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Hypertrophic cardiomyopathy is one of the most frequently diagnosed primary conditions of the heart muscle. It is considered to be inherited, caused by genetic mutations encoding for sarcomere proteins. The marked heterogeneity in clinical manifestations and natural course of the disease, even among family members sharing the same genetic mutation, has raised the question of non-genetic environmental factors contributing to the phenotype. Obesity has been associated with worse cardiovascular outcomes in the general population. Its prevalence is increased in hypertrophic cardiomyopathy, and the two conditions share some similar pathophysiological and clinical characteristics. In this review, we aim to summarise the effects of obesity in the cardiac phenotype, the symptoms and management in patients with hypertrophic cardiomyopathy., (© Royal College of Physicians 2023. All rights reserved.)

Heart failure (HF) remains an important global health issue, substantially contributing to morbidity and mortality. According to epidemiological studies, men and women face nearly equivalent lifetime risks for HF. However, their experiences diverge significantly when it comes to HF subtypes: men tend to develop HF with reduced ejection fraction more frequently, whereas women are predominantly affected by HF with preserved ejection fraction. This divergence underlines the presence of numerous sex-based disparities across various facets of HF, encompassing aspects such as risk factors, clinical presentation, underlying pathophysiology, and response to therapy. Despite these apparent discrepancies, our understanding of them is far from complete, with key knowledge gaps still existing. Current guidelines from various professional societies acknowledge the existence of sex-based differences in HF management, yet they are lacking in providing explicit, actionable recommendations tailored to these differences. In this comprehensive review, we delve deeper into these sex-specific differences within the context of HF, critically examining associated definitions, risk factors, and therapeutic strategies. We provide a specific emphasis on aspects exclusive to women, such as the impact of pregnancy-induced hypertension and premature menopause, as these unique factors warrant greater attention in the broader HF discussion. Additionally, we aim to clarify ongoing controversies and knowledge gaps pertaining to the pharmacological treatment of HF and the sex-specific indications for cardiac implantable electronic devices. By shining a light on these issues, we hope to stimulate a more nuanced understanding and promote the development of more sex-responsive approaches in HF management.

Background: Electronic templates are frequently used in long-term condition (LTC) reviews (for example, asthma) to act as reminders and improve documentation; however, they can restrict patient-centred care and opportunities for patients to discuss concerns and self-management., Aim: The IMPlementing IMProved Asthma self-management as RouTine (IMP 2 ART) programme aimed to develop a patient-centred asthma review template that encourages supported self-management., Design & Setting: This was a mixed-methods study, which integrated qualitative and systematic review data, primary care Professional Advisory Group feedback, and qualitative data from clinician interviews., Method: Aligned with the Medical Research Council complex intervention framework, a template was developed in the following three phases: (1) development phase, which consisted of a qualitative exploration with clinicians and patients, a systematic review, and prototype template development; (2) feasibility pilot phase, which involved feedback from clinicians ( n = 7); and (3) pre-piloting phase, which consisted of delivering the template within the IMP 2 ART implementation strategy (incorporating the template with patient and professional resources) and eliciting clinician feedback ( n = 6)., Results: Template development was guided by the preliminary qualitative work and the systematic review. A prototype template was developed with an opening question to establish patient agendas, and a closing prompt to confirm agendas have been addressed and an asthma action plan provided. The feasibility pilot identified refinements needed, including focusing the opening question on asthma. Pre-piloting ensured integration with the IMP 2 ART strategy., Conclusion: Following the multi-stage development process, the implementation strategy, including the asthma review template, is now being tested in a cluster randomised controlled trial., (Copyright © 2023, The Authors.)

Perceived stigmatization places a large psychosocial burden on patients with some skin conditions. Little is known about the experience of stigmatization across a wide range of skin diseases. This observational cross-sectional study aimed to quantify perceived stigmatization and identify its predictors among patients with a broad spectrum of skin diseases across 17 European countries. Self-report questionnaires assessing perceived stigmatization and its potential predictors were completed by 5,487 dermatology outpatients and 2,808 skin-healthy controls. Dermatological diagnosis, severity, and comorbidity were clinician-assessed. Patients experienced higher levels of perceived stigmatization than controls (p < 0.001, d   = 0.26); patients with psoriasis, atopic dermatitis, alopecia, and bullous disorders were particularly affected. Multivariate regression analyses showed that perceived stigmatization was related to sociodemographic (lower age, male sex, being single), general health-related (higher body mass index, lower overall health), disease-related (higher clinician-assessed disease severity, presence of itch, longer disease duration), and psychological (greater distress, presence of suicidal ideation, greater body dysmorphic concerns, lower appearance satisfaction) variables. To conclude, perceived stigmatization is common in patients with skin diseases. Factors have been identified that will help clinicians and policymakers to target vulnerable patient groups, offer adequate patient management, and to ultimately develop evidence-based interventions.

Context: Prader-Willi syndrome (PWS) is a rare neurobehavioral-metabolic disease caused by the lack of paternally expressed genes in the chromosome 15q11-q13 region, characterized by hypotonia, neurocognitive problems, behavioral difficulties, endocrinopathies, and hyperphagia resulting in severe obesity if not controlled., Objective: The primary end point was change from baseline in hyperphagia using the Hyperphagia Questionnaire for Clinical Trials (HQ-CT). Other end points included Global Impression Scores, and changes in body composition, behaviors, and hormones., Methods: In DESTINY PWS, a 13-week, randomized, double-blind, placebo-controlled, phase 3 trial, 127 participants with PWS aged 4 years and older with hyperphagia were randomly assigned 2:1 to diazoxide choline extended-release tablet (DCCR) or placebo., Results: DCCR did not significantly improve hyperphagia (HQ-CT least-square mean (LSmean) [SE] -5.94 [0.879] vs -4.27 [1.145]; P = .198), but did so in participants with severe hyperphagia (LSmean [SE] -9.67 [1.429] vs -4.26 [1.896]; P = .012). Two of 3 secondary end points were improved (Clinical Global Impression of Improvement [CGI-I]; P = .029; fat mass; P = .023). In an analysis of results generated pre-COVID, the primary (HQ-CT; P = .037) and secondary end points were all improved (CGI-I; P = .015; Caregiver Global Impression of Change; P = .031; fat mass; P = .003). In general, DCCR was well tolerated with 83.3% in the DCCR group experiencing a treatment-emergent adverse event and 73.8% in the placebo group (not significant)., Conclusion: DCCR did not significantly improve hyperphagia in the primary analysis but did in participants with severe baseline hyperphagia and in the pre-COVID analysis. DCCR treatment was associated with significant improvements in body composition and clinician-reported outcomes., Competing Interests: Conflict of Interest N.C. and A.B. are employed by Soleno Therapeutics and own stock in the company. N.C. is an inventor on patents assigned to Soleno Therapeutics. The institution of J.L.M., E.G., N.B., J.A.Y., P.S., K.S.O., E.I.F., L.M.B., A.H.S., M.A., M.G.B., D.S., J.A., T.B., M.L., E.L., and V.M. received funding from Soleno to support the conduct of the clinical trial. L.M.B. reports that the support provided to the organization she is associated with for the conduct of the clinical trial also included some salary support. E.G. reports receipt of lecturing and consulting fees from Soleno. J.A.Y. reports grant support from Soleno Therapeutics and from Rhythm Pharmaceuticals for obesity-related projects, and material support for research from Hikma Pharmaceuticals and Versanis-Bio., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Syndemic theory is described as population-level clustering or co-occurrence of health conditions in the context of shared aetiologies that interact and can act synergistically. These influences appear to act within specific places of high disadvantage. We suggest ethnic inequality in experiences and outcomes of multimorbidity, including psychosis, may be explained through a syndemic framework. We discuss the evidence for each component of syndemic theory in relation to psychosis, using psychosis and diabetes as an exemplar. Following this, we discuss the practical and theoretical adaptations to syndemic theory in order to apply it to psychosis, ethnic inequality and multimorbidity, with implications for research, policy, and practice., (© 2023. The Author(s).)

Access to COVID-19 vaccines on the global scale has been drastically hindered by structural socio-economic disparities. Here, we develop a data-driven, age-stratified epidemic model to evaluate the effects of COVID-19 vaccine inequities in twenty lower middle and low income countries (LMIC) selected from all WHO regions. We investigate and quantify the potential effects of higher or earlier doses availability. In doing so, we focus on the crucial initial months of vaccine distribution and administration, exploring counterfactual scenarios where we assume the same per capita daily vaccination rate reported in selected high income countries. We estimate that more than 50% of deaths (min-max range: [54-94%]) that occurred in the analyzed countries could have been averted. We further consider scenarios where LMIC had similarly early access to vaccine doses as high income countries. Even without increasing the number of doses, we estimate an important fraction of deaths (min-max range: [6-50%]) could have been averted. In the absence of the availability of high-income countries, the model suggests that additional non-pharmaceutical interventions inducing a considerable relative decrease of transmissibility (min-max range: [15-70%]) would have been required to offset the lack of vaccines. Overall, our results quantify the negative impacts of vaccine inequities and underscore the need for intensified global efforts devoted to provide faster access to vaccine programs in low and lower-middle-income countries., (© 2023. The Author(s).)

In gestation, the coronary circulation develops initially in the compact layer and it expands only in fetal development to the trabeculations. Conflicting data have been published as to whether the trabecular layer is hypoperfused relative to the compact wall after birth. If so, this could explain the poor pump function in patients with left ventricular excessive trabeculation, or so-called noncompaction. Here, we review direct and indirect assessments of myocardial perfusion in normal and excessively trabeculated hearts by in vivo imaging by magnetic resonance imaging (MRI), positron emission tomography (PET)/single photon emission computed tomography (SPECT), and echocardiography in addition to histology, injections of labelled microspheres in animals, and electrocardiography. In MRI, PET/SPECT, and echocardiography, flow of blood or myocardial uptake of blood-borne tracer molecules are measured. The imaged trabecular layer comprises trabeculations and blood-filled intertrabecular spaces whereas the compact layer comprises tissue only, and spatio-temporal resolution likely affects measurements of myocardial perfusion differently in the two layers. Overall, studies measuring myocardial uptake of tracers (PET/SPECT) suggest trabecular hypoperfusion. Studies measuring the quantity of blood (echocardiography and MRI) suggest trabecular hyperperfusion. These conflicting results are reconciled if the low uptake from intertrabecular spaces in PET/SPECT and the high signal from intertrabecular spaces in MRI and echocardiography are considered opposite biases. Histology on human hearts reveal a similar capillary density of trabecular and compact myocardium. Injections of labelled microspheres in animals reveal a similar perfusion of trabecular and compact myocardium. In conclusion, trabecular and compact muscle are likely equally perfused in normal hearts and most cases of excessive trabeculation., Competing Interests: Declaration of competing interest Steffen E Petersen provides consultancy to Cardiovascular Imaging Inc., Calgary, Alberta, Canada., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: This study examined longitudinal associations between attention-deficit/hyperactivity disorder (ADHD) symptoms and social isolation across childhood. The study tested the direction of this association across time, while accounting for preexisting characteristics, and assessed whether this association varied by ADHD presentation, informant, sex, and socioeconomic status., Method: Participants included 2,232 children from the Environmental Risk (E-Risk) Longitudinal Twin Study. ADHD symptoms and social isolation were measured at ages 5, 7, 10, and 12. Random-intercept cross-lagged panel models were used to assess the directionality of the association across childhood., Results: Children with increased ADHD symptoms were consistently at increased risk of becoming socially isolated later in childhood, over and above stable characteristics (β = .05-.08). These longitudinal associations were not bidirectional; isolated children were not at risk of worsening ADHD symptoms later on. Children with hyperactive ADHD presentation were more likely to become isolated, compared with inattentive presentation. This was evident in the school setting, as observed by teachers, but not by mothers at home., Conclusion: The study findings highlight the importance of enhancing peer social support and inclusion for children with ADHD, particularly in school settings. This study adds explanatory value beyond traditional longitudinal methods, as the results represent how individual children change over time, relative to their own preexisting characteristics., Diversity & Inclusion Statement: We worked to ensure sex and gender balance in the recruitment of human participants. We worked to ensure that the study questionnaires were prepared in an inclusive way. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented sexual and/or gender groups in science. We actively worked to promote sex and gender balance in our author group. The author list of this paper includes contributors from the location and/or community where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work., (© 2023 The Author(s).)

Whether non-alcoholic fatty liver disease (NAFLD) is a cardiovascular (CV) risk factor is debated. We performed a systematic review and meta-analysis to assess the CV morbidity and mortality related to NAFLD in the general population, and to determine whether CV risk is comparable between lean and non-lean NAFLD phenotypes. We searched multiple databases, including PubMed, Embase, and the Cochrane Library, for observational studies published through 2022 that reported the risk of CV events and mortality. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) for all-cause mortality, CV mortality, myocardial infarction (MI), stroke, atrial fibrillation (AF), and major adverse cardiovascular and cerebrovascular events (MACCE) were assessed through random-effect meta-analysis. We identified 33 studies and a total study population of 10,592,851 individuals (mean age 53±8; male sex 50%; NAFLD 2, 9%). Mean follow-up was 10±6 years. Pooled ORs for all-cause and CV mortality were respectively 1.14 (95% CI, 0.78-1.67) and 1.13 (95% CI, 0.57-2.23), indicating no significant association between NAFLD and mortality. NAFLD was associated with increased risk of MI (OR 1.6; 95% CI, 1.5-1.7), stroke (OR: 1.6; 95% CI, 1.2-2.1), atrial fibrillation (OR: 1.7; 95% CI, 1.2-2.3), and MACCE (OR: 2.3; 95% CI, 1.3-4.2). Compared with non-lean NAFLD, lean NAFLD was associated with increased CV mortality (OR: 1.50; 95% CI, 1.1-2.0), but similar all-cause mortality and risk of MACCE. While NAFLD may not be a risk factor for total and CV mortality, it is associated with excess risk of non-fatal CV events. Lean and non-lean NAFLD phenotypes exhibit distinct prognostic profiles and should receive equitable clinical care., Competing Interests: Conflict of interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Good evidence is available that socioeconomic status (SES) positively correlates with access to orthodontic treatment. There is much less literature, however, on whether socioeconomic inequities affect patients once they are in treatment. SES predicts of treatment outcomes across many health disciplines., Objectives: To determine whether a similar relationship exists with orthodontic treatment and identify, evaluate and summarise the available evidence., Methods: Systematic review with searches of multiple databases to identify studies of children and adolescents who underwent orthodontic treatment, in which parental SES was the variable of interest, and treatment duration, treatment outcome or adherence of patients to the treatment plan were the measured outcomes of interest. Quality appraisal used CASP checklists. Data were synthesised narratively and in tables and graphs., Results: Seventeen studies were included in the final review. The high level of heterogeneity between studies made it hard to draw conclusions from the data as a whole. Many studies also had several quality issues. Some evidence suggested an association between low SES and discontinuation of orthodontic treatment, and between the receipt of state subsidised care and poor appointment attendance., Conclusion: No strong associations can be concluded. There is a need for more high-quality studies, perhaps incorporating access and uptake variables, to capture how different socioeconomic groups interact with orthodontic care., (Copyright© 2023 Dennis Barber Ltd.)

Acute myeloid leukemia (AML) is a hematological malignancy derived from neoplastic myeloid progenitor cells characterized by abnormal clonal proliferation and differentiation. Although novel therapeutic strategies have recently been introduced, the prognosis of AML is still unsatisfactory. So far, the efficacy of chimeric antigen receptor (CAR)-T-cell therapy in AML has been hampered by several factors, including the poor accumulation of the blood-injected cells in the leukemia bone marrow (BM) niche in which chemotherapy-resistant leukemic stem cells reside. Thus, we hypothesized that overexpression of CXCR4, whose ligand CXCL12 is highly expressed by BM stromal cells within this niche, could improve T-cell homing to the BM and consequently enhance their intimate contact with BM-resident AML cells, facilitating disease eradication. Specifically, we engineered conventional CD33.CAR-cytokine-induced killer cells (CIKs) with the wild-type (wt) CXCR4 and the variant CXCR4R334X, responsible for leukocyte sequestration in the BM of patients with warts, hypogammaglobulinemia, immunodeficiency, and myelokathexis syndrome. Overexpression of both CXCR4wt and CXCR4mut in CD33.CAR-CIKs resulted in significant improvement of chemotaxis toward recombinant CXCL12 or BM stromal cell-conditioned medium, with no observed impairment of cytotoxic potential in vitro. Moreover, CXCR4-overexpressing CD33.CAR-CIKs showed enhanced in vivo BM homing, associated with a prolonged retention for the CXCR4R334X variant. However, only CD33.CAR-CIKs coexpressing CXCR4wt but not CXCR4mut exerted a more sustained in vivo antileukemic activity and extended animal survival, suggesting a noncanonical role for CXCR4 in modulating CAR-CIK functions independent of BM homing. Taken together, these data suggest that arming CAR-CIKs with CXCR4 may represent a promising strategy for increasing their therapeutic potential for AML., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

It is well known that skin disease is associated with significant psychosocial morbidity, and that patients with skin disease can present with higher rates of suicidality than the general population. Clinicians often report numerous barriers to detecting and managing suicidality in busy outpatient settings. We aimed to establish the degree of suicidality within our psychodermatology patients and establish key characteristics that may serve as additional risk factors for suicidality. We conducted a retrospective review of clinical letters, patient notes, and a clinical database, for all 69 patients that attended our psychodermatology clinic since it was founded. Two practitioners independently recorded patient baseline demographics, presenting dermatological condition, comorbidities, Dermatology Life Quality Index scores and self-reported suicidal behaviour for each patient. From this we calculated how many patients displayed signs of active suicidality, and identified common themes and characteristics within this patient group. We went onto develop a flow diagram to guide professionals when faced with an actively suicidal patient in clinic., Competing Interests: None to declare., (© 2023 The Authors. Skin Health and Disease published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Introduction: Patellofemoral pain (PFP) is common and predominately affects active populations. Altered biomechanics and psychosocial variables have been reported in people with PFP, but the effects of neuromuscular exercise on these variables is unknown. We aimed to investigate changes in biopsychosocial measures following a two-week neuromuscular intervention in people with PFP., Materials and Methods: We measured pain (visual analogue scale), function (Kujala), activity level (Tegner), psychological well-being (Orebro), lower-limb isometric strength (handheld dynamometry), three-dimensional (3D) lower limb kinematics, and surface electromyography (sEMG), in people with PFP. 3D lower-limb kinematics and sEMG were synchronously sampled during step-up, step-down, and overground running. All measures were repeated after participants had completed a two-week neuromuscular intervention consisting of three exercises completed once per day, five days per week., Results: 18 participants completed pre/post testing (60% females, mean age 30.6 years ±7.0, height 173.4cm ±10.4, mass 70.2kg ±12.4, symptom duration 39.0 months ±58.8), with three of 21 participants lost to follow-up. Across all clinical measures (muscle onsets, muscle activation and kinematics), the 95% bootstrapped confidence intervals (CI) of the mean difference contained the null hypothesis following the two-week neuromuscular intervention, indicating no significant differences., Conclusion: A two-week neuromuscular intervention did not change biomechanical or psychosocial measures in people with PFP. Interventions with a longer duration or greater load magnitude are required to fully evaluate the biopsychosocial mechanisms of effect for exercise in people with PFP., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Lack, Bartholomew, North, Miller and Neal.)

Background: Plantar Heel Pain (PHP) is a common disorder with many treatment pathways and is not self-limiting, hence prognostic information concerning recovery or recalcitrance is needed to guide practice. In this systematic review, we investigate which prognostic factors are associated with favourable or unfavourable PHP outcomes., Methods: MEDLINE, Web of Science, EMBASE, Scopus and PubMed electronic bibliographic databases were searched for studies evaluating baseline patient characteristics associated with outcomes in prospective longitudinal cohorts or after specific interventions. Cohort, clinical prediction rule derivation and single arms of randomised controlled trials were included. Risk of bias was evaluated with method-specific tools and evidence certainty with GRADE., Results: The review included five studies which evaluated 98 variables in 811 participants. Prognostic factors could be categorised as demographics, pain, physical and activity-related. Three factors including sex and bilateral symptoms (HR: 0.49[0.30-0.80], 0.33[0.15-0.72], respectively) were associated with a poor outcome in a single cohort study. The remaining four studies reported twenty factors associated with a favourable outcome following shockwave therapy, anti-pronation taping and orthoses. Heel spur (AUC = 0.88[0.82-0.93]), ankle plantar-flexor strength (Likelihood ratio (LR): 2.17[1.20-3.95]) and response to taping (LR = 2.17[1.19-3.90]) were the strongest factors predicting medium-term improvement. Overall, the study quality was low. A gap map analysis revealed an absence of research that included psychosocial factors., Conclusions: A limited number of biomedical factors predict favourable or unfavourable PHP outcomes. High quality, adequately powered, prospective studies are required to better understand PHP recovery and should evaluate the prognostic value of a wide range of variables, including psychosocial factors., (© 2023. Crown.)

Purpose: Metastatic papillary renal cancer (PRC) has poor outcomes, and new treatments are required. There is a strong rationale for investigating mesenchymal epithelial transition receptor (MET) and programmed cell death ligand-1 (PD-L1) inhibition in this disease. In this study, the combination of savolitinib (MET inhibitor) and durvalumab (PD-L1 inhibitor) is investigated., Methods: This single-arm phase II trial explored durvalumab (1,500 mg once every four weeks) and savolitinib (600 mg once daily; ClinicalTrials.gov identifier: NCT02819596). Treatment-naïve or previously treated patients with metastatic PRC were included. A confirmed response rate (cRR) of > 50% was the primary end point. Progression-free survival, tolerability, and overall survival were secondary end points. Biomarkers were explored from archived tissue (MET-driven status)., Results: Forty-one patients treated with advanced PRC were enrolled into this study and received at least one dose of study treatment. The majority of patients had Heng intermediate risk score (n = 26 [63%]). The cRR was 29% (n = 12; 95% CI, 16 to 46), and the trial therefore missed the primary end point. The cRR increased to 53% (95% CI, 28 to 77) in MET-driven patients (n/N = 9/27) and was 33% (95% CI, 17 to 54) in PD-L1-positive tumors (n/N = 9/27). The median progression-free survival was 4.9 months (95% CI, 2.5 to 10.0) in the treated population and 12.0 months (95% CI, 2.9 to 19.4) in MET-driven patients. The median overall survival was 14.1 months (95% CI, 7.3 to 30.7) in the treated population and 27.4 months (95% CI, 9.3 to not reached [NR]) in MET-driven patients. Grade 3 and above treatment related adverse events occurred in 17 (41%) patients. There was 1 grade 5 treatment-related adverse event (cerebral infarction)., Conclusion: The combination of savolitinib and durvalumab was tolerable and associated with high cRRs in the exploratory MET-driven subset.

Atypical chemokine receptors (ACKRs) scavenge chemokines and can contribute to gradient formation by binding, internalizing, and delivering chemokines for lysosomal degradation. ACKRs do not couple to G-proteins and fail to induce typical signaling induced by chemokine receptors. ACKR3, which binds and scavenges CXCL12 and CXCL11, is known to be expressed in vascular endothelium, where it has immediate access to circulating chemokines. ACKR4, which binds and scavenges CCL19, CCL20, CCL21, CCL22, and CCL25, has also been detected in lymphatic and blood vessels of secondary lymphoid organs, where it clears chemokines to facilitate cell migration. Recently, GPR182, a novel ACKR-like scavenger receptor, has been identified and partially deorphanized. Multiple studies point towards the potential coexpression of these 3 ACKRs, which all interact with homeostatic chemokines, in defined cellular microenvironments of several organs. However, an extensive map of ACKR3, ACKR4, and GPR182 expression in mice has been missing. In order to reliably detect ACKR expression and coexpression, in the absence of specific anti-ACKR antibodies, we generated fluorescent reporter mice, ACKR3GFP/+, ACKR4GFP/+, GPR182mCherry/+, and engineered fluorescently labeled ACKR-selective chimeric chemokines for in vivo uptake. Our study on young healthy mice revealed unique and common expression patterns of ACKRs in primary and secondary lymphoid organs, small intestine, colon, liver, and kidney. Furthermore, using chimeric chemokines, we were able to detect distinct zonal expression and activity of ACKR4 and GPR182 in the liver, which suggests their cooperative relationship. This study provides a broad comparative view and a solid stepping stone for future functional explorations of ACKRs based on the microanatomical localization and distinct and cooperative roles of these powerful chemokine scavengers., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Melgrati et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Stackelberg evolutionary game (SEG) theory combines classical and evolutionary game theory to frame interactions between a rational leader and evolving followers. In some of these interactions, the leader wants to preserve the evolving system (e.g. fisheries management), while in others, they try to drive the system to extinction (e.g. pest control). Often the worst strategy for the leader is to adopt a constant aggressive strategy (e.g. overfishing in fisheries management or maximum tolerable dose in cancer treatment). Taking into account the ecological dynamics typically leads to better outcomes for the leader and corresponds to the Nash equilibria in game-theoretic terms. However, the leader's most profitable strategy is to anticipate and steer the eco-evolutionary dynamics, leading to the Stackelberg equilibrium of the game. We show how our results have the potential to help in fields where humans try to bring an evolutionary system into the desired outcome, such as, among others, fisheries management, pest management and cancer treatment. Finally, we discuss limitations and opportunities for applying SEGs to improve the management of evolving biological systems. This article is part of the theme issue 'Half a century of evolutionary games: a synthesis of theory, application and future directions'.

Introduction: Tumor infiltrating lymphocytes (TILs) are known to be a prognostic and predictive biomarker in breast cancer, particularly in triple negative breast cancer (TNBC) patients. International guidelines have been proposed to evaluate them in the clinical setting as a continuous variable, without a clear defined cut-off. However, there are scenarios where the immune infiltration is heterogeneous that some areas of the patient's tumour have high numbers of TILs while other areas completely lack them. This spontaneous presentation of a heterogeneous immune infiltration could be a great opportunity to study why some tumours present TILs at diagnosis but others do not, while eliminating inter patient's differences., Methods: In this study, we have identified five TNBC patients that showed great TIL heterogeneity, with areas of low (≤5%) and high (≥50%) numbers of TILs in their surgical specimens. To evaluate immune infiltration heterogeneity, we performed and analyzed bulk RNA-sequencing in three independent triplicates from the high and low TIL areas of each patient., Results: Gene expression was homogeneous within the triplicates in each area but was remarkable different between TILs regions. These differences were not only due to the presence of TILs as there were other non-inflammatory genes and pathways differentially expressed between the two areas., Discussion: This highlights the importance of intratumour heterogeneity driving the immune infiltration, and not patient's characteristics like the HLA phenotype, germline DNA or immune repertoire., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Quintana, Arenas, Bernadó, Navarro, González, Esteve-Codina, Moliné, Marti, Curigliano, Schmid, Peg, Arribas and Cortés.)

Background: Guidelines recommend verification of myocardial ischemia by selective second-line myocardial perfusion imaging (MPI) following a coronary computed tomography angiography (CTA) with suspected obstructive coronary artery disease (CAD). Head-to-head data on the diagnostic performance of different MPI modalities in this setting are sparse., Objectives: The authors sought to compare, head-to-head, the diagnostic performance of selective MPI by 3.0-T cardiac magnetic resonance (CMR) and 82 rubidium positron emission tomography (RbPET) in patients with suspected obstructive stenosis at coronary CTA using invasive coronary angiography (ICA) with fractional flow reserve (FFR) as reference., Methods: Consecutive patients (n = 1,732, mean age: 59.1 ± 9.5 years, 57.2% men) referred for coronary CTA with symptoms suggestive of obstructive CAD were included. Patients with suspected stenosis were referred for both CMR and RbPET and subsequently ICA. Obstructive CAD was defined as FFR ≤0.80 or >90% diameter stenosis by visual assessment., Results: In total, 445 patients had suspected stenosis on coronary CTA. Of these, 372 patients completed both CMR, RbPET and subsequent ICA with FFR. Hemodynamically obstructive CAD was identified in 164 of 372 (44.1%) patients. Sensitivities for CMR and RbPET were 59% (95% CI: 51%-67%) and 64% (95% CI: 56%-71%); P = 0.21, respectively, and specificities 84% (95% CI: 78%-89%) and 89% (95% CI: 84%-93%]); P = 0.08, respectively. Overall accuracy was higher for RbPET compared with CMR (73% vs 78%; P = 0.03)., Conclusions: In patients with suspected obstructive stenosis at coronary CTA, CMR, and RbPET show similar and moderate sensitivities but high specificities compared with ICA with FFR. This patient group represents a diagnostic challenge with frequent mismatch between advanced MPI tests and invasive measurements. (Danish Study of Non-Invasive Diagnostic Testing in Coronary Artery Disease 2 [Dan-NICAD 2]; NCT03481712)., Competing Interests: Funding Support and Author Disclosures The study was supported by the Health Research Fund of Central Denmark Region, Aarhus University Research Foundation, and by an institutional research grant from Acarix A/S, Denmark. Dr Winther has received support from the Novo Nordisk Foundation Clinical Emerging Investigator grant (NNF21OC0066981). Dr Benovoy is an employee and shareholder of Circle Cardiovascular Imaging Inc. Dr Petersen has served as a consultant to and is stockowner of Circle Cardiovascular Imaging Inc. Dr Böttcher has participated in advisory boards for Novo Nordisk, AstraZeneca, Pfizer, Boehringer Ingelheim, Bayer, Sanofi, Novartis, AMGEN, CLS-Behring, and Acarix. All other authors have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. All rights reserved.)

Experimental findings for trait impressions from voices are often discussed in relation to potential evolutionary origins. This commentary takes Sutherland and Young's (2022) account of the different potential origins of facial trait impressions to suggest that vocal trait impressions should also be viewed as having been shaped by cultural and individual learning., (© The Author. British Journal of Psychology published by John Wiley & Sons Ltd on behalf of The British Psychological Society.)

Objective: People from ethnic minority backgrounds are less likely to attend colonoscopy, following faecal immunochemical test screening, and are more likely to be diagnosed with colorectal cancer at an advanced stage as a result. The aim of this research was to explore the barriers and facilitators to attending colonoscopy, perceived by ethnic minority groups living in the United Kingdom., Methods: Semi-structured online and telephone interviews were conducted with thirty men and women of Black-African (n = 5), Black-Caribbean (n = 5), South Asian (n = 10) and White British (n = 10) descent. Participants were eligible for screening, but had not necessarily been invited for colonoscopy. All interviews were conducted in the participant's first language and were assessed using Framework-analysis, in line with a conceptual framework developed from previous interviews with healthcare professionals., Results: Five thematic groups of barriers and facilitators were developed: 'Locus of control', 'Cultural attitudes and beliefs', 'Individual beliefs, knowledge and personal experiences with colonoscopy and cancer', 'Reliance on family and friends' and 'Health concerns'. Differences were observed, between ethnic groups, for: 'Locus of control', 'Cultural attitudes and beliefs' and 'Reliance on family and friends'. Black and South Asian participants frequently described the decision to attend colonoscopy as lying with 'God' (Muslims, specifically), 'the doctor', or 'family' (Locus of control). Black and South Asian participants also reported relying on friends and family for 'language, transport and emotional support' (Reliance on family and friends). Black-African participants, specifically, described cancer as 'socially taboo' (Cultural attitudes and beliefs)., Conclusions: The results highlight several targets for culturally-tailored interventions to make colonoscopy more equitable., (© 2023 The Authors. Psycho-Oncology published by John Wiley & Sons Ltd.)

To evaluate the safety and tolerability of the fixed-dose, single-tablet regimen sofosbuvir/velpatasvir (SOF/VEL) for the treatment of hepatitis C virus (HCV) infection in three Phase 3 studies in patients with and without compensated cirrhosis. Data from three registrational trials (ASTRAL-1, NCT02201940; ASTRAL-2, NCT02220998; ASTRAL-3, NCT02201953) were pooled by treatment regimen. Researchers assessed treatment-emergent adverse events (TEAEs) and laboratory abnormalities in patients randomized to SOF/VEL or placebo for 12 weeks in ASTRAL-1 and SOF/VEL for 12 weeks in ASTRAL-2 and ASTRAL-3. Overall, 1035 patients were treated with SOF/VEL, and 116 patients received placebo. Rates of any TEAE were generally similar between patients receiving SOF/VEL (79.4%) and those receiving placebo (76.7%). The majority of TEAEs were mild to moderate, with 23 (2.2%) treatment-emergent serious AEs in patients treated with SOF/VEL. Of these treatment-emergent serious AEs, none led to premature study discontinuation, nor were they considered related to treatment. Presence of compensated cirrhosis, greater age and mild renal impairment did not impact incidence or severity of TEAEs with SOF/VEL treatment. The most common TEAEs (incidence ≥10%) were headache, fatigue, nausea and nasopharyngitis in patients receiving SOF/VEL; similar rates were observed in placebo-treated patients. Three deaths (<1%) were reported in patients treated with SOF/VEL, all posttreatment and none assessed as related to study treatment. Similar to that of placebo, SOF/VEL treatment of HCV infection had a safety/tolerability profile that was not affected by baseline factors, such as the presence of compensated cirrhosis, mild renal impairment or advanced age., (© 2023 The Authors. Journal of Viral Hepatitis published by John Wiley & Sons Ltd.)

Introduction: Tumor-associated macrophages (TAMs) are key components of a tumoral microenvironment and have been shown to impact prognosis in different cancers. Previously reported data showed that TAM morphology correlates with prognosis in colorectal liver metastases (CLMs) after hepatectomy, with smaller TAMs (S-TAMs) conferring a more favorable prognosis than larger ones (L-TAMs). This study aims to externally validate this finding., Material and Methods: The external cohort consisted of 84 formalin-fixed and paraffin-embedded surgical samples of CLMs and peritumoral tissue. Two-micrometer-section slides were obtained; the area and perimeter of 21 macrophages in each slide were recorded. The endpoints were TAMs morphometrics and their prognostic significance in relation to disease-free survival (DFS)., Results: The average macrophage perimeter was 71.5±14.1 μm whilst the average area was 217.7±67.8 μm 2 . At univariate analysis, the TAM area demonstrated a statistically significant association with DFS ( P =0.0006). Optimal area cutoff value was obtained, showing a sensitivity and specificity of 92 and 56%, respectively. S-TAMs and L-TAMs were associated with 3-year DFS rates of 60 and 8.5%, respectively ( P <0.001). Multivariate analysis confirmed the predictive role of TAM area for DFS [hazard ratio (HR)=5.03; 95% CI=1.70-14.94; P =0.003]. Moreover, in a subset of patients ( n =12) characterized by unfavorable ( n =6, recurrence within 3 months) or favorable ( n =6, no recurrence after 48 months) prognosis, TAMs showed a different distribution: L-TAMs were more abundant and closer to the tumor invasive margin in patients that encountered early recurrence and tended to cluster in foci significantly larger ( P =0.02)., Conclusions: This external validation confirms that morphometric characterization of TAMs can serve as a simple readout of their diversity and allows to reliably stratify patient outcomes and predict disease recurrence after hepatectomy for CLMs., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Sepsis arises from diverse and incompletely understood dysregulated host response processes following infection that leads to life-threatening organ dysfunction. Here we showed that neutrophils and emergency granulopoiesis drove a maladaptive response during sepsis. We generated a whole-blood single-cell multiomic atlas (272,993 cells, n = 39 individuals) of the sepsis immune response that identified populations of immunosuppressive mature and immature neutrophils. In co-culture, CD66b + sepsis neutrophils inhibited proliferation and activation of CD4 + T cells. Single-cell multiomic mapping of circulating hematopoietic stem and progenitor cells (HSPCs) (29,366 cells, n = 27) indicated altered granulopoiesis in patients with sepsis. These features were enriched in a patient subset with poor outcome and a specific sepsis response signature that displayed higher frequencies of IL1R2 + immature neutrophils, epigenetic and transcriptomic signatures of emergency granulopoiesis in HSPCs and STAT3-mediated gene regulation across different infectious etiologies and syndromes. Our findings offer potential therapeutic targets and opportunities for stratified medicine in severe infection., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Detecting low dose rates of X-rays is critical for making safer radiology instruments, but is limited by the absorber materials available. Here, we develop bismuth oxyiodide (BiOI) single crystals into effective X-ray detectors. BiOI features complex lattice dynamics, owing to the ionic character of the lattice and weak van der Waals interactions between layers. Through use of ultrafast spectroscopy, first-principles computations and detailed optical and structural characterisation, we show that photoexcited charge-carriers in BiOI couple to intralayer breathing phonon modes, forming large polarons, thus enabling longer drift lengths for the photoexcited carriers than would be expected if self-trapping occurred. This, combined with the low and stable dark currents and high linear X-ray attenuation coefficients, leads to strong detector performance. High sensitivities reaching 1.1  × 10 3  μC Gy air -1  cm -2 are achieved, and the lowest dose rate directly measured by the detectors was 22 nGy air  s -1 . The photophysical principles discussed herein offer new design avenues for novel materials with heavy elements and low-dimensional electronic structures for (opto)electronic applications., (© 2023. The Author(s).)

Hematological toxicity represents the most common grade ≥3 toxicity after chimeric antigen receptor (CAR) T-cell therapy. However, its underlying pathophysiology is incompletely understood and its grading and management remains ill-defined. To inform the forthcoming European Hematology Association/European Society for Blood and Marrow Transplantation (EHA/EBMT) guidelines on the management of "immune effector cell-associated hematotoxicity" (ICAHT), we undertook a survey of experienced clinicians using an online survey focusing on (1) grading, (2) risk-stratification and diagnostic work-up, (3) short-term, and (4) long-term management of ICAHT. There were 81 survey respondents across 18 countries. A high degree of variability was noted for cytopenia grading in regards to depth, duration, and time from CAR-T infusion. The majority of experts favored pre-CAR-T bone marrow studies, especially in case of a high-risk profile. Most respondents felt that the work-up for patients with severe hematotoxicity should rule-out viral infections (96%), substrate deficiency (80%), or coincident sHLH/MAS (serum ferritin, 92%), and should include bone marrow aspiration (86%) and/or biopsy (61%). Clinicians were divided as to whether the occurrence of coincident immunotoxicity should influence the decision to apply G-CSF, and when to initiate G-CSF support. In case of prolonged thrombocytopenia, most survey participants favored thrombopoietin agonists (86%). Conversely, autologous hematopoietic cell boosts represented the preferred choice for neutropenia (63%), although they were frequently not available and no consensus was reached regarding the optimal trigger point. These findings underline the current heterogeneity of practice patterns regarding ICAHT and invite the development of consensus guidelines, which may harmonize grading, establish standard operating procedures for diagnosis, and set management guidelines., Competing Interests: KR: Kite/Gilead: Research Funding and travel support; Novartis: Honoraria; BMS/Celgene: Consultancy, Honoraria; School of Oncology of the German Cancer Consortium (DKTK): fellowship; Else Kröner Forschungskolleg (EKFK) within the Munich Clinician Scientist Program (MCSP): funding. FO: Travel, Accommodations, Expenses: Takeda, Kyowa Kirin International, Medac. CB: inventor of different patents on cancer immunotherapy and genetic engineering; member of Advisory Boards and Consultant for, Intellia, Kite/Gilead, Miltenyi, Kiadis, QuellTx, Janssen, Chroma, Genyo, Pancancer-T, Alia, and received research support from Intellia Therapeutics. AS: Honoraria: Takeda, Bristol Myers Squibb, Merck Sharp and Dohme, Celgene, Janssen, Sanofi, Roche, Novartis, Gilead Sciences, Janssen-Cilag; Consulting or Advisory Role: Takeda, Bristol Myers Squibb, Gilead Sciences, Celgene, Janssen, Novartis; Speakers’ Bureau: Takeda; Travel, Accommodations, Expenses: Kite/Gilead. JGG: Received honoraria from Amgen, BMS Gilead/Kite, Janssen, Novartis, and received research funding from AZ, BMS and Janssen. IY-A: Received honoraria from Novartis, Gilead/Kite, BMS and Janssen. MS: Morphosys: Research Funding; Novartis: Consultancy, Research Funding; Janssen: Consultancy; Seattle Genetics: Research Funding; AMGEN: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Kite/Gilead: Consultancy, Honoraria, Research Funding; Roche AG: Consultancy, Research Funding. None of the mentioned conflicts of interest were related to financing of the content of this article. All the other authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)

COVID-19 dramatically influenced students' and staff's learning and teaching experiences and approaches to learning. While many papers examined individual experiences in the context of higher education, synthesising these papers to determine enabling and hindering influences of digital adaptation was needed to guide the next phase of online learning reforms. This study explored the main dimensions of digital technology adaptation in higher education during the COVID-19 pandemic. The consequences for student and staff experiences and what aspects should be sustained and developed were discussed in this review. A total of 90 articles (published between 1st January 2020 and 30th June 2021) were identified and analysed based on the preferred reporting items for systematic reviews and meta-analyses framework. Four dimensions (with associated sub-factors) were found to influence student and staff experiences: techno-economic; personal and psychological; teaching, learning and assessment; and social. The findings highlighted that an integrated approach, across institutional, technical platforms, and individuals would be required to sustain digital learning initiatives during the crisis time., Supplementary Information: The online version contains supplementary material available at 10.1007/s12528-023-09376-z., Competing Interests: Conflict of interestThe authors declare no conflicts of interest., (© The Author(s) 2023.)

Background: Real-world data evaluating effectiveness and persistence of systemic therapies for patients with psoriasis are limited. Objectives To determine the effectiveness and persistence of acitretin, ciclosporin, fumaric acid esters (FAEs) and methotrexate in patients with moderate-to-severe psoriasis., Methods: Data from the British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR), a prospective, multicentre pharmacovigilance register of patients with moderate-to-severe psoriasis receiving biologic and/or conventional systemic therapies, were analysed. Eligible patients were ≥ 16 years of age receiving a first course of acitretin, ciclosporin, FAEs or methotrexate between 2007 and 2021 with ≥ 6 months' follow-up. Effectiveness was defined as achieving absolute Psoriasis Area and Severity Index (aPASI) ≤ 2 reported ≥ 4 weeks after treatment start date until date of cessation. To identify baseline clinical variables associated with treatment effectiveness, we used multivariable logistic regression models estimating the adjusted odds ratio (aOR) of achieving aPASI ≤ 2. To describe drug persistence associated with ineffectiveness, occurrence of adverse events or other reasons for discontinuation, survival estimates with 95% confidence intervals (CIs) were obtained using a flexible parametric model. Results were obtained using multiple imputed data., Results: In total, 5430 patients were included in the analysis. Overall, 1023 (19%) patients were receiving acitretin, 1401 (26%) patients were on ciclosporin, 347 (6%) patients were on FAEs, and 2659 (49%) patients were receiving methotrexate at registration. The proportion of patients who achieved aPASI ≤ 2 was lower for those treated with acitretin [n = 118 (21%)] compared with those receiving ciclosporin [n = 233 (34%)], FAEs [n = 43 (29%)] and methotrexate [n = 372 (32%)]. Factors associated with ineffectiveness included prior experience to previous nonbiologic systemic therapies (acitretin) (aOR 0.64, 95% CI 0.42-0.96), male sex (methotrexate) (aOR 0.58, 95% CI 0.46-0.74), comorbidities (aOR 0.70, 95% CI 0.51-0.97) and alcohol consumption (≤ 14 units per week) (ciclosporin) (aOR 0.70, 95% CI 0.50-0.98). Persistence associated with all reasons for discontinuation showed better survival for methotrexate compared with acitretin, ciclosporin and FAEs cohorts at 12 months [survival estimate 46.1 (95% CI 44.0-48.3), 31.9 (95% CI 29.4-34.7), 30.0 (95% CI 27.5-32.4) and 35.0 (95% CI 29.9-40.9), respectively]., Conclusions: The real-world effectiveness and persistence of acitretin, ciclosporin, FAEs and methotrexate were generally low. Previous nonbiologic systemic therapies, male sex, comorbidities and alcohol consumption were risk factors associated with treatment ineffectiveness., Competing Interests: Conflicts of interest P.J.H. has received educational grants, consultancy fees and research funding from Janssen, AbbVie, Eli Lilly and LEO Pharma. P.M.L. has received honoraria and/or grants as an investigator, speaker, and/or acted as an advisory board member for AbbVie, Almirall, Amgen, Celgene, Janssen Cilag, Eli Lilly, Pfizer, Sanofi, LEO, UCB Pharma and Novartis. N.J.R. has received travel support, research grants (Newcastle University) and income to Newcastle University for advisory boards/lectures from AbbVie, Almirall, Celgene, Boehringer Ingelheim, Janssen Cilag, Novartis and UCB Pharma. A.B. has received travel bursaries and performed ad hoc consultancy and lecturing roles with AbbVie, Almirall, Galderma, Eli Lilly, Janssen, LEO Pharma, Novartis, UCB Pharma, Pfizer, BMS, MSD and Sanofi. R.B.W. has acted as a consultant and/or speaker for and/or received research grants from AbbVie, Amgen, Almirall, Celgene, Eli Lilly, Pfizer, LEO Pharma, Novartis, Janssen Cilag, Medac, UCB Pharma and Xenoport. C.H.S. reports grants from a Medical Research Council-funded stratified medicine consortium with multiple industry partners, grants from an Innovative Medicines Initiative (Horizon 2020)-funded European consortium with multiple industry partners, and other grants from AbbVie, Novartis, Pfizer, Sanofi, Boehringer Ingelheim and Sobi, outside the submitted work; she is also chair of UK guidelines on biologic therapy in psoriasis. C.E.M.G. has received honoraria and/or research grants from AbbVie, Almirall, Amgen, AnaptysBo, Bristol Myers Squibb, Celgene, Galderma, LEO Pharma, Eli Lilly, GSK-Stiefel, Janssen Cilag, MSD, Novartis, Pfizer, Sandoz and UCB Pharma., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Association of Dermatologists.)

Relapsing or occurring de novo autoimmune hemolytic anemia (AIHA) during pregnancy or puerperium is a poorly described condition. Here, we report 45 pregnancies in 33 women evaluated at 12 centers from 1997 to 2022. Among the 20 women diagnosed with AIHA before pregnancy, 10 had a relapse. An additional 13 patients developed de novo AIHA during gestation/puerperium (2 patients had AIHA relapse during a second pregnancy). Among 24 hemolytic events, anemia was uniformly severe (median Hb, 6.4 g/dL; range, 3.1-8.7) and required treatment in all cases (96% steroids ± intravenous immunoglobulin, IVIG, 58% transfusions). Response was achieved in all patients and was complete in 65% of the cases. Antithrombotic prophylaxis was administered to 8 patients (33%). After delivery, rituximab was administered to 4 patients, and cyclosporine was added to 1 patient. The rate of maternal complications, including premature rupture of membranes, placental detachment, and preeclampsia, was 15%. Early miscarriages occurred in 13% of the pregnancies. Fetal adverse events (22% of cases) included respiratory distress, fetal growth restriction, preterm birth, AIHA of the newborn, and 2 perinatal deaths. In conclusion, the occurrence of AIHA does not preclude the ability to carry out a healthy pregnancy, provided close monitoring, prompt therapy, and awareness of potential maternal and fetal complications., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Creative arts practice can enhance the depth and quality of mental health research by capturing and foregrounding participants' lived experience. Creative methods are emotionally activating and promote multiple perspectives, tolerating ambiguities and uncertainties, which are shared and even celebrated., Key Arguments: Methods such as photovoice use imagery to elucidate narratives that are not easily captured by more traditional interview-based research techniques. However, the use of creative methods and participatory research remains novel as there is little guidance of how to navigate conceptual, practical, and analytical challenges., Conclusion: This paper considers these challenges, and puts forward practical and theory informed recommendations, using as study of photovoice methods for investigating ethnic inequalities in the use of the mental health act (Co-Pact) as a case study., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Objective: Growth hormone insensitivity (GHI) encompasses growth restriction, normal/elevated growth hormone (GH), and low insulin-like growth factor I (IGF1). "Nonclassical" GHI is poorly characterized and is rarely caused by heterozygous dominant-negative (DN) variants located in the intracellular or transmembrane domains of the GH receptor (GHR). We sought to determine the molecular mechanisms underpinning the growth restriction in 2 GHI cases., Methods and Design: A custom-made genetic investigative pipeline was exploited to identify the genetic cause of growth restriction in patients with GHI. Nanoluc binary technology (NanoBiT), in vitro splicing assays, western blotting, and flow cytometry, characterized the novel GHR variants., Results: Novel heterozygous GHR variants were identified in 2 unrelated patients with GHI. In vitro splicing assays indicated both variants activated the same alternative splice acceptor site resulting in aberrant splicing and exclusion of 26 base pairs of GHR exon 9. The GHR variants produced truncated receptors and impaired GH-induced GHR signaling. NanoBiT complementation and flow cytometry showed increased cell surface expression of variant GHR homo/heterodimers compared to wild-type (WT) homodimers and increased recombinant human GH binding to variant GHR homo/heterodimers and GH binding protein (GHBP) cleaved from the variant GHRs. The findings demonstrated increased variant GHR dimers and GHBP with resultant GH sequestration., Conclusion: We identified and characterized 2 novel, naturally occurring truncated GHR gene variants. Intriguingly, these DN GHR variants act via the same cryptic splice acceptor site, highlighting impairing GH binding to excess GHBP as a potential therapeutic approach., (© The Author(s) 2023. Published by Oxford University Press on behalf of (ESE) European Society of Endocrinology.)

Summary: The discovery of differential gene-gene correlations across phenotypical groups can help identify the activation/deactivation of critical biological processes underlying specific conditions. The presented R package, provided with a count and design matrix, extract networks of group-specific interactions that can be interactively explored through a shiny user-friendly interface. For each gene-gene link, differential statistical significance is provided through robust linear regression with an interaction term., Availability and Implementation: DEGGs is implemented in R and available on GitHub at https://github.com/elisabettasciacca/DEGGs. The package is also under submission on Bioconductor., (© The Author(s) 2023. Published by Oxford University Press.)

In the prostate bone metastasis microenvironment, macrophages activate a cascade that involves Activin A, the extracellular matrix, and SRC kinase and drives resistance to anti-androgen therapy. These findings (Li et al., 2023. J. Exp. Med.https://doi.org/10.1084/jem.20221007) have broad implications, including metastasis diversity in different tissue milieus and the interplay between hormones and immunity., (© 2023 Di Mitri et al.)

Asset-based approaches are becoming more common within public health interventions; however, due to variations in terminology, it can be difficult to identify asset-based approaches. The study aimed to develop and test a framework that could distinguish between asset-based and deficit-based community studies, whilst acknowledging there is a continuum of approaches. Literature about asset-based and deficit-based approaches were reviewed and a framework was developed based on the Theory of Change model. A scoring system was developed for each of the five elements in the framework based on this model. Measurement of community engagement was built in, and a way of capturing how much the study involved an asset approach. The framework was tested on 13 studies examining community-based interventions to investigate whether it could characterize asset-based versus deficit-based studies. The framework demonstrated how much the principles underpinning asset-based approaches were present and distinguished between studies where the approach was deficit-based to those that had some elements of an asset-based approach. This framework is useful for researchers and policymakers when determining how much of an intervention is asset-based and identifying which elements of asset-based approaches lead to an intervention working., (© The Author(s) 2023. Published by Oxford University Press.)

Background: Theories propose that visual impairment might increase the risk of psychosis, and vice versa. We aimed to investigate the relationship between visual impairment and psychosis in the UK Biobank cohort., Study Design: In a nested case control study of ~116,000 adults, we tested whether a Schizophrenia Spectrum Disorder (SSD) diagnosis as exposure was associated with visual impairment. We also tested longitudinally whether poorer visual acuity, and thinner retinal structures on Optical Coherence Tomography (OCT) scans in 2009 were associated with psychotic experiences in 2016. We adjusted for age, sex, depression and anxiety symptoms; and socioeconomic variables and vascular risk factors where appropriate. We compared complete case with multiple imputation models, designed to reduce bias potentially introduced by missing data., Results: People with visual impairment had greater odds of SSD than controls in multiply imputed data (Adjusted Odds Ratio [AOR] 1.42, 95 % Confidence Interval [CI] 1.05-1.93, p = 0.021). We also found evidence that poorer visual acuity was associated with psychotic experiences during follow-up (AOR per 0.1 point worse visual acuity score 1.06, 95 % CI 1.01-1.11, p = 0.020; and 1.04, 95 % CI 1.00-1.08, p = 0.037 in right and left eye respectively). In complete case data (15 % of this cohort) we found no clear association, although confidence intervals included the multiple imputation effect estimates. OCT measures were not associated with psychotic experiences., Conclusions: Our findings highlight the importance of eye care for people with psychotic illnesses. We could not conclude whether visual impairment is a likely causal risk factor for psychosis., Competing Interests: Conflict of interest The authors have declared that there are no conflicts of interest in relation to the subject of this study., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Multiple sclerosis is often diagnosed in patients who are planning on having children. Although multiple sclerosis does not negatively influence most pregnancy outcomes, less is known regarding the effects of fetal exposure to novel disease-modifying therapies (DMTs). The withdrawal of some DMTs during pregnancy can modify the natural history of multiple sclerosis, resulting in a substantial risk of pregnancy-related relapse and disability. Drug labels are typically restrictive and favour fetal safety over maternal safety. Emerging data reporting outcomes in neonates exposed to DMTs in utero and through breastfeeding will allow for more careful and individualised treatment decisions. This emerging research is particularly important to guide decision making in women with high disease activity or who are treated with DMTs associated with risk of discontinuation rebound. As increasing data are generated in this field, periodic updates will be required to provide the most up to date guidance on how best to achieve multiple sclerosis stability during pregnancy and post partum, balanced with fetal and newborn safety., Competing Interests: Declaration of interests KMK has received grants from the MS Society of Canada; speaking or consulting fees from Biogen, EMD Serono, Novartis, and Roche; and is an advisory board member for Biogen, Novartis, and Roche, outside the submitted work. RD has received payments to her institution, including grants from Biogen, Merck, Celgene, National MS Society, MS Society UK, Horne Family Trust, and the BMA Foundation; honoraria from Biogen, Janssen, Merck, Novartis, Roche, Sanofi, and Teva; participated on an advisory board for Biogen, Janssen, Merck, Novartis, and Roche; and received support for attending meetings or travel from Biogen, Janssen, Merck, Novartis, Roche, and Sanofi, outside the submitted work. MPA received grants for a sponsored statistician from Merck; consulting fees from Almirall, Bayer Schering Pharma, Biogen-Idec, Sanofi Genzyme, Merck-Serono, Novartis, and Roche; honoraria from Almirall, Bayer Schering Pharma, Biogen-Idec, Merck-Serono, Novartis, Roche, and Sanofi-Genzyme; participated on the data safety and monitoring board or advisory board for Merck, Novartis, Roche, and Sanofi Genzyme; and reports a leadership role as president of The European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), outside the submitted work. RB received investigator-initiated grants from Biogen, Novartis, and F Hoffman LaRoche, and sponsored grants from F Hoffman LaRoche; consulting fees from Alexion, Biogen, EMD Serono, Novartis, F Hoffman Laroche, Genzyme Sanofi, TG Therapeutics, and Janssen. AIC received speaker's honoraria from Bayer Healthcare; and support for attending meetings from Teva, outside the submitted work. MM received grants from the Danish MS Society; consulting fees from Merck, Sanofi, Roche, and Novartis; payment or honoraria from Merck, Sanofi, Roche, Novartis, Biogen, and Bristol Myers Squibb; and participated on the data safety and monitoring board or advisory board for Merck, Sanofi, Roche, Novartis, Biogen, and Bristol Myers Squibb, outside the submitted work. ST received speaker honoraria from Bayer Healthcare and Biogen GmbH, and manuscript writing assistance from Hexal AG, outside the submitted work. MT received grants for a sponsored statistician from Biogen; consulting fees from Almirall, Bayer Schering Pharma, Biogen-Idec, Genzyme, Janssen, Merck-Serono, Novartis, Roche, Sanofi-Aventis, Viela Bio, and Teva Pharmaceuticals; honoraria from Almirall, Bayer Schering Pharma, Biogen-Idec, Genzyme, Janssen, Merck-Serono, Novartis, Roche, Sanofi-Aventis, Viela Bio, and Teva Pharmaceuticals; and reports a leadership role as ECTRIMS vice president, outside the submitted work. SV has received payments to her institution including grants from Biogen, Janssen, Merck, Novartis, Roche, and Sanofi; consulting fees from Biogen, Bristol-Myers Squibb, Celgene, Janssen, Merck, Novartis, Roche, and Sanofi; honoraria from Biogen, Merck, Novartis, Roche, Sanofi, and Teva; participated on the data safety and monitoring board or advisory board for Biogen; support for attending meetings or travel from Biogen, Merck, Novartis, and Roche, outside the submitted work. KH received grants or contracts from Almirall, Biogen, Merck, Novartis, Sanofi Genzyme, Roche, and Teva; payment or honoraria from Almirall, Bayer, Biogen, Merck, Novartis, Sanofi Genzyme, Roche, Teva, Janssen, and Bristol-Myers Squibb; support for attending meetings or travel from Bayer, Biogen, Merck, Roche, Sanofi Genzyme, and Teva; participation on a data safety and monitoring board or advisory board from Biogen, Teva, Roche, Novartis, Jansen, and Merck, outside the submitted work. RA, YF, MH, VGJ, AA, VP declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Multiple sclerosis is a chronic inflammatory disease of the CNS that results from the interplay between heritable and environmental factors. Mounting evidence from different fields of research supports the pivotal role of the Epstein-Barr virus (EBV) in the development of multiple sclerosis. However, translating this knowledge into clinically actionable information requires a better understanding of the mechanisms linking EBV to pathophysiology. Ongoing research is trying to clarify whether EBV causes neuroinflammation via autoimmunity or antiviral immunity, and if the interaction of EBV with genetic susceptibility to multiple sclerosis can explain why a ubiquitous virus promotes immune dysfunction in susceptible individuals. If EBV also has a role in driving disease activity, the characterisation of this role will help diagnosis, prognosis, and treatment in people with multiple sclerosis. Ongoing clinical trials targeting EBV and new anti-EBV vaccines provide hope for future treatments and preventive interventions., Competing Interests: Declaration of interests GG declares consulting or speaker fees from AbbVie, Aslan, Atara Bio, Biogen, Bristol Myers Squibb–Celgene, GlaxoSmithKline, GW Pharma, Janssen–Actelion, Japanese Tobacco, Jazz Pharmaceuticals, LifNano, Merck & Co, Merck KGaA–EMD Serono, Moderna, Novartis, Sanofi Genzyme, Roche-Genentech, and Teva Pharmaceuticals. MS declares speaking honoraria, research support from, and participation on an advisory board for Biogen, Bristol Myers Squibb, Merck, Novartis, Sanofi, Hoffmann-La Roche, and Viatris, and a patent: Epstein-Barr virus genotypic variants and uses thereof as risk predictors, biomarkers and theraputic targets of multiple sclerosis. FA declares participation on an advisory board for Hoffmann-La Roche., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The objective of this study was to evaluate the biological effects and odonto/osteogenic differentiation potential of Biodentine, NeoMTA Plus and TheraCal LC in tooth germ-derived stem cells (TGSCs). TGSCs were exposed to the material extracts. Biocompatibility was tested with MTS cell proliferation assay. Odonto/osteogenic differentiation was assessed with alkaline phosphatase (ALP) activity and mRNA gene expressions (RUNX2, DSPP and DMP-1). Scanning electronic microscopy/energy-dispersive X-ray (SEM/EDX) analysis and pH analysis were also performed for the materials. Data were evaluated using the one-way ANOVA and Tukey's tests. TGSCs remained viable after 7 days of incubation with all tested materials. Biodentine and NeoMTA Plus showed high ALP activity and increased expression of RUNX2, DSPP and DMP-1 compared to that of TheraCal LC. All materials can induce odonto/osteogenic differentiation of MSCs in various levels. Biocompatibility and odonto/osteogenic differentiation potential of Biodentine and NeoMTA Plus are similar and superior to that of TheraCal LC., (© 2022 Australian Society of Endodontology Inc.)

The coronavirus disease 2019 (COVID-19) pandemic has challenged the capacity of health care systems around the world, including substantial disruptions to cardiovascular care across key areas of health care delivery. In this narrative review, we examine the implications of the COVID-19 pandemic for cardiovascular health care, including excess cardiovascular mortality, acute and elective cardiovascular care, and disease prevention. Additionally, we consider the long-term public health consequences of disruptions to cardiovascular care across both primary and secondary care settings. Finally, we review health care inequalities and their driving factors, as highlighted by the pandemic, and consider their importance in the context of cardiovascular health care., Competing Interests: Disclosure Z. Raisi-Estabragh recognizes the National Institute for Health Research (NIHR) Integrated Academic Training program which supports her Academic Clinical Lectureship post and was also supported by British Heart Foundation Clinical Research Training Fellowship No. FS/17/81/33,318. M.A. Mamas has no disclosures., (Copyright © 2022 Elsevier Inc. All rights reserved.)

What is this summary about? This summary presents findings from recent research involving people with psoriasis, based on an article originally published in the Journal of the European Academy of Dermatology and Venereology . Psoriasis is a condition that primarily affects the skin. However, it can also influence people's mental health, social activities, work, and relationships too. Current assessment tools used by doctors and nurses do not cover the complete experience of people with psoriasis, which often include other medical conditions and can leave these individuals feeling that treatment has not been successful. Researchers conducted a study in which people with psoriasis, doctors, and nurses were asked in virtual meetings and via questionnaires what freedom from disease in psoriasis means to them. What were the results? In addition to skin symptoms, the areas of mental health, well-being, treatment, and relationships with healthcare teams were found to be important aspects to be addressed. What do the results of the study mean? Focusing on all five aspects of freedom from disease will help people with psoriasis manage their psoriasis with confidence.

COVID-19 causes significant thrombosis and coagulopathy, with elevated D-dimer a predictor of adverse outcome. The precise mechanism of this coagulopathy remains unclear; one hypothesis is that loss of angiotensin-converting enzyme 2 activity during viral endocytosis leads to pro-inflammatory angiotensin-II accumulation, loss of angiotensin-1-7 and subsequent vascular endothelial activation. We undertook a double-blind randomized, placebo-controlled experimental medicine study to assess the effect of TRV027, a synthetic angiotensin-1-7 analogue on D-dimer in 30 patients admitted to hospital with COVID-19. The study showed a similar rate of adverse events in TRV027 and control groups. There was a numerical decrease in D-dimer in the TRV027 group and increase in D-dimer in the placebo group; however, this did not reach statistical significance (P = .15). A Bayesian analysis demonstrated that there was a 92% probability that this change represented a true drug effect., (© 2022 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)