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Human coronavirus 229E (HCoV-229E) is an alpha coronavirus that infects humans and bats. In common with all positive-strand RNA viruses, 229E infection causes rearrangements of the host’s intracellular membranes to form replication organelles, a highly conserved and vital step in the viral replication cycle. Here, we investigated the role of the ESCRT protein VPS4A in 229E infection. We found that functional VPS4A was required for the formation of replication organelles and localizing viral RNA to these structures in host cells to facilitate viral genome replication. We validated this effect using small molecule inhibitors to VPS4A, significantly reducing virus replication. We also showed that other ESCRTS, like CHMP4B, were required for the virus replication step, whereas VPS37A was involved in the post-replication stages. The absence of a functional VPS4A prevented the remodeling of membranes to form viral replication centers and, therefore, exposed the viral RNA, triggering an inflammatory immune response as indicated by elevated levels of IL-6. Interestingly, we observed the role of VPS4A to be similar for the OC43 coronavirus, indicating it could be conserved across all four coronavirus genera, including SARS-CoV-2. Understanding more about the replication of coronaviruses is imperative to finding more effective ways to control them.

Abstract Retroviruses exploit host proteins to assemble and release virions from infected cells. Previously, most studies focused on interacting partners of retroviral Gag proteins that localize to the cytoplasm or plasma membrane. Given that several full-length Gag proteins have been found in the nucleus, identifying the Gag-nuclear interactome has high potential for novel findings involving previously unknown host processes. Here we systematically compared nuclear factors identified in published HIV-1 proteomic studies and performed our own mass spectrometry analysis using affinity-tagged HIV-1 and RSV Gag proteins mixed with nuclear extracts. We identified 57 nuclear proteins in common between HIV-1 and RSV Gag, and a set of nuclear proteins present in our analysis and ≥ 1 of the published HIV-1 datasets. Many proteins were associated with nuclear processes which could have functional consequences for viral replication, including transcription initiation/elongation/termination, RNA processing, splicing, and chromatin remodeling. Examples include facilitating chromatin remodeling to expose the integrated provirus, promoting expression of viral genes, repressing the transcription of antagonistic cellular genes, preventing splicing of viral RNA, altering splicing of cellular RNAs, or influencing viral or host RNA folding or RNA nuclear export. Many proteins in our pulldowns common to RSV and HIV-1 Gag are critical for transcription, including PolR2B, the second largest subunit of RNA polymerase II (RNAPII), and LEO1, a PAF1C complex member that regulates transcriptional elongation, supporting the possibility that Gag influences the host transcription profile to aid the virus. Through the interaction of RSV and HIV-1 Gag with splicing-related proteins CBLL1, HNRNPH3, TRA2B, PTBP1 and U2AF1, we speculate that Gag could enhance unspliced viral RNA production for translation and packaging. To validate one putative hit, we demonstrated an interaction of RSV Gag with Mediator complex member Med26, required for RNA polymerase II-mediated transcription. Although 57 host proteins interacted with both Gag proteins, unique host proteins belonging to each interactome dataset were identified. These results provide a strong premise for future functional studies to investigate roles for these nuclear host factors that may have shared functions in the biology of both retroviruses, as well as functions specific to RSV and HIV-1, given their distinctive hosts and molecular pathology. Graphical Abstract

BackgroundThe triglyceride (TG) content of low-density lipoprotein (LDL-TG) has been shown to be more predictive of atherosclerotic cardiovascular disease (ASCVD) events than the cholesterol content of LDL (LDL-C). The goal of our study was to develop an equation for estimating LDL-TG (eLDL-TG) based on the standard lipid panel and to compare it to estimated LDL-C as an ASCVD risk biomarker.MethodsUsing least-square regression analysis, the following eLDL-TG equation was developed: eLDL-TG=TG38.5+NonHDL-C5.75+9.75TGNonHDL-C+244HDL-C−2.95. LDL-TG was measured by the β-quantification (BQ) reference method (N = 40,202). LDL-C was calculated by the Sampson-NIH equation. The association of LDL-C and eLDL-TG with ASCVD risk markers was performed in the National Heart and Nutrition Examination Survey (NHANES) (N = 37,053) and with ASCVD events in a primary prevention cohort from the UK Biobank (UKB) (N = 429,367) and the Atherosclerosis Risk in Communities (ARIC) study (N = 14,632).ResultseLDL-TG showed better ASCVD risk stratification of UKB participants than LDL-C (Wilcoxon Chi-Square: 2,099.6 vs. 418.7, respectively). Receiving-operating characteristics analysis revealed that eLDL-TG had a stronger association with ASCVD events than LDL-C (AUC: 0.596 vs. 0.542, respectively) and other conventional lipid markers. Similar findings were found in ARIC. Discordance analysis in UKB showed that the group with low LDL-C/high eLDL-TG had a similar risk as the high LDL-C/high eLDL-TG group. Furthermore, these same two groups with the highest eLDL-TG levels and the highest ASCVD event rate also had higher mean levels of systolic blood pressure, Body Mass Index, hemoglobin A1C, and C-reactive protein than the two lower eLDL-TG groups. Using eLDL-TG > 44.6 mg/dl (80th percentile) as a cut-point leads to a hazard ratio of 1.32 (95% CI, 1.29–1.36) for ASCVD events, which remained significant after adjustment for LDL-C and apoB. Furthemore, using eLDL-TG as a risk-enhancer test leads to reclassification of 50% more high-risk individuals than current lipid-enhancer test rules.ConclusionsLike LDL-C, LDL-TG can also be calculated from the results of the standard lipid panel. Compared to estimated LDL-C, eLDL-TG was a better risk marker for primary prevention and hence could improve initial ASCVD risk stratification.

Summary: The formation, stabilization, and elimination of synapses are tightly regulated during neural development and into adulthood. Pumilio RNA-binding proteins regulate the translation and localization of many synaptic mRNAs and are developmentally downregulated in the brain. We found that simultaneous downregulation of Pumilio 1 and 2 increases both excitatory and inhibitory synapse density in primary hippocampal neurons and promotes synapse maturation. Loss of Pum1 and Pum2 in the mouse brain was associated with an increase in mRNAs involved in mitochondrial function and synaptic translation. These findings reveal a role for developmental Pumilio downregulation as a permissive step in the maturation of synapses and suggest that modulation of Pumilio levels is a cell-intrinsic mechanism by which neurons tune their capacity for synapse stabilization.

Abstract Model‐informed precision dosing using virtual twins (MIPD‐VTs) is an emerging strategy to predict target drug concentrations in clinical practice. Using a high virtualization MIPD‐VT approach (Simcyp version 21), we predicted the steady‐state clozapine concentration and clozapine dosage range to achieve a target concentration of 350 to 600 ng/mL in hospitalized patients with treatment‐resistant schizophrenia (N = 11). We confirmed that high virtualization MIPD‐VT can reasonably predict clozapine concentrations in individual patients with a coefficient of determination (R2) ranging between 0.29 and 0.60. Importantly, our approach predicted the final dosage range to achieve the desired target clozapine concentrations in 73% of patients. In two thirds of patients treated with fluvoxamine augmentation, steady‐state clozapine concentrations were overpredicted two to four‐fold. This work supports the application of a high virtualization MIPD‐VT approach to inform the titration of clozapine doses in clinical practice. However, refinement is required to improve the prediction of pharmacokinetic drug–drug interactions, particularly with fluvoxamine augmentation.

Water treatment residual (WTR) is a burden for many water treatment plants due to the large volumes and associated management costs. In this study, we transform aluminum-salt WTR (Al-WTR) into ceramsite (ASC) to recover phosphate from challenging waters. ASC showed remarkably higher specific surface area (SSA, 70.53 m2/g) and phosphate adsorption capacity (calculated 47.2 mg P/g) compared to previously reported ceramsite materials (< 40 m2/g SSA and < 20 mg P/g). ASC recovered over 94.9% of phosphate across a wide pH range (3 – 11) and generally sustained > 90% of its phosphate recovery at high concentrations of competing anions (i.e., Cl-, F-, SO42-, or HCO3-) or humic acid (HA). We challenged the material with real municipal wastewater at 10°C and achieved simultaneous phosphate (>97.1%) and COD removal (71.2%). Once saturated with phosphate, ASC can be repurposed for landscaping or soil amendment. The economic analysis indicates that ASC can be a competitive alternative to natural clay-based ceramsite, biochar, or other useful materials. Therefore, ASC is an eco-friendly, cost-effective adsorbent for phosphate recovery from complex waters, shedding light upon a circular economy in the water sector.

Objective: Lipoprotein(a) [Lp(a)] has been associated with Atherosclerotic Cardiovascular Disease (ASCVD). Approximately 20 % of the population has elevated Lp(a). Despite its well-recognized role in ASCVD, universal screening remains controversial. The aim of our study is to investigate laboratory testing patterns for Lp(a) in subjects screened with a standard lipid panel at a large tertiary referring US institution. Methods: Data were retrospectively collected at Mayo Clinic from the Mayo Data Explorer (MDE). Subjects were included if they had a lipid panel measured between May 1, 2022, and April 30, 2023. Demographic data, Lp(a) measurements, statins and aspirin prescription and ASCVD events which occurred at any time in the life of a subject were recorded along with respective dates. The cumulative number of Lp(a) laboratory test orders were also tallied from 1994 to 2023 independently of the lipid panel requests. Results: Between May 1, 2022, and April 30, 2023, 257,225 subjects had a lipid panel ordered. Of these, only 386 (0.15 %) had Lp(a) tested within 1 year of the lipid panel, while 2406 (0.94 %) had Lp(a) tested at any time. Lp(a) was tested more frequently in males (67 %) and in subjects who developed Myocardial Infarction (MI) at any time (12 %). Following Lp(a) results, there was no significant change in statin or aspirin prescription associated with Lp(a) levels. Secondary prevention was the main setting for ordering Lp(a) testing, and there was no change in this trend throughout the years. Conclusions: Testing rates for Lp(a) in the general population are low and the main setting remains secondary prevention. Women are less tested than men. When Lp(a) is found to be elevated, often times there is no change in patient management to mitigate the ASCVD risk.

Summary: Tumor self-seeding is a process whereby circulating tumor cells (CTCs) recolonize the primary tumor, which promotes tumor growth, angiogenesis, and invasion. However, the detailed nature and functions of tumor self-seeded cells (TSCs) have not been well defined due to challenges in tracking and isolating TSCs. Here, we report an accurate animal model using photoconvertible tagging to recapitulate the spontaneous process of tumor self-seeding and identify TSCs as a subpopulation of primary tumor cells with enhanced invasiveness and survival. We demonstrate transmembrane-4-L-six-family-1 (TM4SF1) as a marker of TSCs, which promotes migration, invasion, and anchorage-independent survival in cancer cells. By analyzing single-cell RNA sequencing datasets, we identify a potential TSC population with a metastatic profile in patients with cancer, which is detectable in early-stage disease and expands during cancer progression. In summary, we establish a framework to study TSCs and identify emerging cell targets with diagnostic, prognostic, or therapeutic potential in cancers.

University ranking is a technique of measuring the performance of Higher Education Institutions (HEIs) by evaluating them on various criteria like student satisfaction, expenditure, research and teaching quality, citation count, grants, and enrolment. Ranking has been determined as a vital factor that helps students decide which institution to attend. Hence, universities seek to increase their overall rank and use these measures of success in their marketing communications and prominently place their ranked status on their institution's websites. Despite decades of research on ranking methods, a limited number of studies have leveraged predictive analytics and machine learning to rank universities. In this article, we collected 49 Canadian universities’ data for 2017–2021 and divided them based on Maclean's categories into Primarily Undergraduate, Comprehensive, and Medical/Doctoral Universities. After identifying the input and output components, we leveraged various feature engineering and machine learning techniques to predict the universities’ ranks. We used Pearson Correlation, Feature Importance, and Chi-Square as the feature engineering methods, and the results show that “student to faculty ratio,” “total number of citations”, and “total number of Grants” are the most important factors in ranking Canadian universities. Also, the Random Forest machine learning model for the “primarily undergraduate category,” the Voting classifier model for the “comprehensive category” and the Gradient Boosting model for the “medical/doctoral category” performed the best. The selected machine learning models were evaluated based on accuracy, precision, F1 score, and recall.

Abstract Background The accurate measurement of Low-density lipoprotein cholesterol (LDL-C) is critical in the decision to utilize the new lipid-lowering therapies like PCSK9-inhibitors (PCSK9i) for high-risk cardiovascular disease patients that do not achieve sufficiently low LDL-C on statin therapy. Objective To improve the estimation of low LDL-C by developing a new equation that includes apolipoprotein B (apoB) as an independent variable, along with the standard lipid panel test results. Methods Using β-quantification (BQ) as the reference method, which was performed on a large dyslipidemic population (N = 24,406), the following enhanced Sampson-NIH equation (eS LDL-C) was developed by least-square regression analysis: $$eS\,LDL-C= \frac{TC}{1.15}-\frac{HDL-C}{1.25}-\frac{TG}{6.99}-\frac{\left(TG\times NonHDL-C\right)}{1120}+\frac{{TG}^{2}}{8910}+\frac{\left(TG\times ApoB\right)}{1240}+\frac{ApoB}{4.54}-4.73$$ e S L D L - C = TC 1.15 - H D L - C 1.25 - TG 6.99 - T G × N o n H D L - C 1120 + TG 2 8910 + T G × A p o B 1240 + ApoB 4.54 - 4.73 Results The eS LDL-C equation was the most accurate equation for a broad range of LDL-C values based on regression related parameters and the mean absolute difference (mg/dL) from the BQ reference method (eS LDL-C: 4.51, Sampson-NIH equation [S LDL-C]: 6.07; extended Martin equation [eM LDL-C]: 6.64; Friedewald equation [F LDL-C]: 8.3). It also had the best area-under-the-curve accuracy score by Regression Error Characteristic plots for LDL-C

Abstract Background Pubertal growth patterns correlate with future health outcomes. However, the genetic mechanisms mediating growth trajectories remain largely unknown. Here, we modeled longitudinal height growth with Super-Imposition by Translation And Rotation (SITAR) growth curve analysis on ~ 56,000 trans-ancestry samples with repeated height measurements from age 5 years to adulthood. We performed genetic analysis on six phenotypes representing the magnitude, timing, and intensity of the pubertal growth spurt. To investigate the lifelong impact of genetic variants associated with pubertal growth trajectories, we performed genetic correlation analyses and phenome-wide association studies in the Penn Medicine BioBank and the UK Biobank. Results Large-scale growth modeling enables an unprecedented view of adolescent growth across contemporary and 20th-century pediatric cohorts. We identify 26 genome-wide significant loci and leverage trans-ancestry data to perform fine-mapping. Our data reveals genetic relationships between pediatric height growth and health across the life course, with different growth trajectories correlated with different outcomes. For instance, a faster tempo of pubertal growth correlates with higher bone mineral density, HOMA-IR, fasting insulin, type 2 diabetes, and lung cancer, whereas being taller at early puberty, taller across puberty, and having quicker pubertal growth were associated with higher risk for atrial fibrillation. Conclusion We report novel genetic associations with the tempo of pubertal growth and find that genetic determinants of growth are correlated with reproductive, glycemic, respiratory, and cardiac traits in adulthood. These results aid in identifying specific growth trajectories impacting lifelong health and show that there may not be a single “optimal” pubertal growth pattern.

Two conceptual strands of research within the field of cathedral studies have theorised the capacity of Anglican cathedrals to engage more successfully than parish churches with the wider non-churchgoing community. One strand has explored mobilising cathedral metaphors, and the other strand has explored the notion of implicit religion. Both strands illuminate the power of events and installations to soften the boundaries between common ground and sacred space. Drawing on a quantitative survey among 978 people who attended the pre-Christmas son et lumiere at Liverpool Cathedral during December 2022, the present study analyses the qualitative responses of 123 participants who never attend church services. Three categories of themes emerged from these data, concerning the Cathedral itself, the installation, and discordant experience. Contribution: Situated within the science of cathedral studies, this article draws on original qualitative data to illuminate the experiences of participants who never attend church services when engaging with the pre-Christmas son et lumiere at a major cathedral. Conceptualised within the framework of implicit religion, these data confirmed how the son et lumiere succeeded in softening boundaries between the sacred and the secular and provided a deeply moving experience. As one participant said, ‘I am not religious, but I had the best experience ever’.

Rooted in the field of cathedral studies, this paper draws into dialogue three bodies of knowledge: Edward Bailey’s notion of implicit religion that, among other things, highlights the continuing traction of the Christian tradition and Christian practice within secular societies; David Walker’s notion of the multiple ways through which in secular societies people may relate to the Christian tradition as embodied within the Anglican Church and John Fisher’s notion of spiritual wellbeing as conceptualised in relational terms. Against this conceptual background, this paper draws on data provided by 1234 participants attending one of the Christmas Eve carol services in Liverpool Cathedral to explore the perceived impact of attendance on the spiritual health of people who do not believe in God and yet feel that Liverpool Cathedral is their cathedral, and it is this sense of belonging that brings them back at Christmas time. Contribution: Situated within the science of cathedral studies, this paper links in an original way three fields of discourse: Edward Bailey’s notion of implicit religion, David Walker’s notion of the four ways of belonging to God facilitated by the Anglican Church and John Fisher’s conceptualisation and operationalisation of the notion of spiritual wellbeing. The hypothesis developed from this original integration of theoretical perspectives is then tested empirically on data provided by 404 participants at carol services who do not believe in God.

Summary: The brain can generate actions, such as reaching to a target, using different movement strategies. We investigate how such strategies are learned in a task where perched head-fixed mice learn to reach to an invisible target area from a set start position using a joystick. This can be achieved by learning to move in a specific direction or to a specific endpoint location. As mice learn to reach the target, they refine their variable joystick trajectories into controlled reaches, which depend on the sensorimotor cortex. We show that individual mice learned strategies biased to either direction- or endpoint-based movements. This endpoint/direction bias correlates with spatial directional variability with which the workspace was explored during training. Model-free reinforcement learning agents can generate both strategies with similar correlation between variability during training and learning bias. These results provide evidence that reinforcement of individual exploratory behavior during training biases the reaching strategies that mice learn.

Abstract Background Poor medication adherence is a major barrier to HIV control among youth living with HIV (Y-PLWH). The PEERNaija application (app) is an adapted smartphone app grounded in social cognitive and contigency management theories and designed to harness peer-based social incentives and conditional financial incentives to promote medication adherence. The app delivers a multifaceted medication adherence intervention including (1) peer-based social incentives, (2) financial incentives, (3) virtual peer social support, and (4) early clinic-based outreach for non-adherent Y-PLWH. A pilot trial of the app will be conducted in Nigeria, Africa’s most populous country with the 4th largest HIV epidemic, and home to 10% of the world’s four million Y-PLWH. Methods In this randomized controlled trial, we will compare implementation outcomes (feasibility, acceptability, appropriateness measured via validated scales, enrollment and application installation rates, feedback surveys and focus group discussions with participants, and back-end application data), and preliminary efficacy (in improving medication adherence and viral suppression) of the PEERNaija app at 6 months. Participants in Arm 1 (PEERNaija) will receive daily medication reminders, peer-based social incentives, and virtual peer social support. Participants in Arm 2 (PEERNaija +) will additionally receive a conditional financial incentive based on their adherence performance. Eligibility for Y-PLWH includes (1) being aged 14–29 years, (2) being on ART, (3) owning a smartphone, (4) being willing to download an app, and (5) being able to read simple text in English. Discussion This study will serve as the basis for a larger intervention trial evaluating the PEERNaija app (and the integration of mHealth, incentive, and peer-support-based strategies) to improve HIV outcomes in a critically important region of the world for Y-PLWH. Trial registration ClinicalTrials.gov. NCT04930198. First submitted date: May 25, 2021. Study start: August 1, 2021, https://clinicaltrials.gov/ . Protocol version: January 21, 2022.

This study forms part of a research project designed to test the sensing, intuition, feeling and thinking (SIFT) approach to biblical hermeneutics in respect of a wide range of biblical passages. On this occasion, two contrasting approaches to perceiving (a group of eight sensing types and a group of nine intuitive types) were invited to address two questions to John 21:1–12a: What do you see in this passage? What sparks your imagination in this passage? These two contrasting groups generated characteristically different readings of the same text. Contribution: The SIFT approach to biblical hermeneutics is rooted in the reader-perspective school of interpretation and is concerned with identifying the influence of the psychological type profile of the reader on the interpretation of text. The present study adds to a developing body of evidence validating the theory underpinning the SIFT approach and does so by focusing for the first time on the resurrection appearance at the lakeside in John 21.

Summary: Chronic kidney disease is a leading cause of death and disability globally and impacts individuals of African ancestry (AFR) or with ancestry in the Americas (AMS) who are under-represented in genome-wide association studies (GWASs) of kidney function. To address this bias, we conducted a large meta-analysis of GWASs of estimated glomerular filtration rate (eGFR) in 145,732 AFR and AMS individuals. We identified 41 loci at genome-wide significance (p

Working within the sensing, intuition, feeling, thinking (SIFT) approach to biblical hermeneutics, the present study invited a hermeneutical community of 23 type-aware participants to explore the account of the Death of Lazarus as reported in John 11: 1–17 within type-alike groups differentiated according to the participants’ dominant function-orientation. Five groups were constituted differentiating: introverted sensing, introverted intuition, extraverted intuition, introverted and extraverted feeling and introverted and extraverted thinking. These five groups generated distinctive readings of the narrative that were characteristic of the individual type preference. Contribution: The SIFT method, situated within the reader perspective approach to biblical hermeneutics, is concerned with attending to the influence exerted by the psychological type profile of the reader on interpreting the text. The present study goes beyond previous work by comparing the responses of five hermeneutical communities (each distinguished by a different dominant function-orientation) to the same passage of scripture.

Introduction: Chondromalacia patellae (CP) is common among patients with anterior knee pain (AKP), characterized by softening and deterioration of the patellar cartilage. Although the exact etiology is unknown, risk factors include lower extremity muscle weakness, obesity, and female sex. Further, patellar maltracking may play a role in developing CP. Treatment algorithms for CP remain vague and inconsistent as the significance of the diagnosis remains in question. Initial treatment is typically nonoperative with various adjunct modalities. However, surgery may have a role for recalcitrant cases. Objectives: Although CP is a common diagnosis, there is still much to be learned about the significance of this diagnosis and subsequent treatment strategies. Knowledge of this will help to guide providers moving forward. Methods: The authors completed a thorough literature search of available published work through December 31, 2021, discussing CP and its relationship with AKP, and distilled this information into current concepts regarding history, diagnosis, treatment, and future directions. Results: Although much is still unknown about the significance and best treatment strategy for patients with AKP pain and CP, it is likely that in many cases chondromalacia is a finding in the presence of AKP, rather than the cause of the AKP. Conclusions: More work must be done to fully elucidate the underlying causes of CP. However, some of these cases are likely related to subtle maltracking and perhaps can be surgically corrected. In most cases, extensive nonoperative measures and searching for other causes of AKP is most prudent.

Joint attention (JA) is an early-developing behavior that allows caregivers and infants to share focus on an object. Deficits in JA, as measured through face-following pathways, are a defining feature of autism spectrum disorder (ASD) and are observable as early as 12 months of age in infants later diagnosed with ASD. However, recent evidence suggests that JA may be achieved through hand-following pathways by children with and without ASD. Development of JA through multimodal pathways has yet to be studied in infants with an increased likelihood of developing ASD. The current study investigated how 6-, 9- and 12-month-old infants with (FH+) and without (FH-) a family history of ASD engaged in JA. Parent-infant dyads played at home while we recorded the interaction over Zoom and later offline coded for hand movements and gaze. FH+ and FH- infants spent similar amounts of time in JA with their parents, but the cues available before JA were different. Parents of FH+ infants did more work to establish JA and used more face-following than hand-following pathways compared to parents of FH- infants, likely reflecting differences in infant motor or social behavior. These results suggest that early motor differences between FH+ and FH- infants may cascade into differences in social coordination.

Introduction: Palliative care (PC) utilization remains low among pancreatic cancer patients. This study explores the association of PC with mental health service and pharmacotherapy utilization among pancreatic cancer patients. Methods: Retrospective analysis was conducted on a sample of patients in the United States with newly diagnosed pancreatic cancer using Electronic Health Record data from Optum’s Integrated Claims-Clinical data set. Subsequent diagnoses of anxiety and depression and PC consultation encounters were determined using ICD-9/10 codes. Adjusted associations of mental health treatments with PC and patient characteristics were quantified using multiple logistic regression. Results: Among newly diagnosed pancreatic cancer patients (n = 4029), those with PC consultations exhibited a higher prevalence of anxiety (33.9% vs. 22.8%) and depression (36.2% vs. 23.2%). Mental health service use and pharmacotherapy varied, with the highest utilization among patients having both anxiety and depression. Treatment pattern was also influenced by age (aOR 1.832 for age

Introduction The ABCC8 gene regulates insulin secretion and plays a critical role in glucose homeostasis. The effects of an ABCC8 R1420H loss-of-function variant on beta-cell function, incidence of type 2 diabetes, and age-at-onset, prevalence, and progression of diabetes complications were assessed in a longitudinal study in American Indians.Research design and methods We analyzed beta-cell function through the relationship between insulin secretion and insulin sensitivity in members of this population without diabetes aged ≥5 years using standard major axis regression. We used hierarchical logistic regression models to study cross-sectional associations with diabetes complications including increased albuminuria (albumin-to-creatinine ratio (ACR) ≥30 mg/g), severe albuminuria (ACR ≥300 mg/g), reduced estimated glomerular filtration rate (eGFR

Abstract A warmer and drier future combined with rising population trends will result in increased wildfire risk. The design of robust mitigation/adaptation strategies requires the assessment of the economy‐wide risks from potentially more frequent large wildfire events under different futures. This study uses a novel interdisciplinary approach by integrating wildfire climate and land‐use forecasts into probabilistic and simulation models of wildfires to estimate direct impacts using damage curves and indirect impacts as lost Gross Domestic Product (GDP) using a computable general equilibrium model. Based on the financial concept of Value at Risk, a probabilistic measure of extreme economy‐wide impacts was developed using GDP as the representative metric, namely “GDP at Risk (G@R),” under various climatic and socio‐economic scenarios. Using the new metric in the Waikato, New Zealand as a case study, due its primary industries' national relevance, it was identified that there is a 5% probability that the region will experience GDP losses greater or equal to NZ$0.1–1.2 billion (similar to the regional GDP growth in 2021) over a 48‐year period from future potential large wildfires affecting vulnerable primary industries. The regional impacts result in larger national GDP losses by a factor of 5 due to the high dependence of downstream sectors on the regional primary industries. While “G@R” estimates are similar across socio‐economic scenarios, there are no discernible patterns when compared across midcentury climate scenarios. The approach developed could be used to assess the consequences from afforestation projects, driven by mitigation policies, and adaptation strategies to reduce wildfire risk.

Abstract Studies that focus on individual covariates, while ignoring their interactions, may not be adequate for model‐informed precision dosing (MIPD) in any given patient. Genetic variations that influence protein synthesis should be studied in conjunction with environmental covariates, such as cigarette smoking. The aim of this study was to build virtual twins (VTs) of real patients receiving clozapine with interacting covariates related to genetics and environment and to delineate the impact of interacting covariates on predicted clozapine plasma concentrations. Clozapine‐treated patients with schizophrenia (N = 42) with observed clozapine plasma concentrations, demographic, environmental, and genotype data were used to construct VTs in Simcyp. The effect of increased covariate virtualization was assessed by performing simulations under three conditions: “low” (demographic), “medium” (demographic and environmental interaction), and “high” (demographic and environmental/genotype interaction) covariate virtualization. Increasing covariate virtualization with interaction improved the coefficient of variation (R2) from 0.07 in the low model to 0.391 and 0.368 in the medium and high models, respectively. Whereas R2 was similar between the medium and high models, the high covariate virtualization model had improved accuracy, with systematic bias of predicted clozapine plasma concentration improving from −138.48 ng/ml to −74.65 ng/ml. A high level of covariate virtualization (demographic, environmental, and genotype) may be required for MIPD using VTs.

Osteoarthritis (OA) is the most common joint disease in the US and can increase the risk of depression. Both depression and OA disproportionately affect women, yet this study is one of few on depression prevalence, treatment across age groups, and predictors in women with OA. Data were extracted from the 2011–March 2020 National Health and Nutrition Examination Survey (NHANES). Women aged ≥ 45 years with self-reported osteo- or degenerative arthritis were included. Outcomes were depression (assessed with PHQ-9) and treatment (self-reported pharmacotherapy and mental health services). Logistic regression was used to examine associations between age group, covariates, and outcomes. Overall, depression prevalence was 8%, with higher proportions among those 45–64 years old. Aging was associated with reduced odds of depression (Age 65–79: OR 0.68 (95% CI: 0.52–0.89); Age 80+: OR 0.49 (95% CI: 0.33–0.74); vs. Age 45–54). Of those with a positive depression screen, 21.6% documented some form of treatment. Age group was not statistically different between those treated and those not treated. Women aged 45–64 with osteoarthritis may be at increased risk of depression, and most are not treated. As depression is related to increased pain and risk of rehospitalization, future research should prioritize interventions to increase uptake of depression treatment.

Plain Language Summary Identifying cellular factors that regulate HIV-1 RNA processing provides important insights into novel strategies to control this infection. Different members of the SR kinase family have distinct roles in regulating virus expression because they affect distinct steps of transcription/RNA processing. We identify inhibitors of these kinases that suppress HIV-1 gene expression and replication in multiple assay systems at nanomolar concentrations with limited or no cytotoxicity. Our results highlight the therapeutic potential of targeting the post-integration stage of the HIV-1 lifecycle to selectively enhance or reverse provirus latency. A greater understanding of the molecular mechanisms underlying the effects observed will facilitate the development of more targeted approaches to modulate HIV-1 latency on the path toward a “functional” cure for this infection.

Objective: The study objective was to determine the relationship between lung resection and the development of postoperative hiatal hernia. Methods: Preoperative and postoperative computed tomography imaging from 373 patients from the International Early Lung Cancer Action Program and the Initiative for Early Lung Cancer Research on Treatment were compared at a median of 31.1 months of follow-up after resection of clinical early-stage non–small cell lung cancer. Incidence of new hiatal hernia or changes to preexisting hernias were recorded and evaluated by patient demographics, surgical approach, extent of resection, and resection site. Results: New hiatal hernias were seen in 9.6% of patients after lung resection (5.6% after wedge or segmentectomy and 12.4% after lobectomy; P = .047). The median size of new hernias was 21 mm, and the most commonly associated resection site was the left lower lobe (24.2%; P = .04). In patients with preexisting hernias, 53.5% demonstrated a small but significant increase in size from 21 to 22 mm (P

Abstract Clinical and biomarker phenotypic associations for carriers of protein function-altering variants may help to elucidate gene function and health effects in populations. We genotyped 1127 Strong Heart Family Study participants for protein function-altering single nucleotide variants (SNV) and indels selected from a low coverage whole exome sequencing of American Indians. We tested the association of each SNV/indel with 35 cardiometabolic traits. Among 1206 variants (average minor allele count = 20, range of 1 to 1064), ~ 43% were not present in publicly available repositories. We identified seven SNV-trait significant associations including a missense SNV at ABCA10 (rs779392624, p = 8 × 10–9) associated with fasting triglycerides, which gene product is involved in macrophage lipid homeostasis. Among non-diabetic individuals, missense SNVs at four genes were associated with fasting insulin adjusted for BMI (PHIL, chr6:79,650,711, p = 2.1 × 10–6; TRPM3, rs760461668, p = 5 × 10–8; SPTY2D1, rs756851199, p = 1.6 × 10–8; and TSPO, rs566547284, p = 2.4 × 10–6). PHIL encoded protein is involved in pancreatic β-cell proliferation and survival, and TRPM3 protein mediates calcium signaling in pancreatic β-cells in response to glucose. A genetic risk score combining increasing insulin risk alleles of these four genes was associated with 53% (95% confidence interval 1.09, 2.15) increased odds of incident diabetes and 83% (95% confidence interval 1.35, 2.48) increased odds of impaired fasting glucose at follow-up. Our study uncovered novel gene-trait associations through the study of protein-coding variants and demonstrates the advantages of association screenings targeting diverse and high-risk populations to study variants absent in publicly available repositories.

Abstract Background The temporal evolution of SARS-CoV-2 vaccine efficacy and effectiveness (VE) against infection, symptomatic, and severe COVID-19 is incompletely defined. The temporal evolution of VE could be dependent on age, vaccine types, variants of the virus, and geographic region. We aimed to conduct a systematic review and meta-analysis of the duration of VE against SARS-CoV-2 infection, symptomatic COVID-19 and severe COVID-19. Methods MEDLINE, Scopus, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, the World Health Organization Global Literature on Coronavirus Disease, and CoronaCentral databases were searched and studies were selected. Independent reviewers selected randomized controlled trials and cohort studies with the outcome of interest. Independent reviewers extracted data, and assessed the risk of bias. Meta-analysis was performed with the DerSimonian-Laird random-effects model with Hartung-Knapp-Sidik-Jonkman variance correction. The GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach was used to assess certainty (quality) of the evidence. Primary outcomes included VE as a function of time against SARS-CoV-2 infection, symptomatic and severe COVID-19. Results Eighteen studies were included representing nearly 7 million individuals. VE against all SARS-CoV-2 infections declined from 83% in the first month after completion of the original vaccination series to 22% at 5 months or longer. Similarly, VE against symptomatic COVID-19 declined from 94% in the first month after vaccination to 64% by the fourth month. VE against severe COVID-19 for all ages was high overall, with the level being 90% (95% CI, 87–92%) at five months or longer after being fully vaccinated. VE against severe COVID-19 was lower in individuals ≥ 65 years and those who received Ad26.COV2.S. Conclusions VE against SARS-CoV-2 infection and symptomatic COVID-19 waned over time but protection remained high against severe COVID-19. These data can be used to inform public health decisions around the need for booster vaccination.

Purpose: The purposes of this study were to 1) calculate the minimal clinically important difference (MCID) in a population of patients undergoing arthroscopic partial meniscectomy (APM) based on Knee Injury and Osteoarthritis Outcomes Scores (KOOS), 2) quantify the difference between the proportion of patients reaching MCID based on KOOS versus the proportion who considered surgery to be successful based on a “yes” answer to a patient acceptable symptom state (PASS) question, and 3) calculate the percentage of patients experiencing treatment failure (TF). Methods: A large, single-institution clinical database was queried for patients undergoing isolated APM (>40 years of age). Data were collected at regular time intervals, including KOOS and PASS outcome measures. Calculation of MCID using a distribution-based model was performed using preoperative KOOS scores as baseline. Comparison of the proportion of patients surpassing MCID was made to the proportion of patients answering “yes” to a tiered PASS question at 6 months after APM. Proportion of patients experiencing TF was calculated using patients who responded “no” to a PASS question and “yes” to a TF question. Results: Three-hundred and fourteen of 969 patients met inclusion criteria. At 6 months following APM, the percentage of patients meeting or exceeding the MCID for each respective KOOS subscore ranged from 64 to 72% compared to 48% who achieved a PASS (P < .0001 for each subscore). Fourteen percent of patients experienced TF. Conclusions: Six months after APM, approximately one half of the patients achieved a PASS and 15% experienced TF. The difference between achieving MCID based on each of the KOOS subscores and achieving success via PASS ranged from 16% to 24%. Thirty-eight percent of patients undergoing APM did not fit neatly into overt success or failure categorization. Level of Evidence: Level III, retrospective cohort study.

Black men comprise most new HIV infections in the Southern United States and have worse HIV outcomes than their non-Black counterparts. We developed an academic–community partnership in Nashville, Tennessee, to explore opportunities to improve HIV outcomes for Black men. We recruited barbers to an HIV training and focus group discussion about prevention and potential barber/barbershop-based strategies to address HIV-related needs for Black men. We assessed HIV knowledge and stigma with validated scales and conducted thematic analysis on discussion transcripts. HIV-related stigma was low (1.8 of 15 points [ SD = 1.69]) among 13 participants of unknown HIV status (12 men and one woman). HIV knowledge increased among eight (67%) participants after receiving a brief HIV didactic. Participants described general health care barriers (e.g., the social norm that Black men do not go to the doctor until they are “damn near dead”), fears about unwanted HIV disclosure when seeking HIV testing or care, and community fears about negative stereotypes associated with HIV. Participants expressed enthusiasm about receiving more HIV-related training and utilizing communication skills and client/community relationships to serve as health educators and navigators. Barbers highlighted opportunities to disseminate HIV information in barbershops and combine HIV interventions with other health issues, such as COVID-19, and suggested that these interventions may help reduce HIV-related stigma. Our findings suggest that barbers and barbershops are an underutilized resource for disseminating HIV-related health information and engaging Black men in HIV and other important prevention and care activities such as COVID-19.

Summary: The leap of retroviruses and coronaviruses from animal hosts to humans has led to two ongoing pandemics and tens of millions of deaths worldwide. Retrovirus and coronavirus nucleocapsid proteins have been studied extensively as potential drug targets due to their central roles in virus replication, among which is their capacity to bind their respective genomic RNAs for packaging into nascent virions. This review focuses on fundamental studies of these nucleocapsid proteins and how their intrinsic abilities to condense through liquid-liquid phase separation (LLPS) contribute to viral replication. Therapeutic targeting of these condensates and methodological advances are also described to address future questions on how phase separation contributes to viral replication.

Highlights A new algorithm is described for categorizing dyslipidemic patients into Fredrickson-like lipoprotein phenotypes except for Type III. The new lipoprotein phenotypes were validated by NMR-lipoprotein analysis and by agarose gel electrophoresis/beta-quantification in a large number of subjects. The new lipoprotein phenotyping system identifies high-risk cardiovascular patients and helps direct clinical management. A major advance is that the new lipoprotein phenotypes are based on just the standard lipid panel, and thus can be automatically calculated by the clinical laboratory and widely implemented.

Metabolic and bariatric surgery (MBS) is the most effective long-term treatment for Class III obesity. Reduced dietary intake is considered a behavioral driver of post-surgical weight loss, but limited data have examined this association. Therefore, this study examined prospective, longitudinal relationships between dietary intake and weight loss over 24 months following Roux-en-Y Gastric Bypass and Sleeve Gastrectomy. Relationships between weight loss and dietary intake were examined using a validated 24-h dietary recall method. Associations between total energy/macronutrient intake and weight loss outcomes were assessed at 12-, 18-, and 24-months following MBS, defining patients as “responders” and “suboptimal responders”. Consistent with previous literature, 12-month responders and suboptimal responders showed significant associations between weight loss and energy (p = 0.018), protein (p = 0.002), and total fat intake (p = 0.005). However, this study also revealed that many of these associations are no longer significant 24 months post-MBS (p > 0.05), despite consistent weight loss trends. This study suggests a short-term signal between these dietary factors and weight loss outcomes 12 months post-MBS; however, this signal does not persist beyond 12 months. These results are essential for interpreting and designing clinical studies measuring long-term post-surgical weight loss outcomes.

Catastrophic antiphospholipid syndrome (CAPS) involves sudden multiorgan dysfunction from thrombosis due to antibodies that cause platelet activation and endothelial dysfunction. Treatment variably combines anticoagulation, corticosteroid use, therapeutic plasma exchange (TPE), and high-dose intravenous immunoglobulin (IVIG). A 42-year-old male with antiphospholipid syndrome (APS) presented with severe thrombocytopenia, encephalopathy, cardiac ischemia, and acral purpuric cutaneous lesions. CAPS was identified and he received heparin infusion, methylprednisolone, and IVIG. On day 7 he developed new purpuric lesions on his right foot despite detectable arterial pulses representing new microthrombosis refractory to IVIG. He was treated with TPE which resolved the right foot ischemia and eventually his CAPS. To our knowledge, this is the first patient with CAPS reported that failed initial treatment with IVIG and subsequently had excellent response to TPE. Our observations also support recent literature indicating that onset of thrombocytopenia in APS is a warning of progression to CAPS requiring treatment escalation.

How early photosynthesizers managed oxidative stress remains relatively unresolved. Analyses of enzymes dealing with reactive oxygen species traces the evolutionary history of superoxide dismutases and finds evidence of CuZnSOD in the ancestor of all cyanobacteria, dating back to the Archaean.

Recent advances in super-resolution microscopy have made it possible to measure chromatin 3D structure and transcription in thousands of single cells. Here, authors present a deep learning-based approach to characterise how chromatin structure relates to transcriptional state of individual cells and determine which structural features of chromatin regulation are important for gene expression state.

High profile (and controversial) events and installations, like the Helter-Skelter in Norwich and the Crazy Golf Bridges in Rochester, have drawn attention to innovation and public engagement within Anglican cathedrals. The present study contextualised these innovations both empirically and conceptually. The empirical framework draws on cathedral websites to chronicle the wide and diverse range of events and installations hosted by Anglican cathedrals in England and the Isle of Man between 2018 and 2022. The conceptual framework draws on Edward Bailey’s theory of implicit religion to classify and to explore these events and installations. Two insights from the theory of implicit religion emerged as of particular significance. First, the notion of implicit religion softens the boundaries between the sacred and the secular. This was exemplified by eight categories of events: scientific exhibitions, festivals, musical events, art exhibitions, theatre, markets, community events and installations. Second, the notion of implicit religion draws attention to the themes and activities that generate meaning and purpose. This was exemplified by seven themes: social justice and social conscience, violence and reconciliation, remembrance, migration and sanctuary, COVID-19 and lockdowns, personal well-being and nature and environment. Contribution: Situated within the science of cathedral studies, this article identifies the range of innovative events and installations hosted by Anglican Cathedrals in England and the Isle of Man and assesses the significance of these events and installations through Edward Bailey’s lens of implicit religion, discussing first the softening of boundaries between the sacred and the secular and then the generation of meaning and purpose through the core themes raised by these events and installations.

This study applied psychographic segmentation theory to explore the psychological type profile of 1082 visitors to four cathedrals (three in England and one in Wales) and to set this profile alongside the published national normative data. Data provided by the Francis Psychological Type Scales demonstrated that among cathedral visitors there were more introverts (60%), sensing types (72%) and judging types (80%), with a balance between thinking types (49%) and feeling types (51%). Comparisons with the population norms demonstrated that extraverts and perceiving types were significantly underrepresented among visitors to these four cathedrals. The implications of these findings are discussed for enhancing the visitor experience of those currently visiting and for attracting those psychological types currently less likely to visit. Contribution: Situated within the science of cathedral studies, this article demonstrates (by means of applying psychographic segmentation theory and gathering data from four cathedrals) that extraverts and perceiving types were significantly under-represented among cathedral visitors. These data are important for understanding limitations on the reach of cathedrals within the wider community.

Dysbetalipoproteinemia (hyperlipoproteinemia type III, HLP3) is a genetic disorder that results in the accumulation of cholesterol on highly atherogenic remnant particles. Traditionally, the diagnosis of HLP3 depended upon lipoprotein gel electrophoresis or density gradient ultracentrifugation. Because these two methods are not performed by most clinical laboratories, we describe here two new equations for estimating the cholesterol content of VLDL (VLDL-C), which can then be used for the diagnosis of HLP3. Using results from the beta-quantification (BQ) reference method on a large cohort of dyslipidemic patients (N = 24,713), we identified 115 patients with HLP3 based on having a VLDL-C to plasma TG ratio greater than 0.3 and plasma TG between 150 and 1,000 mg/dl. Next, we developed two new methods for identifying HLP3 and compared them to BQ and a previously described dual lipid apoB ratio method. The first method uses results from the standard lipid panel and the Sampson-NIH equation 1 for estimating VLDL-C (S-VLDL-C), which is then divided by plasma TG to calculate the VLDL-C/TG ratio. The second method is similar, but the Sampson-NIH equation 1 is modified or enhanced (eS-VLDL-C) by including apoB as an independent variable for predicting VLDL-C. At a cut-point of 0.194, the first method showed a modest ability for identifying HLP3 (sensitivity = 73.9%; specificity = 82.6%; and area under the curve (AUC) = 0.8685) but was comparable to the existing dual lipid apoB ratio method. The second method based on eS-VLDL-C showed much better sensitivity (96.5%) and specificity (94.5%) at a cut-point of 0.209. It also had an excellent AUC score of 0.9912 and was superior to the two other methods in test classification. In summary, we describe two new methods for the diagnosis of HLP3. The first one just utilizes the results of the standard lipid panel and the Sampson-NIH equation 1 for estimating (VLDL-C) (S-VLDL-C) and can potentially be used as a screening test. The second method (eS-VLDL-C), in which the Sampson-NIH equation 1 is modified to include apoB, is nearly as accurate as the BQ reference method. Because apoB is widely available at most clinical laboratories, the second method should improve both the accessibility and the accuracy of the HLP3 diagnosis.

Working within the sensing, intuition, feeling, thinking (SIFT) approach to biblical hermeneutics, the present study focuses attention on the distinctive voices of introverted intuition and extraverted intuition, by analysing the way in which two small groups, one comprising dominant introverted intuitive types and the other comprising dominant extraverted intuitive types, explored and reflected on the Lucan narrative of the Good Samaritan, a passage rich in material to stimulate the perceiving process. Two distinctive voices emerged from these two groups. Contribution: Situated within the reader perspective approach to biblical hermeneutics, the SIFT method is concerned with identifying the influence of the psychological type of the reader in shaping the interpretation of text. The foundations of the SIFT approach distinguish among the four functions of sensing, intuition, feeling, and thinking. The present study builds on this foundation by developing the nuance of the orientation in which the function is expressed, in this case focusing specifically on the comparison between introverted intuition and extraverted intuition.

The Matthean parable of the labourers in the vineyard is open to multiple interpretations. For some, the parable may speak of God’s unlimited grace and generosity; for others the parable may speak of God’s unfairness. The present study is set within the context of an emerging interest in the concept of grace as a topic for empirical enquiry. The study draws on the theoretical framework provided by the notion of ordinary theology and employs the sensing, intuition, feeling and thinking (SIFT) approach to biblical hermeneutics, which is rooted in Jungian psychological type theory. Data were drawn from two one-day workshops with Church of England Readers (lay ministers). On each occasion the participants were divided into three separate groups according to their preferences for thinking or feeling (the two judging functions proposed by psychological type theory) and within these groups they were invited to explore the messages about grace in Matthew 20:1–15 (Jesus’ parable of the labourers in the vineyard). The rich data gathered from these workshops generated insights into contemporary theologies of grace and also confirmed the hypothesis that a biblical interpretation of grace is shaped by the reader’s psychological type preference for thinking or feeling. While feeling types tended to empathise, thinking types pondered motives and unfairness. Contribution: Situated within the reader perspective approach to biblical hermeneutics, the SIFT method is concerned with identifying the influence of the psychological type of the reader in shaping the interpretation of sacred text. Employing this method, the present study contributes to three fields of scholarship: to the field of homiletics and hermeneutics, to the field of ordinary theology and to the emerging field concerned with the concept of grace as a topic for empirical enquiry.

Abstract Background Anti-Jo-1 autoantibodies which recognize histidyl-tRNA synthetase identify patients with the rare rheumatologic disease, anti-histidyl-tRNA synthetase syndrome (Jo-1 ARS), a phenotypically distinct subset of idiopathic inflammatory myopathies (IIM). Jo-1-binding B cells (JBCs) are implicated in disease pathogenesis, yet they have not been studied directly. We therefore aimed to characterize JBCs to better understand how they expand and function in Jo-1 ARS. Methods We enrolled 10 IIM patients diagnosed with Jo-1 ARS, 4 patients with non-Jo-1 IIM, and 8 age- and sex-matched healthy controls. We phenotypically characterized peripheral blood mononuclear cells (PBMCs) ex vivo using flow cytometry to define the B cell subsets in which JBCs reside. We further tested their ability to differentiate into antibody-secreting cells following stimulation in vitro. Results The majority of JBCs were IgM+ (not class-switched). Compared to non-JBCs in the same donors, JBCs contained a higher percentage of autoimmune-prone CD21lo cells and were increased in the CD21lo IgM+ IgD− CD27+ memory subset relative to healthy donor B cells. Whereas non-JBCs were present in the anergic BND B cell subset, JBCs were nearly absent from this compartment. JBCs were detected among plasmablasts in some donors, but a reduced frequency of JBCs differentiated into CD38hi24− plasmablasts compared to non-JBCs present in the same wells following in vitro stimulation. Conclusions JBCs are enriched for autoimmune-prone CD21lo B cells, some of which exhibit a memory phenotype in the peripheral repertoire of Jo-1 ARS patients. JBCs undergo limited class switch and show reduced capacity to differentiate into antibody-secreting cells. This suggests complex B cell biology exists beyond class-switched cells that differentiate to secrete anti-Jo-1 autoantibody (i.e., what is captured through serum autoantibody studies). New Jo-1 ARS therapies should thus ideally target non-class-switched JBCs in addition to those that have undergone IgG class-switching to most effectively block cross-talk with autoreactive T cells.

Background: Cardiorespiratory fitness (CRF) is associated with important health risk outcomes, including the development of Type 2 diabetes and cardiovascular disease. Measures of maximal or peak oxygen consumption (VO2) are the typical criterion methods for determining CRF; however, in clinical settings, these measures are impractical. Methods: We validated a clinically derived estimate of CRF against predicted maximal VO2 in a sample of healthy, midlife and older adult women (n?=?188). Women completed a clinic evaluation (including treadmill testing), daily diaries about their physical activity, and additional clinical scales. Two models were tested. The first model calculated estimated cardiorespiratory fitness (eCRF) using assigned weights and regressed eCRF on predicted cardiorespiratory fitness (pCRF). The second model used sample-specific, empirical weights. Both models were tested twice, once with retrospective and once with daily diary physical activity reports. Results: The model accounted for 34% of the variance in pCRF when using assigned weights and 41% of the variance in pCRF when using empirical weights. For age, body mass index, and resting heart rate, assigned and estimated weights were similar, but estimates for physical activity differed. There was little improvement in model fit between retrospective and daily diary measurements of physical activity when either assigned (R2?=?0.32) or fitted weights (R2?=?0.40) were used. Conclusions: Midlife and older women's CRF can be estimated from routinely collected clinical measures, demonstrating their utility.

Hispanic/Latinos have been underrepresented in genome-wide association studies (GWAS) for anthropometric traits despite their notable anthropometric variability, ancestry proportions, and high burden of growth stunting and overweight/obesity. To address this knowledge gap, we analyzed densely imputed genetic data in a sample of Hispanic/Latino adults to identify and fine-map genetic variants associated with body mass index (BMI), height, and BMI-adjusted waist-to-hip ratio (WHRadjBMI). We conducted a GWAS of 18 studies/consortia as part of the Hispanic/Latino Anthropometry (HISLA) Consortium (stage 1, n = 59,771) and generalized our findings in 9 additional studies (stage 2, n = 10,538). We conducted a trans-ancestral GWAS with summary statistics from HISLA stage 1 and existing consortia of European and African ancestries. In our HISLA stage 1 + 2 analyses, we discovered one BMI locus, as well as two BMI signals and another height signal each within established anthropometric loci. In our trans-ancestral meta-analysis, we discovered three BMI loci, one height locus, and one WHRadjBMI locus. We also identified 3 secondary signals for BMI, 28 for height, and 2 for WHRadjBMI in established loci. We show that 336 known BMI, 1,177 known height, and 143 known WHRadjBMI (combined) SNPs demonstrated suggestive transferability (nominal significance and effect estimate directional consistency) in Hispanic/Latino adults. Of these, 36 BMI, 124 height, and 11 WHRadjBMI SNPs were significant after trait-specific Bonferroni correction. Trans-ancestral meta-analysis of the three ancestries showed a small-to-moderate impact of uncorrected population stratification on the resulting effect size estimates. Our findings demonstrate that future studies may also benefit from leveraging diverse ancestries and differences in linkage disequilibrium patterns to discover novel loci and additional signals with less residual population stratification.

Takotsubo syndrome is a well described clinical phenomenon that often mimics acute coronary syndrome. We present an atypical case of Takotsubo syndrome, characterized by delayed troponin elevation and electrocardiogram changes suggestive of acute coronary syndrome, but a normal coronary angiogram. We describe the integration of cardiac magnetic resonance imaging to identify syndrome overlap, and discuss the utilization of diagnostic modalities beyond coronary angiogram if clinical equipoise exists, including B-type natriuretic peptide/troponin ratio, intravascular coronary imaging, and cardiac magnetic resonance imaging. Résumé: Le syndrome de Takotsubo est un phénomène clinique bien connu qui se présente souvent comme un syndrome coronarien aigu. Nous rapportons un cas atypique de syndrome de Takotsubo caractérisé par une élévation tardive du taux de troponine et par un tracé électrocardiographique évoquant un syndrome coronarien aigu, alors que la coronarographie ne révèle aucune anomalie. Nous décrivons comment utiliser l’imagerie par résonance magnétique cardiaque pour évaluer le chevauchement des deux syndromes et nous présentons l’utilisation des outils diagnostiques autres que la coronarographie en cas d’incertitude clinique absolue, notamment le rapport peptide natriurétique de type B/troponine, l’imagerie endocoronaire et l’imagerie par résonance magnétique cardiaque.