Health Data Research UK

Single-cell RNA sequencing (scRNA-seq) provides an instantaneous snapshot of the transcriptional state of a cell, which results from the simultaneous activity of many cellular processes. In this issue of Cell Genomics, Chen et al.1 describe the development of CellUntangler, a deep-learning-based model that allows the capture and filtering of multiple biological signals in scRNA-seq data.

Cubital tunnel syndrome is the second most prevalent upper limb compression neuropathy. Limitations in non-operative and surgical treatment warrant an adjunctive preventative approach targeting modifiable risk factors. However, risk factors are poorly characterized given methodologic shortcomings in previous studies. In this case-control study in the UK Biobank (1971 cases, 398,639 controls), multivariable logistic regression with extensive covariate correction was conducted to assess the association between cubital tunnel syndrome and sex, age, ethnicity, socioeconomic deprivation, smoking status, alcohol intake, height, body mass index, plasma lipids, HbA1c, diabetes, hypertension, carpal tunnel syndrome, osteoarthritis, rheumatoid arthritis, hypothyroidism and gastroesophageal reflux disease. Cubital tunnel syndrome was significantly associated with several modifiable risk factors: smoking status (odds ratio 2.08, 95% CI: 1.83-2.37), diabetes with microvascular complications (OR 1.80, 95% CI: 1.40-2.30), hypertension (OR 1.37, 95% CI: 1.24-1.52) and raised body mass index (OR 1.13, 95% CI: 1.08-1.19). Male sex (OR 1.77, 95% CI: 1.54-2.04) and age (OR 0.981, 95% CI: 0.975-0.986) were non-modifiable risk factors. Several comorbidities were associated with cubital tunnel syndrome: carpal tunnel syndrome (OR 11.7, 95% CI: 10.6-12.9), osteoarthritis (OR 2.12, 95% CI: 1.92-2.34), rheumatoid arthritis (OR 1.72, 95% CI: 1.42-2.07), and gastroesophageal reflux disease (OR 1.66, 95% CI: 1.50-1.83). Cubital tunnel syndrome had a weak association with socioeconomic deprivation and no association with ethnicity, height, alcohol intake, plasma lipids, HbA1c and hypothyroidism. Cubital tunnel syndrome is robustly associated with several modifiable risk factors that may be targeted in primary and secondary prevention. III.

The interaction between physical activity and sleep with cardiovascular disease remains poorly understood, despite both being key risk factors. This study investigated the independent and joint associations of device-measured step count and sleep duration with incident major adverse cardiovascular events (MACE). Prospective analysis of UK Biobank participants who wore a wrist-based accelerometer for seven days between 2013 and 2015. Open-source machine learning algorithms derived daily step count and overnight sleep duration. The outcome was incident MACE (cardiovascular death, non-fatal myocardial infarction or stroke, or revascularisation procedure), identified through electronic health record linkage. Cox proportional hazards models were used to examine independent and joint associations of median daily step count (low [<7500], intermediate [7500-11,000], high [>11,000]) and median overnight sleep duration (short [<6.5 h], intermediate [6.5-7.5 h], long [>7.5 h]) with incident MACE. Among 88,012 participants (mean age 62.2 years [standard deviation, SD 7.8]), 3817 were diagnosed with MACE during follow-up (median 7.9 years [interquartile range, IQR 7.3-8.4]). Low step count and short sleep duration were independently associated with a higher risk of MACE, but there was no evidence of an interaction between step count and sleep duration (P for interaction = 0.42). Compared with the reference group-participants with high step count and intermediate sleep duration-the highest risk of MACE was observed in participants with both low step count and short sleep duration (hazard ratio, HR: 1.84, 95% CI: 1.62-2.10, p < 0.0001). The results of this study show that higher daily step count does not fully attenuate the higher risk of cardiovascular disease associated with short sleep duration, reinforcing the importance of sufficient levels of both daily step count and sleep for the prevention of cardiovascular disease. Wellcome Trust (223100/Z/21/Z).

We aimed to 1) investigate associations between leisure time physical activity level cumulated over 20 years and multiple plasma proteins and 2) explore if proteins significantly associated with physical activity are also associated with risk of imminent myocardial infarction (MI), long-term MI and mortality. In the cohort Uppsala Longitudinal Study of Adult Men (ULSAM), leisure time physical activity was self-reported at ages 50, 60, and 70. At age 70, 720 plasma proteins were analyzed in 782 participants with up to 19.3 years of follow-up for MI and 26.3 years follow-up for mortality. In the nested case-cohort study Markers of Imminent Myocardial Infarction (MIMI), plasma proteins were measured in disease-free individuals from six European cohorts. Cases (n=420) were those with acute MI within 6 months of a blood draw, with up to four cohort representatives per case (n=1,598). A higher level of leisure time physical activity level was inversely associated with 12 plasma proteins after adjusting for age, education, smoking and established cardiovascular risk factors (Bonferroni corrected p<0.000069). Of these 12 proteins, IL-6 was associated with increased incidence of imminent MI (HR 1.22 95%CI [1.09-1.37]), TNFRSF11A was associated with increased long-term MI incidence (HR 1.22 [1.01-1.48]) and 11 proteins were associated with increased mortality (HR 1.14-1.30 [1.01-1.42]). These findings confirm and extend our understanding of how physical activity could assert its beneficial effect on cardiovascular health through proteins involved with modulating inflammatory, immune and metabolic pathways. Further research is needed to explore the causal mechanisms behind these associations.

SARS-CoV-2 has emerged as the 5th endemic coronavirus and immunological cross protection between coronaviruses will influence their infectivity and clinical impact. We determined adaptive immunity against the spike protein of each human coronavirus during the course of the COVID-19 pandemic. A characteristic pattern of HCoV immunodominance, dominated by OC43 and 229E, was apparent prior to SARS-CoV-2 and was largely unaffected by SARS-CoV-2 infection, which itself elicited moderate antibody titre. Vaccination or hybrid immunity elicited supraphysiological levels of coronavirus-specific antibodies, only a proportion of which was cross-reactive with SARS-CoV-2 spike indicating substantial backboosting of HCoV-specific responses. SARS-CoV-2 vaccination focused antibody responses against the S1 domain of SARS-CoV-2 spike whilst T cell responses recognised peptides equivalently across S1 and S2. Coronavirus-specific T cells exhibited strong production of IFN-γ, IL-2 and CXCL8. In summary, the entry of SARS-CoV-2 into its ecological niche has impacted marginally on relative immunity against other human coronaviruses although vaccination provides a modest antibody increment which is unlikely to be maintained. Further, although SARS-CoV-2 vaccination elicits spike-specific adaptive immune responses that are focused against the S1 domain, thereby favouring neutralising antibodies, the natural history of HCoV immunity indicates that adaptive responses may transition towards S2 recognition across the life course.

Layer-2 protocols such as rollups can help address Ethereum's throughput limits. An efficient data availability layer is key for layer-2 support in Ethereum, but broadcast methods do not scale. A promising approach is the selective distribution of layer-2 data and its verification by data availability sampling (DAS). Integrating DAS with Ethereum consensus is, however, a challenge, as data must be shared and sampled within 4 seconds of each consensus slot.

BackgroundPreeclampsia is a major cause of maternal and fetal mortality and morbidity. Early risk stratification enables timely preventative therapy in high‐risk women. Polygenic risk scores (PGS) improve prediction in complex diseases, but their added value for preeclampsia remains unclear, particularly in comparison to gold‐standard first‐trimester prediction models and across non‐European ancestries.MethodsWe evaluated the performance of both a preeclampsia and systolic blood pressure PGS in 2 prospective pregnancy cohorts with detailed phenotyping: the Fetal Medicine Foundation study (n=5207; 2127 cases) and the Pregnancy Outcome Prediction study (n=3659; 228 cases). Risk models included (1) clinical factors; (2) clinical factors plus PGS; (3) advanced model including first‐trimester mean arterial pressure, PAPP‐A (pregnancy‐associated plasma protein‐A), and uterine artery pulsatility index; and (4) advanced model plus PGS. Discriminative performance, measured by the area under the receiver operating characteristic curve, was assessed overall and by ancestry.ResultsThe preeclampsia PGS was independently associated with preeclampsia (odds ratio per SD, 1.24 [95% CI, 1.17–1.31]; P<0.001). It modestly improved prediction over clinical models (area under the receiver operating characteristic curve 0.746 versus 0.750; P=0.017) but not over the advanced model (area under the receiver operating characteristic curve 0.817 versus 0.818; P=0.326). The systolic blood pressure PGS showed stronger performance, improving prediction over both models in women of European ancestry. No improvement was observed with either score in women of African ancestry.ConclusionsPGSs for preeclampsia and SBP provide modest added predictive value beyond clinical risk factors in European ancestry women. Limited utility in African ancestry women reflects underrepresentation in the genome‐wide association studies used to develop current scores. As cohort sizes grow and models are refined, PGSs may become important tools for equitable risk stratification in maternal health.

The rarity of severe diseases following COVID-19 infection balanced against rare COVID-19 vaccination-related adverse effects is an important consideration for vaccination policies. We aimed to assess the short-term and long-term risks of vascular and inflammatory diseases following first COVID-19 diagnosis and vaccination in children and young people. In this retrospective, population-based cohort study, we analysed whole-population linked electronic health records for all individuals in England aged younger than 18 years, registered with a general practitioner, and with known age, sex, and region of residence, between Jan 1, 2020, and Dec 31, 2022. Outcomes were arterial thrombotic events, venous thrombotic events, thrombocytopenia, myocarditis or pericarditis, and inflammatory conditions. COVID-19 diagnosis was defined as the earliest record of a positive SARS-CoV-2 PCR or antigen test, or a COVID-19 diagnosis code in primary-care or secondary-care records; COVID-19 vaccination was defined as the earliest documented receipt of the BNT162b2 vaccine (the predominant vaccine during the study period). Adjusted hazard ratios (aHRs) for all outcomes were estimated by time since a first COVID-19 diagnosis during Jan 1, 2020-March 31, 2022 and by time since a first COVID-19 vaccination during Aug 6, 2021-Dec 31, 2022, adjusting for age, sex, ethnicity, region, deprivation, general practitioner contact frequency, and medication use. Of 13 896 125 individuals younger than 18 years (6 784 260 [48·8%] female and 7 111 865 [51·2%] male; 9 979 420 [71·7%] White), 3 903 410 (28·1%) had a COVID-19 diagnosis. COVID-19 diagnosis (compared with no or before diagnosis) was associated with higher risk of arterial thromboembolism (aHR 2·33 [95% CI 1·20-4·51]), venous thromboembolism (4·90 [3·66-6·55]), thrombocytopenia (3·64 [2·21-6·00]), myocarditis or pericarditis (3·46 [2·06-5·80]), and inflammatory conditions (14·84 [11·01-19·99]) in the first week after diagnosis. Incidence declined in weeks 2-4, but remained elevated to beyond 12 months for venous thromboembolism (1·39 [1·14 -1·69]), thrombocytopenia (1·42 [1·01-2·00]), and myocarditis or pericarditis (1·42 [1·05-1·91]). Among 9 245 395 individuals aged between 5 and younger than 18 years who were eligible for vaccination (4 510 490 [48·8%] female and 4 734 905 [51·2%] male; 6 684 140 [72·3%] White), 3 407 560 (36·9%) received a first vaccine. COVID-19 vaccination (compared with no or before vaccination) was associated with elevated risk of myocarditis or pericarditis within the first 4 weeks after vaccination (1·84 [1·25-2·72]). The 6-month absolute excess risks for myocarditis or pericarditis were 2·24 (1·11-3·80) per 100 000 individuals after diagnosis versus before diagnosis or undiagnosed, and 0·85 (0·07-1·91) after vaccination versus before vaccination or unvaccinated. Children and young people have higher risks of rare vascular and inflammatory diseases up to 12 months after a first COVID-19 diagnosis and higher risk of rare myocarditis or pericarditis up to 4 weeks after a first BNT162b2 vaccine, although the risk following vaccination is substantially lower than the risk following infection. These findings are of great importance for national policy makers and caregivers considering vaccination consent for children, and support the public health strategy of COVID-19 vaccination in children and young people to mitigate the more frequent and persistent risks associated with SARS-CoV-2 infection. Wellcome Trust, British Heart Foundation Data Science Centre, and Health Data Research UK.