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SUMMARY Mt. Etna is a perfect laboratory for testing new approaches and new technologies in a very active geodynamic environment. It offers, in fact, the opportunity for measuring active crustal deformation, related to volcanic activity as well as to seismic faulting on its flanks. In this work, a network of low-cost/low-power Global Navigation Satellite System stations has been installed and tested on Mt. Etna, across a very active fault, the Provenzana–Pernicana system, cutting its north-eastern flank. During the test period, a lateral eruption occurred (starting on 2018 December 24), with a forceful dyke intrusion that stressed all the flanks of the volcano, soliciting all the main faults dissecting the edifice. Also the Provenzana–Pernicana fault system, where this network was recording, was activated during the dyke intrusion, producing a significant seismic swarm. The low-cost/low-power network data analysis allowed the fault slip during the intrusion to be clearly traced in time and space at all the stations lying on the hangingwall mobile block of the fault. All the stations lying south of the fault trace showed an eastward displacement, in very good agreement with the usual kinematics of the fault and the temporal duration of the M 3.5 December 24 earthquake, related to the seaward dislocation of the eastern mobile flank of the volcano, promoted and accelerated by dyke emplacement on the upper part of the edifice.

Aims Wearable devices are transforming the electrocardiogram (ECG) into a ubiquitous medical test. This study assesses the association between premature ventricular and atrial contractions (PVCs and PACs) detected on wearable-format ECGs (15 s single lead) and cardiovascular outcomes in individuals without cardiovascular disease (CVD). Methods and results Premature atrial contractions and PVCs were identified in 15 s single-lead ECGs from N = 54 016 UK Biobank participants (median age, interquartile range, age 58, 50–63 years, 54% female). Cox regression models adjusted for traditional risk factors were used to determine associations with atrial fibrillation (AF), heart failure (HF), myocardial infarction (MI), stroke, life-threatening ventricular arrhythmias (LTVAs), and mortality over a period of 11.5 (11.4–11.7) years. The strongest associations were found between PVCs (prevalence 2.2%) and HF (hazard ratio, HR, 95% confidence interval = 2.09, 1.58–2.78) and between PACs (prevalence 1.9%) and AF (HR = 2.52, 2.11–3.01), with shorter prematurity further increasing risk. Premature ventricular contractions and PACs were also associated with LTVA (P < 0.05). Associations with MI, stroke, and mortality were significant only in unadjusted models. In a separate UK Biobank sub-study sample [UKB-2, N = 29,324, age 64, 58–60 years, 54% female, follow-up 3.5 (2.6–4.8) years] used for independent validation, after adjusting for risk factors, PACs were associated with AF (HR = 1.80, 1.12–2.89) and PVCs with HF (HR = 2.32, 1.28–4.22). Conclusion In middle-aged individuals without CVD, premature contractions identified in 15 s single-lead ECGs are strongly associated with an increased risk of AF and HF. These data warrant further investigation to assess the role of wearable ECGs for early cardiovascular risk stratification.

Background Faecal calprotectin (FCAL) is routinely used to monitor mucosal inflammation, and high FCAL values are associated with poor outcomes in IBD. Having previously found clusters characterised by distinct FCAL profiles in a Crohn’s disease (CD) cohort of 356 subjects, we aimed to extend this approach to all IBD patients treated by the Edinburgh IBD Unit. Methods Subjects were required to have a diagnosis of IBD, three FCAL measurements within ten years of diagnosis between January 2005 and September 2019, and be treated by the Edinburgh IBD Unit. All FCAL was measured on the same ELISA essay as part of routine clinical care. Latent class mixed models, an extension of linear mixed effects models with cluster specific fixed effects, were used to model and cluster FCAL trajectories. Fixed and random effects were modelled using natural cubic splines, which allows flexible models with relatively low computational cost when compared to high degree polynomials. Akaike information criterion, Bayesian information criterion and alluvial plots were used to decide on the appropriate number of clusters. CD subjects were modelled independently of UC and IBDU subjects, with similar clusters across disease subtypes given the same numbering for ease of comparison. Hereafter, we will describe the UC and IBDU patients collectively. Results 1,214 CD and 1,194 UC/IBDU subjects met the inclusion criteria. Across follow-up, 10,503 (median 7 per subject) FCAL measurements were available for patients with CD and 7,495 (median 5 per subject) for those with UC/IBDU. Figure 1. Log-transformed ten-year faecal calprotectin profiles for Crohn’s disease subjects. Red curves demonstrate overall profile for each cluster. The blue dotted lines indicate an FCAL of log (250 μg/g), the commonly accepted threshold for biochemical remission. For CD, six clusters were found to be appropriate, whereas five clusters were found to be the most appropriate for UC/ IBDU. The overall cluster prmofiles were remarkably similar between CD and UC/IBDU. Both CD cluster 2 and UC cluster 2, the largest clusters, were characterised by consistently high FCAL across follow-up: remaining above the 250 μg/g threshold commonly used for biochemical remission (blue dotted lines in the figures). Figure 2. Log-transformed ten-year faecal calprotectin profiles for ulcerative colitis subjects Conclusion After grouping CD and UC/IBDU subjects in a large cohort by their 10-year FCAL trajectories, we found remarkably similar trajectories across the two groups. In both cases, we found a large cluster of subjects with consistently elevated FCAL, which warrants further investigation.

Background Ethylene oxide (EtO) is a carcinogenic gas used in chemical production and to sterilize medical equipment that has been linked to risk of breast and lymphohematopoietic cancers in a small number of occupational studies. We investigated the relationship between environmental EtO exposure and risk of these cancers. Methods Using the US Environmental Protection Agency’s Toxics Release Inventory, we estimated historical exposures for National Institutes of Health–AARP Diet and Health Study participants enrolled in 1995-1996. We constructed 2 metrics at 3, 5, and 10 km: 1) distance between residences and EtO-emitting facilities, weighted by the proportion of time the home was downwind of each facility, and 2) distance-weighted, wind direction–adjusted average airborne emissions index (AEI=∑[lbs EtO/km2]). We estimated risk (hazard ratio [HR], 95% confidence interval [CI]) of incident breast cancer (in situ and invasive) among postmenopausal women (n = 173 670) overall and by tumor estrogen receptor status and non-Hodgkin lymphoma in the full cohort (n = 451 945). Results We observed an increased risk of breast cancer associated with EtO-emitting facilities within 10 km (HR[≤10vs>10] = 1.05, 95% CI = 1.00 to 1.10) that appeared stronger for in situ (HR[≤10vs>10] = 1.13, 95% CI = 1.00 to 1.27) than invasive (HR[≤10vs>10] = 1.03, 95% CI = 0.97 to 1.09) disease. Risk of breast cancer in situ was also increased in the top AEI quartiles, and associations weakened with larger distances (HR[Q4vs0] = 1.60, 95% CI = 0.98 to 2.61; HR[Q4vs0] = 1.28, 95% CI = 0.92 to 1.79; HR[Q4vs0] = 1.25, 95% CI = 1.02 to 1.53 at 3, 5, and 10 km, respectively). No differences in breast cancer risk were observed by estrogen receptor status. We found no clear pattern of increased non-Hodgkin lymphoma risk. Conclusions A novel potential association between EtO emissions and risk of in situ, but not invasive, breast cancer warrants additional evaluation.

Background Racial and ethnic differences in survival after a first cancer are well established but have not been examined after a second primary cancer (SPC) despite the increasing incidence among survivors. Methods We examined 39 029 female breast cancer survivors who developed an SPC between 2000 and 2014 in the Surveillance, Epidemiology, and End Results 18 database. Multivariable Cox proportional hazards regression for competing risks data was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for cancer and cardiovascular disease mortality after SPCs comparing Hispanic, Non-Hispanic Asian, and Non-Hispanic Black survivors with Non-Hispanic White survivors. Models were adjusted for sociodemographics, tumor characteristics, and treatments of the first and second cancer. Analyses were stratified by SPC type. Results During 17 years of follow-up, there were 15 117 deaths after SPCs. The risk of cancer death was 12% higher among Non-Hispanic Black survivors (HR = 1.12, 95% CI = 1.05 to 1.19) and 8% higher among Hispanic survivors (HR = 1.08, 95% CI = 1.00 to 1.16) compared with Non-Hispanic White survivors. In subgroup analyses, the strongest associations were observed among Non-Hispanic Black survivors with a second breast or uterine cancer and among Hispanic survivors with a second breast cancer. Non-Hispanic Black survivors also experienced a 44% higher risk of cardiovascular disease death after SPC diagnosis than Non-Hispanic White survivors (HR = 1.44, 95% CI = 1.20 to 1.74). Conclusions Higher cancer mortality among Non-Hispanic Black and Hispanic survivors and higher cardiovascular mortality among Non-Hispanic Black survivors exist among women who survive a first breast cancer to develop an SPC. Studies focused on identifying the contributors to these disparities are needed to enable implementation of effective mitigation strategies.

The Phasmida genus Candovia comprises nine traditionally recognized species, all endemic to Australia. In this study, Candovia diversity is explored through molecular species-delimitation analyses using the COIFol gene fragment and phylogenetic inferences leveraging seven additional mitochondrial and nuclear loci. Molecular results were integrated with morphological observations, leading us to confirm the already described species and to the delineation of several new taxa and of the new genus Paracandovia. New Candovia species from various parts of Queensland and New South Wales are described and illustrated (C. alata sp. nov., C. byfieldensis sp. nov., C. dalgleishae sp. nov., C. eungellensis sp. nov., C. karasi sp. nov., C. koensi sp. nov. andC. wollumbinensis sp. nov.). New combinations are proposed and species removed from synonymy with the erection of the new genus Paracandovia (P. cercata stat. rev., comb. nov., P. longipes stat. rev., comb. nov., P. pallida comb. nov., P. peridromes comb. nov., P. tenera stat. rev., comb. nov.). Phylogenetic analyses suggest that the egg capitulum may have independently evolved multiple times throughout the evolutionary history of these insects. Furthermore, two newly described species represent the first taxa with fully developed wings in this previously considered apterous clade.

Mono- and bi-allelic variants in ALDH18A1 cause a spectrum of human disorders associated with cutaneous and neurological findings that overlap with both cutis laxa and spastic paraplegia. ALDH18A1 encodes the bifunctional enzyme pyrroline-5-carboxylate synthetase (P5CS) that plays a role in the de novo biosynthesis of proline and ornithine. Here we characterize a previously unreported homozygous ALDH18A1 variant (p.Thr331Pro) in four affected probands from two unrelated families, and demonstrate broad-based alterations in amino acid and antioxidant metabolism. These four patients exhibit variable developmental delay, neurological deficits and loose skin. Functional characterization of the p.Thr331Pro variant demonstrated a lack of any impact on the steady-state level of the P5CS monomer or mitochondrial localization of the enzyme, but reduced incorporation of the monomer into P5CS oligomers. Using an unlabeled NMR-based metabolomics approach in patient fibroblasts and ALDH18A1-null human embryonic kidney cells expressing the variant P5CS, we identified reduced abundance of glutamate and several metabolites derived from glutamate, including proline and glutathione. Biosynthesis of the polyamine putrescine, derived from ornithine, was also decreased in patient fibroblasts, highlighting the functional consequence on another metabolic pathway involved in antioxidant responses in the cell. RNA sequencing of patient fibroblasts revealed transcript abundance changes in several metabolic and extracellular matrix-related genes, adding further insight into pathogenic processes associated with impaired P5CS function. Together these findings shed new light on amino acid and antioxidant pathways associated with ALDH18A1-related disorders, and underscore the value of metabolomic and transcriptomic profiling to discover new pathways that impact disease pathogenesis.

Advances in genomics have led to the identification of many risk loci with hundreds of genes and thousands of DNA variants associated with neuropsychiatric disorders. A significant barrier to understanding the genetic underpinnings of complex diseases is the lack of functional characterization of risk genes and variants in biological systems relevant to human health and connecting disease-associated variants to pathological phenotypes. Characterizing gene and DNA variant functions requires genetic perturbations followed by molecular and cellular assays of neurobiological phenotypes. However, generating null or mutant alleles is low throughput, making it impossible to characterize disease-associated variants in large quantities efficiently. CRISPR interference (CRISPRi) and CRISPR activation (CRISPRa) screens can be leveraged to dissect the biological consequences of the tested genes and variants in their native context. Nevertheless, testing non-coding variants associated with complex diseases remains non-trivial. In this review, we first discuss the current challenges of interpreting the function of the non-coding genome and approaches to prioritizing disease-associated variants in the context of the 3D epigenome. Second, we provide a brief overview of high-throughput CRISPRi and CRISPRa screening strategies applicable for characterizing non-coding sequences in appropriate biological systems. Lastly, we discuss the promising prospects of using CRISPR-based technologies to dissect DNA sequences associated with neuropsychiatric diseases.

In this study, atom probe tomography (APT) was used to investigate strontium-containing bioactive glass particles (BG-Sr10) and strontium-releasing bioactive glass-based scaffolds (pSrBG), both of which are attractive biomaterials with applications in critical bone damage repair. We outline the challenges and corresponding countermeasures of this nonconductive biomaterial for APT sample preparation and experiments, such as avoiding direct contact between focussed ion beam micromanipulators and the extracted cantilever to reduce damage during liftout. Using a low imaging voltage (≤3 kV) and current (≤500 pA) in the scanning electron microscope and a low acceleration voltage (≤2 kV) and current (≤200 pA) in the focussed ion beam prevents tip bending in the final stages of annular milling. To optimize the atom probe experiment, we considered five factors: total detected hits, multiple hits, the background level, the charge-state ratio, and the accuracy of the measured compositions, to explore the optimal laser pulse for BG-Sr10 bioactive glass. We show that a stage temperature of 30 K, 200–250 pJ laser pulse energy, 0.3% detection rate, and 200 kHz pulse rate are optimized experimental parameters for bioactive glass. The use of improved experimental preparation methods and optimized parameters resulted in a 90% successful yield of pSrBG samples by APT.

Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): This work was supported by the National Institute for Health Research Biomedical Research Centre at Guy’s and St. Thomas’ Trust and King’s College, the Centre of Excellence in Medical Engineering funded by the Wellcome Trust and Engineering and Physical Sciences Research Council (EPSRC; WT088641/Z/09/Z). M.J.B. is supported by a Medical Research Council New Investigator Grant (MR/N011007/1) and British Heart Foundation (Project grant PG/18/74/34077). This work was supported by EPSRC 2018/19 DTP - EP/R513064/1 grant. This work was supported by a National Heart and Lung Institute Foundation grant awarded to Professor Sanjay Prasad and Dr Richard Jones. This work was supported by a National Heart and Lung Institute Foundation grant awarded to SKP, DJH, REJ, UT and BPH. Additionally, the study was supported by an Intermediate Clinical Research Fellowship awarded to BPH (FS/ICRF/21/26019). Background The presence of ring-like patterns of mid-wall fibrosis identified on late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) is associated with an increased risk of major arrhythmic events (MAE) in non-ischemic cardiomyopathy (NICM). Analysis of tissue bordering core fibrosis and healthy myocardium (Gray Zone [GZ]) has been suggested as an important pro-arrhythmic substrate in this population. Purpose To investigate refined anatomical definitions of the fibrotic ring pattern, including the importance of GZ inclusion in the association with MAE in NICM. Methods LGE CMR data from 292 NICM patients were analysed to delineate both core and GZ fibrosis. Fibrosis quantification masks for each 2D image slice were used, along with AHA 17-segment maps, to identify fibrotic ring patterns: defined by fibrosis extending by 3 or more continuous AHA-segments for any individually-contiguous fibrotic component within each slice (Fig 1A). Ring patterns were assessed separately for core fibrosis and core + GZ, as well as individually in basal, mid-basal and mid-apical regions. In separate analysis, LGE contours were aligned, interpolated, and used to generate 3D computational volumetric models (Fig 1B). Individually-connected scar components were extracted and the 3D circumferential angular variation (3DCAV) of each separate fibrotic structure quantified as a continuous variable (Fig 1C). Association of the presence of ring patterns and 3DCAV with a composite MAE were investigated. Results Of 292 patients, 67(23%) had core fibrotic ring patterns (54 basal, 28 mid-cavity level, 6 apical). Over a median(IQR) of 6(4) years, 16(24%) patients experienced MAE. On univariate Cox analysis, ring pattern core fibrosis was a strong predictor of MAE (Hazard ratio [HR] 2.2, 95% confidence interval [CI] 1.13-4.31, p=0.021). Apical-basal region analysis showed that basal ring pattern was associated with MAE (HR 2.25, 95%CI, 1.13-4.51, p=0.022). Multivariate Cox analysis including raised NYHA Class and severely reduced LVEF, overall ring (HR 2.14, 95%CI, 1.05-4.33, p=0.035) and basal ring pattern (HR 2.9, 95%CI 1.39-6.02, P=0.004) continued to show independent association with the MAE. Analysis of the full 3D geometry of the individual scar components also showed that our novel 3DCAV metric was associated with the MAE on both univariate (HR 1.31, 95%CI 1.08-1.59, P=0.007) and multivariate (HR 1.3, 95%CI, 1.06-1.60, P=0.013). Analysis of core ring patterns outperformed analysis of core+GZ patterns in all cases. Conclusions Our study confirms that ring-like patterns of fibrosis in NICM are strongly associated with MAE in NICM, with patterns predominantly at the basal regions conferring enhanced risk relative to mid-basal and mid-apical regions. Inclusion of GZ quantification in ring-pattern analysis did not enhance risk prediction. Our novel 3D analysis of circumferential fibrosis patterns may provide a more robust quantitative metric for stratification.

Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): This work was supported by the National Institute for Health Research Biomedical Research Centre at Guy’s and St. Thomas’ Trust and King’s College, the Centre of Excellence in Medical Engineering funded by the Wellcome Trust and Engineering and Physical Sciences Research Council (EPSRC; WT088641/Z/09/Z). M.J.B. is supported by a Medical Research Council New Investigator Grant (MR/N011007/1) and British Heart Foundation (Project grant PG/18/74/34077). This work was supported by EPSRC 2018/19 DTP - EP/R513064/1 grant. This work was supported by a National Heart and Lung Institute Foundation grant awarded to Professor Sanjay Prasad and Dr Richard Jones. Background Enhanced risk stratification for implanted defibrillator requirement represents an important area of research in patients with non-ischemic cardiomyopathy (NICM). Myocardial fibrosis represents the major underlying arrhythmic substrate in this population, and its identification on late-gadolinium enhancement cardiovascular magnetic resonance (LGE-CMR) is associated with life-threatening arrhythmia (LTA). Fibrosis entropy, a measure of scar texture heterogeneity, may confer important information regarding the underlying pro-arrhythmic mechanisms of both core scar and areas of intermediate signal intensity (Gray Zone [GZ]). Purpose We sought to: 1) evaluate whether LGE-CMR assessment of left ventricular (LV) tissue entropy had incremental utility to fibrosis presence for arrhythmic risk stratification of patients with NICM; 2) quantify the added utility of GZ entropy in such analysis. Methods This study involved a prospective observational cohort of consecutive patients with NICM and myocardial fibrosis detected on LGE-CMR. Epicardial and endocardial contours obtained from LGE-CMR data were used with a FWHM method to delineate core fibrosis (≥50% maximum signal intensity) and GZ fibrosis (≥35%- Results Of 291 patients with NICM and mid-wall/subepicardial fibrosis, 38 patients (13.1%) experienced LTA over median follow-up of 6.3 years (interquartile range 4.6-9.1 years). On Cox regression analysis, core fibrosis entropy (Hazard ratio [HR] 1.77, 95% CI 1.25-2.54, p=0.001), GZ fibrosis entropy (HR 1.74, 95% CI 1.20-2.54, p=0.004) and combined fibrosis entropy (HR 1.98, 95% CI 1.30-2.52, p=0.001) were associated LTA after adjustment for variables used to guide ICD implantation (LVEF 1) and remained associated in multivariable models accounting separately for core and GZ fibrosis mass. The addition of core fibrosis entropy, GZ fibrosis entropy and combined fibrosis entropy to a baseline clinical model improved the C-statistic from 0.49 to 0.59, 0.62 and 0.62, respectively. LVEF Conclusions Fibrosis entropy on LGE-CMR offers incremental utility to LVEF and fibrosis presence for arrhythmic risk prediction in patients with NICM. The combination of core and GZ fibrosis entropy offers the highest association with risk.

Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): This work was supported by the National Institute for Health Research Biomedical Research Centre at Guy’s and St. Thomas’ Trust and King’s College, the Centre of Excellence in Medical Engineering funded by the Wellcome Trust and Engineering and Physical Sciences Research Council (EPSRC; WT088641/Z/09/Z). M.J.B. is supported by a Medical Research Council New Investigator Grant (MR/N011007/1) and British Heart Foundation (Project grant PG/18/74/34077). This work was supported by EPSRC 2018/19 DTP - EP/R513064/1 grant. This work was supported by a National Heart and Lung Institute Foundation grant awarded to Professor Sanjay Prasad and Dr Richard Jones. Background Arrhythmic risk stratification of patients with stable coronary artery disease (CAD) for defibrillator implantation remains imprecise. Current clinical guidelines center on a basic assessment of adverse cardiac remodelling, an approach with well documented limitations. More advanced analysis of intricate and regional LV remodelling in these patients may shed new insight for enhanced risk prediction of life-threatening arrhythmia in stable CAD. Objective We explored a novel computational 3D LV shape analysis strategy to accurately represent, and quantify, arrhythmogenic LV remodelling patterns in late gadolinium enhancement cardiovascular magnetic resonance images (LGE-CMR) in patients with stable CAD. We assess the utility of our patient-specific 3D LV arrhythmic shape (LVAS) score predicting major arrhythmic event; comparing to the current clinical benchmark of severely reduced LVEF and NYHA functional class. Methods Patients with stable CAD were prospectively recruited into a CMR registry and followed up for a composite endpoint of major arrhythmic events (MAE) consisting of sudden cardiac death (SCD), aborted SCD or haemodynamically unstable VT. Time-to-event data was also recorded. 2D LGE-CMR images were contoured and used as input to an advanced computational shape-analysis approach (Figure 1A). Reconstructed 3D LV shape models were analysed using Principle Component Analysis and Cox-Lasso to characterise the average arrhythmogenic LV shape, which was then used to quantitatively define a patient-specific LV arrhythmic shape (LVAS) score. Results Of 397 patients (mean [SD] LVEF% 45.4 ± 16.0) followed for a median (IQR) of 6 (3) years, 55 (14%) experienced a major arrhythmic event (MAE). The mean (SD) LVEF for patients who experienced MAE was lower than for those that did not (37.1% ± 13.2 vs 46.7% ± 16.0), yet there was no difference in NYHA class. LVAS mean (95% confidence interval [CI]) score was different between event and event-free patients: 2.98 (0.48-6.44) vs 19.83 (10.66-29), P On univariate Cox regression analysis both LVAS score (hazard ratio [HR] 2.1, 95% CI 1.6-2.7, PI was not associated with the primary endpoint (HR 1.5, 95% CI 0.8-2.7, P=0.221). In multivariate Cox regression analysis, LVAS remained independently associated with the primary endpoint after adjusting for LVEFClass I: LVAS score HR 2.1, 95% CI 1.5-3.0, PClass I HR 1.3, 95% CI 0.7-2.5, P=0.443 (Figure 1 B, C). The addition of the LVAS score increased the C-statistic from 0.6 to 0.75 between models. Conclusion A Left Ventricle Arrhythmic Shape score improved arrhythmic risk stratification compared to guideline-based clinical parameters, highlighting a potentially novel approach to identifying candidates for implantable cardioverter defibrillators in stable CAD.

Study Objective To examine the association between light at night (LAN) and multiple sleep health dimensions Methods Among 47 765 Sister Study participants, indoor LAN (TV on in the room, light(s) on in room, light from outside the room, nightlight, no light) and sleep dimensions were self-reported at baseline (2003–2009). We used Poisson regression with robust variance to estimate adjusted prevalence ratios (PR) and 95% confidence intervals (CI) for the cross-sectional associations between LAN and short sleep duration ( Results Compared to sleeping with no light in the bedroom, sleeping with a TV on was associated with a higher prevalence of most dimensions of poor sleep (e.g. short sleep duration: PR = 1.38, 95% CI: 1.32 to 1.45; inconsistent sleep/wake time: PR = 1.55, 95% CI: 1.44 to 1.66; sleep debt: PR = 1.36, 95% CI: 1.29 to 1.44; poor sleep score: PR = 1.58, 95% CI: 1.48-1.68). PARs tended to be higher for non-Hispanic black women compared to non-Hispanic white women. Conclusions Sleeping with a TV on was associated with poor sleep health among US women, and non-Hispanic black women may be disproportionately burdened.

Background and Hypothesis Schizophrenia has been robustly associated with multiple genetic and environmental risk factors. Childhood adversity is one of the most widely replicated environmental risk factors for schizophrenia, but it is unclear if schizophrenia genetic risk alleles contribute to this association. Study Design In this systematic review and meta-analysis, we assessed the evidence for gene-environment correlation (genes influence likelihood of environmental exposure) between schizophrenia polygenic risk score (PRS) and reported childhood adversity. We also assessed the evidence for a gene-environment interaction (genes influence sensitivity to environmental exposure) in relation to the outcome of schizophrenia and/or psychosis. This study was registered on PROSPERO (CRD42020182812). Following PRISMA guidelines, a search for relevant literature was conducted using Cochrane, MEDLINE, PsycINFO, Web of Science, and Scopus databases until February 2022. All studies that examined the association between schizophrenia PRS and childhood adversity were included. Study Results Seventeen of 650 identified studies met the inclusion criteria and were assessed against the Newcastle-Ottawa Scale for quality. The meta-analysis found evidence for gene-environment correlation between schizophrenia PRS and childhood adversity (r = .02; 95% CI = 0.01, 0.03; P = .001), but the effect was small and therefore likely to explain only a small proportion of the association between childhood adversity and psychosis. The 4 studies that investigated a gene-environment interaction between schizophrenia PRS and childhood adversity in increasing risk of psychosis reported inconsistent results. Conclusions These findings suggest that a gene-environment correlation could explain a small proportion of the relationship between reported childhood adversity and psychosis.

Aims Lipoprotein(a) [Lp(a)] levels are generally constant throughout an individual’s lifetime, and current guidelines recommend that a single measurement is sufficient to assess the risk of coronary artery disease (CAD). However, it is unclear whether a single measurement of Lp(a) in individuals with acute myocardial infarction (MI) is indicative of the Lp(a) level six months following the event. Methods and results Lp(a) levels were obtained from individuals with non–ST-elevation myocardial infarction (NSTEMI) or ST-elevation myocardial infarction (STEMI) (n = 99) within 24 h of hospital admission and after six months, who were enrolled in two randomized trials of evolocumab and placebo, and in individuals with NSTEMI or STEMI (n = 9) who enrolled in a small observation arm of the two protocols and did not receive study drug, but whose levels were obtained at the same time points. Median Lp(a) levels increased from 53.5 nmol/L (19, 165) during hospital admission to 58.0 nmol/L (14.8, 176.8) six months after the acute infarction (P = 0.02). Subgroup analysis demonstrated no difference in the baseline, six-month, or change between the baseline and six-month Lp(a) values between the STEMI and NSTEMI groups and between the group which received evolocumab and the group that did not. Conclusion This study demonstrated that Lp(a) levels in individuals with acute MI are significantly higher six months after the initial event. Therefore, a single measurement of Lp(a) in the peri-infarction setting is not sufficient to predict the Lp(a)-associated CAD risk in the post-infarction period. Registration Evolocumab in Acute Coronary Syndrome Trial [EVACS I] NCT03515304, Evolocumab in Patients with Acute Myocardial Infarction [EVACS II], NCT04082442

Introduction The number of transcatheter aortic valve implantations (TAVIs) performed in the UK is increasing exponentially, providing a new treatment avenue for patients with severe symptomatic aortic stenosis previously deemed too frail for surgical intervention. Frailty is known to be associated with poor outcomes following TAVI, however little is known as to whether comprehensive geriatric assessment (CGA), the gold standard intervention for older adults in a range of clinical settings, can change outcomes for older adults undergoing this procedure. Methods Databases EMBASE, MEDLINE, CINAHL and Cochrane CENTRAL, along with the World Health Organisation clinical trials registry platform and Clinicaltrials.gov registry were searched for relevant reports between 01/01/1980 - 26/01/2022 using a pre-specified search strategy. Patients had to be 65 or over and studies had to evaluate single- or multi-domain interventions that may form part of a CGA. Studies were not limited to those only looking at patients living with or at risk of frailty. Results No studies of adequate quality evaluated the effect of CGA on outcomes for older adults undergoing TAVI. 18 studies evaluating CGA-related interventions were identified that met eligibility criteria, with the majority evaluating cardiac rehabilitation (CR) as a post-procedural intervention. Other interventions evaluated included cognitive behavioural therapy, alternative exercise-based interventions and post-procedural protocols that promoted early mobilisation and allied health professional involvement. A high risk of bias and significant methodological flaws were found in the included studies. There was little evidence that post-procedural CR reduces mortality and to support the role of occupational and physical therapy for improving in-hospital outcomes for these patients. Conclusion(s) There is no convincing evidence to support CGA or related single domain interventions to improve outcomes for older adults undergoing TAVI. Further robust research is required to establish whether CGA improves outcomes for this group.

There are unique challenges to identifying causes of and developing strategies for prevention of rare cancers, driven by the difficulty in estimating incidence, prevalence, and survival due to small case numbers. Using a Poisson modeling approach, Salmerón et al. (Am J Epidemiol. 2022;191(3):487–498) built upon their previous work to estimate incidence rates of rare cancers in Europe using a Bayesian framework, establishing a uniform prior for a measure of variability for country-specific incidence rates. They offer a methodology with potential transferability to other settings with similar cancer surveillance infrastructure. However, the approach does not consider the spatiotemporal correlation of rare cancer case counts and other, potentially more appropriate nonnormal probability distributions. In this commentary, we discuss the implications of future work from cancer epidemiology and spatial epidemiology perspectives. We describe the possibility of developing prediction models tailored to each type of rare cancer; incorporating the spatial heterogeneity in at-risk populations, surveillance coverage, and risk factors in these predictions; and considering a modeling framework with which to address the inherent spatiotemporal components of these data. We note that extension of this methodology to estimate subcountry rates at provincial, state, or smaller geographic levels would be useful but would pose additional statistical challenges.

Aims Emerging evidence suggests that remnant cholesterol (RC) promotes atherosclerotic cardiovascular disease (ASCVD). We aimed to estimate RC-related risk beyond low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apoB) in patients without known ASCVD. Methods and results We pooled data from 17 532 ASCVD-free individuals from the Atherosclerosis Risk in Communities study (n = 9748), the Multi-Ethnic Study of Atherosclerosis (n = 3049), and the Coronary Artery Risk Development in Young Adults (n = 4735). RC was calculated as non-high-density lipoprotein cholesterol (non-HDL-C) minus calculated LDL-C. Adjusted Cox models were used to estimate the risk for incident ASCVD associated with log RC levels. We also performed discordance analyses examining relative ASCVD risk in RC vs. LDL-C discordant/concordant groups using difference in percentile units (>10 units) and clinically relevant LDL-C targets. The mean age of participants was 52.3 ± 17.9 years, 56.7% were women and 34% black. There were 2143 ASCVD events over the median follow-up of 18.7 years. After multivariable adjustment including LDL-C and apoB, log RC was associated with higher ASCVD risk [hazard ratio (HR) 1.65, 95% confidence interval (CI) 1.45–1.89]. Moreover, the discordant high RC/low LDL-C group, but not the low RC/high LDL-C group, was associated with increased ASCVD risk compared to the concordant group (HR 1.21, 95% CI 1.08–1.34). Similar results were shown when examining discordance across clinical cutpoints. Conclusions In ASCVD-free individuals, elevated RC levels were associated with ASCVD independent of traditional risk factors, LDL-C, and apoB levels. The mechanisms of RC association with ASCVD, surprisingly beyond apoB, and the potential value of targeted RC-lowering in primary prevention need to be further investigated.

Background Antibody responses following SARS-CoV-2 infection or a single-dose of SARS-CoV-2 vaccine are impaired in patients with inflammatory bowel disease treated with anti-TNF compared to those treated with vedolizumab, a gut-selective anti-integrin α4β7 monoclonal antibody. Here we sought to determine if patients treated with infliximab have attenuated serological and T cell responses and an increased risk of breakthrough COVID-19 infection following primary SARS-CoV-2 vaccination. Methods Anti-spike (S) receptor binding domain (RBD) antibody concentration in 2306 infliximab-treated patients were compared to a cohort of 1045 vedolizumab-treated patients. Our primary outcome was anti-S RBD antibodies 2 to 10 weeks after a second dose of the BNT162b2 or ChAdOx1 nCoV-19 vaccines. Secondary outcomes were anti-spike T cell responses, durability of vaccine responses and risk of breakthrough infections following two doses of vaccine. Results Anti-S RBD antibody concentrations were lower in patients treated with infliximab than in those treated with vedolizumab, following a second dose of BNT162b2 (567.3 U/mL [6.1] vs 4601.1 U/mL [5.3], p Vaccination with the BNT162b2 vaccine compared to the ChAdOx1 nCoV-19 was independently associated with a 3.7-fold [95% CI 3.30 – 4.13] higher anti-S RBD antibody concentration (p < 0.0001) (Fig. 2). There were no significant differences in the magnitude of anti-spike T cell responses observed in infliximab- compared with vedolizumab-treated patients after one or two doses of either vaccine. Antibody half-life was shorter in infliximab- than vedolizumab-treated patients following two-doses of BNT162b2 (4.0 weeks [95% CI 3.8 – 4.1] vs 7.2 weeks [95% CI 6.8 – 7.6]) and ChAdOx1 nCoV-19 (5.3 weeks [95% CI 5.1 – 5.5] vs 9.3 weeks [95% CI 8.5 – 10.2], p value < 0.0001). Breakthrough SARS-CoV-2 infections were more frequent (5.8% (202/3467) vs 3.9% (66/1691), p = 0.0032) and the time to breakthrough shorter in patients treated with infliximab than vedolizumab (p = 0.0023) (Fig. 3). Higher anti-S RBD antibody concentrations following a second dose of SARS-CoV-2 vaccine protected against breakthrough SARS-CoV-2 infection: overall, for every 10-fold rise in anti-S RBD antibody level we observed a 0.8-fold reduction in odds of breakthrough infection ([95% CI 0.70 – 0.99], p = 0.035). Conclusion Infliximab was associated with attenuated, less durable vaccine induced anti-S RBD antibody responses and a 50% increase in breakthrough SARS-CoV-2 infection. Further follow-up is required to assess whether third primary doses can mitigate the effects of infliximab on anti-S RBD antibody responses.

Background Aconitate decarboxylase 1 (ACOD1; also known as IRG-1) is the ubiquitous source of itaconate, which dampens inflammasome activation by preventing HIF1a production of IL-1b and prevents TNF production through NRF2 activation. We reasoned that expression of ACOD1 is an inhibitory pathway within monocytes to curtail their inflammatory function, which could be manipulated in IBD therapy. Methods We performed single-cell RNA sequencing of monocytes from colonoscopic biopsies of treatment naïve IBD patients, as well as complementary analysis of DSS treated C57BL/6J (WT) mice, using single-cell protein-mRNA (Primeflow) technologies for validation. To determine the role of ACOD1 in colitis, Acod1–/– mice were administered 2% DSS in drinking water for 6 days (acute colitis) or 4 days followed by 14 day recovery period (inflammation resolution) and assessed the colon myeloid compartment by multi-parameter flow cytometry. This was complemented with competitive bone marrow chimeric mice to assess the intrinsic role of ACOD1 controlling monocyte survival and proinflammatory status. Transcriptional profiling (Nanostring) was used to determine the molecular pathways influenced by ACOD1. Results We found that ACOD1/Acod1 represented an evolutionarily conserved of feature of inflammation-associated monocytes, with expression present in mucosal but not blood monocytes. Acod1–/– mice demonstrated increased susceptibility to acute intestinal injury with DSS compared to co-housed WT controls, characterised by increased weight loss and colon shortening with significant accumulation of colonic neutrophils and CD64+Ly6C+ MHC-II+/– monocytes. Consistent with Acod1 limiting inflammasome activation, Acod1–/– monocytes demonstrated significantly greater IL-1b producing capabilities than WT controls. To assess Acod1 deficient and sufficient haemopoietic cells in in the same environment, we generated competitive bone marrow chimeric mice. Acod1 deficiency conferred a significant advantage to monocyte recruitment to the colon, characterised by a 10fold increase in Ly6C+ MHC-II–colon monocytes in colitis. Transcriptional profiling of WT and Acod1–/– colonic monocytes revealed significantly greater expression of molecules required for monocyte extravasation, including Sell (CD62L), Icam1, Ccr2 and Itgal (CD11a). In addition, expression of genes indicative of macrophage maturation such as Itgax (CD11c), Cd163 and Cx3cr1 were lower in the context of Acod1 deficiency, suggesting that normal maturation of these cells may be perturbed by loss of Acod1. Conclusion ACOD1/Acod1 represents an evolutionarily conserved, monocyte specific immuno-metabolic pathway that acts to limit monocyte recruitment, fate and pro-inflammatory function within the inflamed intestine.

Background Research pairing ecological momentary assessment (EMA) methodology and ambulatory cortisol during daily life is still rare, as is careful testing of the within-person associations between stress, affect, and cortisol. Using a circumplex approach, we considered both valence and arousal components of affect. Purpose To examine the within-person covariation of momentary cortisol with momentary perceived stress, affective valence, and affective arousal in everyday life. Methods 115 working adults (Mage = 41.2; 76% women; 76% white) completed six EMA surveys per day over 3 days. Each assessment included reports of perceived stress and affect (used to construct indicators of affective valence and arousal), followed by a saliva sample (from which cortisol was assessed). Multi-level models were used to examine the momentary associations between perceived stress, affective valence, affective arousal, and cortisol. Results Moments characterized by higher perceived stress were associated with higher cortisol (p = .036). Affective valence covaried with cortisol (p = .003) such that more positive valence was associated with lower cortisol and more negative valence with higher cortisol. Momentary affective arousal was not related to cortisol (p = .131). When all predictors were tested in the same model, only valence remained a significant predictor of cortisol (p = .047). Conclusion Momentary perceived stress and affective valence, but not affective arousal, were associated with naturalistic cortisol. Cortisol was more robustly associated with affective valence than perceived stress or affective arousal. These findings extend our understanding of how moments of stress and particular characteristics of affective states (i.e., valence but not arousal) may “get under the skin” in daily life.

Introduction Secondary analysis of outcomes after 11,085 hip fracture operations from the prospective UK Anaesthesia Sprint Audit of Practice (ASAP 2) found an association between reduced intraoperative systolic arterial pressure (SAP) and postoperative mortality at five and 30 days. We sought to determine the incidence of hypotension in the postoperative period, rather than just intraoperatively, in a small sample of patients with fractured neck of femur. Method We performed a retrospective review of the notes, electronic vital signs and electronic general practice records from 40 patients with fractured neck of femur. We identified the latest SAP performed at their general practice (if done within one year before admission). We noted the pre-operative baseline SAP reading from the ward as well as the lowest SAP during several time periods: the pre-operative period; the fracture surgery; the recovery room; and during each 24-h period postoperatively until the fifth postoperative day. Results A SAP recording from general practice within the previous year was only accessible in 21 (53%) of patients, but where it was accessible, it was within 20% of the immediate preoperative SAP in 14 (66%) of patients. The incidence of relative hypotension (< 80% preoperative SAP) was 54% in the operating theatre, 41% in the recovery room, 65% on the ward during the remainder of the first postoperative 24 h, 55% during postoperative day 2, 53% during day 3, 33% during day 4 and 41% during day 5. Conclusions Postoperative hypotension was common in our sample. In our analysis, the highest incidence was on the ward during the first 24 hours postoperatively. However, 41% of patients still had hypotension 5 days postoperatively.

Neurofibromatosis Type II (NF2) is an autosomal dominant cancer predisposition syndrome in which germline haploinsufficiency at the NF2 gene confers a greatly increased propensity for tumor development arising from tissues of neural crest derived origin. NF2 encodes the tumor suppressor, Merlin, and its biochemical function is incompletely understood. One well-established function of Merlin is as a negative regulator of group A serine/threonine p21-activated kinases (PAKs). In these studies we explore the role of PAK1 and its closely related paralog, PAK2, both pharmacologically and genetically, in Merlin-deficient Schwann cells and in a genetically engineered mouse model (GEMM) that develops spontaneous vestibular and spinal schwannomas. We demonstrate that PAK1 and PAK2 are both hyper activated in Merlin-deficient murine schwannomas. In preclinical trials, a pan Group A PAK inhibitor, FRAX-1036, transiently reduced PAK1 and PAK2 phosphorylation in vitro, but had insignificant efficacy in vivo. NVS-PAK1-1, a PAK1 selective inhibitor, had a greater but still minimal effect on our GEMM phenotype. However, genetic ablation of Pak1 but not Pak2 reduced tumor formation in our NF2 GEMM. Moreover, germline genetic deletion of Pak1 was well tolerated, while conditional deletion of Pak2 in Schwann cells resulted in significant morbidity and mortality. These data support the further development of PAK1-specific small molecule inhibitors and the therapeutic targeting of PAK1 in vestibular schwannomas and argue against PAK1 and PAK2 existing as functionally redundant protein isoforms in Schwann cells.

Atlantic bluefin tuna (ABT, Thunnus thynnus; Linneaus, 1758) is an ecologically important apex-predator with high commercial value. They were once common off the coast of the United Kingdom (UK), before disappearing in the 1960s. In regions lacking commercial fisheries for ABT, such as the UK and Ireland, spatial data can be scarce. In these cases, sightings and bycatch databases can offset information shortfalls. Here, we document the reappearance of ABT into territorial waters of the UK from 2014 onwards, and increased occurrence off Ireland. We analyse a novel, multi-source dataset comprising occurrence data (2008–2019; 989 sightings and 114 tonnes of bycatch) compiled from a range of sources (scientific surveys, ecotours and fisheries). We show an increasing trend in effort-corrected ABT occurrence in (i) the pelagic ecosystem survey in the western English Channel and Celtic Sea (PELTIC), (ii) an ecotour operator, and (iii) the Irish albacore fishery in on-shelf and off-shelf waters. Sightings of ABT by the PELTIC correlated with modelled abundance estimates of ABT and the Atlantic multidecadal oscillation. These data demonstrate that sightings of ABT have increased off the UK and Ireland since 2014, following the same increasing trend (2010 onwards) as the eastern ABT population.

Introduction United States Air Force Academy (USAFA) cadets are at risk for sustaining concussions; however, several factors inhibit disclosure. We aimed to better understand the role of social support in concussion disclosure. Methods and Materials We used a mixed methods approach with an electronic survey and interviews. The survey used a 9-point Likert scale (1 = strongly disagree and 9 = strongly agree) to assess concussion disclosure. Survey items asked cadets whom they felt most comfortable disclosing a concussion or bell-ringer/ding to, how quickly they would seek medical attention for a suspected concussion or bell-ringer/ding, whether cadets would be generally supportive/unsupportive of another cadet disclosing a concussion to medical staff, and whether other cadets important to them would be generally supportive/unsupportive if they reported a concussion to medical staff. Two multivariate linear regressions, one for concussion and one for bell-ringers/dings, were calculated to determine whether cadet choice of the person they felt most comfortable disclosing a concussion or bell-ringer/ding to predicted whether they would immediately seek medical attention for either condition. Choice of person included Air Officer Commanding (AOC)/Academy Military Trainer (AMT), upper classmen, cadet who had recovered from a concussion, cadet, closest friend, teammate, and squadmate. Descriptive analyses assessed whether cadets felt supported or unsupported by other cadets and by those who were important to them concerning concussion reporting. Thirty-four semi-structured interviews were conducted with cadets to explore their views on concussion disclosure. Results Increased comfort with disclosing a suspected concussion to an AOC/AMT had higher agreement seeking medical attention (β = 0.28, P Conclusions Our results suggested that cadets felt comfortable reporting a suspected concussion or bell-ringer/ding to various peers and that those peers would be supportive of that choice, indicating social support. Future interventions should include educating cadets that peers may come to them, especially if they are AOCs/AMTs or squadmates.

Motivation A fundamental problem for disease treatment is that while antibiotics are a powerful counter to bacteria, they are ineffective against viruses. Often, bacterial and viral infections are confused due to their similar symptoms and lack of rapid diagnostics. With many clinicians relying primarily on symptoms for diagnosis, overuse and misuse of modern antibiotics are rife, contributing to the growing pool of antibiotic resistance. To ensure an individual receives optimal treatment given their disease state and to reduce over-prescription of antibiotics, the host response can in theory be measured quickly to distinguish between the two states. To establish a predictive biomarker panel of disease state (viral/bacterial/no-infection), we conducted a meta-analysis of human blood infection studies using machine learning. Results We focused on publicly available gene expression data from two widely used platforms, Affymetrix and Illumina microarrays as they represented a significant proportion of the available data. We were able to develop multi-class models with high accuracies with our best model predicting 93% of bacterial and 89% viral samples correctly. To compare the selected features in each of the different technologies, we reverse-engineered the underlying molecular regulatory network and explored the neighbourhood of the selected features. The networks highlighted that although on the gene-level the models differed, they contained genes from the same areas of the network. Specifically, this convergence was to pathways including the Type I interferon Signalling Pathway, Chemotaxis, Apoptotic Processes and Inflammatory/Innate Response. Availability Data and code are available on the Gene Expression Omnibus and github. Supplementary information Supplementary data are available at Bioinformatics online.

Objectives Daily driving of diesel-powered tractors has been linked to increased lung cancer risk in farmers, yet few studies have quantified exposure levels to diesel exhaust during tractor driving or during other farm activities. We expanded an earlier task-based descriptive investigation of factors associated with real-time exposure levels to black carbon (BC, a surrogate of diesel exhaust) in Iowa farmers by increasing the sample size, collecting repeated measurements, and applying statistical models adapted to continuous measurements. Methods The expanded study added 43 days of sampling, for a total of 63 sample days conducted in 2015 and 2016 on 31 Iowa farmers. Real-time, continuous monitoring (30-s intervals) of personal BC concentrations was performed using a MicroAeth AE51 microaethelometer affixed with a micro-cyclone. A field researcher recorded information on tasks, fuel type, farmer location, and proximity to burning biomass. We evaluated the influence of these variables on log-transformed BC concentrations using a linear mixed-effect model with random effects for farmer and day and a first-order autoregressive structure for within-day correlation. Results Proximity to diesel-powered equipment was observed for 42.5% of the overall sampling time and on 61 of the 63 sample days. Predicted geometric mean BC concentrations were highest during grain bin work, loading, and harvesting, and lower for soil preparation and planting. A 68% increase in BC concentrations was predicted for close proximity to a diesel-powered vehicle, relative to far proximity, while BC concentrations were 44% higher in diesel vehicles with open cabins compared with closed cabins. Task, farmer location, fuel type, and proximity to burning biomass explained 8% of within-day variance in BC concentrations, 2% of between-day variance, and no between-farmer variance. Conclusion Our findings showed that farmers worked frequently near diesel equipment and that BC concentrations varied between tasks and by fuel type, farmer location, and proximity to burning biomass. These results could support the development of exposure models applicable to investigations of health effects in farmers associated with exposure to diesel engine exhaust.

Introduction The ROSA (Robotic Surgical Assistant) is designed to assist orthopaedic surgeons performing total knee arthroplasty (TKA). It is postulated that the real-time data provided by the ROSA robot aids the surgeon by providing objective values to bone resections and soft tissue balance, enabling better implant selection and positioning. This is thought to improve patient outcomes through reduced post-operative pain, reduced hospital stays and reduced revision rate. To date, the ROSA robot has solely been implemented in tertiary centres in the UK. This study investigates the implementation of the ROSA robot in a district general hospital (DGH) in a geographically isolated region of the UK. Method The ROSA robot was installed in St. Michael’s Hospital, Cornwall in July 2021. Prior to its clinical deployment, six surgeons undertook saw bone training. Following this, six ROSA-assisted TKAs were performed in six weeks between July and August 2021. Logistical challenges to implementation included difficulty in ROSA component delivery given geographical isolation, consultant training time dedicated to ROSA operation in the context of a busy DGH trauma rota and increased operative time during the learning curve. Conclusions Despite the challenges faced, we have demonstrated that ROSA can be implemented in a rural, geographically distanced DGH. Given the use of robotic assistance in other surgical specialties, this is an exciting prospect for elective knee surgery in the future.

Several hundred specimens of the crab Dakoticancer overanusRathbun, 1917 represent a normal size-distributed adult population, with a skewed sex ratio of 21% females to 79% males. Sexual dimorphism is clearly developed in the shape of the sternum and pleon as well as overall carapace size. The Dakoticancer Assemblage displays a variety of intersex conditions, including gonopores (vulvae) on the coxa of the fourth pereiopod and female spermatheca associated with male sternal morphology. Gonopores on the coxae of the fourth pereiopods have been reported for shrimps, clawed lobsters, and palinurid lobsters, but not for brachyurans. Understanding the occurrence of intersex specimens within an extinct species of an extinct section is extremely difficult, as there seem to be no modern analogs concerning gonopores on the fourth pereiopod in Brachyura. The low percentage of affected individuals, about 1%, suggests developmental or genetic conditions were most likely responsible for the intersex individuals. The absence of such individuals in another large collection of a species of the same genus, of more or less the same geologic age, suggests that the factors leading to intersexuality in the Dakoticancer overanus population were endemic to that population.

Background Patients with IBD have increased risk for developing colorectal cancer (CRC), with poorer survival, compared to those without IBD. Despite surveillance colonoscopy, IBD post-colonoscopy CRC (PCCRC) rates are unacceptably high at 28-45%. We define surveillance colonoscopy quality, IBD-dysplasia and IBD-CRC prevalence, IBD-CRC characteristics, and IBD PCCRC rates at a tertiary IBD centre. Methods The GI Reporting Tool (Unisoft Medical Systems) was searched for IBD surveillance colonoscopy reports from April 2008–December 2018. Electronic medical records were reviewed. IBD phenotype and diagnosis date was confirmed on the Lothian IBD Registry. Follow-up was until September 2022. Results 1892 colonoscopies from 1262 patients were included. Median follow-up was 7.1 (4.4, 9.5) years. 885/1262 (70.1%) had UC, 344/1262 (27.3%) had Crohn’s, and 33/1262 (2.6%) had IBD-U. Median disease duration at colonoscopy was 16.8 (11, 24.6) years. 1825/1892 (96.5%) colonoscopies achieved caecal intubation, 1735/1840 (94.3%) adhered to biopsy guidelines and 704/1892 (37%) used chromoendoscopy. Histological inflammation was identified in 873/1823 (47.9%) cases; 57.2% in the right colon. Bowel preparation was poor in 194/1892 (10.3%) procedures and the most documented reason for not performing chromoendoscopy. Poor bowel preparation was associated with 23/60 (38.3%) poorly tolerated and 29/52 (55.8%) incomplete colonoscopies. Moviprep was superior to Picolax (p Dysplasia was identified in 145/1892 (7.7%) colonoscopies: 84/1892 (4.4%) sporadic, 22/1892 (1.2%) IBD-associated, and 39/1892 (2.1%) unspecified. IBD-CRC is rare, at 0.8 cases per 1000 patient years. Within the study period, 20/1262 (1.6%) patients had CRC diagnosed. 17/20 (85%) had UC and 3/20 (15%) had Crohn’s. 15/17 (88%) UC patients had E3 disease. 11/20 (55%) presented with lymph node or distant metastasis. 8/20 (40%) tumours had mucinous differentiation; only 1/15 (6.7%) was well differentiated. IBD-CRC patients had longer disease duration (28.3 (19.7, 37.8) years) compared to patients without CRC (22.25 (16.42, 29.85) years) at follow-up (p=0.028). The 3-year PCCRC rate was 15%. Conclusion IBD-CRC is rare however IBD PCCRC rates are unacceptably high. While this may reflect disease biology, a new approach to IBD surveillance is urgently needed. Interventions could include dedicated IBD surveillance lists, patient education around bowel preparation, and pre-screening for inflammation (e.g. faecal calprotectin). Cancer registry database linkage is now essential for us to identify IBD-CRC cases not identified by surveillance.

Background Switching from originator to biosimilar infliximab (IFX) is effective and safe. However, data on multiple switching are scarce. The Edinburgh IBD unit has undertaken three switch programmes: (1) Remicade to CT-P13 (2016), (2) CT-P13 to SB2 (2020), and (3) SB2 to CT-P13 (2021). The primary endpoint of this study was to assess CT-P13 persistence following switch from SB2. Secondary endpoints included persistence stratified by the number of biosimilar switches (single, double and triple), effectiveness and safety. Methods We performed a prospective, observational, cohort study. All adult IBD patients on IFX biosimilar SB2 underwent an elective switch to CT-P13. Patients were reviewed in a virtual biologic clinic with protocol driven collection of clinical disease activity, CRP, faecal calprotectin (FC), IFX trough / antibody levels, and drug survival. Results 297 patients (CD n=196 [66%], UC/IBDU n=101, [34%]) were switched. This was the third, second and first IFX switch for 67 /297 (22.5%), 138 /297 (46.5%) and 92 /297 (31%) of the cohort respectively. Patients who underwent multiple IFX biosimilar switches had longer disease duration (p=0.0001) and IFX duration (p=0.0001) and were less often on combination therapy with an immunomodulator (p=0.0001). 90.6% of patients remained on IFX during a median follow-up of 7.5 months [6.8-8.1] (figure 1). The number of switches was not independently associated with IFX persistence after adjusting for confounders (table 1). Clinical (p=0.77), biochemical (CRP ≤5mg/mL; p=0.75) and faecal biomarker (FC Conclusion Multiple successive switches from IFX originator to biosimilars are effective and safe in patients with IBD, irrespective of the number of IFX switches.

Background Peri-anal Crohn’s disease (pCD) significantly affects quality of life in patients with CD. The natural history of pCD in the era of biologic therapy is poorly understood. Perianal surgery includes examination under anaesthesia (EUA), drainage of peri-anal sepsis, seton instertion and fistula manipulation. EUA forms part of the standard of care at diagnosis of pCD and therefore can be used as a proxy for incidence of pCD. Methods CD patients were identified from the Lothian IBD registry, a physician validated registry of all IBD cases within Lothian which has been shown to be 94.3% complete. Prospectively collected coding data was used to identify peri-anal surgery, which was validated by review of the electronic health record. Biologic prescription data was extracted from the Lothian biologics database; a physician validated, prospectively collected registry. Time trend analysis was performed for the period 2000 to 2017 by 1) calculating annual incidence rates of peri-anal interventions for all patients with CD and estimating annual percentage change and 2) by calculating cumulative incidence of pCD and biologic prescription in newly diagnosed CD and 3) stratifying by era of diagnosis (Cohort 1: 2000–2008 and Cohort 2: 2009–2017. Results 2937 patients with CD were identified in the study period, with 1108 operations for pCD performed on 381 patients. Rates of surgery fell from 5.1 to 2.0 operations per 100 CD patients per year between 2000 and 2017 (p 1753 new diagnoses of CD were made of whom 247 developed pCD. 5 year risk of pCD was 12.8% (9.5–16.6%) with no significant difference identified between cohort 1 (11.5%) and cohort 2 (13.8%) (p=0.116) (fig 2). The 5 year incidence of biologic prescription for patients with pCD increased from 11.2% in cohort 1 to 58.1% in cohort 2 (p Figure 1: Number of peri-anal interventions per 100 CD patients per year (multiple procedures per patient included). Figure 2: Kaplan Meier curves showing cumulative incidence of pCD stratified by era of diagnosis. Figure 3: Kaplan Meier curves showing cumulative incidence of biologic prescription in patients with CD stratified by era of diagnosis and presence of pCD. Conclusion The incidence of pCD remains unchanged over time. Although we cannot ascribe causality, the overall decrease in surgery for pCD has been paralleled by a marked increase in the use of biologic medication.

Background Considering nearly two-thirds of preschool children in the United States are in some form of child care, child care settings are an opportunity to improve the food environments and reduce the risk of obesity in young children. University of Minnesota Extension developed a culinary nutrition education training for family child care providers. This is relevant for other countries whose child care system includes caring for children in home or center settings that prepare food for children. Objectives Start Strong: Cooking, Feeding and More (SS), consists of four two-hour culinary nutrition education sessions for family providers. The overall goals of SS are to 1) increase providers' knowledge and skills to procure and prepare healthy foods for children and 2) increase providers' knowledge and understanding of Federal food assistance programs to share the information with food-insecure families. Each session includes a cooking skill, nutrition topic, and food assistance program. Results Twelve rural participants who self-identified as female, non-Hispanic White participated in the SS sessions and completed pre, post, and three-month follow-up surveys, to assess the impact of the program on providers' knowledge, confidence, and practice. Based on the paired samples t-tests between pre-to-post and pre-to-follow-up surveys, there were statistically significant increases in providers' confidence in preparing whole grains, using beans and low-cost protein sources, and cooking techniques to reduce. The increase in confidence using cooking techniques to reduce salt was still statistically significant three months after the training. The providers' awareness of Federal food programs between pre-post increased and three months later increased. Conclusions SS increased family child care providers' skills and confidence to prepare healthy foods for children in their care. This increases the likelihood children will make healthy choices now and in the future. Key messages Start Strong is a culinary nutrition education training for family child care providers. Start Strong improves providers’ knowledge and skills to prepare healthy foods for children in their care.

Evidence indicates that common variants found in genome-wide association studies increase risk of disease through gene regulation via expression Quantitative Trait Loci. Using multiple genome-wide methods, we examined if Single Nucleotide Polymorphisms increase risk of Amyotrophic Lateral Sclerosis through expression Quantitative Trait Loci, and whether expression Quantitative Trait Loci expression is consistent across people who had Amyotrophic Lateral Sclerosis and those who did not. In combining public expression Quantitative Trait Loci data with Amyotrophic Lateral Sclerosis genome-wide association studies, we used Summary-data-based Mendelian Randomization to confirm that SCFD1 was the only gene that was genome-wide significant in mediating Amyotrophic Lateral Sclerosis risk via expression Quantitative Trait Loci (Summary-data-based Mendelian Randomization beta = 0.20, standard error = 0.04, P-value = 4.29 × 10−6). Using post-mortem motor cortex, we tested whether expression Quantitative Trait Loci showed significant differences in expression between Amyotrophic Lateral Sclerosis (n = 76) and controls (n = 25), genome-wide. Of 20 757 genes analysed, the two most significant expression Quantitative Trait Loci to show differential in expression between Amyotrophic Lateral Sclerosis and controls involve two known Amyotrophic Lateral Sclerosis genes (SCFD1 and VCP). Cis-acting SCFD1 expression Quantitative Trait Loci downstream of the gene showed significant differences in expression between Amyotrophic Lateral Sclerosis and controls (top expression Quantitative Trait Loci beta = 0.34, standard error = 0.063, P-value = 4.54 × 10−7). These SCFD1 expression Quantitative Trait Loci also significantly modified Amyotrophic Lateral Sclerosis survival (number of samples = 4265, hazard ratio = 1.11, 95% confidence interval = 1.05–1.17, P-value = 2.06 × 10−4) and act as an Amyotrophic Lateral Sclerosis trans-expression Quantitative Trait Loci hotspot for a wider network of genes enriched for SCFD1 function and Amyotrophic Lateral Sclerosis pathways. Using gene-set analyses, we found the genes that correlate with this trans-expression Quantitative Trait Loci hotspot significantly increase risk of Amyotrophic Lateral Sclerosis (beta = 0.247, standard deviation = 0.017, P = 0.001) and schizophrenia (beta = 0.263, standard deviation = 0.008, P-value = 1.18 × 10−5), a disease that genetically correlates with Amyotrophic Lateral Sclerosis. In summary, SCFD1 expression Quantitative Trait Loci are a major factor in Amyotrophic Lateral Sclerosis, not only influencing disease risk but are differentially expressed in post-mortem Amyotrophic Lateral Sclerosis. SCFD1 expression Quantitative Trait Loci show distinct expression profiles in Amyotrophic Lateral Sclerosis that correlate with a wider network of genes that also confer risk of the disease and modify the disease’s duration., Previous research indicates DNA variants that increase risk of Amyotrophic Lateral Sclerosis (ALS) correlate with SCFD1 RNA activity. Iacoangeli et al. report that SCFD1 RNA and DNA variants are differentially active in ALS, which not only increases risk of the disease but modifies its duration, confirming their involvement in ALS., Graphical Abstract Graphical Abstract

Background Natriuretic peptide (NP) testing is recommended by both the European Society of Cardiology (ESC) and the National Institute for Health and Care Excellence (NICE) for people presenting with symptoms of heart failure (HF) in primary care. However, ESC and NICE guidelines suggest different NP referral thresholds: ESC recommend referral at a lower NP level (BNP≥35pg/ml / NT-proBNP≥125pg/ml) compared to NICE (BNP≥100pg/ml/NT-proBNP≥400pg/ml). Purpose We aimed to evaluate NP test performance for HF diagnosis for ESC and NICE guideline-defined thresholds. Methods Population-based cohort study using linked primary and secondary care data from the Clinical Practice Research Datalink in England between 1st January 2000 and 31st December 2018. Participants were adults aged 45 years and above with a NP result: 74,233 had a BNP and 155,347 had a NT-proBNP measurement. The main outcome measures were diagnostic performance of NP test (sensitivity, specificity, positive predictive value, negative predictive value) by threshold. Results A total of 229,580 patients had a NP test and 21,102 (9.2%) were diagnosed with HF. The ESC NT-proBNP threshold of 125pg/ml had a sensitivity of 94.6% (94.2 to 95.0) and specificity of 50.0% (49.7 to 50.3) compared to sensitivity of 81.7% (81.0 to 82.3) and specificity of 80.3% (80.0 to 80.5) for the NICE NT-proBNP 400pg/ml threshold. For both guidelines, nearly all patients with a NP level below the threshold did not have HF (negative predictive value ESC 98.9% (98.8 to 99.0) and NICE 97.7% (97.6 to 97.8). Similar performance was found for BNP. Conclusions The performance of NP testing is dependent on the guideline-specified threshold for referral. In 100 people with HF, using the NICE threshold would falsely reassure 18 patients, whereas the lower ESC threshold would miss just 5 people but twice as many patients would be referred for diagnostic assessment. The optimal NP threshold for referral for HF diagnosis will depend on the healthcare setting. The trade-off between missing HF cases and overwhelming diagnostic services needs to be determined at a national level. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Institute for Health Research

Although the pattern of nodal metastasis and the prognosis of number and location of positive nodes have been well described with esophageal cancer undergoing upfront surgery, little is known about nodal metastasis after neoadjuvant treatment. The aim of this study is to assess the pattern of nodal metastases in esophageal adenocarcinoma treated with neoadjuvant chemoradiation and surgery and evaluate its effect on prognosis. Methods All patients with esophageal adenocarcinoma who had undergone neoadjuvant chemoradiation and an R0 esophagectomy between 2010 and 2018 at our institution were included (n = 577). Pathology reports were reviewed for sites of lymph node metastases. Patients were excluded if nodal stations were not listed separately (n = 40). Age, sex, race, tumor location, TRG, pT stage, number of positive lymph nodes, number of positive nodal stations, and specific nodal stations were analyzed for risk of recurrence using univariable Cox regression, and significant covariates were included in multivariable Cox regression model. Results Of 537 patients, 193(36%) had pathologic nodal metastases. 153 patients(28%) had single-station disease: 135(88%) at the paraesophageal station, 16(10%) at the left gastric, 1 at the subcarinal and 1 at the paratracheal station(0.65% each). 32 patients(6.0%) had two-station and 8(1.5%) had three-station disease. The majority of patients with multiple positive nodal stations had positive nodes in the paraesophageal(90%) and/or left gastric artery stations(60%). On multivariable analysis, the number of positive nodal stations (HR 1.59, CI 1.35–1.84, p Conclusion Patients who have undergone neoadjuvant and R0 esophagectomy for adenocarcinoma often have lymph node metastases at time of surgery, most commonly at the paraesophageal station. The number of nodal stations, along with subcarinal and paraesophageal metastases, were associated with increased risk of recurrence.

Introduction COVID-19 resulted in Regional tiered restrictions being introduced across the UK with subsequent implications for planned and emergency care. Specific to Merseyside Tier 4 and Tier 2 restrictions were introduced in late 2020. At the onset of the pandemic in the Spring, elective work ceased, and emergency admissions were minimal. The purpose of this study was to examine the volume and nature of all emergency admissions to a Urology unit in Merseyside in the 2nd wave of the pandemic during two different tiers of national restrictions. Method A prospective audit examining all emergency urological activity was conducted in Whiston Hospital from October 2020 when the Tier 4 restrictions were introduced to Tier 2 was introduced. Data was obtained by identifying patients using the electronic theatre listing system. Results A total of 52 emergency cases were performed (24 in November Tier 4, 28 in December Tier 2). A total of 12 different procedures were performed. The commonest procedure performed was stent insertion (26), followed by scrotal exploration (7). One patient required transfer to a different hospital. In total 4 calls were made by general surgery and 2 by gynaecology for urological assistance in theatre. Two urology patients returned to theatre. Direct Consultant involvement occurred in 19 cases (37%). Conclusions Unlike the Spring lockdown acute urology operations presented despite regional restrictions. A total of 52 cases were performed with more occurring in Tier 2. Stent insertion was the commonest procedure with the majority of the cases performed by registrars.

Background Robust COVID-19 vaccine-induced antibody (Ab) responses are important for protective anti-viral immunity. Data are urgently needed to determine whether vaccine-induced immunity is impacted by commonly used immunosuppressive drug regimens in IBD. Methods We prospectively recruited 447 adults (90 healthy controls and 357 IBD) at nine UK centres. The IBD study population was established (>12 weeks therapy) on either thiopurine monotherapy (n=78), infliximab (IFX) monotherapy (n=61), thiopurine & IFX combination therapy (n=70), ustekinumab (uste) monotherapy (n=56), vedolizumab (vedo) monotherapy (n=62) or tofacitinib (tofa) monotherapy (n=30). Participants had two doses of either ChAdOx1 nCoV-19, BNT162b2 or mRNA1273 vaccines. The primary outcome was anti-SARS-CoV-2 spike (S1 RBD) Ab concentrations, measured using the Elecsys anti-SARS-CoV-2 spike (S) Ab assay, 53–92 days after second vaccine dose, in participants without prior infection, adjusted by age & vaccine type. Secondary outcomes included proportions failing to generate protective Ab responses (defined cut-off anti-S concentration 15U/mL, which correlated with 20% viral neutralization). Results Geometric mean S Ab concentrations (figure 1) were lower in patients treated with IFX (153U/mL;p Conclusion COVID-19 vaccine-induced Ab responses are significantly reduced in patients treated with IFX, or tofa, and to a lesser extent with uste. No significant reduction was seen in vedo or thiopurine monotherapy-treated patients. Our data suggest that 3rd primary or booster vaccine doses for IBD patients might be tailored to an individual’s immunosuppressive treatment. Financial support was provided as a Research Grant by Pfizer Ltd.

We study the sources of racial disparities in income using anonymized longitudinal data covering nearly the entire U.S. population from 1989 to 2015. We document three results. First, black Americans and American Indians have much lower rates of upward mobility and higher rates of downward mobility than whites, leading to persistent disparities across generations. Conditional on parent income, the black-white income gap is driven by differences in wages and employment rates between black and white men; there are no such differences between black and white women. Hispanic Americans have rates of intergenerational mobility more similar to whites than blacks, leading the Hispanic-white income gap to shrink across generations. Second, differences in parental marital status, education, and wealth explain little of the black-white income gap conditional on parent income. Third, the black-white gap persists even among boys who grow up in the same neighborhood. Controlling for parental income, black boys have lower incomes in adulthood than white boys in 99% of Census tracts. The few areas with small black-white gaps tend to be low-poverty neighborhoods with low levels of racial bias among whites and high rates of father presence among blacks. Black males who move to such neighborhoods earlier in childhood have significantly better outcomes. However, less than 5% of black children grow up in such areas. Our findings suggest that reducing the black-white income gap will require efforts whose impacts cross neighborhood and class lines and increase upward mobility specifically for black men.

In these studies we identified and compared the properties of plant species that showed positive or negative co-occurrence with selenium (Se) hyperaccumulators in their natural habitat. The main questions addressed were: which species are most abundant directly adjacent to hyperaccumulators, and which are absent? How do Se accumulation and tolerance compare in species found to positively or negatively co-occur with hyperaccumulators? Approaches included field surveys, X-ray microprobe analysis of field samples, and a lab Se tolerance and accumulation study. When 54 hyperaccumulators across two naturally seleniferous sites were surveyed for their five nearest neighboring species, and the relative abundance of these species around hyperaccumulators compared to that in the overall vegetation, some species were identified to positively or negatively co-occur with hyperaccumulators. Several positively co-occurring species showed high Se accumulation capability (up to 900 mg Se per kg dry weight), which may reflect Se tolerance. Leaf X-ray microprobe analysis found relatively more organic forms of Se in two positively co-occurring species than in a negatively co-occurring one. There were elevated soil Se levels around Se hyperaccumulators, and neighbors of Se hyperaccumulators had a higher tissue Se concentration as compared to when the same species grew elsewhere in the area. The elevated soil Se levels around Se hyperaccumulators – likely resulting from litter deposition- may significantly affect the local plant community, facilitating Se-tolerant plant community members but lowering the fitness of Se-sensitive members.

Aim Remnant cholesterol has been proposed to promote atherosclerotic cardiovascular disease independent of low-density lipoprotein cholesterol, yet the underlying mechanisms are not well understood. We aimed to study the association of remnant cholesterol with coronary atheroma progression and clinical events. Methods We analyzed data from 5754 patients with coronary artery disease undergoing serial intravascular ultrasonography who were enrolled in 10 trials examining various medical therapies. Remnant cholesterol was calculated as (non-high-density lipoprotein cholesterol – low-density lipoprotein cholesterol (estimated using the Hopkins–Martin equation)). Changes in percentage atheroma volume and 2-year major adverse cardiovascular events were compared across various levels of remnant cholesterol, and multivariable models were used to assess the independent relationship of remnant cholesterol with changes in percentage atheroma volume. Results The mean age was 58.1 ± 9.2 years, 28% were women and 96% received a statin. Percentage atheroma volume progression (changes in percentage atheroma volume > 0) occurred in a linear fashion at on-treatment remnant cholesterol levels of 25 mg/dL or greater. The highest on-treatment remnant cholesterol quartile demonstrated greater percentage atheroma volume progression (+0.53 ± 0.26 vs. –0.15 ± 0.25%, P Conclusions In statin-treated patients with atherosclerotic cardiovascular disease, remnant cholesterol was associated with coronary atheroma progression regardless of conventional lipid parameters, C-reactive protein or clinical risk factors. Higher remnant cholesterol levels also correlated with higher major adverse cardiovascular events. These data support further investigations into remnant cholesterol-lowering interventions in statin-treated patients harboring residual atherosclerotic cardiovascular disease risk.

Phylogenetic trees and data are often stored in incompatible and inconsistent formats. The outputs of software tools that contain trees with analysis findings are often not compatible with each other, making it hard to integrate the results of different analyses in a comparative study. The treeio package is designed to connect phylogenetic tree input and output. It supports extracting phylogenetic trees as well as the outputs of commonly used analytical software. It can link external data to phylogenies and merge tree data obtained from different sources, enabling analyses of phylogeny-associated data from different disciplines in an evolutionary context. Treeio also supports export of a phylogenetic tree with heterogeneous-associated data to a single tree file, including BEAST compatible NEXUS and jtree formats; these facilitate data sharing as well as file format conversion for downstream analysis. The treeio package is designed to work with the tidytree and ggtree packages. Tree data can be processed using the tidy interface with tidytree and visualized by ggtree. The treeio package is released within the Bioconductor and rOpenSci projects. It is available at https://www.bioconductor.org/packages/treeio/.

Background Ambient air pollution is a modifiable risk factor for cardiovascular disease, yet uncertainty remains about the size of risks at lower levels of fine particulate matter (PM2.5) exposure which now occur in the USA and elsewhere. Methods We investigated the relationship of ambient PM2.5 exposure with cause-specific cardiovascular disease mortality in 565 477 men and women, aged 50 to 71 years, from the National Institutes of Health-AARP Diet and Health Study. During 7.5 x 106 person-years of follow up, 41 286 cardiovascular disease deaths, including 23 328 ischaemic heart disease (IHD) and 5894 stroke deaths, were ascertained using the National Death Index. PM2.5 was estimated using a hybrid land use regression (LUR) geostatistical model. Multivariate Cox regression models were used to estimate relative risks (RRs) and 95% confidence intervals (CI). Results Each increase of 10 μg/m3 PM2.5 (overall range, 2.9–28.0 μg/m3) was associated, in fully adjusted models, with a 16% increase in mortality from ischaemic heart disease [hazard ratio (HR) 1.16; 95% CI 1.09-1.22] and a 14% increase in mortality from stroke (HR 1.14; CI 1.02-1.27). Compared with PM2.5 exposure Conclusions Long-term exposure to fine particulate air pollution is associated with ischaemic heart disease and stroke mortality, with excess risks occurring in the range of and below the present US long-term standard for ambient exposure to PM2.5 (12 µg/m3), indicating the need for continued improvements in air pollution abatement for CVD prevention.

Rice accumulates arsenic, an established lung toxicant. Little is known about the association of rice consumption with arsenic-related health effects, particularly interstitial lung disease. Between 2000 and 2002, 6,814 white, black, Hispanic, and Chinese adults from 6 US cities were enrolled in the Multi-Ethnic Study of Atherosclerosis. We included 2,250 participants who had spirometry data, 2,557 with full-lung computed tomography (CT) scans, and 5,710 with cardiac CT scans. Rice consumption and 310 participants with urinary arsenic were assessed at baseline. Spirometry and full-lung CT-derived measures of total lung capacity and high attenuation area (HAA), and interstitial lung abnormalities were measured at examination 5. Cardiac CT-derived HAA was measured at 1–3 visits. Twelve percent of participants reported eating at least 1 serving of rice daily. Comparing data between that group with those who ate less than 1 serving weekly, the mean difference for forced vital capacity was −102 (95% confidence interval (CI): −198, −7) mL, and for forced expiratory volume in 1 second was −90 (95% CI: −170, −11) mL after adjustment for demographics, anthropometrics, dietary factors, and smoking. The cross-sectional adjusted percent difference for total lung capacity was −1.33% (95% CI: −4.29, 1.72) and for cardiac-based HAA was 3.66% (95% CI: 1.22, 6.15). Sensitivity analyses for urinary arsenic were consistent with rice findings. Daily rice consumption was associated with reduced lung function and greater cardiac-based HAA.

The eastern oyster, Crassostrea virginica, forms reefs that provide critical services to the surrounding ecosystem. These reefs are at risk from climate change, in part because altered rainfall patterns may amplify local fluctuations in salinity, impacting oyster recruitment, survival, and growth. As in other marine organisms, warming water temperatures might interact with these changes in salinity to synergistically influence oyster physiology. In this study, we used comparative transcriptomics, measurements of physiology, and a field assessment to investigate what phenotypic changes C. virginica uses to cope with combined temperature and salinity stress in the Gulf of Mexico. Oysters from a historically low salinity site (Sister Lake, LA) were exposed to fully crossed temperature (20°C and 30°C) and salinity (25, 15, and 7 PSU) treatments. Using comparative transcriptomics on oyster gill tissue, we identified a greater number of genes that were differentially expressed (DE) in response to low salinity at warmer temperatures. Functional enrichment analysis showed low overlap between genes DE in response to thermal stress compared with hypoosmotic stress and identified enrichment for gene ontologies associated with cell adhesion, transmembrane transport, and microtubule-based process. Experiments also showed that oysters changed their physiology at elevated temperatures and lowered salinity, with significantly increased respiration rates between 20°C and 30°C. However, despite the higher energetic demands, oysters did not increase their feeding rate. To investigate transcriptional differences between populations in situ, we collected gill tissue from three locations and two time points across the Louisiana Gulf coast and used quantitative PCR to measure the expression levels of seven target genes. We found an upregulation of genes that function in osmolyte transport, oxidative stress mediation, apoptosis, and protein synthesis at our low salinity site and sampling time point. In summary, oysters altered their phenotype more in response to low salinity at higher temperatures as evidenced by a higher number of DE genes during laboratory exposure, increased respiration (higher energetic demands), and in situ differential expression by season and location. These synergistic effects of hypoosmotic stress and increased temperature suggest that climate change will exacerbate the negative effects of low salinity exposure on eastern oysters.

Introduction Nutritional management of children with epidermolysis bullosa (EB) presents multiple challenges including reduced oral intake and mucosal fragility. Laparoscopic-assisted gastrostomy (LAG) tube feeding is effective in improving nutritional status. We aim to review the effectiveness and morbidity of our minimally invasive laparoscopic-assisted approach in EB patients. Method A retrospective, observational cohort study was conducted on all EB patients who underwent LAG tube insertion between 2009 and 2019. Patient demographics, admission details and 12-month clinical outcomes were reported. Results 31 EB patients underwent LAG placement. Median age at insertion was 7.2 (IQR ± 6.5) years, with 8 (25.8%) and 3 (9.7%) of patients requiring oesophageal dilatation and fundoplication, respectively. 71.4% patients experienced minor complications including: overgranulation (35.7%), gastrostomy infection (32.1%), pain (21.4%), mild gastrostomy leakage (17.9%), blockage (10.7%) and late displacement (3.6%). 6 patients (21.4%) developed major complications with extensive gastrostomy site leakage. Only one patient required laparoscopic refashioning for stoma prolapse six years post-insertion. No cases of gastrostomy-related mortality were recorded and an improvement in both mean weight and height Z-scores was observed. Conclusions LAG is well-tolerated in EB patients with improvements in growth and minimal morbidity 12-months post-gastrostomy insertion. An extended follow-up period is required to ascertain long-term impacts of gastrostomy feeding.

Di(2-ethylhexyl) phthalate (DEHP) is a type of phthalate plasticizer found in a variety of consumer products and poses a public health concern due to its metabolic and endocrine disruption activities. Dysregulation of epigenetic modifications, including DNA methylation, has been shown to be an important mechanism for the pathogenic effects of prenatal exposures, including phthalates. In this study, we used an established mouse model to study the effect of perinatal DEHP exposure on the DNA methylation profile in liver (a primary target tissue of DEHP) and blood (a common surrogate tissue) of both juvenile and adult mice. Despite exposure ceasing at 3 weeks of age (PND21), we identified thousands of sex-specific differential DNA methylation events in 5-month old mice, more than identified at PND21, both in blood and liver. Only a small number of these differentially methylated cytosines (DMCs) overlapped between the time points, or between tissues (i.e. liver and blood), indicating blood may not be an appropriate surrogate tissue to estimate the effects of DEHP exposure on liver DNA methylation. We detected sex-specific DMCs common between 3-week and 5-month samples, pointing to specific DNA methylation alterations that are consistent between weanling and adult mice. In summary, this is the first study to assess the genome-wide DNA methylation profiles in liver and blood at two different aged cohorts in response to perinatal DEHP exposure. Our findings cast light on the implications of using surrogate tissue instead of target tissue in human population-based studies and identify epigenetic biomarkers for DEHP exposure.