underlie risk for LOAD. These determinants could be modified in individuals at risk for LOAD well before signs and symptoms appear. Studying brain cells produced from patient-derived induced-pluripotent-stem-cells (iPSC), in culture, will be instrumental in developing such interventions. This paper summarises evidence accrued from iPSC culture models identifying the earliest occurring clinically targetable determinants of LOAD. Results obtained and replicated, thus far, suggest that abnormalities of bioenergetics, lipid metabolism, digestive organelle function and inflammatory activity are primary processes underlying LOAD. The application of cell culture platforms will become increasingly important in research and also on LOAD detection, assessment, and treatment in the years ahead.

Abstract Background Uncovering the functional relevance underlying verbal declarative memory (VDM) genome-wide association study (GWAS) results may facilitate the development of interventions to reduce age-related memory decline and dementia. Methods We performed multi-omics and pathway enrichment analyses of paragraph (PAR-dr) and word list (WL-dr) delayed recall GWAS from 29,076 older non-demented individuals of European descent. We assessed the relationship between single-variant associations and expression quantitative trait loci (eQTLs) in 44 tissues and methylation quantitative trait loci (meQTLs) in the hippocampus. We determined the relationship between gene associations and transcript levels in 53 tissues, annotation as immune genes, and regulation by transcription factors (TFs) and microRNAs. To identify significant pathways, gene set enrichment was tested in each cohort and meta-analyzed across cohorts. Analyses of differential expression in brain tissues were conducted for pathway component genes. Results The single-variant associations of VDM showed significant linkage disequilibrium (LD) with eQTLs across all tissues and meQTLs within the hippocampus. Stronger WL-dr gene associations correlated with reduced expression in four brain tissues, including the hippocampus. More robust PAR-dr and/or WL-dr gene associations were intricately linked with immunity and were influenced by 31 TFs and 2 microRNAs. Six pathways, including type I diabetes, exhibited significant associations with both PAR-dr and WL-dr. These pathways included fifteen MHC genes intricately linked to VDM performance, showing diverse expression patterns based on cognitive status in brain tissues. Conclusions VDM genetic associations influence expression regulation via eQTLs and meQTLs. The involvement of TFs, microRNAs, MHC genes, and immune-related pathways contributes to VDM performance in older individuals.

Abstract X-chromosomal genetic variants are understudied but can yield valuable insights into sexually dimorphic human traits and diseases. We performed a sex-stratified cross-ancestry X-chromosome-wide association meta-analysis of seven kidney-related traits (n = 908,697), identifying 23 loci genome-wide significantly associated with two of the traits: 7 for uric acid and 16 for estimated glomerular filtration rate (eGFR), including four novel eGFR loci containing the functionally plausible prioritized genes ACSL4, CLDN2, TSPAN6 and the female-specific DRP2. Further, we identified five novel sex-interactions, comprising male-specific effects at FAM9B and AR/EDA2R, and three sex-differential findings with larger genetic effect sizes in males at DCAF12L1 and MST4 and larger effect sizes in females at HPRT1. All prioritized genes in loci showing significant sex-interactions were located next to androgen response elements (ARE). Five ARE genes showed sex-differential expressions. This study contributes new insights into sex-dimorphisms of kidney traits along with new prioritized gene targets for further molecular research.

Abstract Background Heart failure (HF) is a complex clinical syndrome with persistently high mortality. High-throughput proteomic technologies offer new opportunities to improve HF risk stratification, but their contribution remains to be clearly defined. We aimed to systematically review prognostic studies using high-throughput proteomics to identify protein signatures associated with HF mortality. Methods We searched four databases and two clinical trial registries for articles published from 2012 to 2023. HF proteomics studies measuring high numbers of proteins using aptamer or antibody-based affinity platforms on human plasma or serum with outcomes of all-cause or cardiovascular death were included. Two reviewers independently screened articles, extracted data, and assessed the risk of bias. A third reviewer resolved conflicts. We assessed the risk of bias using the Risk Of Bias In Non-randomized Studies—of Exposure tool. Results Out of 5131 unique articles identified, nine articles were included in the review. The nine studies were observational; three used the aptamer platform, and six used the antibody platform. We found considerable heterogeneity across studies in measurement panels, HF definitions, ejection fraction categorization, follow-up duration, and outcome definitions, and a lack of risk estimates for most protein associations. Hence, we proceeded with a systematic review rather than a meta-analysis. In two comparable aptamer studies in patients with HF with reduced ejection fraction, 21 proteins were identified in common for the association with all-cause death. Among these, one protein, WAP four-disulfide core domain protein 2 was also reported in an antibody study on HFrEF and for the association with CV death. We proposed standardized reporting criteria to facilitate the interpretation of future studies. Conclusions In this systematic review of nine studies evaluating the association of proteomics with mortality in HF, we identified a limited number of proteins common across several studies. Heterogeneity across studies compromised drawing broad inferences, underscoring the importance of standardized approaches to reporting.

Abstract To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of European ancestry, including reference range thyrotropin (TSH), free thyroxine (FT4), free and total triiodothyronine (T3), proxies for metabolism (T3/FT4 ratio) as well as dichotomized high and low TSH levels. We revealed 259 independent significant associations for TSH (61% novel), 85 for FT4 (67% novel), and 62 novel signals for the T3 related traits. The loci explained 14.1%, 6.0%, 9.5% and 1.1% of the total variation in TSH, FT4, total T3 and free T3 concentrations, respectively. Genetic correlations indicate that TSH associated loci reflect the thyroid function determined by free T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses showed the effects of genetically determined variation in thyroid function on various clinical outcomes, including cardiovascular risk factors and diseases, autoimmune diseases, and cancer. In conclusion, our results improve the understanding of thyroid hormone physiology and highlight the pleiotropic effects of thyroid function on various diseases.

This journal for Rheumato(philes) has provided a vehicle for the interdisciplinary sharing of the challenges and interventions of our specialty. The provision of state-of-the-art information is not at the expense of the basics from which it has grown. From its initial status as a source of discomfort, a review of back pain diagnostics and therapeutics provides a background for facilitating contemporary practice. We have met the enemy in the form of COVID-19, addressing its many rheumatologic complications, and have been introduced to the vagaries of IgG4 disease. Our clinical skills are tested in recognition of primary hypertrophic osteoarthropathy. The relationship of dental health to rheumatoid arthritis and nutritional issues is currently undergoing scientific review. A unique feature, one we seldom seem to discuss, is the evaluation of disease manifestations when the customary tools are not available. The latter brings us full circle in the evolution of our field. When our colleagues found diagnostic or treatment approaches elusive, they did not call for Ghostbusters; they called for us.

Abstract Early in the Universe a chemical equilibrium exists between photons and electron–positron ( $$e^{ - } e^{ + }$$ e - e + ) pairs. In the electron Born self-energy (eBse) model the $$e^{ - } e^{ + }$$ e - e + plasma falls out of equilibrium above a glass transition temperature $$T_{G} = 1.06 \times 10^{17} K$$ T G = 1.06 × 10 17 K determined by the maximum electron/positron number density of $$1/(2R_{e} )^{3}$$ 1 / ( 2 R e ) 3 where $$R_{e}$$ R e is the electron radius. In the glassy phase ( $$T > T_{G}$$ T > T G ) the Universe undergoes exponential acceleration, characteristic of cosmic inflation, with a constant potential energy density $$\psi_{G} = 1.9 \times 10^{50} J/m^{3}$$ ψ G = 1.9 × 10 50 J / m 3 . At lower temperatures $$T < T_{G}$$ T < T G photon- $$e^{ - } e^{ + }$$ e - e + chemical equilibrium is restored and the glassy phase gracefully exits to the $$\Lambda CDM$$ Λ C D M cosmological model when the equation of state $$w = 1/3$$ w = 1 / 3 , corresponding to a cross-over temperature $$T_{X} = 0.94 \times 10^{17} K$$ T X = 0.94 × 10 17 K . In the eBse model the inflaton scalar field is temperature $$T$$ T where the potential energy density $$\psi (T)$$ ψ ( T ) is a plateau potential, in agreement with Planck collaboration 2013 findings. There are no free parameters that require fine tuning to give cosmic inflation in the eBse model.

Abstract The Agronomic Revolution of the early Cambrian refers to the most significant re-structuration of the benthic marine ecosystem in life history. Using a global compilation of trace-fossil records across the Ediacaran-Cambrian transition, this paper investigates the relationship between the benthos and depositional environments prior to, during, and after the Agronomic Revolution to shed light on habitat segregation via correspondence analysis. The results of this analysis characterize Ediacaran mobile benthic bilaterians as facies-crossing and opportunistic, with low levels of habitat specialization. In contrast, the Terreneuvian and Cambrian Series 2 reveal progressive habitat segregation, parallel to matground environmental restriction. This event was conducive to the establishment of distinct endobenthic communities along the marine depositional profile, showing that the increase in styles of animal-substrate interactions was expressed by both alpha and beta ichnodiversity. Habitat segregation at the dawn of the Phanerozoic may illustrate an early extension of the trophic group amensalism at community scale.

Teachers’ professional learning often includes online components. This study examined how a case of 37 teachers utilized a specific online asynchronous professional learning platform designed to support teachers’ growth in learning to teach statistics and data science in secondary schools in the United States. The platform’s features and learning materials were designed based on effective online learning designs, supports for self-guided learning, and research on the teaching and learning of statistics and data science. We paid particular attention to the features we designed into the platform to support self-regulation and personalizing the experiences to meet their preferred learning goals such as allowing for free choice of learning materials, flexibility of when and how long to engage, providing personal recommendations based on user input, internal systems to track progress, and generating certificates of completion. In this study, we used a case study with both quantitative and qualitative data to examine whether teachers had gains in meeting learning goals related to their development in teaching statistics and data science, had sustained engagement, and found the features for personalization supportive for their learning. Results showed, overall, positive growth towards meeting learning goals and making small changes towards improved classroom practice. Most teachers were generally engaged in sustained ways across the study period, though we found six different patterns of completion that highlight ways in which teachers’ goal-directed and self-regulated learning occurred within the busy schedules of educators. Several personalized features, especially the recommendations and tracking system, were highly utilized and perceived as supportive of teachers’ learning.

Gut dysbiosis and an inflamed bowel are growing concerns in mammals, including dogs. Probiotic supplements have been used to restore the natural microbial community and improve gastrointestinal health. Biofilm formation, antimicrobial activities, and immunological responses of probiotics are crucial to improving gut health. Thus, we tested a commercial probiotic blend (LabMAX-3), a canine kibble additive comprising Lactobacillus acidophilus, Lacticaseibacillus casei, and Enterococcus faecium for their ability to inactivate common enteric pathogens; their ability to form biofilms; epithelial cell adhesion; and their anti-inflammatory response in the Madin-Darby Canine Kidney (MDCK) cell line. Probiotic LabMAX-3 blend or individual isolates showed a strong inhibitory effect against Salmonella enterica, Listeria monocytogenes, enterotoxigenic Escherichia coli, and Campylobacter jejuni. LabMAX-3 formed biofilms comparable to Staphylococcus aureus. LabMAX-3 adhesion to the MDCK cell line (with or without lipopolysaccharide (LPS) pretreatment) showed comparable adhesion and biofilm formation (p < 0.05) to L. casei ATCC 334 used as a control. LabMAX-3 had no cytotoxic effects on the MDCK cell line during 1 h exposure. The interleukin-10 (IL-10) and tumor necrosis factor alpha (TNFα) ratio of LabMAX-3, compared to the L. casei control, showed a significant increase (p < 0.05), indicating a more pronounced anti-inflammatory response. The data show that LabMAX-3, a canine kibble supplement, can improve gastrointestinal health.

Abstract Identifying circulating proteins associated with cognitive function may point to biomarkers and molecular process of cognitive impairment. Few studies have investigated the association between circulating proteins and cognitive function. We identify 246 protein measures quantified by the SomaScan assay as associated with cognitive function (p

Abstract Background The role of gender inequities in women’s ability to access maternal health care has mainly been analysed from either women’s or men’s perspective only. In this article, we explore the role of gender inequities in maternal health care utilisation from both men’s and women’s perspectives. Methods Thirty-six interviews were conducted with reproductive age women (n = 24), and men whose wives/partners gave birth within the last three years prior to our study in Zambia (n = 12). Our study sought to improve understanding of the normative environment in which women and men make decisions on maternal health care utilisation in Zambia. Results We found that men and women had different expectations regarding their gender roles in maternal health care utilisation, which created inequities reinforced by societal norms and traditions. Men make most household decisions including those related to reproductive health and they often have the major say in access to maternal health services despite not having holistic maternal health information which creates challenges in maternal health care utilisation. Conclusion The study highlights the need for maternal health care utilisation decisions to be made by both men and women and that men should be fully involved in maternal health care from pregnancy until after child birth. Further, there is urgent need for concerted and sustained efforts to change traditional norms that reinforce these inequities and affect maternal health care utilisation if Zambia is to meet Sustainable Development Goal-3.1.

Objective: Skeletal muscle plasticity and remodeling are critical for adapting tissue function to use, disuse, and regeneration. The aim of this study was to identify genes and molecular pathways that regulate the transition from atrophy to compensatory hypertrophy or recovery from injury. Here, we have used a mouse model of hindlimb unloading and reloading, which causes skeletal muscle atrophy, and compensatory regeneration and hypertrophy, respectively. Methods: We analyzed mouse skeletal muscle at the transition from hindlimb unloading to reloading for changes in transcriptome and extracellular fluid proteome. We then used qRT-PCR, immunohistochemistry, and bulk and single-cell RNA sequencing data to determine Mustn1 gene and protein expression, including changes in gene expression in mouse and human skeletal muscle with different challenges such as exercise and muscle injury. We generated Mustn1-deficient genetic mouse models and characterized them in vivo and ex vivo with regard to muscle function and whole-body metabolism. We isolated smooth muscle cells and functionally characterized them, and performed transcriptomics and proteomics analysis of skeletal muscle and aorta of Mustn1-deficient mice. Results: We show that Mustn1 (Musculoskeletal embryonic nuclear protein 1, also known as Mustang) is highly expressed in skeletal muscle during the early stages of hindlimb reloading. Mustn1 expression is transiently elevated in mouse and human skeletal muscle in response to intense exercise, resistance exercise, or injury. We find that Mustn1 expression is highest in smooth muscle-rich tissues, followed by skeletal muscle fibers. Muscle from heterozygous Mustn1-deficient mice exhibit differences in gene expression related to extracellular matrix and cell adhesion, compared to wild-type littermates. Mustn1-deficient mice have normal muscle and aorta function and whole-body glucose metabolism. We show that Mustn1 is secreted from smooth muscle cells, and that it is present in arterioles of the muscle microvasculature and in muscle extracellular fluid, particularly during the hindlimb reloading phase. Proteomics analysis of muscle from Mustn1-deficient mice confirms differences in extracellular matrix composition, and female mice display higher collagen content after chemically induced muscle injury compared to wild-type littermates. Conclusions: We show that, in addition to its previously reported intracellular localization, Mustn1 is a microprotein secreted from smooth muscle cells into the muscle extracellular space. We explore its role in muscle ECM deposition and remodeling in homeostasis and upon muscle injury. The role of Mustn1 in fibrosis and immune infiltration upon muscle injury and dystrophies remains to be investigated, as does its potential for therapeutic interventions.

Irisin, released from exercised muscle, has been shown to have beneficial effects on numerous tissues but its effects on bone are unclear. We found significant sex and genotype differences in bone from wildtype (WT) mice compared to mice lacking Fndc5 (knockout [KO]), with and without calcium deficiency. Despite their bone being indistinguishable from WT females, KO female mice were partially protected from osteocytic osteolysis and osteoclastic bone resorption when allowed to lactate or when placed on a low-calcium diet. Male KO mice have more but weaker bone compared to WT males, and when challenged with a low-calcium diet lost more bone than WT males. To begin to understand responsible molecular mechanisms, osteocyte transcriptomics was performed. Osteocytes from WT females had greater expression of genes associated with osteocytic osteolysis and osteoclastic bone resorption compared to WT males which had greater expression of genes associated with steroid and fatty acid metabolism. Few differences were observed between female KO and WT osteocytes, but with a low-calcium diet, the KO females had lower expression of genes responsible for osteocytic osteolysis and osteoclastic resorption than the WT females. Male KO osteocytes had lower expression of genes associated with steroid and fatty acid metabolism, but higher expression of genes associated with bone resorption compared to male WT. In conclusion, irisin plays a critical role in the development of the male but not the female skeleton and protects male but not female bone from calcium deficiency. We propose irisin ensures the survival of offspring by targeting the osteocyte to provide calcium in lactating females, a novel function for this myokine.

A cohort of pre-service mathematics students was exposed to a teaching strategy based on retrieval practice and test-potentiated learning. The aim of the study was to determine how high and low prior topic knowledge study participants compare in terms of their procedural fluency and conceptual understanding after exposure to the teaching strategy. A pre-test and post-test repeated measures design was employed in the study to compare within groups. A revised taxonomy table based on Bloom’s taxonomy was utilised to categorise test items. Findings indicate significant differences between pre-test and post-test scores within groups. Results from the independent samples t-test show a significant difference between the two groups. Outcomes confirm that the benefits of retrieval practice are greatest for unfamiliar content. Findings indicate that for low prior topic knowledge students, procedural fluency is enhanced and retained more than conceptual understanding whereas for the high prior topic knowledge students it was the reverse. The strategy was not as effective for improving conceptual understanding. Contribution: How a teaching strategy based on retrieval practice and test-potentiated learning affects the mathematical competencies of procedural fluency and conceptual understanding has not been researched. There is also a dearth of studies that set out to investigate how retrieval practice and test-potentiated learning affect research participants with different levels of prior knowledge. The contribution of this study therefore is to contribute to understanding of how retrieval practice and test-potentiated learning can be utilised to improve learning and teaching of mathematics at the school level.

BackgroundCirculating immune cells have gained interest as biomarkers of hepatic steatosis. Data on the relationships between immune cell subsets and early-stage steatosis in population-based cohorts are limited.MethodsThis study included 1,944 asymptomatic participants of the Multi-Ethnic Study of Atherosclerosis (MESA) with immune cell phenotyping and computed tomography measures of liver fat. Participants with heavy alcohol use were excluded. A liver-to-spleen ratio Hounsfield units (HU) 30% liver fat content, respectively. Logistic regression estimated cross-sectional associations of immune cell subsets with liver fat parameters adjusted for risk factors. We hypothesized that higher proportions of non-classical monocytes, Th1, Th17, and memory CD4+ T cells, and lower proportions of classical monocytes and naive CD4+ T cells, were associated with liver fat. Exploratory analyses evaluated additional immune cell phenotypes (n = 19).ResultsNone of the hypothesized cells were associated with presence of liver fat. Higher memory CD4+ T cells were associated with >30% liver fat content, but this was not significant after correction for multiple hypothesis testing (odds ratio (OR): 1.31, 95% confidence interval (CI): 1.03, 1.66). In exploratory analyses unadjusted for multiple testing, higher proportions of CD8+CD57+ T cells were associated with liver fat presence (OR: 1.21, 95% CI: 1.02, 1.44) and >30% liver fat content (OR: 1.34, 95% CI: 1.07, 1.69).ConclusionsHigher circulating memory CD4+ T cells may reflect liver fat severity. CD8+CD57+ cells were associated with liver fat presence and severity, but replication of findings is required.

Abstract Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.

Abstract Metabolic flexibility of muscle tissue describes the adaptive capacity to use different energy substrates according to their availability. The disruption of this ability associates with metabolic disease. Here, using a Drosophila model of systemic metabolic dysfunction triggered by yorkie-induced gut tumors, we show that the transcription factor REPTOR is an important regulator of energy metabolism in muscles. We present evidence that REPTOR is activated in muscles of adult flies with gut yorkie-tumors, where it modulates glucose metabolism. Further, in vivo studies indicate that sustained activity of REPTOR is sufficient in wildtype muscles to repress glycolysis and increase tricarboxylic acid (TCA) cycle metabolites. Consistent with the fly studies, higher levels of CREBRF, the mammalian ortholog of REPTOR, reduce glycolysis in mouse myotubes while promoting oxidative metabolism. Altogether, our results define a conserved function for REPTOR and CREBRF as key regulators of muscle energy metabolism.

Abstract We assess performance and limitations of polygenic risk scores (PRSs) for multiple blood pressure (BP) phenotypes in diverse population groups. We compare “clumping-and-thresholding” (PRSice2) and LD-based (LDPred2) methods to construct PRSs from each of multiple GWAS, as well as multi-PRS approaches that sum PRSs with and without weights, including PRS-CSx. We use datasets from the MGB Biobank, TOPMed study, UK biobank, and from All of Us to train, assess, and validate PRSs in groups defined by self-reported race/ethnic background (Asian, Black, Hispanic/Latino, and White). For both SBP and DBP, the PRS-CSx based PRS, constructed as a weighted sum of PRSs developed from multiple independent GWAS, perform best across all race/ethnic backgrounds. Stratified analysis in All of Us shows that PRSs are better predictive of BP in females compared to males, individuals without obesity, and middle-aged (40-60 years) compared to older and younger individuals.

Almost two decades ago, Ernesto P. Borges and Bruce M. Boghosian embarked on the intricate task of composing a manuscript to honor the profound contributions of Constantino Tsallis to the realm of statistical physics, coupled with a concise exploration of q-Statistics. Fast-forward to Constantino Tsallis’ illustrious 80th birthday celebration in 2023, where Deniz Eroglu and Ugur Tirnakli delved into Constantino’s collaborative network, injecting renewed vitality into the project. With hearts brimming with appreciation for Tsallis’ enduring inspiration, Eroglu, Boghosian, Borges, and Tirnakli proudly present this meticulously crafted manuscript as a token of their gratitude.

ABSTRACT Eravacycline is a synthetic fluorocycline approved by the U.S. Food and Drug Administration in 2018. This study aimed to describe clinical and microbiological outcomes in addition to associated adverse effects of eravacycline used in U.S. hospitals. Real-world, observational study involving patients receiving ≥72 h of eravacycline at 19 medical centers located in all 5 regions of the United States between October 2018 and August 2022. The primary outcome was clinical success, defined as survival and absence of microbiological recurrence at 30 days from the end of eravacycline therapy and clinical improvement within 96 h of eravacycline initiation. In total, 416 patients met study criteria and were evaluated. Index culture specimens were most often isolated from the respiratory tract (24.8%, n = 103/416), wound(s) (20.9%, n = 87/416), or blood (19.5%, n = 81/416). As definitive therapy, eravacycline was most often used to treat infections caused by Enterobacterales spp. (42.3%, n = 176/416; 24.4%, n = 43/176 carbapenem-resistant), Enterococci spp. (24.0%, n = 100/416; 49.0%, 49/100 vancomycin-resistant), and Acinetobacter spp. (23.3%, n = 97/416; 47.4%, n = 46/97 carbapenem-resistant). Clinical success occurred in 75.7% of patients (n = 315/416). Thirty-nine (9.4%, n = 39/416) patients experienced a treatment emergent adverse event (TEAE) potentially related to eravacycline with the majority (51.3%, n = 20/39) being gastrointestinal intolerance. Only 27 isolates (6.5%, n = 27/416) underwent eravacycline susceptibility testing. Eravacycline is being used to treat a broad range of Gram-negative and Gram-positive bacteria in the United States including those demonstrating multidrug-resistance with consistently low reported drug-related TEAE; however, antimicrobial susceptibility testing and subsequent in vitro susceptibility data of clinical isolates was sparingly performed. IMPORTANCE The rise of multidrug-resistant (MDR) pathogens, especially MDR Gram-negatives, poses a significant challenge to clinicians and public health. These resilient bacteria have rendered many traditional antibiotics ineffective, underscoring the urgency for innovative therapeutic solutions. Eravacycline, a broad-spectrum fluorocycline tetracycline antibiotic approved by the FDA in 2018, emerges as a promising candidate, exhibiting potential against a diverse array of MDR bacteria, including Gram-negative, Gram-positive, anaerobic strains, and Mycobacterium. However, comprehensive data on its real-world application remain scarce. This retrospective cohort study, one of the largest of its kind, delves into the utilization of eravacycline across various infectious conditions in the USA during its initial 4 years post-FDA approval. Through assessing clinical, microbiological, and tolerability outcomes, the research offers pivotal insights into eravacycline’s efficacy in addressing the pressing global challenge of MDR bacterial infections.

A small series of alkyne polycarbodiimides was thoroughly examined using electrospinning technique. To generate various elongated morphologies including fibers with a diameter ranging from 446 nm to 3.3 µm, we utilized solvents such as pyridine, dichloroethane, and tetrachloroethane. The choice of solvent was dictated by particular polycarbodiimide backbone structure bearing alkyne terminated alkyl pendants. In addition to our findings of continuous fibers by the scanning electron microscopy (SEM), we also applied optical microscopy to discover secondary structures, such as hemispheres and beads which may result from concentration/ solubility issues. The major finding is that heavily grafted alkyl polycarbodiimides are more prone to form discrete fibers, i.e., the presence of n-hexyl and n-dodecyl side chains may facilitate electrospinning. Overall, rigid polymer scaffolds carrying modifiable flexible pendants with functional groups seemed to be highly important and practical for various material science applications, such as development of carbonized fibers and novel drug delivery platforms.

Objectives: Dalbavancin has potent activity against Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus, and is approved for treatment of acute bacterial skin and skin structure infections (ABSSSI). We describe real-world use of dalbavancin in patients with ABSSSI, bloodstream infection (BSI), bone and joint infection (BJI), or other infection (OI). Methods: Dalbavancin Utilization Registry Investigating Value and Effectiveness (DRIVE) was a phase 4 observational, multicenter, retrospective study of the real-world use of dalbavancin in adults across the United States. Data collected March 2017 – November 2018, at hospitals, intensive care units, and outpatient parenteral antibiotic therapy units, included patient demographics, diagnosis, microbiology, antibiotic use, clinical outcome, and adverse events up to 60 days after the last dose of dalbavancin. Patients were treated entirely at the physicians’ discretion. All patients who received ≥ 1 dose of dalbavancin between February 2016 and the end of the data collection period were included in the safety population. Patients with clear clinical success or failure of dalbavancin treatment, according to definitions similar to those used in the dalbavancin phase 3 trials, were included in the evaluable population and the post-hoc analysis. Results: The safety population comprised 1168 patients treated at 31 healthcare sites. Median cumulative dalbavancin dose was 1500 mg for all infection categories, most commonly as 1 infusion; 36.9 % of BSI patients and 58.6 % of BJI patients received ≥ 2 infusions; most were treated as outpatients. Serious adverse drug reactions were reported in 0.7 % of patients overall. Clinical success was achieved in 747/815 (91.7 %) evaluable patients with ABSSSI (BSI, 43/48 [89.6 %]; BJI, 75/87 [86.2 %]; OI, 7/7 [100 %]). Conclusions: Dalbavancin demonstrated high rates of real-world clinical success and safety when treating patients for suspected or confirmed Gram-positive infections.

Abstract Objective: To evaluate temporal trends in the prevalence of gram-negative bacteria (GNB) with difficult-to-treat resistance (DTR) in the southeastern United States. Secondary objective was to examine the use of novel β-lactams for GNB with DTR by both antimicrobial use (AU) and a novel metric of adjusted AU by microbiological burden (am-AU). Design: Retrospective, multicenter, cohort. Setting: Ten hospitals in the southeastern United States. Methods: GNB with DTR including Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter spp. from 2015 to 2020 were tracked at each institution. Cumulative AU of novel β-lactams including ceftolozane/tazobactam, ceftazidime/avibactam, meropenem/vaborbactam, imipenem/cilastatin/relebactam, and cefiderocol in days of therapy (DOT) per 1,000 patient-days was calculated. Linear regression was utilized to examine temporal trends in the prevalence of GNB with DTR and cumulative AU of novel β-lactams. Results: The overall prevalence of GNB with DTR was 0.85% (1,223/143,638) with numerical increase from 0.77% to 1.00% between 2015 and 2020 (P = .06). There was a statistically significant increase in DTR Enterobacterales (0.11% to 0.28%, P = .023) and DTR Acinetobacter spp. (4.2% to 18.8%, P = .002). Cumulative AU of novel β-lactams was 1.91 ± 1.95 DOT per 1,000 patient-days. When comparing cumulative mean AU and am-AU, there was an increase from 1.91 to 2.36 DOT/1,000 patient-days, with more than half of the hospitals shifting in ranking after adjustment for microbiological burden. Conclusions: The overall prevalence of GNB with DTR and the use of novel β-lactams remain low. However, the uptrend in the use of novel β-lactams after adjusting for microbiological burden suggests a higher utilization relative to the prevalence of GNB with DTR.

CD44 protein and its variant isoforms are expressed in cancer stem cells (CSCs), and various CD44 isoforms can have different functional roles in cells. Our goal was to investigate how different CD44 isoforms contribute to the emergence of stem cell (SC) overpopulation that drives colorectal cancer (CRC) development. Specific CD44 variant isoforms are selectively expressed in normal colonic SCs and become overexpressed in CRCs during tumor development. We created a unique panel of anti-CD44 rabbit genomic antibodies to 16 specific epitopes that span the entire length of the CD44 molecule. Our panel was used to comprehensively investigate the expression of different CD44 isoforms in matched pairs (n = 10) of malignant colonic tissue and adjacent normal mucosa, using two (IHC & IF) immunostaining approaches. We found that: i) CD44v8–10 is selectively expressed in the normal human colonic SC niche; ii) CD44v8–10 is co-expressed with the SC markers ALDH1 and LGR5 in normal and malignant colon tissues; iii) colon carcinoma tissues frequently (80%) stain for CD44v8–10 while staining for CD44v6 was less frequent (40%). Given that CD44v8–10 expression is restricted to cells in the normal human colonic SC niche and CD44v8–10 expression progressively increases during CRC development, CD44v8–10 expression likely contributes to the SC overpopulation that drives the development and growth of colon cancers. Since the CD44 variant v8–10 epitope is located on CD44’s extracellular region, it offers great promise for targeted anti-CSC treatment approaches.

Introduction: Apparent treatment-resistant hypertension (aTRH) is characterized by the use of four or more antihypertensive (AHT) classes to achieve blood pressure (BP) control. In the current study, we conducted single-variant and gene-based analyses of aTRH among individuals from 12 Trans-Omics for Precision Medicine cohorts with whole-genome sequencing data.Methods: Cases were defined as individuals treated for hypertension (HTN) taking three different AHT classes, with average systolic BP ≥ 140 or diastolic BP ≥ 90 mmHg, or four or more medications regardless of BP (n = 1,705). A normotensive control group was defined as individuals with BP < 140/90 mmHg (n = 22,079), not on AHT medication. A second control group comprised individuals who were treatment responsive on one AHT medication with BP < 140/ 90 mmHg (n = 5,424). Logistic regression with kinship adjustment using the Scalable and Accurate Implementation of Generalized mixed models (SAIGE) was performed, adjusting for age, sex, and genetic ancestry. We assessed variants using SKAT-O in rare-variant analyses. Single-variant and gene-based tests were conducted in a pooled multi-ethnicity stratum, as well as self-reported ethnic/racial strata (European and African American).Results: One variant in the known HTN locus, KCNK3, was a top finding in the multi-ethnic analysis (p = 8.23E-07) for the normotensive control group [rs12476527, odds ratio (95% confidence interval) = 0.80 (0.74–0.88)]. This variant was replicated in the Vanderbilt University Medical Center’s DNA repository data. Aggregate gene-based signals included the genes AGTPBP, MYL4, PDCD4, BBS9, ERG, and IER3.Discussion: Additional work validating these loci in larger, more diverse populations, is warranted to determine whether these regions influence the pathobiology of aTRH.

Abstract Background In 2020, the Health Resources and Services Administration’s HIV/AIDS Bureau funded an initiative to promote implementation of rapid antiretroviral therapy initiation in 14 HIV treatment settings across the U.S. The goal of this initiative is to accelerate uptake of this evidence-based strategy and provide an implementation blueprint for other HIV care settings to reduce the time from HIV diagnosis to entry into care, for re-engagement in care for those out of care, initiation of treatment, and viral suppression. As part of the effort, an evaluation and technical assistance provider (ETAP) was funded to study implementation of the model in the 14 implementation sites. Method The ETAP has used implementation science methods framed by the Dynamic Capabilities Model integrated with the Conceptual Model of Implementation Research to develop a Hybrid Type II, multi-site mixed-methods evaluation, described in this paper. The results of the evaluation will describe strategies associated with uptake, implementation outcomes, and HIV-related health outcomes for patients. Discussion This approach will allow us to understand in detail the processes that sites to implement and integrate rapid initiation of antiretroviral therapy as standard of care as a means of achieving equity in HIV care.

Abstract We compared transcriptomic profiles of cerebral organoids differentiated from induced pluripotent stem cells of eight schizophrenia and eight bipolar disorder patients to identify genes that were differentially expressed in cerebral organoids between two disorders. Gene ontology analysis showed relative up-regulation in schizophrenia organoids of genes related to response to cytokines, antigen binding and clathrin-coated vesicles, while showing up-regulation in bipolar disorder of genes involved in calcium binding. Gene set enrichment analysis revealed enrichment in schizophrenia of genes involved in mitochondrial and oxidative phosphorylation while showing enrichment in bipolar disorder of genes involved in long term potentiation and neuro-transporters. We compared mitochondrial function in cerebral organoids from schizophrenia and bipolar disorder subjects and found that while schizophrenia organoids showed deficits in basal oxygen consumption rate and ATP production when compared to healthy control organoids, while bipolar disorder organoids did not show these deficits. Gene ontology analyses also revealed enrichment in bipolar disorder of genes in ion binding and regulation of transport. Experiments examining the interaction between mitochondria and endoplasmic reticulum in cortical neurons from bipolar disorder subjects showed a significantly lower number of contact sites between mitochondria and endoplasmic reticulum when compared to cortical neurons from schizophrenia patients. These results point to disease-specific deficits in mitochondrial respiration in schizophrenia and in mitochondrial-endoplasmic reticulum interactions in bipolar disorder.

The spatial and frontal QRS-T angles are electrocardiographic (ECG) predictors for arrhythmia. This work used genetic analyses to identify associated loci and pathways, and explore their relationships with other ECG traits and cardiovascular disease.

Antisense RNA technology is a strategy for the treatment of Duchenne muscular dystrophy (DMD), a progressive and universally fatal X-linked neuromuscular disease caused by frameshift mutations in the gene encoding dystrophin. Phosphorodiamidate morpholino oligomers (PMOs) are an antisense RNA platform that is used clinically in patients with DMD to facilitate exon skipping and production of an internally truncated, yet functional, dystrophin protein. Peptide-conjugated PMOs (PPMOs) are a next-generation platform in which a cell-penetrating peptide is conjugated to the PMO backbone, with the goal of increasing cellular uptake. RC-1001 is a PPMO that contains a proprietary cell-penetrating peptide and targets the Dmd mutation in mdx mice. It was evaluated in mdx mice for exon 23 skipping, dystrophin production, and functional efficacy. Single-dose RC-1001 dose dependently increased exon skipping and dystrophin protein levels in striated muscle and is associated with improvements in muscle function. Dystrophin protein levels were durable for 60 days. Three doses, each given 1 month apart, increased exon skipping to 99% in quadriceps and 43% in heart, with dystrophin protein levels at 39% and 9% of wild type, respectively. These findings support clinical development of PPMO therapies for the treatment of DMD.