Uncertainty cues amplify late positive potential responses to aversive emotional stimuli.

Uncertainty is unavoidable, and maladaptive responses to uncertainty may underlie the etiology and maintenance of psychopathology. A general tendency to associate uncertainty with aversive consequences, a type of covariation bias, can amplify aversive emotional experiences. To address questions about uncertainty during emotion regulation, we examined the Late Positive Potential (LPP) - an electrocortical marker of attention to and appraisal of motivationally relevant emotional stimuli - during a task designed to measure the effect of covariation bias and its emotional response consequences. Event-related potentials (ERPs) were recorded while participants (N = 52) were presented with a pre-stimulus cue that either conveyed information about the valence of an upcoming emotional image, or left them in ambiguity. We replicated findings that demonstrate expectancy biases in a priori and online expectancies of emotion-eliciting images, as well as in a posteriori estimates for concurrence of uncertainty cues and aversive images. Moreover, we demonstrate a novel finding that uncertainty cues amplify the LPP in response to subsequent aversive emotional stimuli. These findings advance research by conjoining existing emotion regulation research on the LPP with study of the effects of uncertainty on emotional appraisal and highlight the importance of accounting for stimulus uncertainty in emotion regulation research.

Associations of an HDL apolipoproteomic index with cardiometabolic risk factors before and after exercise training in the HERITAGE Family Study.

BACKGROUND AND AIMS: Previous studies have derived and validated an HDL apolipoproteomic score (pCAD) that predicts coronary artery disease (CAD) risk. However, the associations between pCAD and markers of cardiometabolic health in healthy adults are not known, nor are the effects of regular exercise on pCAD. METHODS: A total of 641 physically inactive adults free of cardiovascular disease from the HERITAGE Family Study completed 20 weeks of exercise training. The pCAD index (range 0-100) was calculated using measurements of apolipoproteins A-I, C-I, C-II, C-III, and C-IV from ApoA-I-tagged serum (higher index = higher CAD risk). The associations between pCAD index and cardiometabolic traits at baseline and their training responses were assessed with Spearman correlation and general linear models. A Bonferroni correction of p < 8.9 × 10-04 was used to determine statistical significance. RESULTS: The mean ± SD baseline pCAD index was 29 ± 32, with 106 (16.5 %) participants classified as high CAD risk. At baseline, pCAD index was positively associated with blood pressure, systemic inflammation, and body composition. HDL size, VO2max, and HDL-C were negatively associated with pCAD index at baseline. Of those classified as high CAD risk at baseline, 52 (49 %) were reclassified as normal risk after training. Following training, pCAD index changes were inversely correlated (p < 1.4 × 10-04) with changes in HDL-C, HDL size, and LDL size. CONCLUSIONS: A higher pCAD index was associated with a worse cardiometabolic profile at baseline but improved with regular exercise. The results from this study highlight the potential role of HDL apolipoproteins as therapeutic targets for lifestyle interventions, particularly in high-risk individuals.

Quality control, safety assessment and preparation approaches of low molecular weight heparin.

Low Molecular Weight Heparins (LMWHs) are well-established for use in the prevention and treatment of thrombotic diseases, and as a substitute for unfractionated heparin (UFH) due to their predictable pharmacokinetics and subcutaneous bioavailability. LMWHs are produced by various depolymerization methods from UFH, resulting in heterogeneous compounds with similar biochemical and pharmacological properties. However, the delicate supply chain of UFH and potential contamination from animal sources require new manufacturing approaches for LMWHs. Various LMWH preparation methods are emerging, such as chemical synthesis, enzymatic or chemical depolymerization and chemoenzymatic synthesis. To establish the sameness of active ingredients in both innovator and generic LMWH products, the Food and Drug Administration has implemented a stringent scientific method of equivalence based on physicochemical properties, heparin source material and depolymerization techniques, disaccharide composition and oligosaccharide mapping, biological and biochemical properties, and in vivo pharmacodynamic profiles. In this review, we discuss currently available LMWHs, potential manufacturing methods, and recent progress for manufacturing quality control of these LMWHs.

Regional wall motion abnormalities in transthoracic echocardiography in patients with significant coronary artery disease and coronary collateral circulation in adults.

BACKGROUND: Coronary collateral circulation is a common finding in patients with chronic total occlusions (CTOs) resulting from chronic coronary artery disease (CAD). Regional wall motion abnormalities (RWMA) on transthoracic echocardiography (TTE) can be used for the diagnosis of CAD. However, little work has been done to investigate the impact of collateral vessels on the diagnostic accuracy of resting TTE for CAD. METHODS: A retrospective chart review was conducted of adults who received a resting TTE and cardiac catheterization within 30 days over a 4-year period at the Temple Baylor Scott & White echocardiography laboratory. Exclusion criteria included catheterization without coronary angiography and prior history of CAD, percutaneous coronary intervention (PCI), or coronary artery bypass graft (CABG). We analyzed RWMA on TTE in patients with CAD and coronary collateral circulation on cardiac catheterization to assess for correlation. RESULTS: Of the 753 patients were included in this study, 453 had CAD, 272 had both CAD and RWMA, 111 had collateral circulation, and 73 had collateral circulation and RWMA. There was no significant difference in RWMA in patients with CAD with and without collateral circulation. There was no significant difference in the sensitivity (60.0 % vs 59.2 %) and specificity (78.4 % vs 73.9 %) after collateral-adjusted interpretation of RWMA and CAD (p = 0.3). DISCUSSION: Our results suggest the average coronary collateral system is of insufficient clinical significance to prevent the development of RWMA on resting TTE.

Evaluating functional connectivity differences between DBS ON/OFF states in essential tremor.

Deep brain stimulation (DBS) targeting the ventral intermediate (Vim) nucleus of the thalamus is an effective treatment for essential tremor (ET). We studied 15 â€‹ET patients undergoing DBS to a major input/output tract of the Vim, the dentato-rubro-thalamic tract (DRTt), using resting state functional MRI (rsfMRI) to evaluate connectivity differences between DBS ON and OFF and elucidate significant regions most influential in impacting tremor control and/or concomitant gait ataxia. Anatomical/functional 1.5T MRIs were acquired and replicated for each DBS state. Tremor severity and gait ataxia severity were scored with DBS ON at optimal stimulation parameters and immediately upon DBS OFF. Whole brain analysis was performed using dual regression analysis followed by randomized permutation testing for multiple correction comparison. Regions of interest (ROI) analysis was also performed. All 15 patients had tremor improvement between DBS ON/OFF (p â€‹< â€‹0.001). Whole brain analysis revealed significant connectivity changes between states in the left pre-central gyrus and left supplemental motor area. Group analysis of ROIs revealed that, with threshold p â€‹< â€‹0.05, in DBS ON vs. OFF both tremor duration and tremor improvement were significantly correlated to changes in connectivity. A sub-group analysis of patients with greater ataxia had significantly decreased functional connectivity between multiple ROIs in the cortex and cerebellum when DBS was ON compared to OFF. Stimulation of the DRTt and concordant improvement of tremor resulted in connectivity changes seen in multiple regions outside the motor network; when combined with both structural and electrophysiologic connectivity, this may help to serve as a biomarker to improve DBS targeting and possibly predict outcome.

Long-Term Efficacy of Teprotumumab in Thyroid Eye Disease: Follow-Up Outcomes in Three Clinical Trials.

Introduction: Thyroid eye disease (TED) is an autoimmune process characterized by extraocular muscle and orbital fat remodeling/expansion resulting in swelling, pain, redness, proptosis, and diplopia. Teprotumumab, an insulin-like growth factor-I receptor inhibitor, demonstrated improvements in TED signs and symptoms in three adequately powered clinical trials of 24 weeks duration. Here we analyze the long-term maintenance of responses with teprotumumab from these trials. Methods: A total of 112 patients who received 7 or 8 infusions of teprotumumab in the Phase 2, Phase 3 (OPTIC study), and OPTIC Extension (OPTIC-X) studies were included in this analysis. Responses, including clinical activity score (CAS ≥2-point improvement), the European Group of Graves' Orbitopathy ophthalmic composite outcome, diplopia (≥1 Gorman grade improvement), proptosis (≥2 mm improvement), Overall (improvement in proptosis + CAS), and disease inactivation (CAS ≤1), were assessed and pooled from study baseline to week 24 (formal study) and up to week 72 (formal follow-up). Graves' Ophthalmopathy quality-of-life (GO-QoL) scores were also assessed. Outcomes included the percentages of observed patient responses from the study baseline. Additional alternative treatments for TED were assessed as a surrogate of persistent benefit from week 24 through week 120 (extended follow-up). Studies differed in the timing of follow-up visits, and data from some visits were unavailable. Results: At week 72, 52/57 (91.2%), 51/57 (89.5%), 35/48 (72.9%), 38/56 (67.9%), and 37/56 (66.1%) of patients were responders for CAS, composite outcome, diplopia, proptosis, and Overall response, respectively. The mean reduction in proptosis was 2.68 mm (SD 1.92, n = 56), mean GO-QoL improvement was 15.22 (SE 2.82, n = 56), and disease inactivation (CAS ≤1) was detected in 40/57 (70.2%). Over 99 weeks following teprotumumab therapy, 19/106 (17.9%) patients reported additional TED therapy during formal and extended follow-up. Conclusion: The long-term response to teprotumumab as observed 51 weeks after therapy was similar to week 24 results in the controlled clinical trials. Inflammatory and ophthalmic composite outcome improvements were seen in 90% of patients with nearly 70% reporting improvement in diplopia and proptosis. Further, 82% of patients in this analysis did not report additional TED treatment (including surgery) over 99 weeks following the final teprotumumab dose.

A genome-scale screen identifies sulfated glycosaminoglycans as pivotal in epithelial cell damage by Candida albicans.

Candidalysin is a cytolytic peptide produced by the opportunistic fungal pathogen Candida albicans. This peptide is a key virulence factor in mouse models of mucosal and hematogenously disseminated candidiasis. Despite intense interest in the role of candidalysin in C. albicans pathogenicity, its host cell targets have remained elusive. To fill this knowledge gap, we performed a genome-wide loss-of-function CRISPR screen in a human oral epithelial cell line to identify specific host factors required for susceptibility to candidalysin-induced cellular damage. Among the top hits were XYLT2 , B3GALT6 and B3GAT3 , genes that function in glycosaminoglycan (GAG) biosynthesis. Deletion of these genes led to the absence of GAGs such as heparan sulfate on the epithelial cell surface and increased resistance to damage induced by both candidalysin and live C. albicans. Biophysical analyses including surface plasmon resonance and atomic force and electron microscopy indicated that candidalysin physically binds to sulfated GAGs, facilitating its oligomerization or enrichment on the host cell surface. The addition of exogenous sulfated GAGs or the GAG analogue dextran sulfate protected cells against candidalysin-induced damage. Dextran sulfate, but not non-sulfated dextran, also inhibited epithelial cell endocytosis of C. albicans and fungal-induced epithelial cell cytokine and chemokine production. In a murine model of vulvovaginal candidiasis, topical dextran sulfate administration reduced host tissue damage and decreased intravaginal IL-1ß and neutrophil levels. Collectively, these data indicate that GAGs are epithelial cell targets of candidalysin and can be used therapeutically to protect cells from candidalysin-induced damage.

miR-100 and miR-125b Contribute to Enhanced 3D Growth and Invasiveness and can be Functionally Transferred to Silence Target Genes in Recipient Cells.

Extracellular communication via the transfer of vesicles and nanoparticles is now recognized to play an important role in tumor microenvironment interactions. Cancer cells upregulate and secrete abundant levels of miR-100 and miR-125b that can alter gene expression by both cell- and non-cell-autonomous mechanisms. We previously showed that these miRNAs activate Wnt signaling in colorectal cancer (CRC) through noncanonical pairing with 5 negative regulators of Wnt signaling. To identify additional targets of miR-100 and miR-125b , we used bioinformatic approaches comparing multiple CRC cell lines, including knockout lines lacking one or both of these miRNAs. From an initial list of 96 potential mRNA targets, we tested 15 targets with 8 showing significant downregulation in the presence of miR-100 and miR-125b . Among these, Cingulin (CGN) and Protein tyrosine phosphatase receptor type-R (PTPRR) are downregulated in multiple cancers, consistent with regulation by increased levels of miR-100 and miR-125b. We also show that increased cellular levels of miR-100 and miR-125b enhance 3D growth and invasiveness in CRC and glioblastoma cell lines. Lastly, we demonstrate that extracellular transfer of miR-100 and miR-125b can silence both reporter and endogenous mRNA targets in recipient cells and also increase the invasiveness of recipient spheroid colonies when grown under 3D conditions in type I collagen.

Global epidemiology of alcohol-associated liver disease in adolescents and young adults.

BACKGROUND AND AIMS: The objective of the study was to analyse the prevalence, incidence, and death of alcohol-associated liver disease (ALD) among adolescents and young adults globally, continentally, and nationally, focusing on trends over time. METHODS: The study analysed data from the Global Burden of Disease (GBD) study between 2000 and 2019. It examined ALD's prevalence, incidence, and death in adolescents and young adults aged 15-29, segmented by region, nation, and sociodemographic index. The analysis utilised Joinpoint regression modelling to calculate the annual per cent change (APC) in the rate of these parameters over time. RESULTS: In 2019, there were 281,450 ALD prevalences, 18,930 incidences, and 3190 deaths among adolescents and young adults globally. From 2000 to 2019, the age-adjusted prevalence rate per 100,000 increased in the 25-29 age group (APC: +0.6%, p = 0.003), remained stable among ages 20-24 (p = 0.302) and ages 15-19 (p = 0.160). Prevalence increased significantly from age 15-19 to 20-24 (19-fold increase) and from age 20-24 to 25-29 (2.5-fold increase). ALD prevalence rates increased in all age groups in adolescents and young adults in Africa and the Eastern Mediterranean region. Around three-quarters of countries and territories experienced an increase in ALD incidence rates in young adults. CONCLUSION: Over two decades, the burden of ALD among adolescents and young adults has increased globally. The study emphasises the importance of public health policies aimed at reducing alcohol consumption and preventing ALD among younger populations.

Alloying and Doping Control in the Layered Metal Phosphide Thermoelectric CaCuP.

We recently identified CaCuP as a potential low cost, low density thermoelectric material, achieving zT = 0.5 at 792 K. Its performance is limited by a large lattice thermal conductivity, κL, and by intrinsically large p-type doping levels. In this paper, we address the thermal and electronic tunability of CaCuP. Isovalent alloying with As is possible over the full solid solution range in the CaCuP1-xAsx series. This leads to a reduction in κL due to mass fluctuations but also to a detrimental increase in p-type doping due to increasing Cu vacancies, which prevents zT improvement. Phase boundary mapping, exploiting small deviations from 1:1:1 stoichiometry, was used to explore doping tunability, finding increasing p-type doping to be much easier than decreasing the doping level. Calculation of the Lorenz number within the single parabolic band approximation leads to an unrealistic low κL for highly doped samples consistent with the multiband behavior in these materials. Overall, CaCuP and slightly Cu-enriched CaCu1.02P yield the best performance, with zT approaching 0.6 at 873 K.

Non-canonical mRNA translation initiation in cell stress and cancer.

The now well described canonical mRNA translation initiation mechanism of m7G 'cap' recognition by cap-binding protein eIF4E and assembly of the canonical pre-initiation complex consisting of scaffolding protein eIF4G and RNA helicase eIF4A has historically been thought to describe all cellular mRNA translation. However, the past decade has seen the discovery of alternative mechanisms to canonical eIF4E mediated mRNA translation initiation. Studies have shown that non-canonical alternate mechanisms of cellular mRNA translation initiation, whether cap-dependent or independent, serve to provide selective translation of mRNAs under cell physiological and pathological stress conditions. These conditions typically involve the global downregulation of canonical eIF4E1/cap-mediated mRNA translation, and selective translational reprogramming of the cell proteome, as occurs in tumor development and malignant progression. Cancer cells must be able to maintain physiological plasticity to acquire a migratory phenotype, invade tissues, metastasize, survive and adapt to severe microenvironmental stress conditions that involve inhibition of canonical mRNA translation initiation. In this review we describe the emerging, important role of non-canonical, alternate mechanisms of mRNA translation initiation in cancer, particularly in adaptation to stresses and the phenotypic cell fate changes involved in malignant progression and metastasis. These alternate translation initiation mechanisms provide new targets for oncology therapeutics development.

An anion exchange membrane sensor detects EGFR and its activity state in plasma CD63 extracellular vesicles from patients with glioblastoma.

We present a quantitative sandwich immunoassay for CD63 Extracellular Vesicles (EVs) and a constituent surface cargo, EGFR and its activity state, that provides a sensitive, selective, fluorophore-free and rapid alternative to current EV-based diagnostic methods. Our sensing design utilizes a charge-gating strategy, with a hydrophilic anion exchange membrane functionalized with capture antibodies and a charged silica nanoparticle reporter functionalized with detection antibodies. With sensitivity and robustness enhancement by the ion-depletion action of the membrane, this hydrophilic design with charged reporters minimizes interference from dispersed proteins, thus enabling direct plasma analysis without the need for EV isolation or sensor blocking. With a LOD of 30 EVs/µL and a high relative sensitivity of 0.01% for targeted proteomic subfractions, our assay enables accurate quantification of the EV marker, CD63, with colocalized EGFR by an operator/sample insensitive universal normalized calibration. We analysed untreated clinical samples of Glioblastoma to demonstrate this new platform. Notably, we target both total and "active" EGFR on EVs; with a monoclonal antibody mAb806 that recognizes a normally hidden epitope on overexpressed or mutant variant III EGFR. Analysis of samples yielded an area-under-the-curve (AUC) value of 0.99 and a low p-value of 0.000033, surpassing the performance of existing assays and markers.

First use of a new extended reality tool for preoperative planning in coronary artery bypass surgery: a case-report.

A 73-year-old male presented with angina symptoms and was diagnosed with three-vessel coronary artery disease by use of computed tomography angiography and coronary angiography. This diagnosis necessitated coronary artery bypass grafting (CABG) surgery. A custom made AI-driven algorithm was used to generate a patient-specific three-dimensional coronary artery model from computed tomography angiography imaging data. This framework enabled precise segmentation and reconstruction of the coronary vasculature, yielding an accurate anatomical and pathological representation. Subsequently, this generated model was integrated into a novel extended reality tool for preoperative planning and intraoperative guidance in CABG surgery. Both preoperatively and intraoperatively, the tool augmented spatial orientation and facilitated precise stenosis localization, thereby enhancing the surgeon's operative proficiency. This case report underscores the utility of advanced extended reality tools in cardiovascular surgery, emphasizing their pivotal role in refining surgical planning and execution.

The career pathways of new family physicians in South Africa from 2008 to 2022.

BACKGROUND:  Family medicine has trained specialist family physicians in South Africa since 2008, but not investigated their career pathways. The study aimed to determine the career pathways of newly qualified family physicians between 2008 and 2022. METHODS:  A cross-sectional descriptive survey of all 186 family physicians via an electronic questionnaire. RESULTS:  Response rate was 44.6% (83/186). Overall, 9.6% emigrated, 10.8% were no longer practising, and 79.5% were still practising in South Africa. Of the latter, 14.5% were in the private sector, 55.4% in the public sector and 9.6% in both. Of those in the public sector, 33.7% were in specialist family physician posts, 12% in medical officer posts, 4.8% in managerial positions and 4.8% in academic positions. Issues relating to safety and security were important to those working in both sectors and relationships with colleagues in the clinical team, to those in the public sector. Overall, participants practised near or within their province of training and were not equitably distributed. CONCLUSION:  Only a third of graduates were in specialist family physician posts in the public sector. Attention needs to be given to retaining more graduates in such posts to achieve the goals of the national position paper. The proportion in the private sector was lower than expected. The reasons for no longer practising medicine should be further explored.Contribution: This is the first study on the career pathways of family physicians in South Africa since the new speciality was created. Understanding these pathways will assist with human resources for health planning.

Mental Wellness Self-Care in Singapore With mindline.sg: A Tutorial on the Development of a Digital Mental Health Platform for Behavior Change.

BACKGROUND: Singapore, like the rest of Asia, faces persistent challenges to mental health promotion, including stigma around unwellness and seeking treatment and a lack of trained mental health personnel. The COVID-19 pandemic, which created a surge in mental health care needs and simultaneously accelerated the adoption of digital health solutions, revealed a new opportunity to quickly scale innovative solutions in the region. OBJECTIVE: In June 2020, the Singaporean government launched mindline.sg, an anonymous digital mental health resource website that has grown to include >500 curated local mental health resources, a clinically validated self-assessment tool for depression and anxiety, an artificial intelligence (AI) chatbot from Wysa designed to deliver digital therapeutic exercises, and a tailored version of the website for working adults called mindline at work. The goal of the platform is to empower Singapore residents to take charge of their own mental health and to be able to offer basic support to those around them through the ease and convenience of a barrier-free digital solution. METHODS: Website use is measured through click-level data analytics captured via Google Analytics and custom application programming interfaces, which in turn drive a customized analytics infrastructure based on the open-source platforms Titanium Database and Metabase. Unique, nonbounced (users that do not immediately navigate away from the site), engaged, and return users are reported. RESULTS: In the 2 years following launch (July 1, 2020, through June 30, 2022), the website received >447,000 visitors (approximately 15% of the target population of 3 million), 62.02% (277,727/447,783) of whom explored the site or engaged with resources (referred to as nonbounced visitors); 10.54% (29,271/277,727) of those nonbounced visitors returned. The most popular features on the platform were the dialogue-based therapeutic exercises delivered by the chatbot and the self-assessment tool, which were used by 25.54% (67,626/264,758) and 11.69% (32,469/277,727) of nonbounced visitors. On mindline at work, the rates of nonbounced visitors who engaged extensively (ie, spent ≥40 seconds exploring resources) and who returned were 51.56% (22,474/43,588) and 13.43% (5,853/43,588) over a year, respectively, compared to 30.9% (42,829/138,626) and 9.97% (13,822/138,626), respectively, on the generic mindline.sg site in the same year. CONCLUSIONS: The site has achieved desired reach and has seen a strong growth rate in the number of visitors, which required substantial and sustained digital marketing campaigns and strategic outreach partnerships. The site was careful to preserve anonymity, limiting the detail of analytics. The good levels of overall adoption encourage us to believe that mild to moderate mental health conditions and the social factors that underly them are amenable to digital interventions. While mindline.sg was primarily used in Singapore, we believe that similar solutions with local customization are widely and globally applicable.

Causally Probing the Role of the Hippocampus in Fear Discrimination: A Precision Functional Mapping-Guided, Transcranial Magnetic Stimulation Study in Participants With Posttraumatic Stress Symptoms.

Background: Fear overgeneralization is a promising pathogenic mechanism of clinical anxiety. A dominant model posits that hippocampal pattern separation failures drive overgeneralization. Hippocampal network-targeted transcranial magnetic stimulation (HNT-TMS) has been shown to strengthen hippocampal-dependent learning/memory processes. However, no study has examined whether HNT-TMS can alter fear learning/memory. Methods: Continuous theta burst stimulation was delivered to individualized left posterior parietal stimulation sites derived via seed-based connectivity, precision functional mapping, and electric field modeling methods. A vertex control site was also stimulated in a within-participant, randomized controlled design. Continuous theta burst stimulation was delivered prior to 2 visual discrimination tasks (1 fear based, 1 neutral). Multilevel models were used to model and test data. Participants were undergraduates with posttraumatic stress symptoms (final n = 25). Results: Main analyses did not indicate that HNT-TMS strengthened discrimination. However, multilevel interaction analyses revealed that HNT-TMS strengthened fear discrimination in participants with lower fear sensitization (indexed by responses to a control stimulus with no similarity to the conditioned fear cue) across multiple indices (anxiety ratings: ß = 0.10, 95% CI, 0.04 to 0.17, p = .001; risk ratings: ß = 0.07, 95% CI, 0.00 to 0.13, p = .037). Conclusions: Overgeneralization is an associative process that reflects deficient discrimination of the fear cue from similar cues. In contrast, sensitization reflects nonassociative responding unrelated to fear cue similarity. Our results suggest that HNT-TMS may selectively sharpen fear discrimination when associative response patterns, which putatively implicate the hippocampus, are more strongly engaged.

Fear overgeneralization is a promising pathogenic mechanism of clinical anxiety that is thought to be driven by deficient hippocampal discrimination. Using hippocampal network­targeted transcranial magnetic stimulation (HNT-TMS) in healthy participants with symptoms of posttraumatic stress, Webler et al. report that HNT-TMS did not strengthen discrimination overall, but it did strengthen fear discrimination in participants with lower fear sensitization. Sensitization reflects nonassociative fear responding unrelated to fear cue similarity and therefore is not expected to engage the hippocampal discrimination function. These results suggest that HNT-TMS may selectively sharpen fear discrimination when the hippocampal discrimination function is more strongly engaged.

Regional and Local Inequalities in Disability Status by Sexual Orientation and Gender Identity: A Cross-Sectional Ecological Analysis of the 2021 Census of England and Wales.

Purpose: To examine regional differences in disability status by sexual orientation and gender identity and to explore local factors that are associated with levels of inequalities for people who identify as lesbian, gay, bisexual, or other sexual orientations (LGB+) or transgender. Methods: This was a cross-sectional ecological analysis of 2021 Census data from England and Wales. The main outcome variable was disability status. The main explanatory variables were sexual orientation and gender identity. Weighed linear regression was used to examine differences in disability status by sexual orientation (LGB+ vs. heterosexual) and gender identity (transgender vs. cisgender). The magnitude of between-group differences was explored by region and, in England, local authority-level urbanization and socioeconomic deprivation. Results: Among 48.5 million census respondents within 331 local authority districts (LADs) across England and Wales, LGB+ and transgender groups were more likely to report having a disability than their heterosexual and cisgender counterparts. Inequalities were prevalent across regions of England and Wales, but were smallest in the Greater London area and largest in the southwest of England. Inequalities were also larger within English LADs that were relatively less urbanized and relatively more socioeconomically deprived. Conclusions: This study identified disparities in disability status by sexual orientation and gender identity, which varied by region and local socioeconomic deprivation and urbanization. More research is needed to better understand how to support disabled LGBT+ people, especially those in less urbanized and more socioeconomically deprived areas.

Drivers of Variation in Opioid Prescribing after Common Surgical Procedures in a Large Multihospital Healthcare System.

BACKGROUND: Misuse of prescription opioids is a well-established contributor to the United States opioid epidemic. The primary objective of this study was to identify which level of care delivery (i.e. patient, prescriber, or hospital) produced the most unwarranted variation in opioid prescribing after common surgical procedures. STUDY DESIGN: Electronic health record (EHR) data from a large multihospital healthcare system was used in conjunction with random-effect models to examine variation in opioid prescribing practices following similar inpatient and outpatient surgical procedures between October 2019 and September 2021. Unwarranted variation was conceptualized as variation resulting from prescriber behavior unsupported by evidence. Covariates identified as drivers of warranted variation included characteristics known to influence pain levels or patient safety. All other model variables, including prescriber specialty and patient race, ethnicity, and insurance status were characterized as potential drivers of unwarranted variation. RESULTS: Among 25,188 procedures with an opioid prescription at hospital discharge, 53.5% exceeded guideline recommendations, corresponding to 13,228 patients receiving the equivalent of >140,000 excess 5mg oxycodone tablets following surgical procedures. Prescribing variation was primarily driven by prescriber-level factors, with approximately half of the total variation in morphine milligram equivalents (MMEs) prescribed observed at the prescriber level and not explained by any measured variables. Unwarranted covariates associated with higher prescribed opioid quantity included non-Hispanic black race, Medicare insurance, smoking history, later hospital discharge times, and prescription by a surgeon rather than a hospitalist or primary care provider. CONCLUSION: Given the large proportion of unexplained variation observed at the provider level, targeting prescribers through education and training may be an effective strategy for reducing postoperative opioid prescribing.

Considerations for using potential surrogate endpoints in cancer screening trials.

The requirement of large-scale expensive cancer screening trials spanning decades creates considerable barriers to the development, commercialisation, and implementation of novel screening tests. One way to address these problems is to use surrogate endpoints for the ultimate endpoint of interest, cancer mortality, at an earlier timepoint. This Review aims to highlight the issues underlying the choice and use of surrogate endpoints for cancer screening trials, to propose criteria for when and how we might use such endpoints, and to suggest possible candidates. We present the current landscape and challenges, and discuss lessons and shortcomings from the therapeutic trial setting. It is hugely challenging to validate a surrogate endpoint, even with carefully designed clinical studies. Nevertheless, we consider whether there are candidates that might satisfy the requirements defined by research and regulatory bodies.