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A recently developed method for analyzing the thermal conductivity vs depth variation near a sample surface has been extended to include inhomogeneous samples with anisotropy. If not considered, the anisotropy ratio in the sample structure can distort the depth-position data of the original test method. The anisotropy ratio is introduced in the original computational scheme in order to improve the depth-position estimations for inhomogeneous structures with anisotropy. The proposed approach has been tested in experiments and shown to improve depth position mapping. [ABSTRACT FROM AUTHOR]

Background: We previously reported significant correlations between a direct measure of insulin sensitivity (IS) and blood levels of proteins measured using the Proximity Extension Assay (PEA) in two European cohorts. However, protein correlations with IS within non-European populations, in response to short-term interventions that improve IS, and any causal associations with IS have not yet been established., Methods: We measured 1,470 proteins using the PEA in the plasma of 1,015 research participants at Stanford University who underwent one or more direct measures of IS. Association analyses were carried out with multivariable linear regression within and across Stanford subgroups and within each of the two European cohorts. Association statistics were also meta-analyzed after transformation and harmonization of the two direct measures of IS. Lastly, we performed genome-wide association studies of IS and used genetic instruments of plasma proteins from the UK Biobank to identify candidate causal proteins for IS through Mendelian Randomization (MR) analysis., Results: In age and sex adjusted model, 810 proteins were associated with baseline IS among 652 self-reported European participants in the Stanford cohort at a false discovery rate (FDR) < 0.05. Effect sizes for these proteins were highly correlated with those observed in 122 South Asian, 92 East Asian, 85 Hispanic, and 52 Black/African American persons (r= 0.68 to 0.83, all P≤4.3×10 -113 ). Meta-analysis of the full Stanford cohort with the two European cohorts (N=2,945) yielded 247 significant protein associations (FDR < 0.05), with 75 remaining significant after further adjustment for body mass index. In a subset of Stanford participants undergoing insulin sensitizing interventions (N=53 taking thiazolidinediones, N=66 with weight loss), 79.6% of protein level changes were directionally consistent with the respective baseline association (observed/expected p=6.7×10 -16 ). MR analyses identified eight candidate causal proteins for IS, among which were SELE and ASGR1, proteins with established drug targets currently under investigation., Conclusion: Plasma proteins measured using the PEA provide a robust signature for IS across diverse populations and after short-term insulin sensitizing interventions highlighting their potential value as universal biomarkers of insulin resistance. A small subset of markers provided insights into potential causal molecular mechanisms and therapeutic targets., Competing Interests: Declaration of competing interest: The authors declare no conflicts of interest.

Aims: In patients with heart failure, treatment patterns in the last years of life have not been assessed at large scale. We aimed to assess whether heart failure treatment patterns up to 5 years prior to death changed over time., Methods and Results: In a cohort study covering the whole Swedish population, we assessed all heart failure patients who died between 1 July 2007 and 31 December 2020 for evidence-based treatments. The proportion on the respective treatment at the time of death was examined by year of death using binomial regression. Looking back in time, treatment discontinuation rates were estimated using Poisson regression on time-split data. Combining these models, the proportion on each medication was estimated up to 5 years prior to death. A total of 364 480 patients died with heart failure during the study period. Half were women, and the median (interquartile range) age at death was 86 (79-90). The use of all heart failure treatments decreased gradually closer to death, but the discontinuation rate of beta blockers decreased over time, resulting in an increasing proportion of patients on treatment at the time of death., Conclusion: In patients with heart failure, a changing pattern of medical treatment during the last years of life was observed, most notably with an increasing use of beta blockers. This may in part be due to a changing pattern of comorbidities over time, with an increase in e.g. hypertension and atrial fibrillation, but a decline in ischaemic heart disease., (© 2024 The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: The full spectrum of side effects from COVID-19 vaccinations and infections, including milder symptoms or health effects that do not lead to health care visits, remains unknown. Person-centered self-reporting of symptoms may offer a solution. Monitoring patient-reported outcomes over time will vary in importance for different patients. Individuals have unique needs and preferences, in terms of both communication methods and how the collected information is used to support care., Objective: This study aims to describe how Symptoms, a system for person-centered self-reporting of symptoms and health-related quality of life, was utilized in investigating COVID-19 vaccine side effects. We illustrate this by presenting data from the Symptoms system in newly vaccinated individuals from the RECOVAC (Register-based large-scale national population study to monitor COVID-19 vaccination effectiveness and safety) study., Methods: During the COVID-19 pandemic, newly vaccinated individuals were identified as the ideal population to query for milder symptoms related to COVID-19 vaccinations and infections. To this end, we used posters in observation areas at 150 vaccination sites across the Västra Götaland region of Sweden, inviting newly vaccinated individuals to use a novel digital system, Symptoms. In the Symptoms system, users can track their symptoms, functioning, and quality of life as often as they wish, using evidence-based patient-reported outcome measures and short numeric rating scales. These scales cover a prespecified list of symptoms based on common COVID-19 symptoms and previously reported vaccine side effects. Participants could also use numeric rating scales for self-defined symptoms if their symptom was not included on the prespecified list., Results: A total of 731 people created user accounts and consented to share data for research between July 21, 2021, and September 27, 2022. The majority of users were female (444/731, 60.7%), with a median age of 38 (IQR 30-47) years. Most participants (498/702, 70.9%) did not report any of the comorbidities included in the questionnaire. Of the 731 participants, 563 (77.0%) reported experiencing 1 or more symptoms. The most common symptom was pain at the injection site (486/563, 86.3%), followed by fatigue (181/563, 32.1%) and headache (169/563, 30.0%). In total, 143 unique symptoms were reported. Of these, 29 were from the prespecified list, while the remaining 114 (79.7%) were self-defined entries in the symptom field. This suggests that the flexibility of the self-directed system-allowing individuals to decide which symptoms they consider worth tracking-may be an important feature., Conclusions: Self-reported symptoms in the Symptoms system appeared to align with previously observed post-COVID-19 vaccination symptoms. The system was relatively easy to use and successfully captured broad, longitudinal data. Its person-centered and self-directed design seemed crucial in capturing the full burden of symptoms experienced by users., (©Emelie Gustafson Hedov, Fredrik Nyberg, Stefan Gustafsson, Huiqi Li, Magnus Gisslén, Johan Sundström. Originally published in JMIR Formative Research (https://formative.jmir.org), 30.10.2024.)

Background: Transportation noise has been linked with cardiometabolic outcomes, yet whether it is a risk factor for atrial fibrillation (AF) remains inconclusive. We aimed to assess whether transportation noise was associated with AF in a large, pooled Nordic cohort., Methods: We pooled data from 11 Nordic cohorts, totaling 161,115 participants. Based on address history from five years before baseline until end of follow-up, road, railway, and aircraft noise was estimated at a residential level. Incident AF was ascertained via linkage to nationwide patient registries. Cox proportional hazards models were utilized to estimate associations between running 5-year time-weighted mean transportation noise (L den ) and AF after adjusting for sociodemographics, lifestyle, and air pollution., Findings: We identified 18,939 incident AF cases over a median follow-up of 19.6 years. Road traffic noise was associated with AF, with a hazard ratio (HR) and 95% confidence interval (CI) of 1.02 (1.00-1.04) per 10-dB of 5-year mean time-weighted exposure, which changed to 1.03 (1.01-1.06) when implementing a 53-dB cut-off. In effect modification analyses, the association for road traffic noise and AF appeared strongest in women and overweight and obese participants. Compared to exposures ≤40 dB, aircraft noise of 40.1-50 and > 50 dB were associated with HRs of 1.04 (0.93-1.16) and 1.12 (0.98-1.27), respectively. Railway noise was not associated with AF. We found a HR of 1.19 (1.02-1.40) among people exposed to noise from road (≥45 dB), railway (>40 dB), and aircraft (>40 dB) combined., Interpretation: Road traffic noise, and possibly aircraft noise, may be associated with elevated risk of AF., Funding: NordForsk., Competing Interests: All other authors declare no competing interests., (© 2024 The Author(s).)

Cell identities are defined by intrinsic transcriptional networks and spatio-temporal environmental factors. Here, we explored multiple factors that contribute to the identity of adipose stem cells, including anatomic location, microvascular neighborhood, and sex. Our data suggest that adipose stem cells serve a dual role as adipocyte precursors and fibroblast-like cells that shape the adipose tissue's extracellular matrix in an organotypic manner. We further find that adipose stem cells display sexual dimorphism regarding genes involved in estrogen signaling, homeobox transcription factor expression and the renin-angiotensin-aldosterone system. These differences could be attributed to sex hormone effects, developmental origin, or both. Finally, our data demonstrate that adipose stem cells are distinct from mural cells, and that the state of commitment to adipogenic differentiation is linked to their anatomic position in the microvascular niche. Our work supports the importance of sex and microvascular function in adipose tissue physiology., (© 2024. The Author(s).)

Imbalances in electrolyte concentrations can have severe consequences, but accurate and accessible measurements could improve patient outcomes. The current measurement method based on blood tests is accurate but invasive and time-consuming and is often unavailable for example in remote locations or an ambulance setting. In this paper, we explore the use of deep neural networks (DNNs) for regression tasks to accurately predict continuous electrolyte concentrations from electrocardiograms (ECGs), a quick and widely adopted tool. We analyze our DNN models on a novel dataset of over 290,000 ECGs across four major electrolytes and compare their performance with traditional machine learning models. For improved understanding, we also study the full spectrum from continuous predictions to a binary classification of extreme concentration levels. Finally, we investigate probabilistic regression approaches and explore uncertainty estimates for enhanced clinical usefulness. Our results show that DNNs outperform traditional models but model performance varies significantly across different electrolytes. While discretization leads to good classification performance, it does not address the original problem of continuous concentration level prediction. Probabilistic regression has practical potential, but our uncertainty estimates are not perfectly calibrated. Our study is therefore a first step towards developing an accurate and reliable ECG-based method for electrolyte concentration level prediction-a method with high potential impact within multiple clinical scenarios., (© 2024. The Author(s).)

Aims: This study aimed to characterize a contemporary population with subtypes of incident or prevalent heart failure (HF) based on reduced (HFrEF), mildly reduced, or preserved (HFpEF) left ventricular ejection fraction (LVEF) and to assess how outcomes, healthcare, treatments, and healthcare costs vary between each subtype of incident HF., Methods and Results: Using Swedish data from the CardioRenal and Metabolic disease Heart Failure (CaReMe HF) study, updated to cover a more recent time period, this population-based study characterized patients from Stockholm County, Sweden, with incident HF (patients with a first HF diagnosis between 1 January 2015 and 31 December 2019) or prevalent HF (patients with a first HF diagnosis before 1 January 2020). Patients with incident HF had LVEF measured by echocardiography within ±90 days of their first HF diagnosis, and patients with prevalent HF within 5 years prior to the index date. The 13 375 patients with prevalent HF (39.2% women, mean age 73.9 years) had multiple comorbidities (cardiovascular diseases, chronic kidney disease, diabetes, and cancer). These were already highly prevalent at the time of the first HF diagnosis in the 8042 patients with incident HF (40.5% women, mean age 72.3 years). Patients with incident HFpEF received less specialist HF care at outpatient secondary care facilities following their first HF diagnosis than those with incident HFrEF. Patients with HFrEF had higher risks of complications and exerted a higher burden, in terms of care for and costs of HF, on the healthcare system., Conclusions: This study of contemporary patients with incident HF demonstrates that those with HFpEF and HFrEF differ considerably in terms of clinical presentation, prognosis, and care, highlighting a potential to improve HF outcomes., (© 2024 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Introduction: Day surgery is often preferred by patients, but it can pose challenges in self-management after discharge. In addition, patients undergoing orthopedic surgery report poorer rates of postoperative recovery than patients undergoing general surgery. Understanding patients' perceptions of feeling safe while undergoing surgery facilitates individualized care and is important since it may affect their recovery., Objective: The aim of this study was to describe patients' perceptions of feeling safe in the perioperative period when undergoing orthopedic day surgery under regional anesthesia., Methods: The design was qualitative and descriptive. Data were collected through a cross-sectional questionnaire containing open-ended questions. Qualitative content analysis with an inductive approach was used for data analysis. Participants' characteristics were presented descriptively. The study population consisted of a consecutive sample of 97 patients who had undergone orthopedic day surgery under regional anesthesia between March and October 2022., Results: The categorization process resulted in the development of two categories describing participants' experience of perioperative feelings of safety when undergoing orthopedic day surgery: having someone near and having a sense of control. The results indicate that the relationship between patients and staff and the perceived feeling of control and participation are factors influencing patients' perception of feeling safe in the perioperative period., Conclusions: In perioperative care, nurses play a vital role in fostering patients' sense of safety by establishing relationships. This ensures that patients can be actively engaged in their own care. Patients also need access to professional and competent staff who strives to add a personal touch and considers their perspective. Since patients undergoing orthopedic day surgery might face a more demanding postoperative recovery than they had initially anticipated, further research is suggested to explore the association between a perceived feeling of safety and postoperative recovery., (© The Author(s) 2024.)

Background: While our understanding of the single-cell gene expression patterns underlying the transformation of vascular cell types during the progression of atherosclerosis is rapidly improving, the clinical and pathophysiological relevance of these changes remains poorly understood., Methods: Single-cell RNA sequencing data generated with SmartSeq2 (≈8000 genes/cell) in 16 588 single cells isolated during atherosclerosis progression in Ldlr -/- Apob 100/100 mice with human-like plasma lipoproteins and from humans with asymptomatic and symptomatic carotid plaques was clustered into multiple subtypes. For clinical and pathophysiological context, the advanced-stage and symptomatic subtype clusters were integrated with 135 tissue-specific (atherosclerotic aortic wall, mammary artery, liver, skeletal muscle, and visceral and subcutaneous, fat) gene-regulatory networks (GRNs) inferred from 600 coronary artery disease patients in the STARNET (Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task) study., Results: Advanced stages of atherosclerosis progression and symptomatic carotid plaques were largely characterized by 3 smooth muscle cells (SMCs), and 3 macrophage subtype clusters with extracellular matrix organization/osteogenic (SMC), and M1-type proinflammatory/Trem2-high lipid-associated (macrophage) phenotypes. Integrative analysis of these 6 clusters with STARNET revealed significant enrichments of 3 arterial wall GRNs: GRN33 (macrophage), GRN39 (SMC), and GRN122 (macrophage) with major contributions to coronary artery disease heritability and strong associations with clinical scores of coronary atherosclerosis severity. The presence and pathophysiological relevance of GRN39 were verified in 5 independent RNAseq data sets obtained from the human coronary and aortic artery, and primary SMCs and by targeting its top-key drivers, FRZB and ALCAM in cultured human coronary artery SMCs., Conclusions: By identifying and integrating the most gene-rich single-cell subclusters of atherosclerosis to date with a coronary artery disease framework of GRNs, GRN39 was identified and independently validated as being critical for the transformation of contractile SMCs into an osteogenic phenotype promoting advanced, symptomatic atherosclerosis., Competing Interests: Disclosures J.L.M. Björkegren and A. Ruusalepp are shareholders of Clinical Gene Networks AB (CGN) that has an invested interest in STARNET.

Objectives: Identify the windows of opportunity for the diagnosis of chronic kidney disease (CKD) and the prevention of its adverse outcomes and quantify the potential population gains of such prevention., Design and Setting: Observational, population-wide study of residents in the Stockholm and Skåne regions of Sweden between 1 January 2015 and 31 December 2020., Participants: All patients who did not yet have a diagnosis of CKD in healthcare but had CKD according to laboratory measurements of CKD biomarkers available in electronic health records., Outcome Measures: We assessed the proportions of the patient population that received a subsequent diagnosis of CKD in healthcare, that used guideline-directed pharmacological therapy (statins, renin-angiotensin aldosterone system inhibitors (RAASi) and/or sodium-glucose cotransporter-2 inhibitors (SGLT2i)) and that experienced adverse outcomes (all-cause mortality, cardiovascular mortality or major adverse cardiovascular events (MACE)). The potential to prevent adverse outcomes in CKD was assessed using simulations of guideline-directed pharmacological therapy in untreated subsets of the study population., Results: We identified 99 382 patients with undiagnosed CKD during the study period. Only 33% of those received a subsequent diagnosis of CKD in healthcare after 5 years. The proportion that used statins or RAASi was of similar size to the proportion that didn't, regardless of how advanced their CKD was. The use of SGLT2i was negligible. In simulations of optimal treatment, 22% of the 21 870 deaths, 27% of the 14 310 cardiovascular deaths and 39% of the 22 224 MACE could have been avoided if every patient who did not use an indicated medication for their laboratory-confirmed CKD was treated with guideline-directed pharmacological therapy for CKD., Conclusions: While we noted underdiagnosis and undertreatment of CKD in this large contemporary population, we also identified a substantial realisable potential to improve CKD outcomes and reduce its burden by treating patients early with guideline-directed pharmacological therapy., Competing Interests: Competing interests: JS reports stock ownership in Anagram kommunikation AB and Symptoms Europe AB. AN has participated as a consultant on advisory board committees and educational activities with Astra Zeneca, Novo Nordisk, Boehringer Ingelhim and Eli Lilly. SK has participated as a consultant on advisory board committees and educational activities with AstraZeneca and Novo Nordisk. JB is an employee of AstraZeneca. TC is an employee and stockowner in Sence Research AB (an independent company in epidemiology and outcomes research) that received funding from AstraZeneca for statistical analysis within this research project. MKS has participated as a consultant on advisory board committees and educational activities with Amgen, AstraZeneca, Boehringer Ingelheim, GSK and NovoNordisk. JÄ has received payment/honoraria from AstraZeneca and Novartis; participated on a data safety monitoring/advisory board for AstraZeneca, Astella and Boehringer Ingelheim. The other authors report no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Heart failure guidelines have recently introduced a narrow category with mildly reduced left ventricular ejection fraction (LVEF) (heart failure with mildly reduced ejection fraction; LVEF 41%-49%) between the previous categories of reduced (heart failure with reduced ejection fraction; LVEF ≤40%) and preserved (heart failure with preserved ejection fraction; LVEF ≥50%) ejection fraction. Grouping of continuous measurements into narrow categories can be questioned if their variability is high., Methods and Results: We constructed a cohort of all 9716 new cases of chronic heart failure with an available LVEF in Stockholm, Sweden, from January 1, 2015, until December 31, 2020. All values of LVEF were collected over time, and patients were followed up until death, moving out of Stockholm, or end of study. Mixed models were used to quantify within-person variance in LVEF, and multistate Markov models, with death as an absorbing state, to quantify the stability of LVEF categories. LVEF values followed a normal distribution. The SD of the within-person variance in LVEF over time was 7.4%. The mean time spent in any LVEF category before transition to another category was on average <1 year for heart failure with mildly reduced ejection fraction. Probabilities of transitioning between categories during the first year were substantial; patients with heart failure with mildly reduced ejection fraction had a probability of <25% of remaining in that category 1 year later., Conclusions: LVEF follows a normal distribution and has considerable variability over time, which may impose a risk for underuse of efficient treatment. The heart failure with mildly reduced ejection fraction category is especially inconstant. Assumptions of a patient's current LVEF should take this variability and the normal distribution of LVEF into account.

Background: This article provides an update of the Reflective Practice Questionnaire (RPQ). The original RPQ consisted of 40-items with 10-sub-scales. In this article, the RPQ is streamlined into a 10-item single reflective practice construct, and a 30-item extended version that includes additional sub-scales of confidence, uncertainty/stress, and work satisfaction., Methods: A total of 501 university students filled out an online questionnaire that contained the original Reflective Practice Questionnaire, and two general measures of reflection: The Self-Reflection and Insight Scale, and the Rumination-Reflection Questionnaire., Results: Based on factor analysis, the RPQ was streamlined into a brief 10-item version, and an extended 30-item version. Small positive correlations were found between the RPQ reflective practice measure and the two measures of general reflection, providing discriminant validity evidence for the RPQ. The RPQ was found to be sensitive to differences among industries, whereas the general measures of reflection were not. Average reflective practice scores were higher for health and education industries compared to retail and food/accommodation industries., Competing Interests: Shane L. Rogers is an Academic Editor for PeerJ. Amit Jotangia is employed by Cygnet Health Care., (© 2024 Rogers et al.)

Myocardial infarction is a leading cause of death globally but is notoriously difficult to predict. We aimed to identify biomarkers of an imminent first myocardial infarction and design relevant prediction models. Here, we constructed a new case-cohort consortium of 2,018 persons without prior cardiovascular disease from six European cohorts, among whom 420 developed a first myocardial infarction within 6 months after the baseline blood draw. We analyzed 817 proteins and 1,025 metabolites in biobanked blood and 16 clinical variables. Forty-eight proteins, 43 metabolites, age, sex and systolic blood pressure were associated with the risk of an imminent first myocardial infarction. Brain natriuretic peptide was most consistently associated with the risk of imminent myocardial infarction. Using clinically readily available variables, we devised a prediction model for an imminent first myocardial infarction for clinical use in the general population, with good discriminatory performance and potential for motivating primary prevention efforts., (© 2024. The Author(s).)

Background: Treatment with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors reduces low-density lipoprotein cholesterol (LDL-C) levels and decreases the incidence of major ischaemic events in clinical trials. However, less is known about the efficacy of PCSK9 inhibition in clinical practice. This study aimed to describe the change in LDL-C levels over time and LDL-C goal achievement in patients with/without atherosclerotic cardiovascular disease (ASCVD), who were prescribed evolocumab in clinical practice, and to describe adherence to and persistence with treatment., Methods: Patients in Sweden with at least one evolocumab prescription filled between July 2015 and May 2020 were included. Medical history and lipid-lowering therapy (LLT) were sourced from national registries. LDL-C levels before and after treatment initiation were assessed using medical records. Persistence with and adherence to evolocumab and oral LLT were assessed up to 12 months after treatment initiation using the refill-gap method and proportion of days covered, respectively., Results: Of the 2,360 patients with at least one prescription for evolocumab, 2,341 were included; 1,858 had ASCVD. Persistence with (76%) and adherence to (86%) evolocumab were high throughout the 12 months following initiation. Mean LDL-C levels decreased by 53% (95% confidence interval [CI]: 51-55%) in patients adherent to evolocumab ( n = 567) and 59% (95% CI: 55-63%) in patients adherent to evolocumab and oral LLT ( n = 186). Similar reductions in LDL-C were observed in patients with/without ASCVD. Reduced LDL-C levels remained stable during follow-up. Amongst patients adherent to evolocumab and those adherent to evolocumab and oral LLT, 23 and 55% achieved the LDL-C goal of <1.4 mmol/L, respectively., Conclusions: The evolocumab LDL-C-lowering effect observed in clinical trials was confirmed in clinical practice in Sweden, particularly in patients also treated with oral LLT. During follow-up, adherence to and persistence with evolocumab were high, with stable reduced levels of LDL-C during observation., Competing Interests: MKS was an employee at Amgen when this study was conducted and declares payment for expert testimony from Amgen and support for attending meetings and/or travel from Amgen. SJ declares grants or contracts from any entity as a steering committee member without personal reimbursement; consulting fees to their institution from Amgen, AstraZeneca and Jansen; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Medtronic; and participation on a data safety monitoring board or advisory board for MedPace. ARF has nothing to declare. GV and LS are Amgen employees and hold Amgen stock. TC is a co-owner of Sence Research (an independent company in epidemiology and biostatistics with both healthcare authorities and private companies as clients) and declares support from Amgen for statistical analyses within this research project; declares grants or contracts to Sence Research from different clients, but no payments directly to TC; declares consulting fees to Sence Research from different clients, but no payments directly to TC; and is a stock-owner of Sence Research. SG is an employee at Sence Research AB. EH declares grants or contracts from Pfizer and Amgen; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Amgen, NovoNordisk, Bayer, AstraZeneca, Amarin and Novartis; participation on a data safety monitoring board or advisory board for Amarin AB, Amgen, Sanofi and Novartis; and leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid, as a co-chair of the Swedish secondary prevention registry, national coordinator DalCore: DAL301 DalGene, and R1500-CL-1643; Aegis II/Perfuse., (© 2024 The Author(s). Published by Upsala Medical Society.)

Aims: To determine what kinds of birth-related experiences of success and failure are described by the participants, and whether there are differences according to fear of childbirth and parity. Studying these experiences is important for understanding the psychological mechanisms behind different childbirth experiences and their impact on maternal mental well-being., Methods: This was a longitudinal mixed methods study. Descriptions of the birth experiences of 113 Finnish participants were gathered in a survey at 4-8 weeks postpartum and analysed with content analysis. Fear of childbirth was determined antenatally with the Wijma Delivery Expectations scale (W-DEQ A).The number of success and failure expressions were compared between people with FOC and others and between primiparous and multiparous people., Results: The contents of the childbirth-related experiences of success and failure were categorised into 12 subcategories, organised under three higher-order categories that were named personal factors , course of childbirth , and support . The most typical expressions of success were in the categories of mode of birth , staff , and mental factors , and the most typical expressions of failure in the categories of staff and mental factors . Experiences of failure were more often expressed by primiparous than multiparous people, but there were no statistically significant differences by FOC. Expressions of success were equally common regardless of parity or FOC., Conclusion: Postpartum people categorise aspects of their birth experiences in terms of success and failure. Primiparous people are more susceptible to experiencing failure at childbirth, but possible differences between people with FOC and other people warrant further investigation.

Purpose: The purpose of this study was to explore the concept of feeling safe, from the patient perspective, in a perioperative context., Method: The eight-step concept analysis approach proposed by Walker and Avant was utilized to examine the attributes of feeling safe. Uses of the concept, defining attributes as well as antecedents, consequences and empirical referents are presented to describe the concept. Case examples are provided in order to assist the understanding of the defining attributes., Results: Feeling safe is defined as: a person that does not feel worried or threatened. Three attributes were identified: Participation, Control and Presence. Knowledge and Relationship are the antecedents of feeling safe, while Feeling Acknowledged and Trust are the consequences. Empirical referents are explored in order to find a way to measuring the perceived feeling of safety., Conclusion: This concept analysis underscores the importance of including patients' perceptions in traditional patient safety work. Patients who feel safe perceive that they participate in their care, that they are in control, and that they feel the presence of both healthcare staff and relatives. The perceived feeling of security could, by extension, promote the postoperative recovery of patients undergoing surgery by positively affect the process of recovery.

Background: Proteomic profiling could potentially disclose new pathophysiological pathways for cardiovascular diseases (CVD) and improve prediction at the individual level. We therefore aimed to study the plasma protein profile associated with the incidence of different CVDs., Methods: Plasma levels of 245 proteins suspected to be linked to CVD or metabolism were measured in 4 Swedish prospective population-based cohorts (SIMPLER [Swedish Infrastructure for Medical Population-Based Life-Course and Environmental Research], ULSAM (Uppsala Longitudinal Study of Adult Men), EpiHealth, and POEM [Prospective Investigation of Obesity, Energy Production, and Metabolism]) comprising 11 869 individuals, free of CVD diagnoses at baseline. Our primary CVD outcome was defined by a combined end point that included either incident myocardial infarction, stroke, or heart failure., Results: Using a discovery/validation approach, 42 proteins were associated with our primary composite end point occurring in 1163 subjects. In separate meta-analyses for each of the 3 CVD outcomes, 49 proteins were related to myocardial infarction, 34 to ischemic stroke, and 109 to heart failure. Thirteen proteins were related to all 3 outcomes. Of those, urokinase plasminogen activator surface receptor, adrenomedullin, and KIM-1 (kidney injury molecule 1) were also related to several markers of subclinical CVD in Prospective Investigation of Obesity, Energy production and Metabolism, reflecting myocardial or arterial pathologies. In prediction analysis, a lasso selection of 11 proteins in ULSAM improved the discrimination of CVD by 3.3% ( P <0.0001) in SIMPLER when added to traditional risk factors., Conclusions: Protein profiling in multiple samples disclosed several new proteins to be associated with subsequent myocardial infarction, stroke, and heart failure, suggesting common pathophysiological pathways for these diseases. KIM-1, urokinase plasminogen activator surface receptor, and adrenomedullin were novel early markers of CVD. A selection of 11 proteins improved the discrimination of CVD., Competing Interests: Disclosures Dr Gustafsson is employed by Sence Research AB. Dr Ärnlöv is a consultant for Boehringer Ingelheim and has financial relationships with Novartis and AstraZeneca. The other authors report no conflicts.

This study aimed to explore the experiences of older migrants' (70+) access to and participation in different meeting places. Qualitative interviews were conducted with participants originating from Finland and four countries in the Western Balkans: Bosnia- Herzegovina, Croatia, Montenegro, and Serbia. The participants used everyday places in the neighborhood, which were not primarily meant to be meeting places, to create and uphold social contacts. These meeting places contributed to experiences of community and trust. Both everyday meeting places and organized meeting places were used to establish and develop relationships that could result in an exchange of both practical and emotional support. Perceptions of "not belonging", limited proficiency in Swedish, and a strained financial situation created barriers to accessing some meeting places. The results of this study demonstrate the significance of meeting places that are not purposefully aimed at older people in general or older people from a specific country., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Mac Innes et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

In this study, the long-term mortality effects associated with exposure to PM 10 (particles with an aerodynamic diameter smaller than or equal to 10 µm), PM 2.5 (particles with an aerodynamic diameter smaller than or equal to 2.5 µm), BC (black carbon), and NO x (nitrogen oxides) were analyzed in a cohort in southern Sweden during the period from 1991 to 2016. Participants (those residing in Malmö, Sweden, born between 1923 and 1950) were randomly recruited from 1991 to 1996. At enrollment, 30,438 participants underwent a health screening, which consisted of questionnaires about lifestyle and diet, a clinical examination, and blood sampling. Mortality data were retrieved from the Swedish National Cause of Death Register. The modeled concentrations of PM 10 , PM 2.5 , BC, and NO x at the cohort participants' home addresses were used to assess air pollution exposure. Cox proportional hazard models were used to estimate the associations between long-term exposure to PM 10 , PM 2.5 , BC, and NO x and the time until death among the participants during the period from 1991 to 2016. The hazard ratios (HRs) associated with an interquartile range (IQR) increase in each air pollutant were calculated based on the exposure lag windows of the same year (lag0), 1-5 years (lag1-5), and 6-10 years (lag6-10). Three models were used with varying adjustments for possible confounders including both single-pollutant estimates and two-pollutant estimates. With adjustments for all covariates, the HRs for PM 10 , PM 2.5 , BC, and NO x in the single-pollutant models at lag1-5 were 1.06 (95% CI: 1.02-1.11), 1.01 (95% CI: 0.95-1.08), 1.07 (95% CI: 1.04-1.11), and 1.11 (95% CI: 1.07-1.16) per IQR increase, respectively. The HRs, in most cases, decreased with the inclusion of a larger number of covariates in the models. The most robust associations were shown for NO x , with statistically significant positive HRs in all the models. An overall conclusion is that road traffic-related pollutants had a significant association with mortality in the cohort.

Background: Genome-wide association studies for glycemic traits have identified hundreds of loci associated with these biomarkers of glucose homeostasis. Despite this success, the challenge remains to link variant associations to genes, and underlying biological pathways., Methods: To identify coding variant associations which may pinpoint effector genes at both novel and previously established genome-wide association loci, we performed meta-analyses of exome-array studies for four glycemic traits: glycated hemoglobin (HbA1c, up to 144,060 participants), fasting glucose (FG, up to 129,665 participants), fasting insulin (FI, up to 104,140) and 2hr glucose post-oral glucose challenge (2hGlu, up to 57,878). In addition, we performed network and pathway analyses., Results: Single-variant and gene-based association analyses identified coding variant associations at more than 60 genes, which when combined with other datasets may be useful to nominate effector genes. Network and pathway analyses identified pathways related to insulin secretion, zinc transport and fatty acid metabolism. HbA1c associations were strongly enriched in pathways related to blood cell biology., Conclusions: Our results provided novel glycemic trait associations and highlighted pathways implicated in glycemic regulation. Exome-array summary statistic results are being made available to the scientific community to enable further discoveries., Competing Interests: Competing interests: Rebecca S. Fine: Rebecca S. Fine is currently employed by Vertex Pharmaceuticals Incorporated. Audrey Y Chu: Currently employed by GlaxoSmithkline. Dennis O. Mook-Kanamori: Dennis Mook-Kanamori is working as a part-time clinical research consultant for Metabolon, Inc. Paul W. Franks: PWF has been a paid consultant for Eli Lilly and Sanofi Aventis and has received research support from several pharmaceutical companies as part of a European Union Innovative Medicines Initiative (IMI) project. Mike A. Nalls: Dr. Mike A. Nalls is supported by a consulting contract between Data Tecnica International LLC and the National Institute on Aging (NIA), National Institutes of Health (NIH), Bethesda, MD, USA. Dr. Nalls also consults for Illumina Inc., the Michael J. Fox Foundation, and the University of California Healthcare. Mark J. Caulfield: MJC is Chief Scientist for Genomics England, a UK government company. Joel N. Hirschhorn: JHN is on the scientific advisory board of Camp4 Therapeutics. Erik Ingelsson: Erik Ingelsson is now an employee of GlaxoSmithKline. Anubha Mahajan: Anubha Mahajan is an employee of Genentech since January 2020, and a holder of Roche stock. Mark I McCarthy: The views expressed in this article are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. MMcC has served on advisory panels for Pfizer, NovoNordisk and Zoe Global, has received honoraria from Merck, Pfizer, Novo Nordisk and Eli Lilly, and research funding from Abbvie, Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, NovoNordisk, Pfizer, Roche, Sanofi Aventis, Servier, and Takeda. As of June 2019, MMcC is an employee of Genentech, and a holder of Roche stock. Inês Barroso: IB and spouse declare stock ownership in GlaxoSmithkline and Incyte Ltd. James B. Meigs: JBM serves as an Academic Associate for Quest Diagnostics R&D Bruce M Psaty serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Dr. Sander W. van der Laan has received Roche funding for unrelated work. Matthias Blüher received honoraria as a consultant and speaker from Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, Lilly, Novo Nordisk, Novartis, Pfizer and Sanofi. Vinicius Tragante: VT became an employee of deCODE genetics/Amgen Inc. after the conclusion of this work Dr Franco is employed by ErasmusAGE, a center for aging research across the life course funded by Nestlé Nutrition (Nestec Ltd.) and Metagenics., (Copyright: © 2023 Willems SM et al.)

Background: Heat waves impact the health of older adults, and occupations are important for health. An overview of research focussed on older adults' occupations in heat waves can be useful for occupational therapy practice., Objective: To identify what the literature shows about older adults' experience and performance of, and participation in, occupations in heat waves., Material and Method: This scoping review included a literature search in five academic databases, four databases for grey literature, and a manual search. Literature in English regarding older adults 60+ and their occupations in heat waves were eligible., Findings: Twelve studies were included. Findings showed that older adults adapt their occupations using bodily, environmental, and social interaction strategies and by changing their daily routines. Personal, environmental, social, and economic factors facilitate and maintain occupations in heat waves., Conclusion: Older adults adapt their occupations in heat waves and different factors impact how they can be adapted. Future research is needed to explore how older adults experience their occupations in heat waves, and to deepen the knowledge about their heat-adaptive strategies., Significance: The findings support the role of occupational therapists in the design and practice of interventions managing the impact of heat waves in daily life.

Aims/hypothesis: The euglycaemic-hyperinsulinaemic clamp (EIC) is the reference standard for the measurement of whole-body insulin sensitivity but is laborious and expensive to perform. We aimed to assess the incremental value of high-throughput plasma proteomic profiling in developing signatures correlating with the M value derived from the EIC., Methods: We measured 828 proteins in the fasting plasma of 966 participants from the Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) study and 745 participants from the Uppsala Longitudinal Study of Adult Men (ULSAM) using a high-throughput proximity extension assay. We used the least absolute shrinkage and selection operator (LASSO) approach using clinical variables and protein measures as features. Models were tested within and across cohorts. Our primary model performance metric was the proportion of the M value variance explained (R 2 )., Results: A standard LASSO model incorporating 53 proteins in addition to routinely available clinical variables increased the M value R 2 from 0.237 (95% CI 0.178, 0.303) to 0.456 (0.372, 0.536) in RISC. A similar pattern was observed in ULSAM, in which the M value R 2 increased from 0.443 (0.360, 0.530) to 0.632 (0.569, 0.698) with the addition of 61 proteins. Models trained in one cohort and tested in the other also demonstrated significant improvements in R 2 despite differences in baseline cohort characteristics and clamp methodology (RISC to ULSAM: 0.491 [0.433, 0.539] for 51 proteins; ULSAM to RISC: 0.369 [0.331, 0.416] for 67 proteins). A randomised LASSO and stability selection algorithm selected only two proteins per cohort (three unique proteins), which improved R 2 but to a lesser degree than in standard LASSO models: 0.352 (0.266, 0.439) in RISC and 0.495 (0.404, 0.585) in ULSAM. Reductions in improvements of R 2 with randomised LASSO and stability selection were less marked in cross-cohort analyses (RISC to ULSAM R 2 0.444 [0.391, 0.497]; ULSAM to RISC R 2 0.348 [0.300, 0.396]). Models of proteins alone were as effective as models that included both clinical variables and proteins using either standard or randomised LASSO. The single most consistently selected protein across all analyses and models was IGF-binding protein 2., Conclusions/interpretation: A plasma proteomic signature identified using a standard LASSO approach improves the cross-sectional estimation of the M value over routine clinical variables. However, a small subset of these proteins identified using a stability selection algorithm affords much of this improvement, especially when considering cross-cohort analyses. Our approach provides opportunities to improve the identification of insulin-resistant individuals at risk of insulin resistance-related adverse health consequences., (© 2023. The Author(s).)

Background: Human plasma contains a wide variety of circulating proteins. These proteins can be important clinical biomarkers in disease and also possible drug targets. Large scale genomics studies of circulating proteins can identify genetic variants that lead to relative protein abundance., Methods: We conducted a meta-analysis on genome-wide association studies of autosomal chromosomes in 22,997 individuals of primarily European ancestry across 12 cohorts to identify protein quantitative trait loci (pQTL) for 92 cardiometabolic associated plasma proteins., Results: We identified 503 (337 cis and 166 trans) conditionally independent pQTLs, including several novel variants not reported in the literature. We conducted a sex-stratified analysis and found that 118 (23.5%) of pQTLs demonstrated heterogeneity between sexes. The direction of effect was preserved but there were differences in effect size and significance. Additionally, we annotate trans-pQTLs with nearest genes and report plausible biological relationships. Using Mendelian randomization, we identified causal associations for 18 proteins across 19 phenotypes, of which 10 have additional genetic colocalization evidence. We highlight proteins associated with a constellation of cardiometabolic traits including angiopoietin-related protein 7 (ANGPTL7) and Semaphorin 3F (SEMA3F)., Conclusion: Through large-scale analysis of protein quantitative trait loci, we provide a comprehensive overview of common variants associated with plasma proteins. We highlight possible biological relationships which may serve as a basis for further investigation into possible causal roles in cardiometabolic diseases., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Adipogenesis is a process in which fat-specific progenitor cells (preadipocytes) differentiate into adipocytes that carry out the key metabolic functions of the adipose tissue, including glucose uptake, energy storage, and adipokine secretion. Several cell lines are routinely used to study the molecular regulation of adipogenesis, in particular the immortalized mouse 3T3-L1 line and the primary human Simpson-Golabi-Behmel syndrome (SGBS) line. However, the cell-to-cell variability of transcriptional changes prior to and during adipogenesis in these models is not well understood. Here, we present a single-cell RNA-Sequencing (scRNA-Seq) dataset collected before and during adipogenic differentiation of 3T3-L1 and SGBS cells. To minimize the effects of experimental variation, we mixed 3T3-L1 and SGBS cells and used computational analysis to demultiplex transcriptomes of mouse and human cells. In both models, adipogenesis results in the appearance of three cell clusters, corresponding to preadipocytes, early and mature adipocytes. These data provide a groundwork for comparative studies on these widely used in vitro models of human and mouse adipogenesis, and on cell-to-cell variability during this process., (© 2023. The Author(s).)

Distinct tissue-specific mechanisms mediate insulin action in fasting and postprandial states. Previous genetic studies have largely focused on insulin resistance in the fasting state, where hepatic insulin action dominates. Here we studied genetic variants influencing insulin levels measured 2 h after a glucose challenge in >55,000 participants from three ancestry groups. We identified ten new loci (P < 5 × 10 -8 ) not previously associated with postchallenge insulin resistance, eight of which were shown to share their genetic architecture with type 2 diabetes in colocalization analyses. We investigated candidate genes at a subset of associated loci in cultured cells and identified nine candidate genes newly implicated in the expression or trafficking of GLUT4, the key glucose transporter in postprandial glucose uptake in muscle and fat. By focusing on postprandial insulin resistance, we highlighted the mechanisms of action at type 2 diabetes loci that are not adequately captured by studies of fasting glycemic traits., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Insulin secretion is critical for glucose homeostasis, and increased levels of the precursor proinsulin relative to insulin indicate pancreatic islet beta-cell stress and insufficient insulin secretory capacity in the setting of insulin resistance. We conducted meta-analyses of genome-wide association results for fasting proinsulin from 16 European-ancestry studies in 45,861 individuals. We found 36 independent signals at 30 loci (p value < 5 × 10 -8 ), which validated 12 previously reported loci for proinsulin and ten additional loci previously identified for another glycemic trait. Half of the alleles associated with higher proinsulin showed higher rather than lower effects on glucose levels, corresponding to different mechanisms. Proinsulin loci included genes that affect prohormone convertases, beta-cell dysfunction, vesicle trafficking, beta-cell transcriptional regulation, and lysosomes/autophagy processes. We colocalized 11 proinsulin signals with islet expression quantitative trait locus (eQTL) data, suggesting candidate genes, including ARSG, WIPI1, SLC7A14, and SIX3. The NKX6-3/ANK1 proinsulin signal colocalized with a T2D signal and an adipose ANK1 eQTL signal but not the islet NKX6-3 eQTL. Signals were enriched for islet enhancers, and we showed a plausible islet regulatory mechanism for the lead signal in the MADD locus. These results show how detailed genetic studies of an intermediate phenotype can elucidate mechanisms that may predispose one to disease., Competing Interests: Declaration of interests J.B.M. is an academic associate for Quest Diagnostics Endocrine R&D. M.E.K. is employed by SYNLAB Holding Deutschland GmbH. C.M.L. receives grants from Bayer Ag and Novo Nordisk and her husband works for Vertex. B.Z. is employed at the Swedish Medical Products Agency, SE-751 03 Uppsala, Sweden; the views expressed in this paper are the personal views of the authors and not necessarily the views of the Swedish government agency. B.Z. has not received any funding or benefits from any sponsor for the present work. J.C.F. receives consulting honoraria from Goldfinch Bio and AstraZeneca and speaker honoraria from Novo Nordisk, AstraZeneca, and Merck for research lectures over which he had full control on content. D.A.L. has received support from Medtronics Ltd and Roche Diagnostics for research unrelated to this paper. W.M. reports grants and personal fees from Siemens Diagnostics, grants and personal fees from Aegerion Pharmaceuticals, grants and personal fees from AMGEN, grants and personal fees from AstraZeneca, grants and personal fees from Danone Research, grants and personal fees from Sanofi, personal fees from Hoffmann LaRoche, personal fees from MSD, grants and personal fees from Pfizer, personal fees from Synageva, grants and personal fees from BASF, grants from Abbott Diagnostics, and grants and personal fees from Numares, outside the submitted work. W.M. is employed by Synlab Holding Deutschland GmbH. R.W. reports lecture fees from Novo Nordisk and Sanofi and served on an advisory board for Akcea Therapeutics, Daiichi Sankyo, Sanofi, and Novo Nordisk. E.W. is now an employee of AstraZeneca., (Copyright © 2023 American Society of Human Genetics. All rights reserved.)

Background: Fibroblast growth factor-23 (FGF-23) is associated with a range of cardiovascular and noncardiovascular diseases in conventional epidemiological studies, but substantial residual confounding may exist. Mendelian randomization approaches can help control for such confounding., Methods: SCALLOP Consortium data of 19,195 participants were used to generate an FGF-23 genetic score. Data from 337,448 UK Biobank participants were used to estimate associations between higher genetically predicted FGF-23 concentration and the odds of any atherosclerotic cardiovascular disease (n=26,266 events), nonatherosclerotic cardiovascular disease (n=12,652), and noncardiovascular diseases previously linked to FGF-23. Measurements of carotid intima-media thickness and left ventricular mass were available in a subset. Associations with cardiovascular outcomes were also tested in three large case-control consortia: CARDIOGRAMplusC4D (coronary artery disease, n=181,249 cases), MEGASTROKE (stroke, n=34,217), and HERMES (heart failure, n=47,309)., Results: We identified 34 independent variants for circulating FGF-23, which formed a validated genetic score. There were no associations between genetically predicted FGF-23 and any of the cardiovascular or noncardiovascular outcomes. In UK Biobank, the odds ratio (OR) for any atherosclerotic cardiovascular disease per 1-SD higher genetically predicted logFGF-23 was 1.03 (95% confidence interval [95% CI], 0.98 to 1.08), and for any nonatherosclerotic cardiovascular disease, it was 1.01 (95% CI, 0.94 to 1.09). The ORs in the case-control consortia were 1.00 (95% CI, 0.97 to 1.03) for coronary artery disease, 1.01 (95% CI, 0.95 to 1.07) for stroke, and 1.00 (95% CI, 0.95 to 1.05) for heart failure. In those with imaging, logFGF-23 was not associated with carotid or cardiac abnormalities., Conclusions: Genetically predicted FGF-23 levels are not associated with atherosclerotic and nonatherosclerotic cardiovascular diseases, suggesting no important causal link., Podcast: This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/CJASN/2023&#95;01&#95;10&#95;CJN05080422.mp3., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Nephrology.)

Background: Transportation noise may induce cardiovascular disease, but the public health implications are unclear., Objectives: The study aimed to assess exposure-response relationships for different transportation noise sources and ischemic heart disease (IHD), including subtypes., Methods: Pooled analyses were performed of nine cohorts from Denmark and Sweden, together including 132,801 subjects. Time-weighted long-term exposure to road, railway, and aircraft noise, as well as air pollution, was estimated based on residential histories. Hazard ratios (HRs) were calculated using Cox proportional hazards models following adjustment for lifestyle and socioeconomic risk factors., Results: A total of 22,459 incident cases of IHD were identified during follow-up from national patient and mortality registers, including 7,682 cases of myocardial infarction. The adjusted HR for IHD was 1.03 [95% confidence interval (CI) 1.00, 1.05] per 10 dB L den for both road and railway noise exposure during 5 y prior to the event. Higher risks were indicated for IHD excluding angina pectoris cases, with HRs of 1.06 (95% CI: 1.03, 1.08) and 1.05 (95% CI: 1.01, 1.08) per 10 dB L den for road and railway noise, respectively. Corresponding HRs for myocardial infarction were 1.02 (95% CI: 0.99, 1.05) and 1.04 (95% CI: 0.99, 1.08). Increased risks were observed for aircraft noise but without clear exposure-response relations. A threshold at around 55 dB L den was suggested in the exposure-response relation for road traffic noise and IHD., Discussion: Exposure to road, railway, and aircraft noise in the prior 5 y was associated with an increased risk of IHD, particularly after exclusion of angina pectoris cases, which are less well identified in the registries. https://doi.org/10.1289/EHP10745.

Background: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery., Results: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism., Conclusions: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk., (© 2022. The Author(s).)

Myocardial infarction diagnosis is a common challenge in the emergency department. In managed settings, deep learning-based models and especially convolutional deep models have shown promise in electrocardiogram (ECG) classification, but there is a lack of high-performing models for the diagnosis of myocardial infarction in real-world scenarios. We aimed to train and validate a deep learning model using ECGs to predict myocardial infarction in real-world emergency department patients. We studied emergency department patients in the Stockholm region between 2007 and 2016 that had an ECG obtained because of their presenting complaint. We developed a deep neural network based on convolutional layers similar to a residual network. Inputs to the model were ECG tracing, age, and sex; and outputs were the probabilities of three mutually exclusive classes: non-ST-elevation myocardial infarction (NSTEMI), ST-elevation myocardial infarction (STEMI), and control status, as registered in the SWEDEHEART and other registries. We used an ensemble of five models. Among 492,226 ECGs in 214,250 patients, 5,416 were recorded with an NSTEMI, 1,818 a STEMI, and 485,207 without a myocardial infarction. In a random test set, our model could discriminate STEMIs/NSTEMIs from controls with a C-statistic of 0.991/0.832 and had a Brier score of 0.001/0.008. The model obtained a similar performance in a temporally separated test set of the study sample, and achieved a C-statistic of 0.985 and a Brier score of 0.002 in discriminating STEMIs from controls in an external test set. We developed and validated a deep learning model with excellent performance in discriminating between control, STEMI, and NSTEMI on the presenting ECG of a real-world sample of the important population of all-comers to the emergency department. Hence, deep learning models for ECG decision support could be valuable in the emergency department., (© 2022. The Author(s).)

Air pollution is one of the leading causes of morbidity and mortality worldwide. Low-emission zones (LEZ) have been increasingly implemented in cities throughout Europe as a measure to reduce the adverse health effects and premature deaths associated with traffic-related air pollution. In the present study, a health impact analysis was conducted to estimate the effect of a hypothetical LEZ on mortality and morbidity in Malmö, Sweden. Baseline health statistics were gathered from health registers and applied to each resident according to individual-level data on age and/or sex. Concentration-response parameters were derived from current epidemiological literature, specifically meta-analyses. A Gaussian dispersion model (AERMOD) combined with a detailed emission database was used to calculate NO 2 emissions from traffic, which could be applied on an individual-level using data on each person's residential coordinates. The adjusted exposure scenario replaced all vehicles on municipal roads having Euro 5 or lower emission standards with Euro 6 equivalents. This LEZ would, on average, decrease NO 2 concentrations by 13.4%, preventing an estimated 9-26 deaths in Malmö each year. Additionally, 12 respiratory disease hospitalizations, 8 childhood asthma cases, and 9 cases of hypertensive disorders of pregnancy were estimated to be avoided annually. These results suggest that LEZs can effectively improve air quality, reduce greenhouse gas emissions, and safeguard public health., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Smooth muscle cells (SMCs) execute important physiological functions in numerous vital organ systems, including the vascular, gastrointestinal, respiratory, and urogenital tracts. SMC differ morphologically and functionally at these different anatomical locations, but the molecular underpinnings of the differences remain poorly understood. Here, using deep single-cell RNA sequencing combined with in situ gene and protein expression analysis in four murine organs-heart, aorta, lung, and colon-we identify a molecular basis for high-level differences among vascular, visceral, and airway SMC, as well as more subtle differences between, for example, SMC in elastic and muscular arteries and zonation of elastic artery SMC along the direction of blood flow. Arterial SMC exhibit extensive organotypic heterogeneity, whereas venous SMC are similar across organs. We further identify a specific SMC subtype within the pulmonary vasculature. This comparative SMC cross-organ resource offers insight into SMC subtypes and their specific functions., Competing Interests: Declaration of interests C.B. holds a research grant from AstraZeneca BioPharmaceuticals R&D. U.L. holds a research grant from Merck KGaA but receives no personal remuneration from them., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40-50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes 1 . Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel 2 ) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10-20% (14-24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries., (© 2022. The Author(s).)