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Background: Biologic asthma therapies reduce exacerbations and long-term oral corticosteroids (LTOCS) use in randomized controlled trials (RCTs); however, there are limited data on outcomes among patients ineligible for RCTs. Hence, we investigated responsiveness to biologics in a real-world population of adults with severe asthma., Methods: Adults in the International Severe Asthma Registry (ISAR) with ≥24 weeks of follow-up were grouped into those who did, or did not, initiate biologics (anti-IgE, anti-IL5/IL5R, anti-IL4/13). Treatment responses were examined across four domains: forced expiratory volume in 1 second (FEV 1 ) increase by ≥100 mL, improved asthma control, annualized exacerbation rate (AER) reduction ≥50%, and any LTOCS dose reduction. Super-response criteria were: FEV 1 increase by ≥500 mL, new well-controlled asthma, no exacerbations, and LTOCS cessation or tapering to ≤5 mg/day., Results: 5.3% of ISAR patients met basic RCT inclusion criteria; 2116/8451 started biologics. Biologic initiators had worse baseline impairment than non-initiators, despite having similar biomarker levels. Half or more of initiators had treatment responses: 59% AER reduction, 54% FEV 1 increase, 49% improved control, 49% reduced LTOCS, of which 32%, 19%, 30%, and 39%, respectively, were super-responses. Responses/super-responses were more frequent in biologic initiators than in non-initiators; nevertheless, ~40-50% of initiators did not meet response criteria., Conclusions: Most patients with severe asthma are ineligible for RCTs of biologic therapies. Biologics are initiated in patients who have worse baseline impairments than non-initiators despite similar biomarker levels. Although biologic initiators exhibited clinical responses and super-responses in all outcome domains, 40-50% did not meet the response criteria., (© 2024 The Author(s). Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

The prevalence of pyramidal cells (PCs) in the mammalian cerebral cortex underscore their value as they play a crucial role in various brain functions, ranging from cognition, sensory processing, to motor output. PC morphology significantly influences brain connectivity and plays a critical role in maintaining normal brain function. Pathological alterations to PC morphology are thought to contribute to the aetiology of neurodevelopmental disorders such as autism spectrum disorder (ASD) and schizophrenia. This review explores the relationship between abnormalities in PC morphology in key cortical areas and the clinical manifestations in schizophrenia and ASD. We focus largely on human postmortem studies and provide evidence that dendritic segment length, complexity and spine density are differentially affected in these disorders. These morphological alterations can lead to disruptions in cortical connectivity, potentially contributing to the cognitive and behavioural deficits observed in these disorders. Furthermore, we highlight the importance of investigating the functional and structural characteristics of PCs in these disorders to illuminate the underlying pathogenesis and stimulate further research in this area., (© 2024 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Venous thromboembolism (VTE) continues to cause significant morbidity and excess mortality in patients with multiple myeloma. The report by Costa and colleagues demonstrates superiority of direct oral anticoagulants over aspirin in terms of VTE prevention, without increased bleeding complications seen. Commentary on: Costa et al. Direct oral anticoagulants versus aspirin for primary thromboprophylaxis in patients with multiple myeloma undergoing outpatient therapy: A systematic review and updated meta-analysis. Br J Haematol 2023;203:395-403., (© 2023 British Society for Haematology and John Wiley & Sons Ltd.)

Purpose: The purpose of this study was to examine the effectiveness of omega-3 fatty acids in comparison to a placebo in the management of dry eye disease., Methods: A systematic literature search was performed including randomised controlled trials (RCTs) comparing omega-3 versus placebo in the management of dry eye disease in human subjects. There were no language or time restrictions. Eligible trials were assessed for bias and assigned a risk-of-bias score. Data extraction was carried out using a standardised data extraction form, and meta-analysis was performed using a random effects model for continuous data. The outcome measures were Ocular Surface Disease Index (OSDI) scores, tear breakup time (TBUT) measurements, corneal staining and Schirmer's score. Statistical heterogeneity was defined as substantial if the I 2 test achieved a value >60%., Results: Eight parallel RCTs including 1107 subjects met eligibility criteria. None of the included studies achieved low risk of bias. Data synthesis demonstrated an improvement in the mean change in OSDI score from baseline to final assessment. Omega-3 supplementation conferred no evident improvement in corneal staining, TBUT or Schirmer's score. There was considerable statistical heterogeneity in all four outcome measures., Conclusions: This updated systematic review and meta-analysis indicates that omega-3 supplementation improves subjective symptoms in patients with dry eye disease., (© 2022 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Introduction: Adverse drug reactions (ADRs) can have significant negative impact on peoples' daily lives, with physical, economic, social and/or psychological effects. Patient reporting of ADRs has been facilitated by pharmacovigilance systems across Europe. However, capturing data on patients' experiences of ADRs has proved challenging. Existing patient reports to the UK Yellow Card Scheme contain free-text comments which could be useful sources of information., Objectives: To investigate patients' experiences of ADRs and their impact on patients as described in free-text data within patient Yellow Card (YC) reports submitted to the Medicines and Healthcare products Regulatory Agency., Methods: A qualitative review of narrative texts was conducted on free-text data from 2255 patient YC reports from July to December 2015., Results: Three key narrative themes emerged from analysis of the free-text data in 2255 reports: (1) identification of ADRs, (2) severity and impact of ADRs, and (3) management of ADRs. Temporal associations were the most common method of identification followed by differential diagnoses and confirmation with information sources such as healthcare professionals (HCPs). A combination of explicit and implicit impacts were described: physical, psychological, economic and social effects often persisted and caused serious disruption to many patients' lives. A range of strategies were used to manage ADRs, including consultation with HCPs, stopping/reducing the medicine or taking medicines to alleviate symptoms., Conclusion: Free-text data from YC reports has been an underutilised resource to date, but this research has confirmed its potential value to pharmacovigilance and medication safety research., (© 2022 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

To evaluate the quality of whole-exome sequencing (WES) reporting in the epilepsy literature. We aimed to assess the quality of reporting of WES in epilepsy. We compared studies based on journal type and if outcome reporting biases exist. We used a self-constructed benchmark to quantitatively analyze studies. We included 451 publications. Reporting was heterogeneous with poor reporting of (1) ACMG guideline application 13% and (2) Human Phenotype Ontology (HPO) numbers in 3% of studies, 3) VUS in 19%. Predictors of reporting included journal type and journal impact factor. Date of publication and publication type were not predictors of poor reporting. Pairwise comparisons of genetics versus neurology journals using relative risks yielded significant differences in reporting of ACMG guideline application (RR 1.88, 95% CI 1.04-3.38); HPO numbers (RR 8.62, 95% CI 1.08-63.37) and deposition of findings to ClinVar (RR 2.50, 95% CI 1.03-6.1). Reporting of WES literature is heterogeneous in quality, and poor reporting hinders collaboration and accession of data into large databases like OMIM and OrphaNet. This study highlights reporting bias in this area and, formal structural guidelines like the CONSORT guidelines used in the reporting of clinical trials are needed to address the issue., (© 2022 Wiley Periodicals LLC.)

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a novel entity that emerged in March 2021 following reports of unusual thrombosis after ChAdOx1 nCoV-19, (AstraZeneca) vaccination. Following the recognition of this syndrome, multiple consensus guidelines have been released to risk stratify patients presenting with possible symptoms after ChAdOx1 nCoV-19 vaccination. All guidelines rapidly identify VITT in patients with the complete triad of thrombocytopenia, thrombosis and elevated D-dimers after ChAdOx1 nCoV-19 vaccination. However, with earlier recognition of the associated symptoms, the clinical manifestations are likely to be more heterogeneous and represent an evolving spectrum of disease. In this setting, current guidelines may lack the sensitivity to detect early cases of VITT and risk missed or delayed diagnoses. The broad clinical phenotype and challenges associated with diagnosis of VITT are highlighted in our present case series of four patients with confirmed VITT. Dependent on the guidance used, each patient could have been classified as a low probability of VITT at presentation. The present study highlights the issues associated with the recognition of VITT, the limitations of current guidance and the need for heightened clinical vigilance as our understanding of the pathophysiology of this novel condition evolves., (© 2021 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Endothelial cell (EC) activation plays a key role in the pathogenesis of pulmonary microvascular occlusion, which is a hallmark of severe coronavirus disease 2019 (COVID-19). Consistent with EC activation, increased plasma von Willebrand factor antigen (VWF:Ag) levels have been reported in COVID-19. Importantly however, studies in other microangiopathies have shown that plasma VWF propeptide (VWFpp) is a more sensitive and specific measure of acute EC activation. In the present study, we further investigated the nature of EC activation in severe COVID-19. Markedly increased plasma VWF:Ag [median (interquatile range, IQR) 608·8 (531-830)iu/dl] and pro-coagulant factor VIII (FVIII) levels [median (IQR) 261·9 (170-315) iu/dl] were seen in patients with severe severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Sequential testing showed that these elevated VWF-FVIII complex levels remained high for up to 3 weeks. Similarly, plasma VWFpp levels were also markedly elevated [median (IQR) 324·6 (267-524) iu/dl]. Interestingly however, the VWFpp/VWF:Ag ratio was reduced, demonstrating that decreased VWF clearance contributes to the elevated plasma VWF:Ag levels in severe COVID-19. Importantly, plasma VWFpp levels also correlated with clinical severity indices including the Sequential Organ Failure Assessment (SOFA) score, Sepsis-Induced Coagulopathy (SIC) score and the ratio of arterial oxygen partial pressure to fractional inspired oxygen (P/F ratio). Collectively, these findings support the hypothesis that sustained fulminant EC activation is occurring in severe COVID-19, and further suggest that VWFpp may have a role as a biomarker in this setting., (© 2020 British Society for Haematology and John Wiley & Sons Ltd.)

Objectives: Although trainees and trainers find feedback interactions beneficial, difficulties in giving and receiving feedback are reported. Few studies have explored what drives trainees to seek feedback. This study explores how workplace-based assessments (WBAs) influence the ways surgical trainees seek feedback and feedback interactions., Methods: Utilising a template analysis approach, we conducted 10 focus groups with 42 surgical trainees from four regions across the UK. Data were independently coded by three researchers, incorporating three a priori themes identified from a previous quantitative study. Further themes emerged from exploration of these data. The final template, agreed by the three researchers, was applied to all focus group transcripts. The themes were linked in a diagrammatical form to allow critical exploration of the data., Results: Trainees' perceptions of the purpose of WBA for learning or an assessment of learning, and their relationship with their trainer impacted upon how trainees chose to use WBA. Perceiving WBA as a test led trainees to 'play the game': seek positive and avoid negative feedback through WBA. Perceiving WBA as a chance to learn led trainees to seek negative feedback. Some trainees sought negative feedback outside WBA. Negative feedback was more important for changing practice compared with positive feedback, which enabled trainees to 'look good' but had less of an effect on changing clinical practice. The timing of feedback relative to WBA was also important, with immediate feedback being more beneficial for learning; however, delayed feedback was still sought using WBA., Discussion: Trainees' perceptions of the purpose of WBA and their relationship with their trainer informed when they chose to seek feedback. Trainees who perceived WBA as a test were led to 'play the game' by seeking positive and avoiding negative feedback. Outside of WBA, trainees sought negative feedback, which was most important for change in practice., (© 2017 John Wiley & Sons Ltd and The Association for the Study of Medical Education.)

Keratoconus can behave more aggressively in pediatric than in adult patients. We systematically reviewed the literature to determine the effectiveness of corneal collagen cross-linking (CXL) in children. For this study, MEDLINE ® and Cochrane databases were searched for all studies examining the effects of standard, trans-epithelial or accelerated CXL protocols in patients age 18 years or younger. Primary outcomes were; uncorrected visual acuity (UCVA) and maximum keratometry (Kmax) and secondary outcomes were; best-corrected visual acuity (BCVA), mean refractive spherical equivalent (MRSE), central corneal thickness (CCT) and endothelial cell density (ECD). Standardized mean differences (SMD) and 95% confidence intervals were calculated, comparing baseline values with those at 6, 12 and 24 months. A total of 13 papers, published between May 2011 and December 2014 examining 490 eyes of 401 patients with a mean age of 15.25 (±1.5) years, were included in the qualitative analysis in this review. Nine papers were included in the meta-analysis, showing significant improvement in UCVA and BCVA and stable Kmax at 12 months, and stable UCVA, improved BCVA and improved Kmax at 24 months in the standard protocol group UCVA, BCVA and KMax were stable at 12 months in the trans-epithelial group. Mean refractive spherical equivalent (MRSE), CCT and ECD remained stable in both groups. In conclusion it was found that standard CXL may be effective in halting progression of keratoconus in pediatric patients at 1 year. However, larger, more long-term studies are required to ascertain its effectiveness., (© 2016 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Aims: Adverse drug reactions (ADRs) account for 3.2-7% of acute hospital admissions. The aim of this study was to assess prospectively knowledge of ADRs in patients admitted through the emergency department of a teaching hospital., Methods: Three hundred and ninety-nine patients were admitted on acute medical call during study periods in September 2002 and May 2003. One hundred gave their perception of the risk of ADRs using visual analogue scales, where 0 indicates minimum and 10 maximum risk. The medications studied were warfarin, proton pump inhibitors (PPIs), corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin. Responses are compared against a medical control group., Results: Corticosteroids were ranked most dangerous by patients (median score, 25th-75th centiles: 5.4, 2.9-8.7). Medical staff ranked NSAIDs as highest risk (6.2, 4.0-7.5). Patients identified NSAIDs as low risk (2.1, 0.7-4.9), perceiving the risk of cardiac arrhythmias and disturbance in liver biochemistry to be equivalent to risk of upper gastrointestinal ulceration and bleeding. Risk of haemorrhage was ranked as the most common ADR for warfarin by patients (8.6, 3.3-9.5) and medical staff (8.8, 7.6-9.3)., Conclusions: Patients underrate the risk of ADRs of their medications. While there is a good level of knowledge of ADRs amongst warfarin and aspirin users, there is a clear lack of knowledge regarding the risk of upper GI bleeding in NSAID users. Increased education may reduce the incidence of ADRs but it is more likely that it will serve to meet increasing patient expectations.