Rare presentations of small bowel endometriosis.

Despite endometriosis being a relatively common chronic gynecological condition in women of childbearing age, small bowel endometriosis is rare. Presentations can vary from completely asymptomatic to reported symptoms of abdominal pain, bloating, and diarrhea. The following two cases depict very atypical manifestations of ileal endometriosis that presented as obscure intermittent gastrointestinal bleeding and bowel obstruction requiring surgical intervention. The first case describes a previously healthy 40-year-old woman with severe symptomatic iron deficiency anemia and intermittent melena. A small bowel enteroscopy diagnosed multiple ulcerated strictures in the distal small bowel as the likely culprit. Despite nonsteroidal anti-inflammatory drug-induced enteropathy being initially considered as the likely etiology, histopathological examination of the resected distal ileal segment revealed evidence of endometriosis. The second case describes a 66-year-old with a presumptive diagnosis of Crohn's disease who reported a 10-year history of intermittent perimenstrual abdominal pain, diarrhea, and nausea with vomiting. Following two subsequent episodes of acute bowel obstruction and surgical resection of the patient's stricturing terminal ileal disease, histopathological examination demonstrated active chronic inflammation with endometriosis. Small bowel endometriosis should be considered as an unusual differential diagnosis in women who may present with obscure gastrointestinal bleeding from the small bowel or recurrent bowel obstruction.

An efficient inducible model for the control of gene expression in renin cells.

Fate mapping and genetic manipulation of renin cells have relied on either non-inducible Cre lines that can introduce developmental effects of gene deletion or BAC transgene-based inducible models that may be prone to spurious and/or ectopic gene expression. To circumvent these problems, we generated an inducible mouse model in which CreERT2 is under the control of the endogenous Akr1b7 gene, an independent marker of renin cells that is expressed in a few extrarenal tissues. We confirmed the proper expression of Cre using Akr1b7CreERT2/+;R26RmTmG/+ mice in which Akr1b7+/renin+ cells become GFP+ upon tamoxifen administration. In embryos and neonates, GFP was found in Juxtaglomerular cells, along the arterioles, and in the mesangium, and in adults, GFP was present mainly in Juxtaglomerular cells. In mice treated with captopril and a low salt diet to induce recruitment of renin cells, GFP extended along the afferent arterioles and in the mesangium. We generated Akr1b7CreERT2/+;Ren1cFl/-;R26RmTmG/+ mice to conditionally delete renin in adult mice and found a marked reduction in kidney renin mRNA and protein, and mean arterial pressure in mutant animals. When subjected to a homeostatic threat, mutant mice were unable to recruit renin+ cells. Most importantly, these mice developed concentric vascular hypertrophy ruling out potential developmental effects on the vasculature due to the lack of renin. We conclude that Akr1b7CreERT2 mice constitute an excellent model for the fate mapping of renin cells and for the spatial and temporal control of gene expression in renin cells.

Fast clustering and cell-type annotation of scATAC data using pre-trained embeddings.

Data from the single-cell assay for transposase-accessible chromatin using sequencing (scATAC-seq) are now widely available. One major computational challenge is dealing with high dimensionality and inherent sparsity, which is typically addressed by producing lower dimensional representations of single cells for downstream clustering tasks. Current approaches produce such individual cell embeddings directly through a one-step learning process. Here, we propose an alternative approach by building embedding models pre-trained on reference data. We argue that this provides a more flexible analysis workflow that also has computational performance advantages through transfer learning. We implemented our approach in scEmbed, an unsupervised machine-learning framework that learns low-dimensional embeddings of genomic regulatory regions to represent and analyze scATAC-seq data. scEmbed performs well in terms of clustering ability and has the key advantage of learning patterns of region co-occurrence that can be transferred to other, unseen datasets. Moreover, models pre-trained on reference data can be exploited to build fast and accurate cell-type annotation systems without the need for other data modalities. scEmbed is implemented in Python and it is available to download from GitHub. We also make our pre-trained models available on huggingface for public use. scEmbed is open source and available at https://github.com/databio/geniml. Pre-trained models from this work can be obtained on huggingface: https://huggingface.co/databio.

Inhibition of Renin Expression Is Regulated by an Epigenetic Switch From an Active to a Poised State.

BACKGROUND: Renin-expressing cells are myoendocrine cells crucial for the maintenance of homeostasis. Renin is regulated by cAMP, p300 (histone acetyltransferase p300)/CBP (CREB-binding protein), and Brd4 (bromodomain-containing protein 4) proteins and associated pathways. However, the specific regulatory changes that occur following inhibition of these pathways are not clear. METHODS: We treated As4.1 cells (tumoral cells derived from mouse juxtaglomerular cells that constitutively express renin) with 3 inhibitors that target different factors required for renin transcription: H-89-dihydrochloride, PKA (protein kinase A) inhibitor; JQ1, Brd4 bromodomain inhibitor; and A-485, p300/CBP inhibitor. We performed ATAC-seq, single-cell RNA sequencing, CUT&Tag, and chromatin immunoprecipitation sequencing for H3K27ac and p300 binding on biological replicates of treated and control As4.1 cells. RESULTS: In response to each inhibitor, Ren1 expression was significantly reduced and reversible upon washout. Chromatin accessibility at the Ren1 locus did not markedly change but was globally reduced at distal elements. Inhibition of PKA led to significant reductions in H3K27ac and p300 binding specifically within the Ren1 super-enhancer region. Further, we identified enriched TF (transcription factor) motifs shared across each inhibitory treatment. Finally, we identified a set of 9 genes with putative roles across each of the 3 renin regulatory pathways and observed that each displayed differentially accessible chromatin, gene expression, H3K27ac, and p300 binding at their respective loci. CONCLUSIONS: Inhibition of renin expression in cells that constitutively synthesize and release renin is regulated by an epigenetic switch from an active to poised state associated with decreased cell-cell communication and an epithelial-mesenchymal transition. This work highlights and helps define the factors necessary for renin cells to alternate between myoendocrine and contractile phenotypes.

A shared threat-anticipation circuit is dynamically engaged at different moments by certain and uncertain threat.

Temporal dynamics play a central role in models of emotion: "fear" is widely conceptualized as a phasic response to certain-and-imminent danger, whereas "anxiety" is a sustained response to uncertain-or-distal harm. Yet the underlying human neurobiology remains contentious. Leveraging an ethnoracially diverse sample, translationally relevant paradigm, and theory-driven modeling approach, we demonstrate that certain and uncertain threat recruit a shared threat-anticipation circuit. This circuit exhibits persistently elevated activation when anticipating uncertain threat encounters and a transient burst of activation in the moments before certain encounters. For many scientists and clinicians, feelings are the defining feature of human fear and anxiety. Here we used an independently validated brain signature to covertly decode the momentary dynamics of anticipatory distress for the first time. Results mirrored the dynamics of neural activation. These observations provide fresh insights into the neurobiology of threat-elicited emotions and set the stage for more ambitious clinical and mechanistic research.

Blunted ventral striatal reactivity to social reward is associated with more severe motivation and pleasure deficits in psychosis.

Among individuals living with psychotic disorders, social impairment is common, debilitating, and challenging to treat. While the roots of this impairment are undoubtedly complex, converging lines of evidence suggest that social motivation and pleasure (MAP) deficits play a key role. Yet most neuroimaging studies have focused on monetary rewards, precluding decisive inferences. Here we leveraged parallel social and monetary incentive delay fMRI paradigms to test whether blunted reactivity to social incentives in the ventral striatum-a key component of the distributed neural circuit mediating appetitive motivation and hedonic pleasure-is associated with more severe MAP symptoms in a transdiagnostic sample enriched for psychosis. To maximize ecological validity and translational relevance, we capitalized on naturalistic audiovisual clips of an established social partner expressing positive feedback. Although both paradigms robustly engaged the ventral striatum, only reactivity to social incentives was associated with clinician-rated MAP deficits. This association remained significant when controlling for other symptoms, binary diagnostic status, or ventral striatum reactivity to monetary incentives. Follow-up analyses suggested that this association predominantly reflects diminished striatal activation during the receipt of social reward. These observations provide a neurobiologically grounded framework for conceptualizing the social-anhedonia symptoms and social impairments that characterize many individuals living with psychotic disorders and underscore the need to establish targeted intervention strategies.

Improving Healthcare Professionals' Access to Addiction Medicine Education Through VHA Addiction Scholars Program.

Introduction: The seemingly inexorable rise of opioid-related overdose deaths despite the reduced number of COVID-19 pandemic deaths demands novel responses and partnerships in our public health system's response. Addiction medicine is practiced in a broad range of siloed clinical environments that need to be included in addiction medicine training beyond the traditional fellowship programs. Our objective in this project was to implement a knowledge-based, live virtual training program that would provide clinicians and other healthcare professionals with an overview of addiction, substance use disorders (SUD), and clinical diagnosis and management of opioid use disorder (OUD). Methods: The Veterans Health Administration (VHA) Emergency Department Opioid Safety Initiative (ED OSI) offered a four-day course for healthcare professionals interested in gaining knowledge and practical skills to improve VHA-based SUD care. The course topics centered around the diagnosis and treatment of SUD, with a focus on OUD. Additionally, trainees received six months of support to develop addiction medicine treatment programs. Evaluations of the course were performed immediately after completion of the program and again at the six-month mark to assess its effectiveness. Results: A total of 56 clinicians and other healthcare professionals participated in the Addiction Scholars Program (ASP). The participants represented nine Veteran Integrated Service Networks and 21 different VHA medical facilities. Nearly 70% of participants completed the initial post-survey. Thirty-eight respondents (97.4%) felt the ASP series contained practical examples and useful information that could be applied in their work. Thirty-eight respondents (97.4%) felt the workshop series provided new information or insights into the diagnosis and treatment of SUD. Eleven capstone projects based on the information acquired during the ASP were funded (a total of $407,178). Twenty participants (35.7%) completed the six-month follow-up survey. Notably, 90% of respondents reported increased naloxone prescribing and 50% reported increased prescribing of buprenorphine to treat patients with OUD since completing the course. Conclusion: The ASP provided healthcare professionals with insight into managing SUD and equipped them with practical clinical skills. The students translated the information from the course to develop medication for opioid use disorder (M-OUD) programs at their home institutions.

Neuroticism/negative emotionality is associated with increased reactivity to uncertain threat in the bed nucleus of the stria terminalis, not the amygdala.

Neuroticism/Negative Emotionality (N/NE)-the tendency to experience anxiety, fear, and other negative emotions-is a fundamental dimension of temperament with profound consequences for health, wealth, and wellbeing. Elevated N/NE is associated with a panoply of adverse outcomes, from reduced socioeconomic attainment to psychiatric illness. Animal research suggests that N/NE reflects heightened reactivity to uncertain threat in the bed nucleus of the stria terminalis (BST) and central nucleus of the amygdala (Ce), but the relevance of these discoveries to humans has remained unclear. Here we used a novel combination of psychometric, psychophysiological, and neuroimaging approaches to rigorously test this hypothesis in an ethnoracially diverse, sex-balanced sample of 220 emerging adults selectively recruited to encompass a broad spectrum of N/NE. Cross-validated robust-regression analyses demonstrated that N/NE is preferentially associated with heightened BST activation during the uncertain anticipation of a genuinely distressing threat (aversive multimodal stimulation), whereas N/NE was unrelated to BST activation during certain-threat anticipation, Ce activation during either type of threat anticipation, or BST/Ce reactivity to threat-related faces. It is often assumed that different threat paradigms are interchangeable assays of individual differences in brain function, yet this has rarely been tested. Our results revealed negligible associations between BST/Ce reactivity to the anticipation of threat and the presentation of threat-related faces, indicating that the two tasks are non-fungible. These observations provide a framework for conceptualizing emotional traits and disorders; for guiding the design and interpretation of biobank and other neuroimaging studies of psychiatric risk, disease, and treatment; and for informing mechanistic research.Significance statement Neuroticism/Negative Emotionality (N/NE) is a core dimension of mammalian temperament. Elevated levels of N/NE confer risk for a panoply of adversities-from reduced wealth and divorce to depression and death-yet the underlying neurobiology remains unclear. Here we show that N/NE is associated with heightened activation in the bed nucleus of the stria terminalis (BST) during the uncertain anticipation of a genuinely distressing threat. In contrast, N/NE was unrelated to BST reactivity during the certain anticipation of threat or the acute presentation of 'threat-related' faces, two popular probes of the emotional brain. These findings refine our understanding of what has been termed the single most important psychological risk factor in public health, with implications for on-going biobank and therapeutics research.

Phase I clinical trial of the feasibility and safety of direct peritoneal resuscitation in liver transplantation.

BACKGROUND: Direct peritoneal resuscitation (DPR) is associated with improved outcomes in trauma. Animal models suggest DPR has favorable effects on the liver. We sought to evaluate its safety and assess for improved outcomes in liver transplantation (LT). METHODS: LT patients with renal dysfunction and/or obesity were enrolled in a phase-I clinical trial. DPR lasted 8-24 â€‹h depending on postoperative disposition. Primary outcome was percent of patients completing DPR. Secondary outcomes evaluated complications. Controls with either obesity (control-1) or both risk factors (obesity â€‹+ â€‹renal dysfunction, control-2) were analyzed. RESULTS: Fifteen patients were enrolled (seven with both criteria and eight with obesity alone). DPR was completed in 87 â€‹% of patients, with one meeting stopping criteria. Controls included 45 (control-1) and 24 (control-2) patients. Return to operating room, graft loss, and late infections were lower with DPR. CONCLUSION: DPR appears to be safe in closed abdomens following LT, warranting a follow-up phase-II trial to assess efficacy.

Label-free fluorescence lifetime imaging for the assessment of cell viability in living tumor fragments.

Significance: To enable non-destructive longitudinal assessment of drug agents in intact tumor tissue without the use of disruptive probes, we have designed a label-free method to quantify the health of individual tumor cells in excised tumor tissue using multiphoton fluorescence lifetime imaging microscopy (MP-FLIM). Aim: Using murine tumor fragments which preserve the native tumor microenvironment, we seek to demonstrate signals generated by the intrinsically fluorescent metabolic co-factors nicotinamide adenine dinucleotide phosphate [NAD(P)H] and flavin adenine dinucleotide (FAD) correlate with irreversible cascades leading to cell death. Approach: We use MP-FLIM of NAD(P)H and FAD on tissues and confirm viability using standard apoptosis and live/dead (Caspase 3/7 and propidium iodide, respectively) assays. Results: Through a statistical approach, reproducible shifts in FLIM data, determined through phasor analysis, are shown to correlate with loss of cell viability. With this, we demonstrate that cell death achieved through either apoptosis/necrosis or necroptosis can be discriminated. In addition, specific responses to common chemotherapeutic treatment inducing cell death were detected. Conclusions: These data demonstrate that MP-FLIM can detect and quantify cell viability without the use of potentially toxic dyes, thus enabling longitudinal multi-day studies assessing the effects of therapeutic agents on tumor fragments.

Utilizing gas flux from automated head chamber systems to estimate dietary energy values for beef cattle fed a finishing diet.

Dietary net energy for maintenance (NEm) and gain (NEg) can be estimated using calculations based on live performance or adjusted-final body weight, which is calculated based on carcass characteristics. These values are commonly referred to as performance-adjusted (pa) NEm (paNEm) and NEg (paNEg). The NEm and NEg of a diet can also be estimated by adding recovered energy (RE) with heat production (HP) derived from an automated head chamber system (AHCS), which we will term gas-adjusted (ga) NEm (gaNEm) and NEg (gaNEg). Furthermore, HP from the Brouwer equation requires an estimate of urinary nitrogen (UN) excretion, which can be calculated based on N intake, blood urea N, UN concentration, and urine creatinine, or it could be zeroed. Alternatively, HP can be calculated using an alternative equation based on the respiratory quotient. Demonstrating agreement between pa and ga derived dietary energy values provides an opportunity to validate using the AHCS for energetic experiments and this comparison has not been conducted previously. Accordingly, the objective of this experiment was to assess the agreement between live and carcass paNEm and paNEg with gaNEm and gaNEg, where HP was calculated using 4 different approaches. Estimates of HP were not different (P = 0.99) between the 4 approaches employed, indicating that all options investigated are appropriate. Live paNEm and paNEg had a higher agreement (Lin's concordance correlation coefficient [CCC] = 0.91) with gaNEm and gaNEg than carcass values (CCC ≤ 0.84). These results suggest that researchers can implement the AHCS to provide good estimates of dietary energy values in finishing beef cattle that are unrestrained.

Automated head chamber systems (AHCS) implemented into beef cattle research allow estimation of gas flux, heat production (HP), and calculated gas-adjusted dietary net energy for maintenance (gaNEm) and gain (gaNEg) values when paired with recovered energy. However, a comparison between AHCS-derived values and performance-adjusted NEm (paNEm) and NEg (paNEg) from either live performance (live paNEm and paNEg) or carcass data (carcass paNEm and paNEg) has not been conducted. Accordingly, the objectives of this experiment were to evaluate the agreement between gaNEm and gaNEg, estimated using different approaches for calculating HP, with live paNEm and paNEg or carcass paNEm and paNEg. Accounting for urinary nitrogen or methane when calculating HP does not appreciably influence HP estimates or subsequent calculations to estimate dietary NEm and NEg. There was excellent agreement between live paNEm and gaNEm, and between paNEg and gaNEg. Measures of precision, accuracy, and agreement were lower for carcass than for live-derived values when compared to gaNEm and gaNEg but were still acceptable. These results suggest that researchers can implement the AHCS to provide estimates of HP, gas flux, and estimates of dietary energy values in unrestrained finishing beef cattle-fed diets ranging in crude protein content (10.8% to 12.5%). Additional research is warranted on the use of the AHCS to conduct energetic studies across varying diets and production systems, particularly grazing systems.

Coagulopathy in Penetrating Ballistic Cranial Trauma: A 7-Year Experience.

BACKGROUND AND OBJECTIVES: Penetrating ballistic cranial trauma (PBCT) carries significant mortality when compared with blunt trauma. The development of coagulopathy in PBCT is a strong predictor of mortality. The goal of the study was to describe the incidence and risk factors of coagulopathy in PBCT and to report the value of tranexamic acid administration in PBCT. METHODS: We retrospectively analyzed 270 patients who presented with PBCT to a single, Level 1 trauma center between 2016 and 2023. RESULTS: A total of 47% (127/270) of patients with PBCT developed coagulopathy at presentation. Fifty-seven patients received tranexamic acid at presentation, which did not affect the development of coagulopathy. Coagulopathic patients were more likely to have more serious injury patterns (bihemispheric [adjusted odds ratio, aOR: 2.6 CI: 1.4-4.9, P = .004] or transventricular trajectories [aOR: 4.9 CI: 1.9-19.6, P = .03]). In addition, they presented with a larger base deficit (aOR: 0.9 CI: 1.002-1.2 per mEq/L, P = .006) which negatively correlated with the international normalized ratio (ρ: -0.46, P < .0001, Spearman correlation). Using thromboelastography helped to identify an additional 20% of patients who presented with normal coagulation on conventional testing. CONCLUSION: Coagulopathy is prevalent in approximately 50% of patients with PBCT and is persistent despite treatment in a substantial subset of patients. The addition of thromboelastography with its increased coagulopathy sensitivity can potentially guide treatment more efficiently than traditional coagulopathy laboratory tests and fibrinogen alone. Patients with a significant base deficit on arterial blood gas are at higher risk for coagulopathy.

Alpha-defensin binding expands human adenovirus tropism.

Mammalian α-defensins are a family of abundant effector peptides of the mucosal innate immune system. Although primarily considered to be antimicrobial, α-defensins can increase rather than block infection by certain prominent bacterial and viral pathogens in cell culture and in vivo . We have shown previously that exposure of mouse and human adenoviruses (HAdVs) to α-defensins is able to overcome competitive inhibitors that block cell binding, leading us to hypothesize a defensin-mediated binding mechanism that is independent of known viral receptors. To test this hypothesis, we used genetic approaches to demonstrate that none of several primary receptors nor integrin co-receptors are needed for human α-defensin-mediated binding of HAdV to cells; however, infection remains integrin dependent. Thus, our studies have revealed a novel pathway for HAdV binding to cells that bypasses viral primary receptors. We speculate that this pathway functions in parallel with receptor-mediated entry and contributes to α-defensin-enhanced infection of susceptible cells. Remarkably, we also found that in the presence of α-defensins, HAdV tropism is expanded to non-susceptible cells, even when viruses are exposed to a mixture of both susceptible and non-susceptible cells. Therefore, we propose that in the presence of sufficient concentrations of α-defensins, such as in the lung or gut, integrin expression rather than primary receptor expression will dictate HAdV tropism in vivo . In summary, α-defensins may contribute to tissue tropism not only through the neutralization of susceptible viruses but also by allowing certain defensin-resistant viruses to bind to cells independently of previously described mechanisms. Author Summary: In this study, we demonstrate a novel mechanism for binding of human adenoviruses (HAdVs) to cells that is dependent upon interactions with α-defensin host defense peptides but is independent of known viral receptors and co-receptors. To block normal receptor-mediated HAdV infection, we made genetic changes to both host cells and HAdVs. Under these conditions, α-defensins restored cell binding; however, infection still required the function of HAdV integrin co-receptors. This was true for multiple types of HAdVs that use different primary receptors and for cells that are either naturally devoid of HAdV receptors or were engineered to be receptor deficient. These observations suggest that in the presence of concentrations of α-defensins that would be found naturally in the lung or intestine, there are two parallel pathways for HAdV binding to cells that converge on integrins for productive infection. Moreover, these binding pathways function independently, and both operate in mixed culture. Thus, we have found that viruses can co-opt host defense molecules to expand their tropism.

Alpha-defensin binding expands human adenovirus tropism.

Mammalian α-defensins are a family of abundant effector peptides of the mucosal innate immune system. Although primarily considered to be antimicrobial, α-defensins can increase rather than block infection by certain prominent bacterial and viral pathogens in cell culture and in vivo. We have shown previously that exposure of mouse and human adenoviruses (HAdVs) to α-defensins is able to overcome competitive inhibitors that block cell binding, leading us to hypothesize a defensin-mediated binding mechanism that is independent of known viral receptors. To test this hypothesis, we used genetic approaches to demonstrate that none of several primary receptors nor integrin co-receptors are needed for human α-defensin-mediated binding of HAdV to cells; however, infection remains integrin dependent. Thus, our studies have revealed a novel pathway for HAdV binding to cells that bypasses viral primary receptors. We speculate that this pathway functions in parallel with receptor-mediated entry and contributes to α-defensin-enhanced infection of susceptible cells. Remarkably, we also found that in the presence of α-defensins, HAdV tropism is expanded to non-susceptible cells, even when viruses are exposed to a mixture of both susceptible and non-susceptible cells. Therefore, we propose that in the presence of sufficient concentrations of α-defensins, such as in the lung or gut, integrin expression rather than primary receptor expression will dictate HAdV tropism in vivo. In summary, α-defensins may contribute to tissue tropism not only through the neutralization of susceptible viruses but also by allowing certain defensin-resistant viruses to bind to cells independently of previously described mechanisms.

Clinical decision aids and computed tomography coronary angiography in patients with suspected acute coronary syndrome.

BACKGROUND: The HEART score, the T-MACS model and the GRACE score support early decision-making for acute chest pain, which could be complemented by CT coronary angiography (CTCA). However, their performance has not been directly compared. METHODS: In this secondary analysis of a multicentre randomised controlled trial of early CTCA in intermediate-risk patients with suspected acute coronary syndrome, C-statistics and performance metrics (using the predefined cut-offs) of clinical decision aids and CTCA, alone and then in combination, for the index hospital diagnosis of acute coronary syndrome and for 30-day coronary revascularisation were assessed in those who underwent CTCA and had complete data. RESULTS: Among 699 patients, 358 (51%) had an index hospital diagnosis of acute coronary syndrome, for which the C-statistic was higher for CTCA (0.80), followed by the T-MACS model (0.78), the HEART score (0.74) and the GRACE score (0.60). The negative predictive value was higher for the absence of coronary artery disease on CTCA (0.90) or a T-MACS estimate of <0.05 (0.83) than a HEART score of <4 (0.81) and a GRACE score of <109 (0.55). For 30-day coronary revascularisation, CTCA had the greatest C-statistic (0.80) with a negative predictive value of 0.96 and 0.92 in the absence of coronary artery disease and obstructive coronary artery disease, respectively. The combination of the T-MACS estimates and the CTCA findings was most discriminative for the index hospital diagnosis of acute coronary syndrome (C-statistic, 0.88) and predictive of 30-day coronary revascularisation (C-statistic, 0.85). No patients with a T-MACS estimate of <0.05 and normal coronary arteries had acute coronary syndrome during index hospitalisation or underwent coronary revascularisation within 30 days. CONCLUSIONS: In intermediate-risk patients with suspected acute coronary syndrome, the T-MACS model combined with CTCA improved discrimination of the index hospital diagnosis of acute coronary syndrome and prediction of 30-day coronary revascularisation. TRIAL REGISTRATION NUMBER: NCT02284191.

A Case Report of Sepsis Secondary to Perforated Cholecystitis in the Presence of Severe Aortic Stenosis: Diagnosis and Management.

Gallbladder perforation is a rare complication of acute cholecystitis that is associated with significant morbidity and mortality. Many cases of gallbladder perforation are not diagnosed until surgery, as the physical symptoms closely mimic acute cholecystitis. Gallbladder perforation is most common among older males with associated comorbidities, and preoperative assessment of comorbidities, particularly cardiac, is critical to determine the appropriate clinical course. We report a case of a 77-year-old male who presented initially with low blood pressure and right upper quadrant pain (RUQ) after not feeling well for five days. CT of the abdomen/pelvis with IV contrast demonstrated acute perforated cholecystitis, and general surgery was consulted for a cholecystectomy. Due to the patient's past medical history of severe aortic stenosis (AS), cholecystectomy was deferred and a cholecystostomy tube was placed by interventional radiology. This report aims to provide an example of a case of perforated cholecystitis with sepsis and how it can be diagnosed and managed non-surgically in the presence of pre-existing severe AS.

Psychometric validation of a patient-reported experience measure for older adults attending the emergency department: the PREM-ED 65 study.

INTRODUCTION: Optimising emergency department (ED) patient experience is vital to ensure care quality. However, there are few validated instruments to measure the experiences of specific patient groups, including older adults. We previously developed a draft 82-item Patient Reported Experience Measure (PREM-ED 65) for adults ≥65 attending the ED. This study aimed to derive a final item list and provide initial validation of the PREM-ED 65 survey. METHODS: A cross-sectional study involving patients in 18 EDs in England. Adults aged 65 years or over, deemed eligible for ED discharge, were recruited between May and August 2021 and asked to complete the 82-item PREM at the end of the ED visit and 7-10 days post discharge. Test-retest reliability was assessed 7-10 days following initial attendance. Analysis included descriptive statistics, including per-item proportions of responses, hierarchical item reduction, exploratory factor analysis (EFA), reliability testing and assessment of criterion validity. RESULTS: Five hundred and ten initial surveys and 52 retest surveys were completed. The median respondent age was 76. A similar gender mix (men 47.5% vs women 50.7%) and reason for attendance (40.3% injury vs 49.0% illness) was observed. Most participants self-reported their ethnicity as white (88.6%).Hierarchical item reduction identified 53/82 (64.6%) items for exclusion, due to inadequate engagement (n=33), ceiling effects (n=5), excessive inter-item correlation (n=12) or significant differential validity (n=3). Twenty-nine items were retained.EFA revealed 25 out of the 29 items demonstrating high factor loadings (>0.4) across four scales with an Eigenvalue >1. These scales were interpreted as measuring 'relational care', 'the ED environment', 'staying informed' and 'pain assessment'. Cronbach alpha for the scales ranged from 0.786 to 0.944, indicating good internal consistency. Test-retest reliability was adequate (intraclass correlation coefficient 0.67). Criterion validity was fair (r=0.397) when measured against the Friends and Families Test question. CONCLUSIONS: Psychometric testing demonstrates that the 25-item PREM-ED 65 is suitable for administration to adults ≥65 years old up to 10 days following ED discharge.

Adolescent social anxiety is associated with diminished discrimination of anticipated threat and safety in the bed nucleus of the stria terminalis.

Social anxiety-which typically emerges in adolescence-lies on a continuum and, when extreme, can be devastating. Socially anxious individuals are prone to heightened fear, anxiety, and the avoidance of contexts associated with potential social scrutiny. Yet most neuroimaging research has focused on acute social threat. Much less attention has been devoted to understanding the neural systems recruited during the uncertain anticipation of potential encounters with social threat. Here we used a novel fMRI paradigm to probe the neural circuitry engaged during the anticipation and acute presentation of threatening faces and voices in a racially diverse sample of 66 adolescents selectively recruited to encompass a range of social anxiety and enriched for clinically significant levels of distress and impairment. Results demonstrated that adolescents with more severe social anxiety symptoms experience heightened distress when anticipating encounters with social threat, and reduced discrimination of uncertain social threat and safety in the bed nucleus of the stria terminalis (BST), a key division of the central extended amygdala (EAc). Although the EAc-including the BST and central nucleus of the amygdala-was robustly engaged by the acute presentation of threatening faces and voices, the degree of EAc engagement was unrelated to the severity of social anxiety. Together, these observations provide a neurobiologically grounded framework for conceptualizing adolescent social anxiety and set the stage for the kinds of prospective-longitudinal and mechanistic research that will be necessary to determine causation and, ultimately, to develop improved interventions for this often-debilitating illness.