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Coronary artery calcium (CAC) scans contain valuable information beyond the Agatston Score which is currently reported for predicting coronary heart disease (CHD) only. We examined whether new artificial intelligence (AI) applied to CAC scans can predict non-CHD events, including heart failure, atrial fibrillation, and stroke. We applied AI-enabled automated cardiac chambers volumetry and calcified plaque characterization to CAC scans (AI-CAC) of 5830 asymptomatic individuals (52.2% women, age 61.7 ± 10.2 years) in the multi-ethnic study of atherosclerosis during 15 years of follow-up, 1773 CVD events accrued. The AUC at 1-, 5-, 10-, and 15-year follow-up for AI-CAC vs. Agatston score was (0.784 vs. 0.701), (0.771 vs. 0.709), (0.789 vs. 0.712) and (0.816 vs. 0.729) (p < 0.0001 for all), respectively. AI-CAC plaque characteristics, including number, location, density, plus number of vessels, significantly improved CHD prediction in the CAC 1-100 cohort vs. Agatston Score. AI-CAC significantly improved the Agatston score for predicting all CVD events., (© 2024. The Author(s).)

Objective/background: Unmet needs in perinatal mental healthcare are an important public health issue particularly in the context of a stressful life event such as the COVID-19 pandemic but data on the extent of this problem are needed., Aim: The aim of this study is to determine the (1) proportion of women with clinically significant symptoms of perinatal depression, anxiety or comorbid symptoms of depression and anxiety, receiving mental healthcare overall and by country and (2) factors associated with receiving mental healthcare., Method: Women in the perinatal period (pregnancy or up to 6 months postpartum) participating in the Riseup-PPD-COVID-19 cross-sectional study, reported on sociodemographic, social support health-related factors, and COVID-19 related factors, and on symptoms of depression (Edinburgh Postnatal Depression Scale [EPDS]) and anxiety (Generalised Anxiety Disorder [GAD-7]) using self-report questionnaires. Clinically significant symptoms were defined as EPDS ≥ 13 for depression and GAD-7 ≥ 10 for anxiety. Mental healthcare was defined as self-reported current mental health treatment., Results: Of the 11 809 participants from 12 countries included in the analysis, 4 379 (37.1%) reported clinically significant symptoms of depression (n = 1 228; 10.4%; EPDS ≥ 13 and GAD-7 ⟨ 10), anxiety (n = 848; 7.2%; GAD-7 ≥ 10 and EPDS ⟨ 13) or comorbid symptoms of depression and anxiety (n = 2 303; 19.5%; EPDS ≥ 13 and GAD-7 ≥ 10). Most women with clinically significant symptoms of depression, anxiety, or comorbid symptoms of depression and anxiety were not receiving mental healthcare (89.0%). Variation in the proportion of women with clinically significant symptoms of depression and/or anxiety reporting mental healthcare was high (4.7% in Turkey to 21.6% in Brazil). Women in the postpartum (vs. pregnancy) were less likely (OR 0.72; 95% CI 0.59-0.88), whereas women with previous mental health problems (vs. no previous mental health problems) (OR 5.56; 95% CI 4.41-7.01), were more likely to receive mental healthcare., Conclusion: There are high unmet needs in mental healthcare for women with clinically significant symptoms of perinatal depression and/or anxiety across countries during the COVID-19 pandemic. Studies beyond the COVID-19 pandemic and covering the whole range of mental health problems in the perinatal period are warranted to understand the gaps in perinatal mental healthcare., (© 2024 The Authors. Acta Psychiatrica Scandinavica published by John Wiley & Sons Ltd.)

Background: Epigenome-wide association studies have identified multiple DNA methylation sites (CpGs) associated with alcohol consumption, an important lifestyle risk factor for cardiovascular diseases. This study aimed to test the hypothesis that an alcohol consumption epigenetic risk score (ERS) is associated with blood pressure (BP) traits., Results: We implemented an ERS based on a previously reported epigenetic signature of 144 alcohol-associated CpGs in meta-analysis of participants of European ancestry. We found a one-unit increment of ERS was associated with eleven drinks of alcohol consumed per day, on average, across several cohorts (p < 0.0001). We examined the association of the ERS with systolic blood pressure (SBP), diastolic blood pressure (DBP), and hypertension (HTN) in 3,898 Framingham Heart Study (FHS) participants. Cross-sectional analyses in FHS revealed that a one-unit increment of the ERS was associated with 1.93 mm Hg higher SBP (p = 4.64E-07), 0.68 mm Hg higher DBP (p = 0.006), and an odds ratio of 1.78 for HTN (p < 2E-16). Meta-analysis of the cross-sectional association of the ERS with BP traits in eight independent external cohorts (n = 11,544) showed similar relationships with BP levels, i.e., a one-unit increase in ERS was associated with 0.74 mm Hg (p = 0.002) higher SBP and 0.50 mm Hg (p = 0.0006) higher DBP, but not with HTN. Longitudinal analyses in FHS (n = 3260) and five independent external cohorts (n = 4021) showed that the baseline ERS was not associated with a change in BP over time or with incident HTN., Conclusions: Our findings demonstrate that the ERS has potential clinical utility in assessing lifestyle factors related to cardiovascular risk, especially when self-reported behavioral data (e.g., alcohol consumption) are unreliable or unavailable., (© 2024. The Author(s).)

Competing Interests: Competing interests: None declared.

Background: MicroRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally regulate gene expression. Perturbations in plasma miRNA levels are known to impact disease risk and have potential as disease biomarkers. Exploring the genetic regulation of miRNAs may yield new insights into their important role in governing gene expression and disease mechanisms., Results: We present genome-wide association studies of 2083 plasma circulating miRNAs in 2178 participants of the Rotterdam Study to identify miRNA-expression quantitative trait loci (miR-eQTLs). We identify 3292 associations between 1289 SNPs and 63 miRNAs, of which 65% are replicated in two independent cohorts. We demonstrate that plasma miR-eQTLs co-localise with gene expression, protein, and metabolite-QTLs, which help in identifying miRNA-regulated pathways. We investigate consequences of alteration in circulating miRNA levels on a wide range of clinical conditions in phenome-wide association studies and Mendelian randomisation using the UK Biobank data (N = 423,419), revealing the pleiotropic and causal effects of several miRNAs on various clinical conditions. In the Mendelian randomisation analysis, we find a protective causal effect of miR-1908-5p on the risk of benign colon neoplasm and show that this effect is independent of its host gene (FADS1)., Conclusions: This study enriches our understanding of the genetic architecture of plasma miRNAs and explores the signatures of miRNAs across a wide range of clinical conditions. The integration of population-based genomics, other omics layers, and clinical data presents opportunities to unravel potential clinical significance of miRNAs and provides tools for novel miRNA-based therapeutic target discovery., (© 2024. The Author(s).)

Extracellular vesicles (EVs) are physiological vectors for the intercellular transport of a variety of molecules. Among these, small RNAs, and especially microRNAs (miRNAs), have been identified as prevalent components, and there has thus been a robust investigation of EVs for therapeutic miRNAs delivery. However, intrinsic levels of EV-associated miRNAs are generally too low to enable efficient and effective therapeutic outcomes. We hypothesized that miRNA localization to EVs could be improved by limiting competing interactions that occur throughout the miRNA biogenesis process. Using miR-146a-5p as a model, modulation of transcription, nuclear export, and enzymatic cleavage steps of miRNA biogenesis were tested for impact on EV miRNA loading. Working in HEK293T cells, various alterations in the EV biogenesis pathway were shown to impact miRNA localization to EVs. The system was then applied in induced pluripotent stem cells (iPSCs), a more promising substrate for therapeutic EV production, and EVs were separated and assessed for anti-inflammatory efficacy in vitro and in a murine colitis model, where the preservation of function was validated. Overall, the results highlight necessary considerations when designing a cell culture system for the devoted production of miRNA-loaded EVs.

Background: Peripheral veno-arterial extracorporeal membrane oxygenation (pECMO) has become the first-line device in refractory cardiogenic shock (rCS). Some pECMO complications can preclude any bridging strategies and a peripheral-to-central ECMO (cECMO) switch can be considered as a bridge-to-decision. We conducted this study to appraise the in-hospital survival and the bridging strategies in patients undergoing peripheral-to-central ECMO switch., Methods: This retrospective monocenter study included patients admitted to a ECMO-dedicated intensive care unit from February 2006 to January 2023. Patients with rCS requiring pECMO switched to cECMO were included. Patients were not included when the cECMO was the first mechanical circulatory support., Results: Eighty patients, with a median [IQR25-75] age of 44 [29-53] years at admission and a female-to-male sex ratio of 0.6 were included in the study. Refractory pulmonary edema was the main switching reason. Thirty patients (38%) were successfully bridged to: heart transplantation (n = 16/80, 20%), recovery (n = 10/80, 12%) and ventricle assist device (VAD, n = 4/30, 5%) while the others died on cECMO (n = 50/80, 62%). The most frequent complications were the need for renal replacement therapy (76%), hemothorax or tamponade (48%), need for surgical revision (34%), mediastinitis (28%), and stroke (28%). The in-hospital and one-year survival rates were 31% and 27% respectively. Myocardial infarction as the cause of the rCS was the only variable independently associated with in-hospital mortality (HR 2.5 [1.3-4.9], p = 0.009)., Conclusions: The switch from a failing pECMO support to a cECMO as a bridge-to-decision is a possible strategy for a very selected population of young patients with a realistic chance of heart function recovery or heart transplantation. In this setting, cECMO allows patients triage preventing from wasting expensive and limited resources., (© 2024. The Author(s).)

The linear mixed model (LMM) has become a standard in genetic association studies to account for population stratification and relatedness in the samples to reduce false positives. Much recent progresses in LMM focused on approximate computations. Exact methods remained computationally demanding and without theoretical assurance. The computation is particularly challenging for multiomics studies where tens of thousands of phenotypes are tested for association with millions of genetic markers. We present IDUL and IDUL† that use iterative dispersion updates to fit LMMs, where IDUL† is a modified version of IDUL that guarantees likelihood increase between updates. Practically, IDUL and IDUL† produced identical results, both are markedly more efficient than the state-of-the-art Newton-Raphson method, and in particular, both are highly efficient for additional phenotypes, making them ideal to study genetic determinants of multiomics phenotypes. Theoretically, the LMM likelihood is asymptotically unimodal, and therefore the gradient ascent algorithm IDUL† is asymptotically exact. A software package implementing IDUL and IDUL† for genetic association studies is freely available at https://github.com/haplotype/IDUL., Competing Interests: Conflicts of interest The author(s) declare no conflicts of interest., (Published by Oxford University Press on behalf of The Genetics Society of America 2024.)

Objective: There is often unfamiliarity with the care of artificial airway devices (ie, endotracheal tubes, tracheostomies, and laryngectomies). The objective of this study was to design an Airway Quality Improvement Program (AQIP) to improve airway care., Methods: This was a retrospective chart review of a prospectively-initiated AQIP. The AQIP has 3 parts: 1) Mandatory "airway signs" 2) In-service teaching with a corresponding order set and 3) an overhead "Surgical Airway Emergency" page involving automatic pages to Anesthesia, Otolaryngology, and Respiratory Therapy. Pre- and post-intervention survey data was collected. The incidence of airway emergency was the primary patient outcome and was hypothesized to decrease after AQIP intervention., Results: Airway emergencies decreased 8.4% after AQIP ( P  = .45). Length of stay decreased after AQIP, 47.0 ± 76.5 days compared to 23.5 ± 23.6 ( P  = .004). Two hundred eight-one nurses and 76 respiratory therapists were educated. Pre-AQIP comfortability scores improved for the routine care of endotracheal tubes, tracheostomies, and laryngectomies, 4.3 ± 0.9, 4.3 ± 0.8, and 3.5 ± 1.2, compared to 4.7 ± 0.6, 4.5 ± 0.7, and 4.4 ± 0.7 post-AQIP ( P  = .0006, P  = .02, P  = .0001). The same improvement was noted for emergency airway care. Tracheostomy vs. laryngectomy recognition increased from 66.5 to 97.0% ( P  = .0001). Quiz questions regarding emergency airway management for laryngectomies improved from 76.2 to 93.8% ( P  = .0001)., Conclusion: The AQIP was associated with decreased length of hospital stay and improved competency in airway care among hospital staff. Further application of AQIP is needed for replication in other institutions and long-term application., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: The leading nonhereditary cause of childhood sensorineural hearing loss has been attributed to congenital cytomegalovirus (cCMV). Sensorineural hearing loss can be unilateral (UHL) or bilateral (BHL), and may be progressive. Our objective was to describe the characteristics, clinical nature and follow-up of ears in cCMV-associated UHL., Methods: This 16-year retrospective study was performed at Schneider's Medical Center, Israel. Data were collected from all cCMV infants with UHL at birth who were treated with antiviral treatment initiated within the first 4 weeks of life and had a follow-up period of at least 1 year., Results: We enrolled 67 infants diagnosed with UHL at birth: 17 (25%) with mild hearing loss, 22 (33%) with moderate hearing loss and 28 (42%) with severe hearing loss. At the last follow-up visit, 7 (41%) ears in the mild hearing loss group improved to normal hearing, 8 (47%) ears exhibited no change and 2 (12%) ears deteriorated. In the moderate hearing loss group, 9 (41%) ears improved, 7 (32%) remained static and 6 (27%) deteriorated to the severe hearing loss group. One (4%) ear in the severe hearing loss group showed improvement. Of the 67 ears with normal hearing at birth, 4 (6%) ears deteriorated., Conclusions: This study assessed and elucidated the characteristics, clinical nature and long-term follow-up of both the affected and unaffected ears diagnosed with UHL due to cCMV. These data are crucial when medical and/or surgical interventions are considered., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Amyloids are associated with over 50 human diseases and have inspired significant effort to identify small molecule remedies. Here, we present an in vivo platform that efficiently yields small molecule inhibitors of amyloid formation. We previously identified small molecules that kill the nematode C. elegans by forming membrane-piercing crystals in the pharynx cuticle, which is rich in amyloid-like material. We show here that many of these molecules are known amyloid-binders whose crystal-formation in the pharynx can be blocked by amyloid-binding dyes. We asked whether this phenomenon could be exploited to identify molecules that interfere with the ability of amyloids to seed higher-order structures. We therefore screened 2560 compounds and found 85 crystal suppressors, 47% of which inhibit amyloid formation. This hit rate far exceeds other screening methodologies. Hence, in vivo screens for suppressors of crystal formation in C. elegans can efficiently reveal small molecules with amyloid-inhibiting potential., (© 2024. The Author(s).)

Migraine is a highly prevalent and disabling pain disorder that affects >1 billion people worldwide. One central hypothesis points to the cranial meninges as a key site underlying migraine headache genesis through complex interplay between meningeal sensory nerves, blood vessels, and adjacent immune cells. How these interactions might generate migraine headaches remains incompletely understood and a subject of much debate. In this review we discuss clinical and preclinical evidence supporting the concept that meningeal sterile inflammation, involving neurovascular and neuroimmune interactions, underlies migraine headache genesis. We examine downstream signaling pathways implicated in the development of migraine pain in response to exogenous events such as infusing migraine-triggering chemical substances. We further discuss cortex-to-meninges signaling pathways that could underlie migraine pain in response to endogenous events, such as cortical spreading depolarization (CSD), and explore future directions for the field., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

MicroRNAs, crucial in regulating protein-coding gene expression, are implicated in various diseases. We performed a genome-wide association study of plasma miRNAs (ex-miRNAs) in 3,743 Framingham Heart Study (FHS) participants and identified 1,027 cis- ex-miRNA-eQTLs ( cis- exQTLs) for 37 ex-miRNAs, with 55% replication in an independent study. Colocalization analyses suggested potential genetic coregulation of ex-miRNAs with whole blood mRNAs. Mendelian randomization indicated 29 ex-miRNAs potentially influencing 35 traits. Notably, the chromosome 14q23 and 14q32 miRNA clusters emerged as the top signal, contributing over 50% of the significant cis- exQTL results, and were associated with a diverse range of traits including platelet count. Correlations of 10 ex-miRNAs (such as miR-376c-3p) in 14q32 with platelet count and volume were confirmed in FHS participants. These findings shed light on the genetic basis of ex-miRNA expression and their involvement in complex traits., Competing Interests: The authors declare no conflict of interest.

Proteins often harness extensive motions of domains and subunits to promote their function. Deciphering how these movements impact activity is key for understanding life's molecular machinery. The enzyme adenylate kinase is an intriguing example for this relationship; it ensures efficient catalysis by large-scale domain motions that lead to the enclosure of the bound substrates ATP and AMP. At high concentrations, AMP also operates as an allosteric inhibitor of the protein. Surprisingly, the enzyme is activated by urea, a compound commonly acting as a denaturant. Combining single-molecule FRET spectroscopy and enzymatic activity studies, we find that urea interferes with two key mechanisms that contribute to enzyme efficacy. First, urea promotes the open conformation of the enzyme, aiding the proper positioning of the substrates. Second, urea decreases AMP affinity, paradoxically facilitating a more efficient progression towards the catalytically active complex. These results signify the important interplay between conformational dynamics and chemical steps, including binding, in the activity of enzymes. State-of-the-art tools, such as single-molecule fluorescence spectroscopy, offer new insights into how enzymes balance different conformations to regulate activity., Competing Interests: The authors declare no competing financial interests.

We rigorously assessed a comprehensive association testing framework for heteroplasmy, employing both simulated and real-world data. This framework employed a variant allele fraction (VAF) threshold and harnessed multiple gene-based tests for robust identification and association testing of heteroplasmy. Our simulation studies demonstrated that gene-based tests maintained an appropriate type I error rate at α = 0.001. Notably, when 5 % or more heteroplasmic variants within a target region were linked to an outcome, burden-extension tests (including the adaptive burden test, variable threshold burden test, and z-score weighting burden test) outperformed the sequence kernel association test (SKAT) and the original burden test. Applying this framework, we conducted association analyses on whole-blood derived heteroplasmy in 17,507 individuals of African and European ancestries (31 % of African Ancestry, mean age of 62, with 58 % women) with whole genome sequencing data. We performed both cohort- and ancestry-specific association analyses, followed by meta-analysis on both pooled samples and within each ancestry group. Our results suggest that mtDNA-encoded genes/regions are likely to exhibit varying rates in somatic aging, with the notably strong associations observed between heteroplasmy in the RNR1 and RNR2 genes (p < 0.001) and advance aging by the Original Burden test. In contrast, SKAT identified significant associations (p < 0.001) between diabetes and the aggregated effects of heteroplasmy in several protein-coding genes. Further research is warranted to validate these findings. In summary, our proposed statistical framework represents a valuable tool for facilitating association testing of heteroplasmy with disease traits in large human populations., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors have nothing to disclose, except for the disclosure from following authors. Dr. Abecasis reports grants from National Heart Lung and Blood Institute (NIH), during the conduct of the study; personal fees and other from Regeneron Pharmaceuticals, outside the submitted work; Dr. Psaty serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson; outside the submitted work., (Copyright © 2024 Elsevier B.V. and Mitochondria Research Society. All rights reserved.)

Systemic low-grade inflammation is a feature of chronic disease. C-reactive protein (CRP) is a common biomarker of inflammation and used as an indicator of disease risk; however, the role of inflammation in disease is not completely understood. Methylation is an epigenetic modification in the DNA which plays a pivotal role in gene expression. In this study we evaluated differential DNA methylation patterns associated with blood CRP level to elucidate biological pathways and genetic regulatory mechanisms to improve the understanding of chronic inflammation. The racially and ethnically diverse participants in this study were included as 50% White, 41% Black or African American, 7% Hispanic or Latino/a, and 2% Native Hawaiian, Asian American, American Indian, or Alaska Native (total n  = 13,433) individuals. We replicated 113 CpG sites from 87 unique loci, of which five were novel ( CADM3 , NALCN, NLRC5, ZNF792 , and cg03282312), across a discovery set of 1,150 CpG sites associated with CRP level ( p  < 1.2E-7). The downstream pathways affected by DNA methylation included the identification of IFI16 and IRF7 CpG-gene transcript pairs which contributed to the innate immune response gene enrichment pathway along with NLRC5 , NOD2 , and AIM2 . Gene enrichment analysis also identified the nuclear factor-kappaB transcription pathway. Using two-sample Mendelian randomization (MR) we inferred methylation at three CpG sites as causal for CRP levels using both White and Black or African American MR instrument variables. Overall, we identified novel CpG sites and gene transcripts that could be valuable in understanding the specific cellular processes and pathogenic mechanisms involved in inflammation.

Background: Sarcopenia, commonly observed in patients treated with hemodialysis, correlates with low serum phosphate levels. Although normophosphatemia is desired, dietary phosphate restriction is difficult to achieve and may result in undesirable protein restriction., Objective: We aimed to evaluate whether hyperphosphatemia is associated with higher muscle strength in patients receiving hemodialysis treatment., Design: A single-center prospective observational study., Setting: Ambulatory prevalent patients undergoing hemodialysis treatments in a dialysis unit of a tertiary hospital., Patients: Participants included prevalent patients treated with hemodialysis. All patients were above 18 years. Only patients with residual kidney function below 200 mL/24 hours were included to avoid bias., Measurements: Muscle strength was measured by handgrip strength (HGS). Each patient repeated 3 measurements, and the highest value was recorded. Handgrip strength cutoffs for low muscle strength were defined as <27 kg in men and <16 kg in women. Biochemical parameters, including serum phosphate level, were driven from routine monthly blood tests. Hyperphosphatemia was defined as serum phosphate above 4.5 mg/dL., Methods: Handgrip strength results were compared to nutritional, anthropometric, and biochemical parameters-in particular phosphate level. Long-term mortality was recorded., Results: Seventy-four patients were included in the final analysis. Handgrip strength was abnormally low in 33 patients (44.5%). Patients with abnormal HGS were older and more likely to have diabetes mellitus and lower albumin and creatinine levels. There was no correlation between HGS and phosphate level ( r = 0.008, P = .945). On multivariable analysis, predictors of higher HGS were body mass index and creatinine. Diabetes mellitus and female sex predicted lower HGS. Hyperphosphatemia correlated with protein catabolic rate, blood urea nitrogen, and creatinine. On multivariable analysis, predictors of hyperphosphatemia were higher creatinine level, normal albumin level, and heart failure. During mean follow-up time of 7.66 ± 3.9 months, 11 patients died. Mortality was significantly higher in patients with abnormally low HGS compared with normal HGS (odds ratio = 9.32, P = .02)., Limitations: A single-center study. All measurements were performed at one time point without repeated assessments. Direct dietary intake, degree of physical activity, and medication compliance were not assessed., Conclusion: Hyperphosphatemia correlated with increased protein intake as assessed by protein catabolic rate in patients treated with hemodialysis; however, neither correlated with higher muscle strength as measured by HGS.Trial registration: MOH 202125213., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Objective: This study aimed to fine-tune a large language model (LLM) for domain-specific text generation in surgical and anesthesia residency education., Summary Background Data: With growing interest in artificial intelligence (AI) for medical training, the potential of LLMs to transform residency education is explored., Methods: The 7-billion parameter base model "Vicuna v1.5" was trained on 266,342 lines of text from 821 peer-reviewed documents. We evaluated the model with 150 surgical or anesthesia queries and assessed accuracy, token count, and inference speed across various reasoning tasks. Tests of significance were conducted using ANOVA and chi-square analysis., Results: Our model achieved 65.3% accuracy, excelling in surgical case-based tasks. We found no significant difference in accuracy between knowledge domains (P=0.081), though longer response generation demonstrated poorer accuracy, with significant accuracy variation based on output length (P ​= ​0.002)., Conclusions: LLMs show potential in enhancing residency education. Our model's efficiency and task-specific accuracy highlights such promise, though limits in parameter count diminishes accuracy of longer response generation. Our findings showcase how AI may be integrated effectively within future residency training., Competing Interests: Declaration of competing interest The authors have no competing interests or relevant funding to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: Despite systemic thrombolysis, a few patients with high-risk pulmonary embolism (PE) remain hemodynamically unstable. Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is a considerable lifesaving therapy but systemic thrombolysis before cannulation could carry a high risk of hemorrhage and alter the prognosis., Methods: Between June 2012 and June 2023, we retrospectively analyzed from three intensive care units in Sorbonne University, ECMO-related complications and 90-day mortality for high-risk PE patients who received ECMO without previous systemic thrombolysis compared to those cannulated after systemic thrombolysis failure. Hospital discharge survivors were assessed for long-term health-related quality of life and echocardiographic evaluations., Results: 72 high-risk PE patients [median age 48 (37-61) years, Simplified Acute Physiology Score II (SAPS II) 74 (60-85)] were placed on VA-ECMO for 5 (5-7) days. 31 (43%) patients underwent pre-ECMO thrombolysis (thrombolysis ECMO group, T +) compared to 41 patients (57%, no thrombolysis ECMO group, T-). There was more pre-ECMO cardiac arrest in the thrombolysis ECMO group (94% vs. 67%, p = 0.02). Ninety-day survival was not different between groups (39% vs 46%, log-rank test, p = 0.31). There was no difference in severe hemorrhages (61% vs 59%, p = 1). Twenty-five over 28 patients attended follow-up at a median time of 69 (52-95) months. Long-term quality of life was acceptable and none of them experienced chronic thromboembolic pulmonary hypertension., Conclusions: Ninety-day survival and bleeding events rates did not differ in patients treated with VA-ECMO after systemic thrombolysis compared to those who were not. Recent systemic thrombolysis, as a single parameter, should not be considered as a contraindication for VA-ECMO in high-risk PE., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Clonal hematopoiesis of indeterminate potential (CHIP), whereby somatic mutations in hematopoietic stem cells confer a selective advantage and drive clonal expansion, not only correlates with age but also confers increased risk of morbidity and mortality. Here, we leverage genetically predicted traits to identify factors that determine CHIP clonal expansion rate. We used the passenger-approximated clonal expansion rate method to quantify the clonal expansion rate for 4,370 individuals in the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) cohort and calculated polygenic risk scores for DNA methylation aging, inflammation-related measures and circulating protein levels. Clonal expansion rate was significantly associated with both genetically predicted and measured epigenetic clocks. No associations were identified with inflammation-related lab values or diseases and CHIP expansion rate overall. A proteome-wide search identified predicted circulating levels of myeloid zinc finger 1 and anti-Müllerian hormone as associated with an increased CHIP clonal expansion rate and tissue inhibitor of metalloproteinase 1 and glycine N-methyltransferase as associated with decreased CHIP clonal expansion rate. Together, our findings identify epigenetic and proteomic patterns associated with the rate of hematopoietic clonal expansion., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Short peptides are attractive building blocks for the fabrication of self-assembled materials with significant biological, chemical, and physical properties. The microscopic and macroscopic properties of assemblies are usually closely related to the dimensionality of formed hydrogen bond networks. Here, two completely different supramolecular architectures connected by distinct hydrogen bond networks were obtained by simply adding a hydroxyl group to switch from cyclo-tryptophan-alanine (cyclo-WA) to cyclo-tryptophan-serine (cyclo-WS). While hydroxyl-bearing cyclo-WS molecules provided an additional hydrogen bond donor that links to adjacent molecules, forming a rigid three-dimensional network, cyclo-WA arranged into a water-mediated zipper-like structure with a softer two-dimensional layer template. This subtle alteration resulted in a 14-fold enhancement of Young's modulus values in cyclo-WS compared to cyclo-WA. Both cyclo-dipeptides exhibit biocompatibility, high fluorescence, and piezoelectricity. The demonstrated role of dimensionality of hydrogen bond networks opens new avenues for rational design of materials with precise morphologies and customizable properties for bioelectronic applications., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Introduction: Achieving cessation in people with established smoking patterns remains a challenge. Increasing cigarette prices has been one of the most successful strategies for lowering smoking rates. The extent to which it has remained effective in encouraging cessation among adults in recent years and how the effectiveness has varied by sociodemographic characteristics is unclear., Aims and Methods: Using repeated cross-sectional data collected by the Tobacco Use Supplement of the Current Population Survey, we investigate the relationship between cigarette prices and cessation from 2003 to 2019 in adults at least 25 years old. We examine the associations between price and cessation in the population overall and by sex, race and ethnicity, and socioeconomic status., Results: We found mixed support for associations between greater local prices and cessation. Unadjusted models showed that greater local prices were associated with greater odds of cessation, but the associations did not persist after controlling for sociodemographic characteristics. The associations did not significantly differ by respondent characteristics. Sensitivity analysis using alternative specifications and retail state price as the main predictor showed similar results. Sensitivity analysis with controls for e-cigarette use in the 2014-2019 period showed that greater local price was associated with cessation among adults with less than a high school degree. When stratified by year of data collection, results show that greater local prices were associated with cessation after 2009., Conclusions: Overall, the study adds to the conflicting evidence on the effectiveness of increasing prices on smoking cessation among adults with established smoking patterns., Implications: Higher cigarette prices have been one of the most successful tools for lowering smoking prevalence. It remains unclear how effective they have been in recent years in encouraging adults with established smoking patterns to quit. The study's results show that greater local prices were associated with higher odds of cessation, but the association did not persist after sociodemographic adjustment. In a sensitivity analysis, greater local price was associated with cessation among people with less than a high school degree in models controlling for e-cigarette use. We also found evidence that greater local price was associated with cessation after 2009. More comprehensive smoke-free coverage was also associated with greater odds of cessation. The study's results highlight that encouraging cessation among adults with an established smoking pattern remains a challenging policy problem even when cigarette prices rise., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Crystalline riboflavin (vitamin B 2 ) performs an important biological role as an optically functional material in the tapetum lucidum of certain animals, notably lemurs and cats. The tapetum lucidum is a reflecting layer behind the retina, which serves to enhance photon capture and vision in low-light settings. Motivated by the aim of rationalizing its biological role, and given that the structure of biogenic solid-state riboflavin remains unknown, we have used a range of experimental and computational techniques to determine the solid-state structure of synthetic riboflavin. Our multitechnique approach included microcrystal XRD, powder XRD, three-dimensional electron diffraction (3D-ED), high-resolution solid-state 13 C NMR spectroscopy, and dispersion-augmented density functional theory (DFT-D) calculations. Although an independent report of the crystal structure of riboflavin was published recently, our structural investigations reported herein provide a different interpretation of the intermolecular hydrogen-bonding arrangement in this material, supported by all the experimental and computational approaches utilized in our study. We also discuss, more generally, potential pitfalls that may arise in applying DFT-D geometry optimization as a bridging step between structure solution and Rietveld refinement in the structure determination of hydrogen-bonded materials from powder XRD data. Finally, we report experimental and computational values for the refractive index of riboflavin, with implications for its optical function., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Introduction: In 2015, the National Institute of Dental and Craniofacial Research (NIDCR) launched the Multidisciplinary Collaborative Research Consortium to Reduce Oral Health Disparities in Children, supporting four randomized trials testing strategies to improve preventive care. A Coordinating Center provides scientific expertise, data acquisition and quality assurance services, safety monitoring, and final analysis-ready datasets. This paper describes the trials' economic analysis strategies, placing these strategies within the broader context of contemporary economic analysis methods., Methods: The Coordinating Center established a Cost Collaborative Working Group to share information from the four trials about the components of their economic analyses. Study teams indicated data sources for their economic analysis using a set of structured tables. The Group meets regularly to share progress, discuss challenges, and coordinate analytic approaches., Results: All four trials will calculate incremental cost-effectiveness ratios; two will also conduct cost-utility analyses using proxy diseases to estimate health state utilities. Each trial will consider at least two perspectives. Key process measures include dental services provided to child participants. The non-preference-weighted Early Childhood Oral Health Impact Scale (ECOHIS) will measure oral health-related quality of life. All trials are measuring training, implementation, personnel and supervision, service, supplies, and equipment costs., Conclusions: Consistent with best practices, all four trials have integrated economic analysis during their planning stages. This effort is critical since poor quality or absence of essential data can limit retrospective analysis. Integrating economic analysis into oral health preventive intervention research can provide guidance to clinicians and practices, payers, and policymakers., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Spetz, Rose, Kahn, Lin, Levy, Pugach, Hyde, Borrelli, Henshaw, Martin, Nelson, Ramos-Gomez and Gansky.)

Although both short and long sleep duration are associated with elevated hypertension risk, our understanding of their interplay with biological pathways governing blood pressure remains limited. To address this, we carried out genome-wide cross-population gene-by-short-sleep and long-sleep duration interaction analyses for three blood pressure traits (systolic, diastolic, and pulse pressure) in 811,405 individuals from diverse population groups. We discover 22 novel gene-sleep duration interaction loci for blood pressure, mapped to 23 genes. Investigating these genes' functional implications shed light on neurological, thyroidal, bone metabolism, and hematopoietic pathways that necessitate future investigation for blood pressure management that caters to sleep health lifestyle. Non-overlap between short sleep (12) and long sleep (10) interactions underscores the plausible nature of distinct influences of both sleep duration extremes in cardiovascular health. Several of our loci are specific towards a particular population background or sex, emphasizing the importance of addressing heterogeneity entangled in gene-environment interactions, when considering precision medicine design approaches for blood pressure management., Competing Interests: Declarations CONFLICT OF INTEREST C.L.M. has received funding from AstraZeneca not related to the current study. B.M.P. serves on the steering committee of the Yale Open Data Access Project funded by Johnson & Johnson. D.C. receives consultancy fees from Roche Diagnostics and Trimedics and speaker fees from Servier. D.A.L. has received support from Medtronic LTD and Roche Diagnostics for biomarker research not related to the current study. The remaining authors declare no competing interests.

With age, hematopoietic stem cells can acquire somatic mutations in leukemogenic genes that confer a proliferative advantage in a phenomenon termed "clonal hematopoiesis of indeterminate potential" (CHIP). How these mutations confer a proliferative advantage and result in increased risk for numerous age-related diseases remains poorly understood. We conducted a multiracial meta-analysis of epigenome-wide association studies (EWAS) of CHIP and its subtypes in four cohorts (N=8196) to elucidate the molecular mechanisms underlying CHIP and illuminate how these changes influence cardiovascular disease risk. The EWAS findings were functionally validated using human hematopoietic stem cell (HSC) models of CHIP. A total of 9615 CpGs were associated with any CHIP, 5990 with DNMT3A CHIP, 5633 with TET2 CHIP, and 6078 with ASXL1 CHIP (P <1×10 -7 ). CpGs associated with CHIP subtypes overlapped moderately, and the genome-wide DNA methylation directions of effect were opposite for TET2 and DNMT3A CHIP, consistent with their opposing effects on global DNA methylation. There was high directional concordance between the CpGs shared from the meta-EWAS and human edited CHIP HSCs. Expression quantitative trait methylation analysis further identified transcriptomic changes associated with CHIP-associated CpGs. Causal inference analyses revealed 261 CHIP-associated CpGs associated with cardiovascular traits and all-cause mortality (FDR adjusted p-value <0.05). Taken together, our study sheds light on the epigenetic changes impacted by CHIP and their associations with age-related disease outcomes. The novel genes and pathways linked to the epigenetic features of CHIP may serve as therapeutic targets for preventing or treating CHIP-mediated diseases., Competing Interests: Competing interests F.P. is an employee of Biomodal. L.M.R serves as a consultant for the NHLBI TOPMed Administrative Coordinating Center (through Westat). P.N. reports research grants from Allelica, Amgen, Apple, Boston Scientific, Genentech / Roche, and Novartis, personal fees from Allelica, Apple, AstraZeneca, Blackstone Life Sciences, Creative Education Concepts, CRISPR Therapeutics, Eli Lilly & Co, Foresite Labs, Genentech / Roche, GV, HeartFlow, Magnet Biomedicine, Merck, and Novartis, scientific advisory board membership of Esperion Therapeutics, Preciseli, TenSixteen Bio, and Tourmaline Bio, scientific co-founder of TenSixteen Bio, equity in MyOme, Preciseli, and TenSixteen Bio, and spousal employment at Vertex Pharmaceuticals, all unrelated to the present work. Psaty serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. No other authors have competing interests. The Jimma University Internal Review Board approved the study ensuring all procedures involving human participation adhere to ethical guidelines established by both the Institution and National Research Committee before any research began.

Context: Central congenital hypothyroidism (CCH) is a thyroid hormone deficiency at birth caused by inadequate pituitary stimulation of the thyroid gland. Although primary CH has been studied extensively, studies on CCH are sparse., Objectives: To assess the prevalence of CCH in Israel and describe its clinical features, neonatal screening results, and outcomes., Design: Multicenter cross-sectional retrospective chart review., Setting: Nine pediatric endocrine units throughout Israel., Patients: Patients diagnosed with CCH in 1987-2021 were categorized into early (within 14 days of life) and late (after 14 days) diagnosis groups. Newborn screening (NBS) results were retrospectively retrieved from the national NBS program dataset., Results: CCH prevalence in Israel was about 1:42,800 live births. Subjects were 94 patients (54 males), of these, 84% had multiple pituitary hormone deficiencies and 16% had isolated CCH. The median age at diagnosis was 50 days (range, 1-8760), with 66% having moderate to severe hypothyroidism. NBS detected only three infants. Early diagnosis occurred in 34% due to hypopituitarism, while 66% were diagnosed later due to growth and developmental delays. Neurodevelopmental sequelae included mental retardation (12%), learning difficulties (18%), delayed speech (27%), and motor clumsiness (19%), with no significant differences in outcomes between early and late diagnosis., Conclusions: Despite high rates of neurodevelopmental sequelae, no differences were found between early and late diagnosis groups. Further research is needed to assess the impact of delayed diagnosis on neurological outcomes in newborns with CCH. Improved strategies for detecting CHH in newborns are also necessary., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Introduction: Coronary artery calcium (CAC) scans contain useful information beyond the Agatston CAC score that is not currently reported. We recently reported that artificial intelligence (AI)-enabled cardiac chambers volumetry in CAC scans (AI-CAC™) predicted incident atrial fibrillation in the Multi-Ethnic Study of Atherosclerosis (MESA). In this study, we investigated the performance of AI-CAC cardiac chambers for prediction of incident heart failure (HF)., Methods: We applied AI-CAC to 5750 CAC scans of asymptomatic individuals (52% female, White 40%, Black 26%, Hispanic 22% Chinese 12%) free of known cardiovascular disease at the MESA baseline examination (2000-2002). We used the 15-year outcomes data and compared the time-dependent area under the curve (AUC) of AI-CAC volumetry versus NT-proBNP, Agatston score, and 9 known clinical risk factors (age, gender, diabetes, current smoking, hypertension medication, systolic and diastolic blood pressure, LDL, HDL for predicting incident HF over 15 years., Results: Over 15 years of follow-up, 256 HF events accrued. The time-dependent AUC [95% CI] at 15 years for predicting HF with AI-CAC all chambers volumetry (0.86 [0.82,0.91]) was significantly higher than NT-proBNP (0.74 [0.69, 0.77]) and Agatston score (0.71 [0.68, 0.78]) (p ​< ​0.0001), and comparable to clinical risk factors (0.85, p ​= ​0.4141). Category-free Net Reclassification Index (NRI) [95% CI] adding AI-CAC LV significantly improved on clinical risk factors (0.32 [0.16,0.41]), NT-proBNP (0.46 [0.33,0.58]), and Agatston score (0.71 [0.57,0.81]) for HF prediction at 15 years (p ​< ​0.0001)., Conclusion: AI-CAC volumetry significantly outperformed NT-proBNP and the Agatston CAC score, and significantly improved the AUC and category-free NRI of clinical risk factors for incident HF prediction., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Right ventricular failure (RVF) is a major cause of early mortality after heart transplantation (HT). Isoproterenol (Iso) has chronotropic, inotropic, and vasodilatory properties, which might improve right ventricle function in this setting. We aimed to investigate the hemodynamic effects of isoproterenol on patients with post-HT RVF. We conducted a 1-yr retrospective observational study including patients receiving isoproterenol (Iso) and dobutamine for early RVF after HT. A comprehensive multiparametric hemodynamic evaluation was performed successively three times: no isoproterenol, low doses: 0.025 µg/kg/min, and high doses: 0.05 µg/kg/min (henceforth, respectively, called no Iso, low Iso, and high Iso). From June 2022 to June 2023, 25 patients, median [interquartile range (IQR) 25-75] age 54 [38-61] yr, were included. Before isoproterenol was introduced, all patients received dobutamine, and 15 (60%) were on venoarterial extracorporeal membrane oxygenation (VA-ECMO). Isoproterenol significantly increased heart rate from 84 [77-99] (no Iso) to 91 [88-106] (low Iso) and 102 [90-122] beats/min (high Iso, P < 0.001). Similarly, cardiac index rose from 2.3 [1.4-3.1] to 2.7 [1.8-3.4] and 3 [1.9-3.7] L/min/m 2 ( P < 0.001) with a concomitant increase in indexed stroke volume (28 [17-34] to 31 [20-34] and 33 [23-35] mL/m 2 , P < 0.05). Effective pulmonary arterial elastance and pressures were not modified by isoproterenol. Pulmonary vascular resistance (PVR) tended to decrease from 2.9 [1.4-3.6] to 2.3 [1.3-3.5] wood units (WU), P = 0.06. Right ventricular ejection fraction/systolic pulmonary artery pressure (sPAP) evaluating right ventricle-pulmonary artery (RV-PA) coupling increased after isoproterenol from 0.8 to 0.9 and 1%·mmHg -1 ( P = 0.001). In conclusion, in post-HT RVF, isoproterenol exhibits chronotropic and inotropic effects, thereby improving RV-PA coupling and resulting in a clinically relevant increase in the cardiac index. NEW & NOTEWORTHY This study offers a detailed and comprehensive hemodynamic investigation at the bedside, illustrating the favorable impact of isoproterenol on right ventricular-pulmonary arterial coupling and global hemodynamics. It elucidates the physiological effects of an underused inotropic strategy in a critical clinical scenario. By enhancing cardiac hemodynamics, isoproterenol has the potential to expedite right ventricular recovery and mitigate primary graft dysfunction, thereby reducing the duration of mechanical support and intensive care unit stay posttransplantation.

Machine learning methods have been used in identifying omics markers for a variety of phenotypes. We aimed to examine whether a supervised machine learning algorithm can improve identification of alcohol-associated transcriptomic markers. In this study, we analysed array-based, whole-blood derived expression data for 17 873 gene transcripts in 5508 Framingham Heart Study participants. By using the Boruta algorithm, a supervised random forest (RF)-based feature selection method, we selected twenty-five alcohol-associated transcripts. In a testing set (30 % of entire study participants), AUC (area under the receiver operating characteristics curve) of these twenty-five transcripts were 0·73, 0·69 and 0·66 for non-drinkers v . moderate drinkers, non-drinkers v . heavy drinkers and moderate drinkers v . heavy drinkers, respectively. The AUC of the selected transcripts by the Boruta method were comparable to those identified using conventional linear regression models, for example, AUC of 1958 transcripts identified by conventional linear regression models (false discovery rate < 0·2) were 0·74, 0·66 and 0·65, respectively. With Bonferroni correction for the twenty-five Boruta method-selected transcripts and three CVD risk factors (i.e. at P < 6·7e-4), we observed thirteen transcripts were associated with obesity, three transcripts with type 2 diabetes and one transcript with hypertension. For example, we observed that alcohol consumption was inversely associated with the expression of DOCK4 , IL4R , and SORT1 , and DOCK4 and SORT1 were positively associated with obesity, and IL4R was inversely associated with hypertension. In conclusion, using a supervised machine learning method, the RF-based Boruta algorithm, we identified novel alcohol-associated gene transcripts.

Background: Coronary artery calcium (CAC) scans contain valuable information beyond the Agatston Score which is currently reported for predicting coronary heart disease (CHD) only. We examined whether new artificial intelligence (AI) algorithms applied to CAC scans may provide significant improvement in prediction of all cardiovascular disease (CVD) events in addition to CHD, including heart failure, atrial fibrillation, stroke, resuscitated cardiac arrest, and all CVD-related deaths., Methods: We applied AI-enabled automated cardiac chambers volumetry and automated calcified plaque characterization to CAC scans (AI-CAC) of 5830 individuals (52.2% women, age 61.7±10.2 years) without known CVD that were previously obtained for CAC scoring at the baseline examination of the Multi-Ethnic Study of Atherosclerosis (MESA). We used 15-year outcomes data and assessed discrimination using the time-dependent area under the curve (AUC) for AI-CAC versus the Agatston Score., Results: During 15 years of follow-up, 1773 CVD events accrued. The AUC at 1-, 5-, 10-, and 15-year follow up for AI-CAC vs Agatston Score was (0.784 vs 0.701), (0.771 vs. 0.709), (0.789 vs.0.712) and (0.816 vs. 0.729) (p<0.0001 for all), respectively. The category-free Net Reclassification Index of AI-CAC vs. Agatston Score at 1-, 5-, 10-, and 15-year follow up was 0.31, 0.24, 0.29 and 0.29 (p<.0001 for all), respectively. AI-CAC plaque characteristics including number, location, and density of plaque plus number of vessels significantly improved NRI for CAC 1-100 cohort vs. Agatston Score (0.342)., Conclusion: In this multi-ethnic longitudinal population study, AI-CAC significantly and consistently improved the prediction of all CVD events over 15 years compared with the Agatston score.

Background: Extracellular microRNAs (miRNAs) are a class of noncoding RNAs that remain stable in the extracellular milieu, where they contribute to various physiological and pathological processes by facilitating intercellular signaling. Previous studies have reported associations between miRNAs and cardiovascular diseases (CVDs); however, the plasma miRNA signatures of CVD and its risk factors have not been fully elucidated at the population level., Methods and Results: Plasma miRNA levels were measured in 4440 FHS (Framingham Heart Study) participants. Linear regression analyses were conducted to test the cross-sectional associations of each miRNA with 8 CVD risk factors. Prospective analyses of the associations of miRNAs with new-onset obesity, hypertension, type 2 diabetes, CVD, and all-cause mortality were conducted using proportional hazards regression. Replication was carried out in 1999 RS (Rotterdam Study) participants. Pathway enrichment analyses were conducted and target genes were predicted for miRNAs associated with ≥5 risk factors in the FHS. In the FHS, 6 miRNAs (miR-193b-3p, miR-122-5p, miR-365a-3p, miR-194-5p, miR-192-5p, and miR-193a-5p) were associated with ≥5 risk factors. This miRNA signature was enriched for pathways associated with CVD and several genes annotated to these pathways were predicted targets of the identified miRNAs. Furthermore, miR-193b-3p, miR-194-5p, and miR-193a-5p were each associated with ≥2 risk factors in the RS. Prospective analysis revealed 8 miRNAs associated with all-cause mortality in the FHS., Conclusions: These findings highlight associations between miRNAs and CVD risk factors that may provide valuable insights into the underlying pathogenesis of CVD.

Genome-wide association studies (GWAS) have identified numerous body mass index (BMI) loci. However, most underlying mechanisms from risk locus to BMI remain unknown. Leveraging omics data through integrative analyses could provide more comprehensive views of biological pathways on BMI. We analyzed genotype and blood gene expression data in up to 5,619 samples from the Framingham Heart Study (FHS). Using 3,992 single nucleotide polymorphisms (SNPs) at 97 BMI loci and 20,692 transcripts within 1 Mb, we performed separate association analyses of transcript with BMI and SNP with transcript (P BMI and P SNP , respectively) and then a correlated meta-analysis between the full summary data sets (P META ). We identified transcripts that met Bonferroni-corrected significance for each omic, were more significant in the correlated meta-analysis than each omic, and were at least nominally associated with BMI in FHS data. Among 308 significant SNP-transcript-BMI associations, we identified seven genes ( NT5C2 , GSTM3 , SNAPC3 , SPNS1 , TMEM245 , YPEL3 , and ZNF646 ) in five association regions. Using an independent sample of blood gene expression data, we validated results for SNAPC3 and YPEL3 . We tested for generalization of these associations in hypothalamus, nucleus accumbens, and liver and observed significant (P META <0.05 & P META

SNP & P META

BMI ) results for YPEL3 in nucleus accumbens and NT5C2 , SNAPC3 , TMEM245 , YPEL3 , and ZNF646 in liver. The identified genes help link the genetic variation at obesity risk loci to biological mechanisms and health outcomes, thus translating GWAS findings to function., Competing Interests: CONFLICTS OF INTEREST None to report.

Background: Life's Essential 8 (LE8) is an enhanced metric for cardiovascular health. The interrelations among LE8, biomarkers of aging, and disease risks are unclear., Methods and Results: LE8 score was calculated for 5682 Framingham Heart Study participants. We implemented 4 DNA methylation-based epigenetic age biomarkers, with older epigenetic age hypothesized to represent faster biological aging, and examined whether these biomarkers mediated the associations between the LE8 score and cardiovascular disease (CVD), CVD-specific mortality, and all-cause mortality. We found that a 1 SD increase in the LE8 score was associated with a 35% (95% CI, 27-41; P =1.8E-15) lower risk of incident CVD, a 36% (95% CI, 24-47; P =7E-7) lower risk of CVD-specific mortality, and a 29% (95% CI, 22-35; P =7E-15) lower risk of all-cause mortality. These associations were partly mediated by epigenetic age biomarkers, particularly the GrimAge and the DunedinPACE scores. The potential mediation effects by epigenetic age biomarkers tended to be more profound in participants with higher genetic risk for older epigenetic age, compared with those with lower genetic risk. For example, in participants with higher GrimAge polygenic scores (greater than median), the mean proportion of mediation was 39%, 39%, and 78% for the association of the LE8 score with incident CVD, CVD-specific mortality, and all-cause mortality, respectively. No significant mediation was observed in participants with lower GrimAge polygenic score., Conclusions: DNA methylation-based epigenetic age scores mediate the associations between the LE8 score and incident CVD, CVD-specific mortality, and all-cause mortality, particularly in individuals with higher genetic predisposition for older epigenetic age.

Objective: To derive childhood-onset SLE (cSLE) specific remission definitions for future treat-to-target (T2T) trials, observational studies, and clinical practice., Methods: The cSLE International T2T Task Force conducted Delphi surveys exploring paediatric perspectives on adult-onset SLE remission targets. A modified nominal group technique was used to discuss, refine, and agree on the cSLE remission target criteria., Results: The Task Force proposed two definitions of remission: 'cSLE clinical remission on steroids (cCR)' and 'cSLE clinical remission off steroids (cCR-0)'. The common criteria are: (1) Clinical-SLEDAI-2 K = 0; (2) PGA score < 0.5 (0-3 scale); (4) stable antimalarials, immunosuppressive, and biologic therapy (changes due to side-effects, adherence, weight, or when building up to target dose allowed). Criterion (3) in cCR is the prednisolone dose ≤0.1 mg/kg/day (maximum 5 mg/day), whereas in cCR-0 it is zero., Conclusions: cSLE definitions of remission have been proposed, maintaining sufficient alignment with the adult-SLE definition to facilitate life-course research., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests in relation to this manuscript., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Modern life science research is a collaborative effort. Few research groups can single-handedly support the necessary equipment, expertise and personnel needed for the ever-expanding portfolio of technologies that are required across multiple disciplines in today's life science endeavours. Thus, research institutes are increasingly setting up scientific core facilities to provide access and specialised support for cutting-edge technologies. Maintaining the momentum needed to carry out leading research while ensuring high-quality daily operations is an ongoing challenge, regardless of the resources allocated to establish such facilities. Here, we outline and discuss the range of activities required to keep things running once a scientific imaging core facility has been established. These include managing a wide range of equipment and users, handling repairs and service contracts, planning for equipment upgrades, renewals, or decommissioning, and continuously upskilling while balancing innovation and consolidation., (© 2024 The Authors. Journal of Microscopy published by John Wiley & Sons Ltd on behalf of Royal Microscopical Society.)

We report two cases of carotid-cochlea dehiscence involving the cochlear apex, with, to our knowledge, the first description of this anomaly in two members of a family (mother-daughter). Pure tone audiometry revealed a bilateral mild sensorineural hearing loss predominantly on the left in the daughter, and a left mild mixed hearing loss with a predominance of sensorineural loss in the medium frequencies in the mother Carotid-cochlear dehiscence is a rare anomaly with a multiform expression, which should be investigated in cases of third mobile window symptoms, but also atypical sensorineural hearing loss, or before any cochlear implantation. Laryngoscope, 134:2912-2914, 2024., (© 2023 The American Laryngological, Rhinological and Otological Society, Inc.)

We construct non-linear machine learning (ML) prediction models for systolic and diastolic blood pressure (SBP, DBP) using demographic and clinical variables and polygenic risk scores (PRSs). We developed a two-model ensemble, consisting of a baseline model, where prediction is based on demographic and clinical variables only, and a genetic model, where we also include PRSs. We evaluate the use of a linear versus a non-linear model at both the baseline and the genetic model levels and assess the improvement in performance when incorporating multiple PRSs. We report the ensemble model's performance as percentage variance explained (PVE) on a held-out test dataset. A non-linear baseline model improved the PVEs from 28.1 to 30.1% (SBP) and 14.3% to 17.4% (DBP) compared with a linear baseline model. Including seven PRSs in the genetic model computed based on the largest available GWAS of SBP/DBP improved the genetic model PVE from 4.8 to 5.1% (SBP) and 4.7 to 5% (DBP) compared to using a single PRS. Adding additional 14 PRSs computed based on two independent GWASs further increased the genetic model PVE to 6.3% (SBP) and 5.7% (DBP). PVE differed across self-reported race/ethnicity groups, with primarily all non-White groups benefitting from the inclusion of additional PRSs. In summary, non-linear ML models improves BP prediction in models incorporating diverse populations., (© 2024. The Author(s).)

Quantum computing (QC) has opened the door to advancements in machine learning (ML) tasks that are currently implemented in the classical domain. Convolutional neural networks (CNNs) are classical ML architectures that exploit data locality and possess a simpler structure than a fully connected multi-layer perceptrons (MLPs) without compromising the accuracy of classification. However, the concept of preserving data locality is usually overlooked in the existing quantum counterparts of CNNs, particularly for extracting multifeatures in multidimensional data. In this paper, we present an multidimensional quantum convolutional classifier (MQCC) that performs multidimensional and multifeature quantum convolution with average and Euclidean pooling, thus adapting the CNN structure to a variational quantum algorithm (VQA). The experimental work was conducted using multidimensional data to validate the correctness and demonstrate the scalability of the proposed method utilizing both noisy and noise-free quantum simulations. We evaluated the MQCC model with reference to reported work on state-of-the-art quantum simulators from IBM Quantum and Xanadu using a variety of standard ML datasets. The experimental results show the favorable characteristics of our proposed techniques compared with existing work with respect to a number of quantitative metrics, such as the number of training parameters, cross-entropy loss, classification accuracy, circuit depth, and quantum gate count.

Clonal hematopoiesis (CH) is characterized by the acquisition of a somatic mutation in a hematopoietic stem cell that results in a clonal expansion. These driver mutations can be single nucleotide variants in cancer driver genes or larger structural rearrangements called mosaic chromosomal alterations (mCAs). The factors that influence the variations in mCA fitness and ultimately result in different clonal expansion rates are not well understood. We used the Passenger-Approximated Clonal Expansion Rate (PACER) method to estimate clonal expansion rate as PACER scores for 6,381 individuals in the NHLBI TOPMed cohort with gain, loss, and copy-neutral loss of heterozygosity mCAs. Our mCA fitness estimates, derived by aggregating per-individual PACER scores, were correlated (R 2  = 0.49) with an alternative approach that estimated fitness of mCAs in the UK Biobank using population-level distributions of clonal fraction. Among individuals with JAK2 V617F clonal hematopoiesis of indeterminate potential or mCAs affecting the JAK2 gene on chromosome 9, PACER score was strongly correlated with erythrocyte count. In a cross-sectional analysis, genome-wide association study of estimates of mCA expansion rate identified a TCL1A locus variant associated with mCA clonal expansion rate, with suggestive variants in NRIP1 and TERT., (© 2024. The Author(s).)

Hypertension affects more than one billion people worldwide. Here we identify 113 novel loci, reporting a total of 2,103 independent genetic signals (P < 5 × 10 -8 ) from the largest single-stage blood pressure (BP) genome-wide association study to date (n = 1,028,980 European individuals). These associations explain more than 60% of single nucleotide polymorphism-based BP heritability. Comparing top versus bottom deciles of polygenic risk scores (PRSs) reveals clinically meaningful differences in BP (16.9 mmHg systolic BP, 95% CI, 15.5-18.2 mmHg, P = 2.22 × 10 -126 ) and more than a sevenfold higher odds of hypertension risk (odds ratio, 7.33; 95% CI, 5.54-9.70; P = 4.13 × 10 -44 ) in an independent dataset. Adding PRS into hypertension-prediction models increased the area under the receiver operating characteristic curve (AUROC) from 0.791 (95% CI, 0.781-0.801) to 0.826 (95% CI, 0.817-0.836, ∆AUROC, 0.035, P = 1.98 × 10 -34 ). We compare the 2,103 loci results in non-European ancestries and show significant PRS associations in a large African-American sample. Secondary analyses implicate 500 genes previously unreported for BP. Our study highlights the role of increasingly large genomic studies for precision health research., (© 2024. The Author(s).)

Leukemias are among the most prevalent types of cancer worldwide. Bone marrow mesenchymal stem cells (MSCs) participate in the development of a suitable niche for hematopoietic stem cells, and are involved in the development of diseases such as leukemias, to a yet unknown extent. Here we described the effect of secretome of bone marrow MSCs obtained from healthy donors and from patients with acute myeloid leukemia (AML) on leukemic cell lineages, sensitive (K562) or resistant (K562-Lucena) to chemotherapy drugs. Cell proliferation, viability and death were evaluated, together with cell cycle, cytokine production and gene expression of ABC transporters and cyclins. The secretome of healthy MSCs decreased proliferation and viability of both K562 and K562-Lucena cells; moreover, an increase in apoptosis and necrosis rates was observed, together with the activation of caspase 3/7, cell cycle arrest in G0/G1 phase and changes in expression of several ABC proteins and cyclins D1 and D2. These effects were not observed using the secretome of MSCs derived from AML patients. In conclusion, the secretome of healthy MSCs have the capacity to inhibit the development of leukemia cells, at least in the studied conditions. However, MSCs from AML patients seem to have lost this capacity, and could therefore contribute to the development of leukemia.

Land use changes are heralded as a major driver of biodiversity loss. However, recent findings show that cities, perhaps the most radical habitat transformation, sustain increasing numbers of threatened species. This emerging trend has been mostly chronicled for vertebrates from landlocked cities, although loss of biodiversity and rates or urbanization are higher in coastal marine systems. To advance our understanding on how threatened species may conquer human-dominated systems, we studied the threatened edible crab Cardisoma guanhumi and assessed how it is proliferating in croplands and urban systems at different spatial scales and whether populations show consequences of long-term exploitation. We gathered the data on crab populations covering the whole distribution range, including three countries reporting this as a threatened species. The abundance, distribution, and size structure of crab populations among different land uses at local scales were compared and published data for populations thriving in different habitats throughout their distribution range were compiled. We found that at local scale this species is able to thrive in natural and human-disturbed habitats, where food sources are heavily altered. At larger scales, the species showed no differences in abundance and size structure among natural and anthropogenic habitats. In areas near the southern distribution edge, crab populations were more abundant and composed of larger animals in urban areas and croplands than those in natural habitats, suggesting that human-disturbed systems are stepping stones to extend the geographic range. However, we found a long-term reduction in maximum body size, exacerbated by land use changes, that likely reflects exploitation regimes consistently targeting larger crabs. Despite its status as a threatened species, the long history of human exploitation combined with livestock farming practices may explain the proliferation of this crab in human-dominated systems, which emphasize the need to consider conservation in human-dominated systems., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)

Background: During the first COVID-19 pandemic wave, COVID-19-associated pulmonary aspergillosis (CAPA) has been reported in up to 11-28% of critically ill COVID-19 patients and associated with increased mortality. As new SARS-CoV-2 variants emerged, the characteristics of critically ill COVID-19 patients have evolved, particularly in the era of Omicron. The purpose of this study is to investigate the characteristics of CAPA in the era of new variants., Methods: This is a prospective multicenter observational cohort study conducted in France in 36 participating intensive care units (ICU), between December 7th, 2021 and April 26th 2023. Diagnosis criteria of CAPA relied on European Confederation of Medical Mycology (ECMM)/International Society for Human & Animal Mycology (ISHAM) consensus criteria., Results: 566 patients were included over the study period. The prevalence of CAPA was 5.1% [95% CI 3.4-7.3], and rose to 9.1% among patients who required invasive mechanical ventilation (IMV). Univariable analysis showed that CAPA patients were more frequently immunosuppressed and required more frequently IMV support, vasopressors and renal replacement therapy during ICU stay than non-CAPA patients. SAPS II score at ICU admission, immunosuppression, and a SARS-CoV-2 Delta variant were independently associated with CAPA in multivariable logistic regression analysis. Although CAPA was not significantly associated with day-28 mortality, patients with CAPA experienced a longer duration of mechanical ventilation and ICU stay., Conclusion: This study contributes valuable insights into the prevalence, characteristics, and outcomes of CAPA in the era of Delta and Omicron variants. We report a lower prevalence of CAPA (5.1%) among critically-ill COVID-19 patients than previously reported, mainly affecting intubated-patients. Duration of mechanical ventilation and ICU stay were significantly longer in CAPA patients., (© 2024. The Author(s).)

Objective: Whether employees' health status is associated with the effectiveness of workplace health promotion programs is unknown. The objective of this study was to determine if the effect of a workplace healthy eating intervention differed by baseline chronic disease status., Methods: This was a secondary analysis of a randomized controlled trial conducted September 2016 to February 2018 among US hospital employees to test the effect of a 12-month behavioral intervention (personalized feedback, peer comparisons, and financial incentives) on diet and weight. Participants were classified as having chronic disease (yes/no) based on self-reported hypertension, hyperlipidemia, heart disease, stroke, pre-diabetes, diabetes, cancer or another serious illness. BMI was measured at study visits and calories purchased were measured from cafeteria sales data over 24 months. Mixed models with random effects assessed heterogeneity of treatment effects by chronic disease., Results: Participants (N = 548) were mostly female (79.7 %) and white (81.2 %); 224 (40.9 %) had chronic disease. Among those with chronic disease, intervention participants reduced caloric intake by 74.4 [22.3] kcal more than control, with a smaller difference between intervention and control (-1.9 [18.7] kcal) (three-way p-interaction = 0.02). The effect on BMI for those with chronic disease (0.47 [0.21] kg/m 2 ) indicated weight stability among intervention participants and weight gain among controls while the effect (-0.56 [0.18] kg/m 2 ) for those without chronic disease was the opposite (three-way p-interaction < 0.01)., Conclusions: Those with chronic diseases had greater reductions in calories purchased and gained less weight. Employers with limited resources for health promotion might consider tailoring programs to employees at highest risk., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: This study was funded by grant No. R01HL125486 (Thorndike) from the NIH. The project was also supported in part by NIH grants R01DK114735 (Thorndike), 1UL1TR001102 (Nadler), K24 HL163073 (Thorndike), and T32HL098048 (Cheng). The sponsor had no role in the conduct or reporting of this research. No authors have financial disclosures to report., (© 2024 The Authors.)