Status Epilepticus Identification and Treatment Among Emergency Medical Services Agencies.

This cross-sectional study examines the association between unidentified status epilepticus and prehospital benzodiazepine treatment.

Clinical upstaging after neoadjuvant chemotherapy impacting eligibility for vaginal-sparing cystectomy: identifying bladder cancer patients who may benefit from interim imaging.

INTRODUCTION AND OBJECTIVES: Limited data exists on the frequency with which clinical progression during neoadjuvant chemotherapy (NAC) for muscle invasive bladder cancer (MIBC) impacts eligibility for a vaginal-sparing surgical approach or on the utility of interim imaging assessment. We sought to evaluate the incidence of clinical upstaging following NAC that would render a patient ineligible for a vaginal-sparing cystectomy. METHODS: 89 female patients with non-metastatic MIBC treated with NAC and radical cystectomy (RC) (2012-2023) were retrospectively reviewed. Tumor location(s) was determined from transurethral resection of bladder tumor operative reports. Pre- and post-NAC clinical staging was determined from imaging. Outcomes of interest included clinical upstaging and upstaging to vaginal invasion after NAC. RESULTS: 75/89 patients had pre- and post-NAC imaging. 55 had no change in clinical staging, six patients were upstaged (4 cT2→cT3, 2 cT3→cT4), and 14 patients were downstaged (13 cT3→cT2, 1 cT4→cT2). Of the 75 patients with pre- and post-NAC imaging, 39 had trigone tumors. Of these, 28 had no change in clinical staging, two were upstaged (1 cT2→cT3, 1 cT3→cT4) and nine were downstaged (8 cT3→cT2, 1 cT4→cT2). Overall, 6/75 (8%) of patients demonstrated clinical upstaging after NAC. 2/39 (5%) of patients with trigone tumors clinically progressed after NAC and both had vaginal invasion (pT4) on final pathology. CONCLUSIONS: Although clinical upstaging after NAC was infrequent, 5% of patients with trigonal MIBC were rendered ineligible for vaginal-sparing cystectomy following NAC due to progression. Interim imaging assessment may identify non-responders and preserve eligibility for vaginal-sparing RC.

Impact of pathologic re-review on grade, clinical stage, and risk stratification for patients with nonmuscle invasive bladder cancer.

OBJECTIVES: Pathologic re-review of transurethral resection of bladder tumor (TURBT) specimen is a common practice at our tertiary care center, but its impact on disease risk stratification remains unknown. We sought to determine how pathologic re-review of specimen initially read at an outside institution changed grade, clinical T (cT) stage, and AUA non-muscle-invasive bladder cancer (NMIBC) risk stratification. METHODS AND MATERIALS: The laboratory information system was searched for patients who underwent TURBT from 2021 to 2022, yielding 561 records. 173 patients met inclusion criteria: 113 with

Body morphometry may predict parastomal hernia following radical cystectomy with ileal conduit.

OBJECTIVE: To investigate whether preoperative body morphometry analysis can identify patients at risk of parastomal hernia (PH), which is a common complication after radical cystectomy (RC). PATIENTS AND METHODS: All patients who underwent RC between 2010 and 2020 with available cross-sectional imaging preoperatively and at 1 and 2 years postoperatively were included. Skeletal muscle mass and total fat mass (FM) were determined from preoperative axial computed tomography images obtained at the level of the L3 vertebral body using Aquarius Intuition software. Sarcopenia and obesity were assigned based on consensus definitions of skeletal muscle index (SMI) and FM index (FMI). PH were graded using both the Moreno-Matias and European Hernia Society criteria. Binary logistic regression and recursive partitioning were used to identify patients at risk of PH. The Kaplan-Meier method with log-rank and Cox proportional hazards models included clinical and image-based parameters to identify predictors of PH-free survival. RESULTS: A total of 367 patients were included in the final analysis, with 159 (43%) developing a PH. When utilising binary logistic regression, high FMI (odds ratio [OR] 1.63, P < 0.001) and low SMI (OR 0.96, P = 0.039) were primary drivers of risk of PH. A simplified model that only relied upon FMI, SMI, and preoperative albumin improved the classification of patients at risk of PH. On Kaplan-Meier analysis, patients who were obese or obese and sarcopenic had significantly worse PH-free survival (P < 0.001). CONCLUSION: Body morphometry analysis identified FMI and SMI to be the most consistent predictors of PH after RC.

Differences in Cardiovascular Health at the Intersection of Race, Ethnicity, and Sexual Identity.

Importance: An understanding of the intersectional effect of sexual identity, race, and ethnicity on disparities in cardiovascular health (CVH) has been limited. Objective: To evaluate differences in CVH at the intersection of race, ethnicity, and sexual identity using the American Heart Association's Life's Essential 8 measure. Design, Setting, and Participants: This cross-sectional study was conducted from July 27 to September 6, 2023, using National Health and Nutrition Examination Survey data from 2007 to 2016. Participants were noninstitutionalized, nonpregnant adults (aged 18-59 years) without cardiovascular disease or stroke. Exposures: Self-reported sexual identity, categorized as heterosexual or sexual minority (SM; lesbian, gay, bisexual, or "something else"), and self-reported race and ethnicity, categorized as non-Hispanic Black (hereafter, Black), Hispanic, non-Hispanic White (hereafter, White), and other (Asian, multiracial, or any other race and ethnicity). Main Outcome and Measures: The primary outcome was overall CVH score, which is the unweighted mean of 8 CVH metrics, assessed from questionnaire, dietary, and physical examination data. Regression models stratified by sex, race, and ethnicity were developed for the overall CVH score and individual CVH metrics, adjusting for age, survey year, and socioeconomic status (SES) factors. Results: The sample included 12 180 adults (mean [SD] age, 39.6 [11.7] years; 6147 [50.5%] male, 2464 [20.2%] Black, 3288 [27.0%] Hispanic, 5122 [42.1%] White, and 1306 [10.7%] other race and ethnicity). After adjusting for age, survey year, and SES, Black (ß, -3.2; 95% CI, -5.8 to -0.6), Hispanic (ß, -5.9; 95% CI, -10.3 to -1.5), and White (ß, -3.3; 95% CI, -6.2 to -0.4) SM female adults had lower overall CVH scores compared with their heterosexual counterparts. There were no statistically significant differences for female adults of other race and ethnicity (ß, -2.8; 95% CI, -9.3 to 3.7) and for SM male adults of any race and ethnicity compared with their heterosexual counterparts (Black: ß, 2.2 [95% CI, -1.2 to 5.7]; Hispanic: ß, -0.9 [95% CI, -6.3 to 4.6]; White: ß, 1.5 [95% CI, -2.2 to 5.2]; other race and ethnicity: ß, -2.2 [95% CI, -8.2 to 3.8]). Conclusions and Relevance: In this cross-sectional study, CVH differed across race and ethnicity categories in SM females, suggesting that different communities within the larger SM population require tailored interventions to improve CVH. Longitudinal studies are needed to identify the causes of CVH disparities, particularly in Black and Hispanic SM females and inclusive of other racial and ethnic identities.

Outcome of tenoscopically guided palmar/plantar annular ligament desmotomy for the treatment of palmar/plantar annular ligament constriction without concurrent intrathecal soft-tissue injury in a UK horse population.

OBJECTIVE: To determine the outcome of tenoscopically guided palmar/plantar annular ligament (PAL) desmotomy to treat PAL constriction without concurrent intrathecal soft-tissue injury, notably of the digital flexor tendons and manica flexoria. STUDY DESIGN: Retrospective multicenter cohort study. ANIMALS: Sixty-five horses. METHODS: Horses from four UK equine hospitals, with digital flexor tendon sheath (DFTS) tenosynovitis, which underwent tenoscopically guided PAL desmotomy for treatment of PAL constriction between 2017 and 2022 were included. All horses had lameness isolated to the DFTS/PAL, and PAL constriction was diagnosed tenoscopically when there was difficulty maneuvering the endoscope into or through the fetlock canal. Horses with tearing of the digital flexor tendons and/or manica flexoria, or any other intrathecal pathology, were excluded. Follow up was via structured telephone questionnaire. RESULTS: Follow up (median 25 months) was available for 61 horses with cobs and ponies predominating. Forty-two returned to their previous level of work, or a higher level, postoperatively and 50 owners were satisfied with the outcome of surgery. Eleven horses returned to lower level exercise, and six were retired/euthanized as they did not regain soundness. Fifty-two horses achieved soundness (median 3 months postoperatively). CONCLUSION: Tenoscopically guided PAL desmotomy for the treatment of PAL constriction in the absence of intrathecal soft tissue injury had a good prognosis for return to previous levels of exercise in a UK horse population. CLINICAL SIGNIFICANCE: The prognosis for horses undergoing tenoscopically guided PAL desmotomy to treat PAL constriction in the absence of intrathecal injury is better than previously described. Cobs and ponies seem to be predisposed to PAL constriction in agreement with the previous literature.

Association between the gut microbiome and carotenoid plumage phenotype in an avian hybrid zone.

Vertebrates host complex microbiomes that impact their physiology. In many taxa, including colourful wood-warblers, gut microbiome similarity decreases with evolutionary distance. This may suggest that as host populations diverge, so do their microbiomes, because of either tight coevolutionary dynamics, or differential environmental influences, or both. Hybridization is common in wood-warblers, but the effects of evolutionary divergence on the microbiome during secondary contact are unclear. Here, we analyse gut microbiomes in two geographically disjunct hybrid zones between blue-winged warblers (Vermivora cyanoptera) and golden-winged warblers (Vermivora chrysoptera). We performed 16S faecal metabarcoding to identify species-specific bacteria and test the hypothesis that host admixture is associated with gut microbiome disruption. Species identity explained a small amount of variation between microbiomes in only one hybrid zone. Co-occurrence of species-specific bacteria was rare for admixed individuals, yet microbiome richness was similar among admixed and parental individuals. Unexpectedly, we found several bacteria that were more abundant among admixed individuals with a broader deposition of carotenoid-based plumage pigments. These bacteria are predicted to encode carotenoid biosynthesis genes, suggesting birds may take advantage of pigments produced by their gut microbiomes. Thus, host admixture may facilitate beneficial symbiotic interactions which contribute to plumage ornaments that function in sexual selection.

Rare variant associations with birth weight identify genes involved in adipose tissue regulation, placental function and insulin-like growth factor signalling.

Investigating the genetic factors influencing human birth weight may lead to biological insights into fetal growth and long-term health. Genome-wide association studies of birth weight have highlighted associated variants in more than 200 regions of the genome, but the causal genes are mostly unknown. Rare genetic variants with robust evidence of association are more likely to point to causal genes, but to date, only a few rare variants are known to influence birth weight. We aimed to identify genes that harbour rare variants that impact birth weight when carried by either the fetus or the mother, by analysing whole exome sequence data in UK Biobank participants. We annotated rare (minor allele frequency <0.1%) protein-truncating or high impact missense variants on whole exome sequence data in up to 234,675 participants with data on their own birth weight (fetal variants), and up to 181,883 mothers who reported the birth weight of their first child (maternal variants). Variants within each gene were collapsed to perform gene burden tests and for each associated gene, we compared the observed fetal and maternal effects. We identified 8 genes with evidence of rare fetal variant effects on birth weight, of which 2 also showed maternal effects. One additional gene showed evidence of maternal effects only. We observed 10/11 directionally concordant associations in an independent sample of up to 45,622 individuals (sign test P=0.01). Of the genes identified, IGF1R and PAPPA2 (fetal and maternal-acting) have known roles in insulin-like growth factor bioavailability and signalling. PPARG, INHBE and ACVR1C (all fetal-acting) have known roles in adipose tissue regulation and rare variants in the latter two also showed associations with favourable adiposity patterns in adults. We highlight the dual role of PPARG in both adipocyte differentiation and placental angiogenesis. NOS3, NRK, and ADAMTS8 (fetal and maternal-acting) have been implicated in both placental function and hypertension. Analysis of rare coding variants has identified regulators of fetal adipose tissue and fetoplacental angiogenesis as determinants of birth weight, as well as further evidence for the role of insulin-like growth factors.

Genetic modifiers of rare variants in monogenic developmental disorder loci.

Rare damaging variants in a large number of genes are known to cause monogenic developmental disorders (DDs) and have also been shown to cause milder subclinical phenotypes in population cohorts. Here, we show that carrying multiple (2-5) rare damaging variants across 599 dominant DD genes has an additive adverse effect on numerous cognitive and socioeconomic traits in UK Biobank, which can be partially counterbalanced by a higher educational attainment polygenic score (EA-PGS). Phenotypic deviators from expected EA-PGS could be partly explained by the enrichment or depletion of rare DD variants. Among carriers of rare DD variants, those with a DD-related clinical diagnosis had a substantially lower EA-PGS and more severe phenotype than those without a clinical diagnosis. Our results suggest that the overall burden of both rare and common variants can modify the expressivity of a phenotype, which may then influence whether an individual reaches the threshold for clinical disease.

Degron tagging for rapid protein degradation in mice.

Degron tagging allows proteins of interest to be rapidly degraded, in a reversible and tuneable manner, in response to a chemical stimulus. This provides numerous opportunities for understanding disease mechanisms, modelling therapeutic interventions and constructing synthetic gene networks. In recent years, many laboratories have applied degron tagging successfully in cultured mammalian cells, spurred by rapid advances in the fields of genome editing and targeted protein degradation. In this At a Glance article, we focus on recent efforts to apply degron tagging in mouse models, discussing the distinct set of challenges and opportunities posed by the in vivo environment.

Design and Implementation of a Specialised Millimetre-Wave Exposure System for Investigating the Radiation Effects of 5G and Future Technologies.

As the fifth-generation (5G) network is introduced in the millimetre-wave (mmWave) spectrum, and the widespread deployment of 5G standalone (SA) is approaching, it becomes essential to establish scientifically grounded exposure limits in the mmWave frequency band. To achieve this, conducting experiments at specific frequencies is crucial for obtaining reliable evidence of potential biological impacts. However, there is a literature gap where experimental research either does not utilise the mmWave high band (e.g., the 26 Gigahertz (GHz) band) or most studies mainly rely on computational approaches. Moreover, some experimental studies do not establish reproducible test environment and exposure systems. Addressing these gaps is vital for a comprehensive exploration of the biological implications associated with mmWave exposure. This study was designed to develop and implement a mmWave exposure system operating at 26 GHz. The step-by-step design and development of the system are explained. This specialised system was designed and implemented within an anechoic chamber to minimise external electromagnetic (EM) interference, creating a controlled and reproducible environment for experiments involving high-frequency EM fields. The exposure system features a 1 cm radiation spot size, enabling highly localised exposure for various biological studies. This configuration facilitates numerous dosimetry studies related to mmWave frequencies.

Spindle checkpoint activation by fungal orthologs of the S. cerevisiae Mps1 kinase.

There is an ongoing need for antifungal agents to treat humans. Identification of new antifungal agents can be based on screening compounds using whole cell assays. Screening compounds that target a particular molecule is possible in budding yeast wherein sophisticated strain engineering allows for controlled expression of endogenous or heterologous genes. We have considered the yeast Mps1 protein kinase as a reasonable target for antifungal agents because mutant or druggable forms of the protein, upon inactivation, cause rapid loss of cell viability. Furthermore, extensive analysis of the Mps1 in budding yeast has offered potential tactics for identifying inhibitors of its enzymatic activity. One such tactic is based on the finding that overexpression of Mps1 leads to cell cycle arrest via activation of the spindle assembly checkpoint. We have endeavored to adapt this assay to be based on the overexpression of Mps1 orthologs from pathogenic yeast in hopes of having a whole-cell assay system to test the activity of these orthologs. Mps1 orthologous genes from seven pathogenic yeast or other pathogenic fungal species were isolated and expressed in budding yeast. Two orthologs clearly produced phenotypes similar to those produced by the overexpression of budding yeast Mps1, indicating that this system for heterologous Mps1 expression has potential as a platform for identifying prospective antifungal agents.

Effects of radiofrequency electromagnetic field (RF-EMF) exposure on male fertility: A systematic review of experimental studies on non-human mammals and human sperm in vitro.

BACKGROUND: The World Health Organization is coordinating an international project aimed at systematically reviewing the evidence regarding the association between radiofrequency electromagnetic field (RF-EMF) exposure and adverse health effects. Reproductive health outcomes have been identified among the priority topics to be addressed. OBJECTIVES: To evaluate the effect of RF-EMF exposure on male fertility of experimental mammals and on human sperm exposed in vitro. METHODS: Three electronic databases (PubMed, Scopus and EMF Portal) were last searched on September 17, 2022. Two independent reviewers screened the studies, which were considered eligible if met the following criteria: 1) Peer-reviewed publications of sham controlled experimental studies, 2) Non-human male mammals exposed at any stage of development or human sperm exposed in vitro, 3) RF-EMF exposure within the frequency range of 100 kHz-300 GHz, including electromagnetic pulses (EMP), 4) one of the following indicators of reproductive system impairment:Two reviewers extracted study characteristics and outcome data. We assessed risk of bias (RoB) using the Office of Health Assessment and Translation (OHAT) guidelines. We categorized studies into 3 levels of overall RoB: low, some or high concern. We pooled study results in a random effects meta-analysis comparing average exposure to no-exposure and in a dose-response meta-analysis using all exposure doses. For experimental animal studies, we conducted subgroup analyses for species, Specific Absorption Rate (SAR) and temperature increase. We grouped studies on human sperm exposed in vitro by the fertility status of sample donors and SAR. We assessed the certainty of the evidence using the GRADE approach after excluding studies that were rated as "high concern" for RoB. RESULTS: One-hundred and seventeen papers on animal studies and 10 papers on human sperm exposed in vitro were included in this review. Only few studies were rated as "low concern" because most studies were at RoB for exposure and/or outcome assessment. Subgrouping the experimental animal studies by species, SAR, and temperature increase partly accounted for the heterogeneity of individual studies in about one third of the meta-analyses. In no case was it possible to conduct a subgroup analysis of the few human sperm in vitro studies because there were always 1 or more groups including less than 3 studies. Among all the considered endpoints, the meta-analyses of animal studies provided evidence of adverse effects of RF-EMF exposure in all cases but the rate of infertile males and the size of the sired litters. The assessment of certainty according to the GRADE methodology assigned a moderate certainty to the reduction of pregnancy rate and to the evidence of no-effect on litter size, a low certainty to the reduction of sperm count, and a very low certainty to all the other meta-analysis results. Studies on human sperm exposed in vitro indicated a small detrimental effect of RF-EMF exposure on vitality and no-effect on DNA/chromatin alterations. According to GRADE, a very low certainty was attributed to these results. The few studies that used EMP exposure did not show effects on the outcomes. A low to very low certainty was attributed to these results. DISCUSSION: Many of the studies examined suffered of severe limitations that led to the attribution of uncertainty to the results of the meta-analyses and did not allow to draw firm conclusions on most of the endpoints. Nevertheless, the associations between RF-EMF exposure and decrease of pregnancy rate and sperm count, to which moderate and low certainty were attributed, are not negligible, also in view of the indications that in Western countries human male fertility potential seems to be progressively declining. It was beyond the scope of our systematic review to determine the shape of the dose-response relationship or to identify a minimum effective exposure level. The subgroup and the dose-response fitting analyses did not show a consistent relationship between the exposure levels and the observed effects. Notably, most studies evaluated RF-EMF exposure levels that were higher than the levels to which human populations are typically exposed, and the limits set in international guidelines. For these reasons we cannot provide suggestions to confirm or reconsider current human exposure limits. Considering the outcomes of this systematic review and taking into account the limitations found in several of the studies, we suggest that further investigations with better characterization of exposure and dosimetry including several exposure levels and blinded outcome assessment were conducted. PROTOCOL REGISTRATION: Protocols for the systematic reviews of animal studies and of human sperm in vitro studies were published in Pacchierotti et al., 2021. The former was also registered in PROSPERO (CRD42021227729 https://www.crd.york.ac.uk/prospero/display_record.php?RecordID = 227729) and the latter in Open Science Framework (OSF Registration DOI https://doi.org/10.17605/OSF.IO/7MUS3).

Better translation via collaboration: The MRC National Mouse Genetics Network.

The MRC National Mouse Genetics Network (NMGN) has been established in the UK to bring together researchers from academia and industry across the country from a wide range of disease areas and research backgrounds to rapidly facilitate clinical translation of mouse research findings and foster an environment of interdisciplinary learning.

University makes me angry: Investigating stimulus-response (S-R) and cognitive-mediation (C-M) emotion beliefs in undergraduate students.

Emotion regulation through cognitive reappraisal is well-studied, but less so are the predispositional and superordinate beliefs that influence reappraisal. Recently, researchers developed the cognitive mediation beliefs questionnaire (CMBQ), which measures two emotion beliefs, namely stimulus-response (S-R) generation beliefs and cognitive mediation (C-M) change beliefs. In working populations S-R generation beliefs are inversely related to cognitive reappraisal tendencies and positive mental health, and positively related to emotion reactivity. C-M change beliefs are positively related to cognitive reappraisal tendencies, and inversely related to emotion reactivity and positive mental health. As yet, there is no evidence for the validity of the CMBQ within student samples, or for the associations between its subscales and cognitive reappraisal, emotion reactivity, and positive mental health. Therefore, in the present study the CMBQ is tested for factorial, convergent (associations with cognitive reappraisal), and concurrent (associations with emotion reactivity and positive mental health) validity in a cohort of 621 undergraduate students in the United Kingdom (U.K.). Results indicate support for the factorial and convergent validity of the CMBQ, with mixed evidence for the concurrent validity of the CMBQ. A CM-SR discrepancy score appeared to provide a promising variable when associated with emotion reactivity and positive mental health. The findings are discussed in terms of practical and research implications of the findings.

Fully Automated Versions of Clinically Validated Nephrometry Scores Demonstrate Superior Predictive Utility versus Human Scores.

OBJECTIVE: To automate the generation of three validated nephrometry scoring systems on preoperative computerised tomography (CT) scans by developing artificial intelligence (AI)-based image processing methods. Subsequently, we aimed to evaluate the ability of these scores to predict meaningful pathological and perioperative outcomes. PATIENTS AND METHODS: A total of 300 patients with preoperative CT with early arterial contrast phase were identified from a cohort of 544 consecutive patients undergoing surgical extirpation for suspected renal cancer. A deep neural network approach was used to automatically segment kidneys and tumours, and then geometric algorithms were used to measure the components of the concordance index (C-Index), Preoperative Aspects and Dimensions Used for an Anatomical classification of renal tumours (PADUA), and tumour contact surface area (CSA) nephrometry scores. Human scores were independently calculated by medical personnel blinded to the AI scores. AI and human score agreement was assessed using linear regression and predictive abilities for meaningful outcomes were assessed using logistic regression and receiver operating characteristic curve analyses. RESULTS: The median (interquartile range) age was 60 (51-68) years, and 40% were female. The median tumour size was 4.2 cm and 91.3% had malignant tumours. In all, 27% of the tumours were high stage, 37% high grade, and 63% of the patients underwent partial nephrectomy. There was significant agreement between human and AI scores on linear regression analyses (R ranged from 0.574 to 0.828, all P < 0.001). The AI-generated scores were equivalent or superior to human-generated scores for all examined outcomes including high-grade histology, high-stage tumour, indolent tumour, pathological tumour necrosis, and radical nephrectomy (vs partial nephrectomy) surgical approach. CONCLUSIONS: Fully automated AI-generated C-Index, PADUA, and tumour CSA nephrometry scores are similar to human-generated scores and predict a wide variety of meaningful outcomes. Once validated, our results suggest that AI-generated nephrometry scores could be delivered automatically from a preoperative CT scan to a clinician and patient at the point of care to aid in decision making.

Hyperglycaemia is a causal risk factor for upper limb pathologies.

BACKGROUND: Diabetes (regardless of type) and obesity are associated with a range of musculoskeletal disorders. The causal mechanisms driving these associations are unknown for many upper limb pathologies. We used genetic techniques to test the causal link between glycemia, obesity and musculoskeletal conditions. METHODS: In the UK Biobank's unrelated European cohort (N = 379 708) we performed mendelian randomisation (MR) analyses to test for a causal effect of long-term high glycaemia and adiposity on four musculoskeletal pathologies: frozen shoulder, Dupuytren's disease, carpal tunnel syndrome and trigger finger. We also performed single-gene MR using rare variants in the GCK gene. RESULTS: Using MR, we found evidence that long-term high glycaemia has a causal role in the aetiology of upper limb conditions. A 10-mmol/mol increase in genetically predicted haemoglobin A1C (HbA1c) was associated with frozen shoulder: odds ratio (OR) = 1.50 [95% confidence interval (CI), 1.20-1.88], Dupuytren's disease: OR = 1.17 (95% CI, 1.01-1.35), trigger finger: OR = 1.30 (95% CI, 1.09-1.55) and carpal tunnel syndrome: OR = 1.20 (95% CI, 1.09-1.33). Carriers of GCK mutations have increased odds of frozen shoulder: OR = 7.16 (95% CI, 2.93-17.51) and carpal tunnel syndrome: OR = 2.86 (95% CI, 1.50-5.44) but not Dupuytren's disease or trigger finger. We found evidence that an increase in genetically predicted body mass index (BMI) of 5 kg/m2 was associated with carpal tunnel syndrome: OR = 1.13 (95% CI, 1.10-1.16) and associated negatively with Dupuytren's disease: OR = 0.94 (95% CI, 0.90-0.98), but no evidence of association with frozen shoulder or trigger finger. Trigger finger (OR 1.96 (95% CI, 1.42-2.69) P = 3.6e-05) and carpal tunnel syndrome [OR 1.63 (95% CI, 1.36-1.95) P = 8.5e-08] are associated with genetically predicted unfavourable adiposity increase of one standard deviation of body fat. CONCLUSIONS: Our study consistently demonstrates a causal role of long-term high glycaemia in the aetiology of upper limb musculoskeletal conditions. Clinicians treating diabetes patients should be aware of these complications in clinic, specifically those managing the care of GCK mutation carriers. Upper limb musculoskeletal conditions should be considered diabetes complications.

Iron and risk of dementia: Mendelian randomisation analysis in UK Biobank.

BACKGROUND: Brain iron deposition is common in dementia, but whether serum iron is a causal risk factor is unknown. We aimed to determine whether genetic predisposition to higher serum iron status biomarkers increased risk of dementia and atrophy of grey matter. METHODS: We analysed UK Biobank participants clustered into European (N=451284), African (N=7477) and South Asian (N=9570) groups by genetic similarity to the 1000 genomes project. Using Mendelian randomisation methods, we estimated the association between genetically predicted serum iron (transferrin saturation [TSAT] and ferritin), grey matter volume and genetic liability to clinically defined dementia (including Alzheimer's disease [AD], non-AD dementia, and vascular dementia) from hospital and primary care records. We also performed time-to-event (competing risks) analysis of the TSAT polygenic score on risk of clinically defined non-AD dementia. RESULTS: In Europeans, higher genetically predicted TSAT increased genetic liability to dementia (Odds Ratio [OR]: 1.15, 95% Confidence Intervals [CI] 1.04 to 1.26, p=0.0051), non-AD dementia (OR: 1.27, 95% CI 1.12 to 1.45, p=0.00018) and vascular dementia (OR: 1.37, 95% CI 1.12 to 1.69, p=0.0023), but not AD (OR: 1.00, 95% CI 0.86 to 1.15, p=0.97). Higher TSAT was also associated with increased risk of non-AD dementia in participants of African, but not South Asian groups. In survival analysis using a TSAT polygenic score, the effect was independent of apolipoprotein-E ε4 genotype (with adjustment subdistribution Hazard Ratio: 1.74, 95% CI 1.33 to 2.28, p=0.00006). Genetically predicted TSAT was associated with lower grey matter volume in caudate, putamen and thalamus, and not in other areas of interest. DISCUSSION: Genetic evidence supports a causal relationship between higher TSAT and risk of clinically defined non-AD and vascular dementia, in European and African groups. This association appears to be independent of apolipoprotein-E ε4.

Characterizing emergency department and inpatient health care utilization after seizure-related hospitalization: A retrospective cohort study.

OBJECTIVE: Seizure care is a significant driver of health care costs in both emergency department (ED) and inpatient settings, but the majority of studies have focused on inpatient admissions as the only metric of health care utilization. This study aims to better characterize ED and inpatient encounters among patients with seizure to inform care and policy. METHODS: Using statewide administrative data from the Healthcare Cost and Utilization Project State Inpatient Databases and State Emergency Department Databases from Florida and New York, we identified patients with a seizure-related index hospitalization between January 1, 2016, and December 31, 2018. Among this cohort, we examined the incidence and characteristics of subsequent acute care visits in the ED and inpatient settings for 365 days after initial hospital discharge. RESULTS: A total of 54 456 patients had an eligible seizure-related hospitalization. Patients were 49% female, predominantly White (64%) and non-Hispanic (84%), and used a public primary payer (68%). There were 36 838 (68%) patients with at least one acute care visit in the year following discharge. Overall, patients had a median of 2 (interquartile [IQR] = 1-5) subsequent acute care visits and the median time to first acute care visit was 53 days (IQR = 15-138). Of the 154 369 subsequent acute care visits, 97 399 (63%) were ED-only visits, 56 970 (37%) were readmissions, and 37 176 (24%) were seizure-related. There were 18 786 patients (35%) with four or more acute care visits over 365 days of follow-up. Patients with four or more visits contributed 84% of acute care visits and 78% of costs after initial hospitalization. SIGNIFICANCE: The majority of patients hospitalized for seizure return to the ED or hospital at least once in the year after discharge. A small portion of patients account for the majority of ED and inpatient visits as well as health care costs associated with this population, identifying a subgroup of patients who may benefit from improved inpatient and outpatient management.

Does physical activity moderate the association between shorter leukocyte telomere length and incident coronary heart disease? Data from 54,180 UK Biobank participants.

Telomere shortening is a biological aging hallmark. The effect of short telomere length may be targeted by increased physical activity to reduce the risk of multiple aging-related diseases, including coronary heart disease (CHD). The objective was to assess the moderation effect of accelerometer-based physical activity (aPA) on the association between shorter leukocyte telomere length (LTL) relatively in the population sample and incident CHD. Data were from the UK Biobank participants with well-calibrated accelerometer data for at least 6.5 days (n = 54,180). Relative mean LTL at baseline (5-6 years prior to aPA assessment) was measured in T/S ratio, using a multiplex quantitative polymerase chain reaction (qPCR) technology, by comparing the amount of the telomere amplification product (T) to that of a single-copy gene (S). aPA measures included total number of events (at least 10-s continued physical activity > 32 milligravities [mg]), total volume, mean duration, mean intensity, and peak intensity of all events. LTL, aPA measures, and their interactions were associated with incident CHD (mean follow-up 6.8 years) using Cox proportional hazards models adjusting for covariates. Longer LTL (relative to the sample distribution) was associated with reduced incidence of CHD (adjusted hazard ratio [aHR] = 0.94 per standard deviation [SD] increase in LTL, [95% CI, 0.90 to 0.99], P = .010). Incidence of CHD was reduced by higher total volume of aPA (aHR = 0.82 per SD increase in LTL, [95% CI, 0.71 to 0.95], P = .010) but increased by higher total number of events (aHR = 1.11 per SD increase in LTL, [95% CI, 1.02 to 1.21], P = .020) after controlling for other aPA measures and covariates. However, none of the interactions between LTL and aPA measures was statistically significant (P = .171).