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Autism spectrum disorder (ASD) is a highly heterogeneous neurodevelopmental disorder characterized by communication and social behavior deficits. The presence of restricted and repetitive behaviors often accompanies these deficits, and these characteristics can range from mild to severe. The past several decades have seen a significant rise in the prevalence of ASD. The etiology of ASD remains unknown; however, genetic and environmental risk factors play a role. Multiple hypotheses converge to suggest that neuroinflammation, or at least the interaction between immune and neural systems, may be involved in the etiology of some ASD cases or groups. Repeated evidence of innate immune dysfunction has been seen in ASD, often associated with worsening behaviors. This evidence includes data from circulating myeloid cells and brain resident macrophages/microglia in both human and animal models. This comprehensive review presents recent findings of innate immune dysfunction in ASD, including aberrant innate cellular function, evidence of neuroinflammation, and microglia activation.

We report two new radio detections of cataclysmic variables (CVs), and place them in context with radio and X-ray detections of other CVs. We detected QS Vir, a low accretion-rate CV; V2400 Oph, a discless intermediate polar; and recovered the polar AM Her in the Very Large Array Sky Survey 2–4 GHz radio images. The radio luminosities of these systems are higher than typically expected from coronal emission from stars of similar spectral types, and neither system is expected to produce jets, leaving the origin of the radio emission a puzzle. The radio emission mechanism for these two CVs may be electron–cyclotron maser emission, synchrotron radiation, or a more exotic process. We compile published radio detections of CVs, and X-ray measurements of these CVs, to illustrate their locations in the radio–X-ray luminosity plane, a diagnostic tool often used for X-ray binaries, active galactic nuclei, and radio stars. Several radio-emitting CVs, including these two newly detected CVs, seem to lie near the principal radio/X-ray track followed by black hole X-ray binaries at low luminosity, suggesting additional complexity in classifying unknown systems using their radio and X-ray luminosities alone.

Diabetes mellitus is a common condition that requires intensive treatment and markedly impacts the welfare of affected cats. The aim of this study was to identify diabetes mellitus-associated perturbations in the feline pancreatic islet microenvironment. The utility of "clear, unobstructed brain/body imaging cocktails and computational analysis" (CUBIC) for three-dimensional pancreatic analysis was investigated.Formalin-fixed paraffin-embedded tissues from cats with diabetes mellitus, or control cats without pancreatic pathology, were retrospectively identified. Immunohistochemistry for synaptophysin and ionised calcium binding adaptor molecule 1, and immunofluorescence for insulin and synaptophysin, were used to assess changes in islets. An image analysis pipeline was developed to analyse images acquired from two-dimensional immunofluorescence. CUBIC was used to optically clear selected pancreas samples before immunofluorescence and deep three-dimensional confocal microscopy.Diabetic cats have a significant reduction in synaptophysin-positive islet area. Whilst islets from diabetic patients have similar numbers of β cells to islets from control cats, significantly lower intensity of insulin expression can be observed in the former. CUBIC facilitates clear visualisation of pancreatic islets in three dimensions.The data presented support the theory that there is a decrease in function of β cells before their destruction, suggesting a potentially significant step in the pathogenesis of feline diabetes mellitus. In parallel, we demonstrate CUBIC as a valuable new tool to visualise the shape of feline pancreatic islets and to interrogate pathology occurring in the islets of diabetic pets.

Senescence is a widely appreciated tumour suppressive mechanism, which acts as a barrier to cancer development by arresting cell cycle progression in response to harmful stimuli. However, senescent cell accumulation becomes deleterious in aging and contributes to a wide range of age-related pathologies. Furthermore, senescence has beneficial roles and is associated with a growing list of normal physiological processes including wound healing and embryonic development. Therefore, the biological role of senescent cells has become increasingly nuanced and complex. The emergence of sophisticated, next-generation profiling technologies, such as single-cell RNA sequencing, has accelerated our understanding of the heterogeneity of senescence, with distinct final cell states emerging within models as well as between cell types and tissues. In order to explore data sets of increasing size and complexity, the senescence field has begun to employ machine learning (ML) methodologies to probe these intricacies. Most notably, ML has been used to aid the classification of cells as senescent, as well as to characterise the final senescence phenotypes. Here, we provide a background to the principles of ML tasks, as well as some of the most commonly used methodologies from both traditional and deep ML. We focus on the application of these within the context of senescence research, by addressing the utility of ML for the analysis of data from different laboratory technologies (microscopy, transcriptomics, proteomics, methylomics), as well as the potential within senolytic drug discovery. Together, we aim to highlight both the progress and potential for the application of ML within senescence research.

Most people are motivated to self-expand, collecting new attributes and experiences in a process that boosts well-being, but people with low self-concept clarity resist it. Perhaps, then, there is a tradeoff between self-expansion and self-concept clarity. Across a 2-week daily dairy, we found no evidence for such a tradeoff—self-expanding was not associated with lower self-concept clarity, either that day, the next day, or the period as a whole. In fact, self-expansion was associated with higher self-concept clarity, but especially for people with lower initial self-concept clarity. Although they were less likely to self-expand on a daily basis, when they did self-expand, they reported higher self-concept clarity and, in turn, greater satisfaction with life. These findings suggest that self-expansion in daily life does not come at the cost of a coherent self-concept and that despite their reluctance, people with lower self-concept clarity may experience associated benefits from self-expanding.

Introduction Laryngopharyngeal reflux (LPR) is difficult to diagnose and treat owing to uncertainty relating to the underlying pathology. The initial management of LPR includes lifestyle modifications and oral medications. In patients who have failed to respond to proton pump inhibitor (PPI) therapy, anti-reflux surgery is considered; laparoscopic fundoplication is the surgery of choice. The primary aim of this review is to identify whether fundoplication is effective in improving signs and symptoms of LPR. The secondary aim is to identify whether patients who have had a poor response to PPIs are likely to have symptom improvement with surgery. The objective of the study is to establish the effect of laparoscopic fundoplication on the reflux symptom index score (RSI). Methods PubMed, Embase, Medline and Cochrane databases were used to search according to the PRISMA guidelines. Original articles assessing the efficacy of fundoplication in relieving symptoms of LPR were included. For each study, the efficacy endpoints and safety outcomes were recorded. Findings Nine studies from 844 initial records met the inclusion criteria: one prospective case control study, one retrospective case–control study, four prospective case series and three retrospective case series involving 287 fundoplications. All nine studies found fundoplication to be effective in improving symptoms of LPR (p Conclusion Current evidence suggests laparoscopic fundoplication is an effective treatment for LPR and should be considered if medical management is unsuccessful.

We present a high time resolution, multi-frequency linear polarization analysis of Very Large Array (VLA) radio observations during some of the brightest radio flaring (~1 Jy) activity of the 2015 outburst of V404 Cygni. The VLA simultaneously captured the radio evolution in two bands (each with two 1 GHz base-bands), recorded at 5/7 GHz and 21/26 GHz, allowing for a broadband polarimetric analysis. Given the source's high flux densities, we were able to measure polarization on timescales of ~13 minutes, constituting one of the highest temporal resolution radio polarimetric studies of a black hole X-ray binary (BHXB) outburst to date. Across all base-bands, we detect variable, weakly linearly polarized emission (, 24 pages, 9 figures, accepted by MNRAS

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Journal of glaciology 40, 1 - 9 (2022). doi:10.1017/jog.2022.40, Over the last 25 years, radiowave detection of neutrino-generated signals, using cold polar ice as the neutrino target, has emerged as perhaps the most promising technique for detection of extragalactic ultra-high energy neutrinos (corresponding to neutrino energies in excess of 0.01 Joules, or $10^{17}$ electron volts). During the summer of 2021 and in tandem with the initial deployment of the Radio Neutrino Observatory in Greenland (RNO-G), we conducted radioglaciological measurements at Summit Station, Greenland to refine our understanding of the ice target. We report the result of one such measurement, the radio-frequency electric field attenuation length $L_\alpha$. We find an approximately linear dependence of $L_\alpha$ on frequency with the best fit of the average field attenuation for the upper 1500 m of ice: $\langle L_\alpha \rangle = \big( (1154 \pm 121) - (0.81 \pm 0.14) (\nu/$MHz$)\big)$ m for frequencies $\nu \in [145 - 350]$ MHz., Published by Soc., Cambridge

Population health management (PHM) dashboards using electronic health record (EHR) data can teach trainees about the population they serve while also delivering data on their clinical practice. Yet, few studies have demonstrated their use. In this pilot study, we assessed baseline resident perceptions of population health metrics for continuity clinic panels by comparing resident estimates with EHR-reported values delivered by individualized PHM dashboards.A descriptive, comparative study was conducted at a primary continuity clinic site for pediatric residents in January 2018. Residents were surveyed about population health metrics for their patient panels, including demographics, utilization, and medical diagnoses. We compared resident estimates to corresponding EHR-reported values using 2-tailed paired t tests.A total of 42 out of 55 eligible residents (76%) completed the survey. Compared with EHR-reported values, residents estimated higher percentages of emergency department utilization (22.1% vs 10.3%, P.01) and morbidity, including medical complexity (15.6% vs 5.9%, P.01), overweight (38.1% vs 11.7%, P.01), obesity (20.5% vs 15.8%, P = .02), and asthma (34.6% vs 21.4%, P.01).In this pilot study of PHM dashboards, resident perceptions of continuity clinic population health metrics did not align with EHR data. Estimates were higher for measures of utilization and morbidity. PHM dashboards may help trainees better understand their patient populations and serve as a consistent source of objective practice data. However, further research and investment is needed to evaluate dashboard implementation and impact on trainee and patient outcomes.

Background Inflammation and increases in inflammatory cytokines are common findings in psychiatric disorders such as schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD). Meta-analyses of studies that measured circulating cytokines have provided evidence of innate inflammation across all three disorders, with some overlap of inflammatory cytokines such as IL-6 and TNF-α. However, differences across disorders were also identified, including increased IL-4 in BD that suggest different immune mechanisms may be involved depending on the type of disorder present. Methods We sought to identify if the presence or absence of an affective disorder in first-episode psychotic (FEP) patients was associated with variations in cytokine production after stimulation of peripheral blood mononuclear cells (PBMC). 98 participants were recruited and grouped into healthy controls (n = 45) and first-episode psychosis patients (n = 53). Psychosis patients were further grouped by presence (AFF; n = 22) or lack (NON; n = 31) of an affective disorder. We cultured isolated PBMC from all participants for 48 h at 37 °C under four separate conditions; (1) culture media alone for baseline, or the following three stimulatory conditions: (2) 25 ng/mL lipopolysaccharide (LPS), (3) 10 ng/mL phytohemagglutinin (PHA), and (4) 125 ng/ml α-CD3 plus 250 ng/ml α-CD28. Supernatants collected at 48 h were analyzed using multiplex Luminex assay to identify differences in cytokine and chemokine production. Results from these assays were then correlated to patient clinical assessments for positive and negative symptoms common to psychotic disorders. Results We found that PBMC from affective FEP patients produced higher concentrations of cytokines associated with both innate and adaptive immunity after stimulation than non-affective FEP patients and healthy controls. More specifically, the AFF PBMC produced increased tumor necrosis fctor (TNF)-α, interleukin (IL)-1β, IL-6, and others associated with innate inflammation. PBMC from AFF also produced increased IL-4, IL-17, interferon (IFN)γ, and other cytokines associated with adaptive immune activation, depending on stimulation. Additionally, inflammatory cytokines that differed at rest and after LPS stimulation correlated with Scale for the Assessment of Negative Symptoms (SANS) scores. Conclusions Our findings suggest that immune dysfunction in affective psychosis may differ from that of primary psychotic disorders, and inflammation may be associated with increased negative symptoms. These findings could be helpful in determining clinical diagnosis after first psychotic episode.

This study reports on outcomes for 169 caregivers enrolled in the Michigan Stroke Transitions Trial (MISTT), an RCT of social work case management for stroke patients returning home. A mixed-model approach examined the mean change from 7- to 90-days post-discharge with group-by-time interactions for differences between treatment groups. Caregivers reported few life changes or depressive symptoms from caregiving. There was no significant change over time or treatment effects. Negative aspects of stroke caregiving may take longer to develop. Focused caregiver assessment at discharge and a better understanding of how caregiving develops over time may improve the type and timing of support.

OBJECTIVE To describe the surgical removal of intra-articular loose bodies (LBs) from the cervical articular process joints (APJs) in five horses and to describe the outcome of the surgery. STUDY DESIGN Short case series. ANIMALS Five client-owned horses with naturally occurring LBs within the cervical APJs. METHODS Medical records were reviewed of horses that were diagnosed with LBs of the cervical APJs on computed tomography (CT), where the LBs were subsequently removed surgically. Details of case selection and surgical technique were reviewed along with postoperative complications and clinical outcome. Histopathology was performed on LBs in some cases. RESULTS Surgery was performed on six APJs in five horses. Of the 14 LBs identified with CT, 13 were successfully removed from the C4/C5, C5/C6 and C6/C7 articulations. No surgical complications were encountered, and clinical signs of cervical dysfunction improved in all horses. All clinical cases returned to ridden work by 6 months post surgery. Histopathologic examination revealed the removed structures to be osteochondral or chondral loose bodies consisting of cartilaginous proliferation with or without ossification and central necrosis. CONCLUSIONS Surgical removal of LBs is achievable from the cervical APJs and can result in the resolution of cervical pain. This procedure offers a new treatment option for management of selected horses with cervical pain, following thorough assessment and CT imaging.

Access to healthcare is challenging for both Veterans and the nation's general population. To keep up with national primary healthcare needs, the Department of Veteran Affairs (VA) implemented Home Based Primary Care (HBPC). After a structure remodel at a Texas VA medical center, 40% of nurse practitioners (NPs) left the HBPC department in one year. The Anticipated Turnover Scale and the Misener NP Job Satisfaction Scale were administered online (n = 7), and results were used to complete a program evaluation. Forty-three percent of participants indicated intent to leave, and 56% of answers indicated job dissatisfaction. Seven categories were identified to mitigate voluntary turnover: Recognition; Shared governance; Orientation; Full practice authority; Collaboration; Organizational workflow maps; and Mentoring. Implementation of recommendations resulting from this project may help retain NPs in both VA and non-VA organizations, reduce organizational costs, support optimal patient outcomes, and increase access to healthcare.

Objective Stepped-care models of treatment are underexplored in eating disorders. To enhance treatment outcomes, and informed by literature about adaptations to family-based treatment (FBT), we developed an FBT-based stepped-care model for adolescents with anorexia nervosa (AN) that was consistent with family preference (i.e., tailored) and responsive to adolescent needs (i.e., intensity). The aim of this study was to evaluate the effectiveness of this model in terms of remission at end-of-treatment. Method Adolescents (N = 82), aged 12-18 years (M = 15.1, SD = 1.8) and meeting Diagnostic and Statistical Manual of Mental Disorders 5th Edition criteria for AN, were assessed at baseline, Weeks 24 and 48. FBT was tailored to family preference and clinical need, with 16-18 sessions by Week 24. This was followed by three FBT booster sessions or an extension of FBT plus booster sessions (Week 48). The primary outcome was defined as weight > 95% of %median body mass index plus within 1 SD of the Eating Disorder Examination (EDE) global score community norms. Results Remission rates were 45.1% and 52.4% at Weeks 24 and 48, respectively. Commensurable improvements were evident across secondary outcomes (e.g., EDE subscale scores). As a reference point, remission rates compared positively with results from a recent randomized clinical trial from the same center and at the same time points (Week 24:45.1% vs. 32.1% and Week 48:52.4% vs. 30.2%). Controlling for propensity score, no statistically significant differences were observed. Discussion This stepped-care model, designed to be responsive to the individual needs of adolescents and their families, achieved encouraging rates of remission. This study provides an important signal that supports future clinical trials of stepped-care models for adolescents with AN.

To expand understanding of imbricated journalism and high aestheticism at the fin de siècle, this essay examines Vernon Lee's journalism and slow essay serials, a form spread over space (viz., different periodicals) and marked by irregular temporal issue of installments before finding new cohesion when retroactively constructed as a book. Lee's prolific periodical publication, especially her aesthetic criticism, is rarely approached as journalism. Newly available letters and Lee's negotiations with editors clarify the occluded history of Lee's journalism and her slow essay serials, a distinctive serial form at the fin de siècle, which this article conceptualizes in closing.

Linked to major volcanic eruptions around 536 and 540 CE, the onset of the Late Antique Little Ice Age has been described as the coldest period of the past two millennia. The exact timing and spatial extent of this exceptional cold phase are, however, still under debate because of the limited resolution and geographical distribution of the available proxy archives. Here, we use 106 wood anatomical thin sections from 23 forest sites and 20 tree species in both hemispheres to search for cell-level fingerprints of ephemeral summer cooling between 530 and 550 CE. After cross-dating and double-staining, we identified 89 Blue Rings (lack of cell wall lignification), nine Frost Rings (cell deformation and collapse), and 93 Light Rings (reduced cell wall thickening) in the Northern Hemisphere. Our network reveals evidence for the strongest temperature depression between mid-July and early-August 536 CE across North America and Eurasia, whereas more localised cold spells occurred in the summers of 532, 540-43, and 548 CE. The lack of anatomical signatures in the austral trees suggests limited incursion of stratospheric volcanic aerosol into the Southern Hemisphere extra-tropics, that any forcing was mitigated by atmosphere-ocean dynamical responses and/or concentrated outside the growing season, or a combination of factors. Our findings demonstrate the advantage of wood anatomical investigations over traditional dendrochronological measurements, provide a benchmark for Earth system models, support cross-disciplinary studies into the entanglements of climate and history, and question the relevance of global climate averages.

This paper provides an overview of the United States (US) Department of Energy's (DOE's) Energy Exascale Earth System Model version 2 (E3SMv2) fully coupled Regionally Refined Model (RRM) and documents the overall atmosphere, land, and river results from the Coupled Model Intercomparison Project 6 (CMIP6) DECK (Diagnosis, Evaluation, and Characterization of Klima) and historical simulations – a first-of-kind set of climate production simulations using RRM. The North American (NA) RRM (NARRM) is developed as the high-resolution configuration of E3SMv2 with the primary goal of more explicitly addressing DOE's mission needs regarding impacts to the US energy sector facing Earth system changes. The NARRM features finer horizontal resolution grids centered over NA, consisting of 25→100 km atmosphere and land, 0.125° river routing model, and 14→60 km ocean and sea ice. By design, the computational cost of NARRM is ∼3x of the uniform low-resolution (LR) model at 100 km but only ∼10–20 % of a globally uniform high-resolution model at 25 km. A novel hybrid timestep strategy for the atmosphere is key for NARRM to achieve improved climate simulation fidelity within the high-resolution patch without sacrificing the overall global performance. The global climate, including climatology, time series, sensitivity, and feedback, is confirmed to be largely identical between NARRM and LR as quantified with typical climate metrics. Over the refined NA area, NARRM is generally superior to LR, including for precipitation and clouds over the contiguous US (CONUS), summertime marine stratocumulus clouds off the coast of California, liquid and ice phase clouds near the North polar region, extratropical cyclones, and spatial variability in land hydrological processes. The improvements over land are related to the better resolved topography in NARRM, whereas those over ocean are attributable to the improved air-sea interactions with finer grids for both atmosphere and ocean/sea ice. Some features appear insensitive to the resolution change analyzed here, for instance the diurnal propagation of organized mesoscale convective systems over CONUS, and the warm-season land-atmosphere coupling at the Southern Great Plains. In summary, our study presents a realistically efficient approach to leverage the RRM framework for a standard Earth system model release and high-resolution climate production simulations.

This study aimed to investigate the immediate and continual perturbation to the gut microbiota of offspring in the weeks post-weaning and how these may be modulated by treating pregnant C57BL/6J dams with antibiotics (ABX). We used a broad-spectrum antibiotic cocktail consisting of ampicillin 1 mg/mL, neomycin 1 mg/mL, and vancomycin 0.5 mg/mL, or vancomycin 0.5 mg/mL alone, administered ad-lib orally to dams via drinking water during gestation and stopped after delivery. We analyzed the gut microbiota of offspring, cytokine profiles in circulation, and the brain to determine if there was evidence of a gut-immune-brain connection. Computationally predicted metabolic pathways were calculated from 16s rRNA sequencing data. ABX treatment can negatively affect the gut microbiota, including reduced diversity, altered metabolic activity, and immune function. We show that the maternal ABX-treatment continues to alter the offspring’s gut microbiota diversity, composition, and metabolic pathways after weaning, with the most significant differences evident in 5-week-olds as opposed to 4-week-olds. Lower levels of chemokines and inflammatory cytokines, such as interleukin (IL)-1α and IL-2, are also seen in the periphery and brains of offspring, respectively. In conclusion, this study shows maternal antibiotic administration alters gut microbiome profiles in offspring, which undergoes a continuous transformation, from week to week, at an early age after weaning.

Introduction The diagnosis of apical hypertrophic cardiomyopathy (ApHCM) is contingent on demonstrating apical maximum wall thickness (MWT) of ≥15mm; the same threshold as other HCM subtypes. However, the myocardium naturally tapers towards the apex in healthy individuals, so ≥15mm MWT is proportionately higher in the apex than in naturally thicker basal segments. Using cardiac magnetic resonance (CMR), relative ApHCM has been described (typical ECG features, loss of apical tapering, cavity obliteration but hypertrophy Purpose We aimed to redefine the optimal diagnostic threshold for ApHCM using segment-specific criteria based on a large cohort of healthy control subjects. Methods Segmental wall thickness was measured using healthy subjects from the UK Biobank using a clinically validated machine learning algorithm1,2. A normative reference range was established for all 16 segments, conditioned to body surface area (BSA), sex and age. Derived segment-specific wall thickness thresholds were used to define optimal disease thresholds for patients clinically managed with overt (MWT ≥15mm) and relative ApHCM (MWT Results 4118 UK biobank subjects were used to define normal segmental thicknesses and reference ranges. These were applied to ApHCM (73 overt, 31 relative). There were no apical wall thickness age related differences. The upper limit of the 95% confidence interval corresponded to a combined maximum apical MWT for both males and females of 10.4mm using non-indexed measurement, or 5.6mm/m2 when indexed to BSA. Non-indexed segmental threshold identified 100% of ApHCM patients (true positives), 81% (25 of 31) relative ApHCM and 3% (115 of 4118) of healthy UK biobank subjects (false positives). Indexed segmental thresholds improved the diagnostic potential in relative ApHCM without an increase in false positives (100% of ApHCM patients, 84% (26 of 31) of relative ApHCM patients, and 3% healthy UK biobank (127 of 4118). Conclusion We propose new diagnostic criteria for ApHCM using segmental indexed apical wall thickness of >5.6 mm/m2 to better identify inappropriate apical hypertrophy in those whose wall thickness does not meet current criteria for diagnosis. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): British Heart Foundation

Background/Introduction Left ventricular (LV) mid-cavity obstruction (LVMCO) in hypertrophic cardiomyopathy (HCM) is an uncommon phenotypic feature predisposed to the formation of myocardial fibrosis and apical aneurysms (LVAA). These features may be independently proarrhythmic, and LVAA is considered a class 2a indication for implantable cardioverter defibrillator (ICD) in current US, but not European guidelines for the primary prevention of sudden cardiac death (SCD). Cardiac magnetic resonance (CMR) imaging is the preferred modality for detecting these and other phenotypic features critical to SCD risk assessment. Purpose To assess the ability of CMR imaging parameters to predict occurrence of non-sustained ventricular tachycardia (NSVT) in HCM patients with Doppler-derived evidence of LVMCO. Methods Multi-modality imaging records were retrospectively assessed to identify HCM patients with Doppler-LVMCO and CMR scans. CMR images were assessed by an investigator blinded to clinical status. Late gadolinium enhancement (LGE) was quantified using the full-width, half-maximum technique. CMR imaging parameters were assessed for predictive ability using Cox proportional hazards during univariate and multivariate analyses, accounting for time to event (NSVT or censorship of follow-up). Results The study cohort included 58 patients (57±11 years, 74% male) with a median follow-up of 6.2 (IQR 4.3) years. Mean mid-cavity gradient was 33±23 mmHg. NSVT was detected in 27/58 (47%) patients, was 4 beats or longer in 23/27 (85%) and was monomorphic in 21/27 (77%). On univariate analysis, predictors of NSVT during follow-up include LV mass index (HR 1.02, 95% CI 1.00–1.04, p=0.03), LGE in grams (HR 1.04, 95% CI 1.01–1.06, p=0.005), and LVAA (HR 2.57, 95% CI 1.14–5.79, p=0.023). After multivariate adjustment (Table 2), none were significantly associated. Conclusions In LVMCO, magnitude of LV hypertrophy, extent of LGE and the presence of an apical aneurysm may not be independent predictors of ventricular arrhythmias. SCD algorithms based on qualitative assessments of these features may overestimate risk. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): National Institute of Health Research (NIHR)

BackgroundSecondary infection (SI) diagnosis in COVID-19 is challenging, due to overlapping clinical presentations, practical limitations in obtaining samples from the lower respiratory tract (LRT), and low sensitivity of microbiologic cultures.Research QuestionCan metagenomic sequencing of plasma microbial cell-free DNA (mcfDNA-Seq) help diagnose SIs complicating COVID-19?Study Design and MethodsWe enrolled 42 inpatients with COVID-19 classified as microbiologically-confirmed SI (Micro-SI, n=8), clinically-diagnosed SI (Clinical-SI, n=13, i.e. empiric antimicrobials), or no clinical suspicion for SI (No-Suspected-SI, n=21) at time of enrollment. From baseline and follow-up plasma samples (days 5 and 10 post-enrollment), we quantified mcfDNA for all detected microbes by mcfDNA sequencing and measured nine host-response biomarkers. From LRT samples among intubated subjects, we quantified bacterial burden with 16S rRNA gene quantitative PCR.ResultsWe performed mcfDNA-Seq in 82 plasma samples. Sequencing was successful in 60/82 (73.2%) samples, which had significantly lower levels of human cfDNA than failed samples (p10 mcfDNA, p=0.03).InterpretationHigh circulating levels of mcfDNA in a substantial proportion of patients with COVID-19 without clinical suspicion for SI suggest that SIs may often remain undiagnosed. McfDNA-Seq, when clinically available, can offer a non-invasive diagnostic tool for pathogen identification, with prognostic value on host inflammatory response and clinical outcomes.

Granulomas are complex cellular structures composed predominantly of macrophages and lymphocytes that function to contain and kill invading pathogens. Here, we investigated the single-cell phenotypes associated with antimicrobial responses in human leprosy granulomas by applying single-cell and spatial sequencing to leprosy biopsy specimens. We focused on reversal reactions (RRs), a dynamic process whereby some patients with disseminated lepromatous leprosy (L-lep) transition toward self-limiting tuberculoid leprosy (T-lep), mounting effective antimicrobial responses. We identified a set of genes encoding proteins involved in antimicrobial responses that are differentially expressed in RR versus L-lep lesions and regulated by interferon-γ and interleukin-1β. By integrating the spatial coordinates of the key cell types and antimicrobial gene expression in RR and T-lep lesions, we constructed a map revealing the organized architecture of granulomas depicting compositional and functional layers by which macrophages, T cells, keratinocytes and fibroblasts can each contribute to the antimicrobial response. Modlin and colleagues examined the skin lesions of human leprosy patients using single-cell RNA sequencing coupled to cellular spatial mapping. Their analysis maps the architecture of granulomas in leprosy lesions from patients with leprosy with localized disease (tuberculoid leprosy, reversal reaction) to those with progressive infection (lepromatous leprosy).

Direct-to-consumer genetic and genomic testing (DTCGT) has paved the way for consumers to gain information about their genetic makeup. Consumers may seek DTCGT to estimate ethnic background, identify genetic relations, or obtain raw DNA information that can be used for other purposes, such as testing for paternity and identifying genetically linked illnesses. Despite robust progress in genetic and genomic testing, most people have a low exposure threshold to DTCGT. Patient consumers may unnecessarily experience anxiety if they do not have a health care provider (HCP) to consult and review their results. Presently, there is a knowledge gap in how accurately HCPs can interpret and communicate genetic test results to patients compared with genetic specialists who may be inaccessible to underserved populations. Genetic and genomic information is rapidly progressing in health care and can identify patients at increased risk for certain diseases and improve patient care and outcomes. Appropriate use of genetic and genomic testing and knowing the limitations and difficulties of current testing available are integral to the success of HCPs in using these results in health promotion and improving quality of life. Health care providers should be aware of DTCGT recommendations and implications for patients, be prepared to counsel patients who present with testing results in hand, seeking advisement, and be competent in determining the need for further diagnostic testing or referral to a specialist genetic counselor.

Introduction Hip fractures are a global health burden, with an incidence that is projected to increase from 66,000/year currently in the United Kingdom to 100,000/year by 2033. The classification of intertrochanteric fractures is key to the treatment algorithms advising on their surgical management. The AO/OTA classification is the most commonly used system, initially published in 1990 and subsequently shown to have poor inter- and intra-observer reliability, it was revised in 2018 with the main aim of re-classifying and further defining the 31-A2 group. Methods 150 plain film anteroposterior and lateral plain film radiographs of intertrochanteric fractures from three hospitals were classified using the 2018 AO/OTA classification of intertrochanteric fractures by six Orthopaedic Surgeons (2 Consultants, 4 Trainees), all were blinded to the definitive surgical treatment for patients. Radiographs were re-classified after a minimum of 3-months, Cohen's Kappa for inter-observer reliability was calculated from first round classifications and intra-observer reliability from first and second classifications. Results Mean Kappa for inter-observer reliability for AO group classification (e.g. 31-A1) was 0.479 (0.220 - 0.771, for sub-group classification (e.g. 31-A1.1) reliability reduced to 0.376 (0.276 - 0.613). Intra-observer reliability was comparable for both group and sub-group classifications, 0.661 and 0.587 respectively. Conclusions The revised 2018 AO/OTA classification aimed to simply the classification of intertrochanteric fractures, however it remains unreliable with only a “moderate” inter-observer reliability at group level with this falling to “fair” when sub-group classifications are made. Identification of stable and unstable injuries using the new AO/OTA system remains fraught with difficulties and appears difficult to apply with consistent accuracy.

Funding Acknowledgements Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Dr Hughes is supported by the British Heart Foundation (grant number FS/17/82/33222). Introduction The imaging criteria for diagnosis of apical hypertrophic cardiomyopathy (ApHCM) is a maximum wall thickness (MWT) ≥15mm. CMR enables detection of subtle phenotypic features (e.g. loss of apical tapering, cavity obliteration) and coupled with characteristic electrocardiogram changes, ApHCM can be diagnosed without overt hypertrophy. However, these patients are not captured by current diagnostic criteria. Purpose We sought to use a machine learning tool to quantify wall thickness and identify patients with ‘relative’ ApHCM that do not reach current diagnostic thresholds. Methods CMR images from 4118 healthy participants from the UK Biobank were segmented automatically with a clinically validated machine learning algorithm and wall thickness measured at all point in the myocardium by solving a solution to Laplace’s equation. MWT were pooled into 16 AHA segments and indexed to body surface area (BSA). The non-indexed and indexed segmental upper limit of normal was calculated as the mean + 3 standard deviations (the equivalent of 95% confidence interval after correcting for multiple [16] comparisons using the Bonferroni method). Results 73 overt ApHCM subjects (MWT>15mm) and 31 relative ApHCM subjects underwent CMR scanning. In healthy controls, the non-indexed (and indexed) upper limits were calculated for the apical-anterior 10.2mm (5.2 mm/m2), apical-septal 11.1mm (5.6 mm/m2), apical-inferior 10.5mm (5.3 mm/m2) and apical-lateral 10.1mm (5.2 mm/m2) segments. With a non-indexed cut-off, all (73 of 73) overt ApHCM and 84% (26 of 31) relative ApHCM were classified as having an abnormally thick apex. 3% (127 of 4118) of the healthy UK Biobank cohort were classified as abnormal, as expected. Using an indexed cut-off, all overt ApHCM and 87% (27/31) relative ApHCM were classified as abnormal, and 3% (123 of 4118) of the healthy UK Biobank cohort were misclassified. Conclusion We can successfully classify 87% of relative ApHCM patients from a normative reference range derived from a large cohort of healthy patients – a significant improvement on existing methods. We show that the specificity and sensitivity is increased when MWT is indexed to BSA. For practical clinical application, we recommend a cut-off of 10mm or an indexed cut-off of 5mm/m2 in any apical segment to diagnose apical LVH. Overt and relative apical HCM examplesHealthy controls AHA maps (non-indexed)

Despite its high prevalence, the cellular and molecular mechanisms of chronic obstructive pulmonary disease (COPD) are far from being understood. Here, we determine disease-related changes in cellular and molecular compositions within the alveolar space and peripheral blood of a cohort of COPD patients and controls. Myeloid cells were the largest cellular compartment in the alveolar space with invading monocytes and proliferating macrophages elevated in COPD. Modeling cell-to-cell communication, signaling pathway usage, and transcription factor binding predicts TGF-β1 to be a major upstream regulator of transcriptional changes in alveolar macrophages of COPD patients. Functionally, macrophages in COPD showed reduced antigen presentation capacity, accumulation of cholesteryl ester, reduced cellular chemotaxis, and mitochondrial dysfunction, reminiscent of impaired immune activation.

Several recent studies have used transcriptomics to investigate luteal changes during the maternal recognition of the pregnancy period in ruminants. Although these studies have contributed to our understanding of luteal function during early pregnancy, few attempts have been made to integrate information across these studies and distinguish key luteal transcripts or functions that are repeatably identified across multiple studies. Therefore, in this study, two independent studies of the luteal transcriptome during early pregnancy were combined and compared. In the first study, corpora lutea (CL) from day 20 of pregnancy were compared with CL collected on day 14 of pregnancy, prior to embryonic signaling. The cattle were nonlactating. In the second study, CL from day 20 of pregnancy were compared with CL collected from day 20 cyclic cattle that had been confirmed as not yet undergoing luteal regression. These were lactating cattle. Three methods were used to compare these two datasets, to identify key luteal regulators. In the first method, all transcripts with Benjamini-Hochberg-adjusted P-value (Q value)0.05 in both datasets were considered. This yielded 22 transcripts, including several classical interferon-stimulated genes, as well as regulators of transforming growth factor-beta (TGFB) and latent TGFB-binding proteins (LTBP)1 and 2. In the second, less conservative method, all transcripts with P0.01 and changed in the same direction in both datasets were considered. This yielded an additional 20 transcripts that were not identified in the first analysis, for a total of 42 common transcripts. These transcripts were regulators of functions such as inflammatory balance and matrix remodeling. In the third method, transcripts with Q0.10 were subject to pathway analysis, and common pathways were identified. Retinoic acid signaling and classical interferon signaling pathways were identified with this method. Finally, regulation by interferon tau (IFNT) was investigated. Among the 42 transcripts identified, 32 were regulated by IFNT in cultured luteal cells (Q0.05). Among those not regulated by IFNT were LTBP1 and 2, which are TGFB-binding proteins. In summary, common transcripts from two studies of the luteal transcriptome during early pregnancy were combined and shared changes were identified. This not only generated a list of potential key luteal regulators, which were mostly IFNT regulated, but also included transcripts not regulated by IFNT, including LTBP1 and 2.Reproductive efficiency is necessary for the financial and environmental sustainability of cattle production. A critical component of this efficiency is the maintenance of pregnancy. The corpus luteum (CL) is a transient ovarian endocrine gland that produces progesterone—the hormone that maintains pregnancy in all mammals. With each new reproductive cycle, a new CL is formed from the remnant of the ovulatory follicle, and at the end of each cycle, in the absence of a pregnancy, the CL regresses in response to prostaglandin F2α from the uterus. In contrast, in the presence of a pregnancy, the CL is rescued from regression by the embryo, in a process known as maternal recognition of pregnancy. The embryo is known to alter uterine function, but its effect on the CL has remained a mystery until recent years. In this study, we compared two independent studies of global changes in the CL of pregnancy, to identify the most important luteal changes that occur during early pregnancy. We confirmed evidence for embryonic signaling to the CL and generated a list of candidate genes that are the likeliest regulators of changes to luteal function in early pregnancy. This list includes regulators of tissue integrity and inflammation.

INTRODUCTIONChest imaging is necessary for diagnosis of COVID-19 pneumonia, but current risk stratification tools do not consider radiographic severity. We quantified radiographic heterogeneity among inpatients with COVID-19 with the Radiographic Assessment of Lung Edema (RALE) score on Chest X-rays (CXRs).METHODSWe performed independent RALE scoring by ≥2 reviewers on baseline CXRs from 425 inpatients with COVID-19 (discovery dataset), we recorded clinical variables and outcomes, and measured plasma host-response biomarkers and SARS-CoV-2 RNA load from subjects with available biospecimens.RESULTSWe found excellent inter-rater agreement for RALE scores (intraclass correlation co-efficient=0.93). The required level of respiratory support at the time of baseline CXRs (supplemental oxygen or non-invasive ventilation [n=178]; invasive-mechanical ventilation [n=234], extracorporeal membrane oxygenation [n=13]) was significantly associated with RALE scores (median [interquartile range]: 20.0[14.1-26.7], 26.0[20.5-34.0] and 44.5[34.5-48.0], respectively, pCONCLUSIONReproducible assessment of radiographic severity revealed significant associations with clinical and physiologic severity, host-response biomarkers and clinical outcome in COVID-19 pneumonia. Incorporation of radiographic severity assessments may provide prognostic and treatment allocation guidance in patients hospitalized with COVID-19.

Background Following evidence published in the Pharmacists in Emergency Departments (PIED 2016) study Health Education England funded novel advanced clinical practitioner training for pharmacists (ACP-p), to support service delivery.Objective To explore experiences and clinical activity of trainee ACP-p, and opinions and recommendations of both trainees and clinical supervisors.Setting Five Urgent/Emergency Care Departments in London UK.Method Longitudinal mixed-methods study in three phases of registered UK pharmacists appointed as trainee ACP-p. Phase 1 (May-July 2019) – early semi-structured interviews and focus group using an experiences, opinions and recommendations (EOR) framework, Phase 2 (January-December 2019) – prospective recording of trainee clinical activity, standardised using bespoke spreadsheet, Phase 3 (November-December 2019) – as Phase 1 but at conclusion of training.Main outcome measure Experiences, clinical activity, opinions and recommendations of study participants.Results Twelve (92 %) eligible trainee ACP-p and five supervisors were recruited. Identified themes were: trainee personality, educational components, length of programme, support/supervision, career transition, university and placement training alignment, recommendations. Success was dependent on effective support and supervision. Clinical supervisors should be allocated adequate supervision time. Trainees, their supervisors and emergency department staff should be given a clear brief. Study participants agreed that the programme could be successful. Trainee ACP-p reported that they could manage 82 % of 713 pre-selected clinical presentations. Additional training needs include: ECGs, X-rays and CT scans.Conclusions Pharmacists can successfully train as ACP-p in this setting over a two-year period. This career transition needs careful management and clear structures. Training ACP-p is a useful way of enhancing skills and supporting clinical services to large numbers of patients.

Tracking wood formation in semiarid regions during the seasonal march of precipitation extremes has two important applications. It can provide (i) insight into the adaptive capacities of trees to drought and (ii) a basis for a richer interpretation of tree-ring data, assisting in a deeper understanding of past and current climate. In the southwestern USA, the anatomical signature of seasonally bimodal precipitation is the ‘false ring’—a band of latewood-like cells in the earlywood. These occur when a particularly deep drought during the early growing season ends abruptly with timely, mid-growing season monsoonal rains. Such conditions presented in southern Arizona in 2014, enabling us to explore false-ring formation in ponderosa pine (Pinus ponderosa Lawson and C. Lawson) and Douglas-fir (Pseudotsuga menziesii Mirb. Franco) in mixed-conifer forest at 2573 m above sea level. We ask: what were the cell-by-cell timings and durations in the phases of wood cell development in 2014? How do these seasonal patterns relate to strongly fluctuating environmental conditions during the growing season? We took weekly microcores from March through November from six ponderosa pine and seven Douglas-fir trees at a well-instrumented flux tower site. Thin sections were prepared, and we counted cells in cambial, expansion, cell wall thickening and mature phases. For ponderosa pine trees forming a false ring, the first impact of intensifying seasonal drought was seen in the enlarging phase and then, almost a month later, in cambial activity. In this species, recovery from drought was associated with recovery first in cambial activity, followed by cell enlargement. This timing raised the possibility that cell division may be affected by atmospheric moisture increases before soil recharge. In both species, the last false-ring cells matured during the summer rainy season. Bimodal cambial activity coincident with moisture availability was observed in both species, whether or not they formed a false ring. This deeper knowledge of the precise timing of both developmental and environmental events should help define mechanistic connections among these factors in creating bimodal growth patterns.

We present new radial velocity measurements from the Magellan and the Anglo-Australian Telescopes for 174 previously known and 122 newly confirmed globular clusters (GCs) around NGC 5128, the nearest accessible massive early-type galaxy at D=3.8 Mpc. Remarkably, 28 of these newly confirmed GCs are at projected radii >50' ($\gtrsim 54$ kpc), extending to $\sim 130$ kpc, in the outer halo where few GCs had been confirmed in previous work. We identify several subsets of GCs that spatially trace halo substructures that are visible in red giant branch star maps of the galaxy. In some cases, these subsets of GCs are kinematically cold, and may be directly associated with and originate from these specific stellar substructures. From a combined kinematic sample of 645 GCs, we see evidence for coherent rotation at all radii, with a higher rotation amplitude for the metal-rich GC subpopulation. Using the tracer mass estimator, we measure a total enclosed mass of $2.5\pm0.3 \times 10^{12} M_{\odot}$ within $\sim 120$ kpc, an estimate that will be sharpened with forthcoming dynamical modeling. The combined power of stellar mapping and GC kinematics makes NGC 5128 an ongoing keystone for understanding galaxy assembly at mass scales inaccessible in the Local Group., 24 pages, 13 figures, submitted to AAS Journals

To our knowledge, we are the only centre in the UK where Achilles tenotomies (TA) for CTEV Ponseti correction are performed in outpatient clinic under local anaesthetic by an Advanced Physiotherapy Practitioner (APP) in orthopaedics. This study aims to present the outcomes and safety of this practice.Retrospective analysis of cases of idiopathic CTEV undergoing Ponseti correction January 2020 to October 2022. Demographic data: Pirani score and number of casts before boots and bar. Patients were divided into five groups: Group 1: TA performed by an Orthopaedic consultant under general anaesthetic (GA) in theatre. Group 2: TA performed by an Orthopaedic consultant under local anaesthetic (LA) in theatre. Group 3: TA performed by APP under GA in theatre. Group 4: TA performed by APP under LA in theatre. Group 5: TA performed by an APP under LA in outpatient clinic. Complications recorded: revision TA, infection, neurovascular injury or need for re-casting. Mean follow up 18 months.45 feet included. Mean Pirani score 5.5, age started casting 33 days and total number of casts 6. No significant difference in demographic details between groups. 6, 4, 20, 5 and 10 tenotomies were performed in groups 1, 2, 3, 4, and 5 respectively. Complications were 1 revision tenotomy from group 2, one from group 4 and 1 renewal of cast from 3.This study demonstrates that TAs performed in outpatient clinic under LA by an APP is safe and feasible. No increase in complications were observed compared to TAs performed by orthopaedic consultants.