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Aging; Arteriosclerosis; Hemodynamics Envelliment; Arteriosclerosi; Hemodinàmica Envejecimiento; Arteriosclerosis; Hemodinámica Arterial pulse waves (PWs) such as blood pressure and photoplethysmogram (PPG) signals contain a wealth of information on the cardiovascular (CV) system that can be exploited to assess vascular age and identify individuals at elevated CV risk. We review the possibilities, limitations, complementarity, and differences of reduced-order, biophysical models of arterial PW propagation, as well as theoretical and empirical methods for analyzing PW signals and extracting clinically relevant information for vascular age assessment. We provide detailed mathematical derivations of these models and theoretical methods, showing how they are related to each other. Finally, we outline directions for future research to realize the potential of modeling and analysis of PW signals for accurate assessment of vascular age in both the clinic and in daily life. This article is based upon work from COST Action “Network for Research in Vascular Ageing” (VascAgeNet, CA18216), supported by COST (European Cooperation in Science and Technology, www.cost.eu). This work was supported by British Heart Foundation Grants PG/15/104/31913 (to J.A. and P.H.C.), FS/20/20/34626 (to P.H.C.), and AA/18/6/34223, PG/17/90/33415, SPG 2822621, and SP/F/21/150020 (to A.D.H.); Kaunas University of Technology Grant INP2022/16 (to B.P.); European Research Executive Agency, Marie-Sklodowska Curie Actions Individual Fellowship Grant 101038096 (to S.P.); Istinye University, BAP Project Grant 2019B1 (to S.P.); “la Caixa” Foundation Grant LCF/BQ/PR22/11920008 (to A.G.); and National Institute for Health and Care Research Grant AI AWARD02499 and EU Horizon 2020 Grant H2020 848109 (to A.D.H.).

Background and Objectives: Blood banks use a haemoglobin (Hb) threshold before blood donation to minimize donors' risk of anaemia. Hb prediction models may guide decisions on which donors to invite, and should ideally also be generally applicable, thus in different countries and settings. In this paper, we compare the outcome of various prediction models in different settings and highlight differences and similarities. Materials and Methods: Donation data of repeat donors from the past 5 years of Australia, Belgium, Finland, the Netherlands and South Africa were used to fit five identical prediction models: logistic regression, random forest, support vector machine, linear mixed model and dynamic linear mixed model. Only donors with five or more donation attempts were included to ensure having informative data from all donors. Analyses were performed for men and women separately and outcomes compared. Results: Within countries and overall, different models perform similarly well. However, there are substantial differences in model performance between countries, and there is a positive association between the deferral rate in a country and the ability to predict donor deferral. Nonetheless, the importance of predictor variables across countries is similar and is highest for the previous Hb level. Conclusion: The limited impact of model architecture and country indicates that all models show similar relationships between the predictor variables and donor deferral. Donor deferral is found to be better predictable in countries with high deferral rates. Therefore, such countries may benefit more from deferral prediction models than those with low deferral rates.

PURPOSE A previous study by the International Berlin-Frankfurt-Münster Study Group (I-BFM-SG) on childhood KMT2A-rearranged ( KMT2A-r) AML demonstrated the prognostic value of the fusion partner. This I-BFM-SG study investigated the value of flow cytometry-based measurable residual disease (flow-MRD) and evaluated the benefit of allogeneic stem-cell transplantation (allo-SCT) in first complete remission (CR1) in this disease. METHODS A total of 1,130 children with KMT2A-r AML, diagnosed between January 2005 and December 2016, were assigned to high-risk (n = 402; 35.6%) or non–high-risk (n = 728; 64.4%) fusion partner-based groups. Flow-MRD levels at both end of induction 1 (EOI1) and 2 (EOI2) were available for 456 patients and were considered negative (RESULTS The high-risk group had inferior EFS (30.3% high risk v 54.0% non-high risk; P < .0001), CIR (59.7% v 35.2%; P < .0001), and OS (49.2% v 70.5%; P < .0001). EOI2 MRD negativity was associated with superior EFS (n = 413; 47.6% MRD negativity v n = 43; 16.3% MRD positivity; P < .0001) and OS (n = 413; 66.0% v n = 43; 27.9%; P < .0001), and showed a trend toward lower CIR (n = 392; 46.1% v n = 26; 65.4%; P = .016). Similar results were obtained for patients with EOI2 MRD negativity within both risk groups, except that within the non–high-risk group, CIR was comparable with that of patients with EOI2 MRD positivity. Allo-SCT in CR1 only reduced CIR (hazard ratio, 0.5 [95% CI, 0.4 to 0.8]; P = .00096) within the high-risk group but did not improve OS. In multivariable analyses, EOI2 MRD positivity and high-risk group were independently associated with inferior EFS, CIR, and OS. CONCLUSION EOI2 flow-MRD is an independent prognostic factor and should be included as risk stratification factor in childhood KMT2A-r AML. Treatment approaches other than allo-SCT in CR1 are needed to improve prognosis.

Immunogenic cell death (ICD) refers to an immunologically distinct process of regulated cell death that activates, rather than suppresses, innate and adaptive immune responses. Such responses culminate into T cell-driven immunity against antigens derived from dying cancer cells. The potency of ICD is dependent on the immunogenicity of dying cells as defined by the antigenicity of these cells and their ability to expose immunostimulatory molecules like damage-associated molecular patterns (DAMPs) and cytokines like type I interferons (IFNs). Moreover, it is crucial that the host's immune system can adequately detect the antigenicity and adjuvanticity of these dying cells. Over the years, several well-known chemotherapies have been validated as potent ICD inducers, including (but not limited to) anthracyclines, paclitaxels, and oxaliplatin. Such ICD-inducing chemotherapeutic drugs can serve as important combinatorial partners for anti-cancer immunotherapies against highly immuno-resistant tumors. In this Trial Watch, we describe current trends in the preclinical and clinical integration of ICD-inducing chemotherapy in the existing immuno-oncological paradigms. ispartof: ONCOIMMUNOLOGY vol:12 issue:1 ispartof: location:United States status: accepted

Neuromusculoskeletal models can be used to evaluate aberrant muscle function in cerebral palsy (CP), for example by estimating muscle and joint contact forces during gait. However, to be accurate, models should include representative musculotendon parameters. We aimed to estimate personalised parameters that capture the mechanical behaviour of the plantarflexors in children with CP and typically developing (TD) children. Ankle angle (using motion capture), torque (using a load-cell), and medial gastrocnemius fascicle lengths (using ultrasound) were measured during slow passive ankle dorsiflexion rotation for thirteen children with spastic CP and thirteen TD children. Per subject, the measured rotation was input to a scaled OpenSim model to simulate the torque and fascicle length output. Musculotendon model parameters were personalised by the best match between simulated and experimental torque–angle and fascicle length-angle curves according to a least-squares fit. Personalised tendon slack lengths were significantly longer and optimal fibre lengths significantly shorter in CP than model defaults and than in TD. Personalised tendon compliance was substantially higher in both groups compared to the model default. The presented method to personalise musculotendon parameters will likely yield more accurate simulations of subject-specific muscle mechanics, to help us understand the effects of altered musculotendon properties in CP.

A significant proportion of events in paediatric acute myeloid leukaemia (AML) are caused by resistant disease (RD). We investigated clinical and biological characteristics in 66 patients with RD from 1013 children with AML registered and treated according to the NOPHO-AML 93, NOPHO-AML 2004, DB AML-01 and NOPHO-DBH AML 2012 protocols. Risk factors for RD were age10 years or older and a white-blood-cell count (WBC) of 100 × 10 9 /L or more at diagnosis. The five-year overall survival (OS) was 38% (95% confidence interval [CI]: 28%-52%). Of the 63 children that received salvage therapy with chemotherapy, 59% (N = 37) achieved complete remission (CR) with OS 57% (95% CI: 42%-75%) compared to 12% (95% CI: 4%-35%) for children that did not achieve CR. Giving more than two salvage chemotherapy courses did not increase CR rates. OS for all 43 patients receiving allogeneic haematopoietic stem cell transplantation (HSCT) was 49% (95% CI: 36%-66%). Those achieving CR and proceeding to HSCT had an OS of 56% (95% CI: 41%-77%, N = 30). This study showed that almost 40% of children with primary resistant AML can be cured with salvage therapy followed by HSCT. Children that did not achieve CR after two salvage courses with chemotherapy did not benefit from additional chemotherapy.

Treatment of chronic myeloid leukemia has improved significantly with the introduction of tyrosine kinase inhibitors (TKIs), and treatment guidelines based on numerous clinical trials are available for chronic phase disease. However for CML in the blast phase (CML-BP), prognosis remains poor and treatment options are much more limited. The spectrum of treatment strategies for children and adolescents with CML-BP has largely evolved empirically and includes treatment principles derived from adult CML-BP and pediatric acute leukemia. Given this heterogeneity of treatment approaches, we formed an international panel of pediatric CML experts to develop recommendations for consistent therapy in children and adolescents with this high-risk disease based on the current literature and national standards. Recommendations include detailed information on initial diagnosis and treatment monitoring, differentiation from Philadelphia-positive acute leukemia, subtype-specific selection of induction therapy, and combination with tyrosine kinase inhibitors. Given that allogeneic hematopoietic stem cell transplantation currently remains the primary curative intervention for CML-BP, we also provide recommendations for the timing of transplantation, donor and graft selection, selection of a conditioning regimen and prophylaxis for graft-versus-host disease, post-transplant TKI therapy, and management of molecular relapse. Management according to the treatment recommendations presented here is intended to provide the basis for the design of future prospective clinical trials to improve outcomes for this challenging disease.

BACKGROUND: The optimal treatment for patients with pathological node-positive (pN1) prostate cancer (PCa) is unclear. OBJECTIVE: To evaluate whether whole-pelvis radiotherapy (WPRT) improves clinical relapse-free survival (cRFS) in comparison to prostate-only radiotherapy (PORT) in pN1 PCa. DESIGN, SETTING, AND PARTICIPANTS: PROPER was a phase 3 trial randomizing patients to WPRT or PORT. All patients had pN1cM0 PCa with fewer than five lymph nodes involved. INTERVENTION: All patients underwent pelvic lymph node dissection followed by radical prostatectomy/primary radiotherapy + 2 yr of androgen deprivation therapy (ADT). Patients were randomized to PORT (arm A) or WPRT (arm B). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was cRFS. The secondary endpoints were overall survival (OS), biochemical relapse-free survival (bRFS), and toxicity. The study was stopped because of poor accrual in June 2021 after the inclusion of 69 patients. We report on OS, bRFS, cRFS, and acute and late toxicity. RESULTS AND LIMITATIONS: The median follow-up was 30 mo in arm A (n = 33) and 36 mo in arm B (n = 31). The 3-yr OS rate was 92% ± 5% in arm A and 93% ± 5% in arm B (p = 0.61). None of the patients died of PCa. The 3-yr bRFS was 79% ± 9% in arm A and 92% ± 5% in arm B (p = 0.08). The 3-yr cRFS rate was 88% ± 6% in arm A and 92% ± 5% in arm B (p = 0.31). No pelvic recurrence was observed in arm B. Acute grade 2 gastrointestinal toxicity was higher with WPRT (15% in arm A vs 45% in arm B; p = 0.03). Limitations are the early closure because of poor accrual and the limited follow-up. CONCLUSIONS: The results of our trial are hypothesis-generating but add evidence supporting the recommendation to offer WPRT to patients with pN1 PCa. However, WPRT is associated with more acute gastrointestinal toxicity. PATIENT SUMMARY: We looked at the impact of radiotherapy to the whole pelvis (WPRT) for patients with prostate cancer that had spread to the lymph nodes. Although the trial was closed early because of poor enrolment, we found that WPRT improves survival free from relapse, and no recurrences were observed in the pelvis. WPRT is associated with more acute side effects on the gastrointestinal system in comparison to radiotherapy to just the prostate. ispartof: EUROPEAN UROLOGY FOCUS vol:9 issue:2 pages:317-324 ispartof: location:Netherlands status: published

The prefrontal cortex plays a crucial role in cognitive processes, both during anticipatory and reactive modes of cognitive control. Transcranial Direct Current Stimulation (tDCS) can modulate these cognitive resources. How-ever, there is a lack of research exploring the impact of tDCS on emotional material processing in the prefrontal cortex, particularly in regard to proactive and reactive modes of cognitive control. In this study, 35 healthy volun-teers underwent both real and sham tDCS applied to the right prefrontal cortex in a counterbalanced order, and then completed the Cued Emotion Control Task (CECT). Pupil dilation, a measure of cognitive resource allocation, and behavioral outcomes, such as reaction time and accuracy, were collected. The results indicate that, as com-pared to sham stimulation, active right-sided tDCS reduced performance and resource allocation in both proactive and reactive modes of cognitive control. These findings highlight the importance of further research on the effects of tDCS applied to the right prefrontal cortex on cognitive engagement, particularly for clinical trials utilizing the present electrode montage in combination with cognitive interventions.

Skipping of BRCA2 exon 3 (∆E3) is a naturally occurring splice event, complicating clinical classification of variants that may alter ∆E3 expression. This study used multiple evidence types to assess pathogenicity of 85 variants in/near BRCA2 exon 3. Bioinformatically predicted spliceogenic variants underwent mRNA splicing analysis using minigenes and/or patient samples. ∆E3 was measured using quantitative analysis. A mouse embryonic stem cell (mESC) based assay was used to determine the impact of 18 variants on mRNA splicing and protein function. For each variant, population frequency, bioinformatic predictions, clinical data and existing mRNA splicing and functional results were collated. Variant class was assigned using a gene-specific adaptation of ACMG/AMP guidelines, following a recently proposed points-based system. mRNA and mESC analysis combined identified six variants with transcript and/or functional profiles interpreted as loss of function. Cryptic splice site use for acceptor site variants generated a transcript encoding a shorter protein that retains activity. Overall, 69/85 (81%) variants were classified using the point-based approach. Our analysis shows the value of applying gene-specific ACMG/AMP guidelines using a points-based approach and highlights the consideration of cryptic splice site usage to appropriately assign PVS1 code strength. This article is protected by copyright. All rights reserved.

Purpose Having advanced cancer presents many challenges for patients and family caregivers. The FOCUS program is a psychoeducational nurse-led intervention, developed in the USA, to support dyads of patients with cancer and their family caregivers to live with the illness. The program includes a conversation manual and information resources for dyads. We aimed to develop a version of the program for dyads facing advanced cancer in six European countries. Method The Participatory and Iterative Process Framework for Language Adaptation (PIPFLA) was used to guide the translation of the program to the local contexts of Belgium, Denmark, Ireland, Italy, the Netherlands, and the UK. In several rounds, potential program users (e.g., nurses, clinicians, patients, family caregivers) and researchers from all six countries reviewed program materials and advised on adaptations. Results The PIPFLA process resulted in one European version of the program in different languages (FOCUS +). The FOCUS + conversation manual is uniform across all countries. The main adaptations included additional attention to both family caregiver and patient needs; more emphasis on self-management, advance care planning, and shared responsibilities; discussing the dyad’s outlook rather than optimism; addressing the role of nurses as educational rather than therapeutic; and more suggestions to refer dyads to health care professionals for specific care needs. The information resources for dyads were adapted to fit with local contexts. Conclusion The PIPFLA methodology is an efficient and effective framework to thoroughly translate and culturally adapt a complex USA-based program for use in six European countries in collaboration with end users.

Objective: This study examined associations of minority stressors (i.e., victimization, internalized homonegativity, and stigma consciousness), and coping styles (i.e., active, avoidant, and passive) with suicidal ideation and suicide attempts (suicidality) among sexual and gender minority (SGM) young adults, and whether coping style moderated these associations. Methods: Logistic regression analyses examined these associations among 1432 SGM young adults (ages 18–29). Results: Minority stressors and passive coping were associated with a higher likelihood of suicidality. Avoidant coping was associated with a lower likelihood of lifetime suicidal ideation and attempts among sexual minority participants, and active coping with a lower likelihood of past-year suicidal ideation among sexual minority participants. Moderation analyses among sexual minority participants showed that when avoidant coping was high, associations between low victimization (compared with no victimization) and lifetime suicide attempts, and stigma consciousness and lifetime suicide attempts became non-significant, and the association between internalized homonegativity and lifetime suicide attempts became significant. Among gender minority participants, when passive coping was high the association between low victimization and lifetime suicidal ideation became significant. Conclusion: This study underlines the importance of minority stress and coping for suicidality among SGM young adults and the need for more research regarding the role of coping.

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Background Non-binary and genderqueer (NBGQ) individuals do not identify with a binary gender identity. Some but not all NBGQ individuals identify as transgender, and it is currently unclear on which aspects of mental and sexual well-being NBGQ and binary transgender individuals may differ. Aim To compare NBGQ, binary transgender and cisgender individuals on variables related to mental well-being, sexual well-being, and sexual self-concept discrepancies. Methods We conducted an online questionnaire study in 125 transgender men, 72 transgender women, 78 NBGQ individuals, 98 cisgender men, and 107 cisgender women. Results For most variables, NBGQ individuals did not differ from binary transgender individuals. These two groups differed only on gender dysphoria and transgender specific body image worries, which were both lower in the NBGQ group. Compared to the cisgender group, NBGQ individuals scored higher on gender dysphoria, actual/ought sexual self-concept discrepancies, and actual/ideal sexual self-concept discrepancies, and lower on general life satisfaction and sexual esteem related to body perception. Discussion These results offer a first quantitative analysis of sexual well-being in NBGQ individuals, and highlight that - while both groups face unique challenges - NBGQ individuals encounter similar difficulties concerning mental and sexual well-being as binary transgender individuals.

BACKGROUND: Centralisation of specialist cancer services is occurring in many countries, often without evaluating the potential impact before implementation. We developed a health service planning model that can estimate the expected impacts of different centralisation scenarios on travel time, equity in access to services, patient outcomes, and hospital workload, using rectal cancer surgery as an example.METHODS: For this population-based modelling study, we used routinely collected individual patient-level data from the National Cancer Registration and Analysis Service (NCRAS) and linked to the NHS Hospital Episode Statistics (HES) database for 11 888 patients who had been diagnosed with rectal cancer between April 1, 2016, and Dec 31, 2018, and who subsequently underwent a major rectal cancer resection in 163 National Health Service (NHS) hospitals providing rectal cancer surgery in England. Five centralisation scenarios were considered: closure of lower-volume centres (scenario A); closure of non-comprehensive cancer centres (scenario B); closure of centres with a net loss of patients to other centres (scenario C); closure of centres meeting all three criteria in scenarios A, B, and C (scenario D); and closure of centres with high readmission rates (scenario E). We used conditional logistic regression to predict probabilities of affected patients moving to each of the remaining centres and the expected changes in travel time, multilevel logistic regression to predict 30-day emergency readmission rates, and linear regression to analyse associations between the expected extra travel time for patients whose centre is closed and five patient characteristics, including age, sex, socioeconomic deprivation, comorbidity, and rurality of the patients' residential areas (rural, urban [non-London], or London). We also quantified additional workload, defined as the number of extra patients reallocated to remaining centres.FINDINGS: Of the 11 888 patients, 4130 (34·7%) were women, 5249 (44·2%) were aged 70 years and older, and 5005 (42·1%) had at least one comorbidity. Scenario A resulted in closures of 43 (26%) of the 163 rectal cancer surgery centres, affecting 1599 (13·5%) patients; scenario B resulted in closures of 112 (69%) centres, affecting 7029 (59·1%) patients; scenario C resulted in closures of 56 (34%) centres, affecting 3142 (26·4%) patients; scenario D resulted in closures of 24 (15%) centres, affecting 874 (7·4%) patients; and scenario E resulted in closures of 16 (10%) centres, affecting 1000 (8·4%) patients. For each scenario, there was at least a two-times increase in predicted travel time for re-allocated patients with a mean increase in travel time of 23 min; however, the extra travel time did not disproportionately affect vulnerable patient groups. All scenarios resulted in significant reductions in 30-day readmission rates (range 4-48%). Three hospitals in scenario A, 41 hospitals in in scenario B, 13 hospitals in scenario C, no hospitals in scenario D, and two hospitals in scenario E had to manage at least 20 extra patients annually.INTERPRETATION: This health service planning model can be used to to guide complex decisions about the closure of centres and inform mitigation strategies. The approach could be applied across different country or regional health-care systems for patients with cancer and other complex health conditons.FUNDING: National Institute for Health Research.

BackgroundOver the last decades, a decrease in short-term mortality in cancer patients admitted to the ICU has been described in literature. However, it is unclear whether this decrease also results in a decrease in long-term mortality. Therefore, we examined the 1-year mortality of cancer patients (either haematological or solid) with an unplanned ICU admission.Methods and dataAll adult patients registered in the National Intensive Care Evaluation registry with an unplanned ICU admission in the Netherlands between 2008 and 2017 were included. The primary outcome was 1-year mortality, analysed with a mixed-effects cox-proportional hazard regression. We examined the trend in mortality rates over the inclusion period. Furthermore, we compared the 1-year mortality of cancer patients to that of patients without cancer. ResultsWe included 470,305 patients: 10,401 with haematological cancer, 35,920 with solid tumours, and 423,984 without cancer. The 1-year mortality rates were 60.1%, 46.2%, and 28.3% (pConclusionThe 1-year mortality in cancer patients with an unplanned ICU admission (either haematological or solid) was significantly higher than that of patients without cancer. A visual inspection showed a slight decrease in 1-year mortality in haematological patients, while the 1-year mortality in patients with a solid tumour varied per year. After hospital discharge, a considerable part of the patients with a malignancy died within 1 year. Physicians should discuss the long-term prognosis after an ICU admission with patients and relatives in order to manage treatments and expectations. Future research should focus on identifying cancer patients who will benefit from an ICU admission.

Nigus Kabtu Belete, Darik Temesgen Assefa, Tesfaye Feleke Gadore, Manaye Yihune Teshale, Eshetu Zerihun Tariku School of Public Health, College of Medicine and Health Science, Arba Minch University, Arba Minch, EthiopiaCorrespondence: Nigus Kabtu Belete, Tel +251914552360, Email nigushabtu2014@gmail.comIntroduction: Overweight/obesity is an emerging public health problem in low income countries. Currently sub-Saharan African countries are facing a double burden of malnutrition. Evidence has shown that overweight/obesity is becoming a problem for people living with HIV. But little is known in our setting. Thus, this study is designed to assess the association between overweight/obesity and ART drug regimen among adult HIV patients in Gamo zone public health facilities southern Ethiopia.Objective: To assess the association between overweight/obesity and ART drug regimen among adult HIV patients in Gamo zone public health facilities southern Ethiopia.Methods: Institution-based cross-sectional study was conducted from April 10 to May 10, 2022, among systematically selected adult HIV patients. The data were collected by using a structured interviewer-administered questionnaire, patient record review, and physical measurements. Multivariate logistic regression model was used to assess the association between dependent and independent variables. A p-value < 0.05 with its 95% CI was considered as a statistically significant and interpreted accordingly.Results: The magnitude of overweight/obesity were 13.5% (95% CI:(10.4– 17.2)). Being male (2.484(1.308, 4.716)), duration on ART (took for ≥ 5 years) ((2.249(1.218, 4.152)), and ART drug regime (3.789(1.965, 7.304)) were significantly associated with overweight/obesity.Conclusion: Overweight/obesity is significantly associated to ART drug regimen type among adult HIV patients. Furthermore, sex and duration on ART drug were found significantly associated with overweight/obesity of adult HIV patients.Keywords: obesity, overweight, HIV, anti-retroviral therapy, drug, Gamo zone, Ethiopia

Children and adolescents are no longer a priority in the most recent European Programme of Work (EPW) 2020-2025 of the World Health Organization (WHO) Regional Office for Europe. In this position statement we provide arguments for why we think this population should be explicitly addressed in this important and influential document. We firstly emphasize the persistent health problems and inequalities in access to care for children and adolescents that are challenging to solve, and thus require a continuous focus. Secondly, we urge the WHO to prioritize children and adolescents in their EPW due to the new and emerging health problems related to global issues. Finally, we explain why permanent prioritization of children and adolescents is essential for the future of children and of society.

Background: Oral health during pregnancy is of high importance because of the impacts physiological alterations have on oral health and because adverse pregnancy outcomes can result from oral and dental conditions. Previous studies demonstrated a high dental visit avoidance among pregnant women due to barriers such as cost and misbeliefs. Objectives: The main objective of this thesis was to investigate the unmet dental and oral needs during pregnancy, and associated factors, through two complementary studies. Methods: A systematic literature review was conducted regarding misbeliefs about oral health and dental visits during pregnancy. A survey-based study was conducted on a clinic-based sample of pregnant women in London, Ontario. Results: The most common misbeliefs discussed in the 45 studies included in our Systematic Review were related to the safety of dental care services utilization and treatments, and the supposed impacts of pregnancy on oral health. The pilot study recruited 67 of 76 eligible subjects, of whom 76.1% reported having good to excellent oral health and 82.1% had visited a dentist within the last two years. Of 51 who had no dental visit during pregnancy, 12 believed it was not necessary, while cost was a barrier for 18 individuals. Age (p=0.001), education (p=0.003), and dental flossing frequency (p=0.035) were significantly associated with self-reported oral health. Women with dental insurance (p=0.022) and good to excellent oral health status (p=0.029) were more likely to have visited a dentist within the last two years. Oral health status and dental visit patterns of the study sample were poorer than the Canadian general population, and may reflect the clinic which was a disadvantaged population. Conclusion: Educational interventions regarding oral health awareness and policies improving access to dental insurance may improve the unmet oral and dental needs and access to dental care services. Further analyses of more diverse populations and larger samples are required to provide a better understanding of the unmet oral needs and dental visit patterns during pregnancy.

Preoperative clinical MRI protocols for gliomas, brain tumors with dismal outcomes due to their infiltrative properties, still rely on conventional structural MRI, which does not deliver information on tumor genotype and is limited in the delineation of diffuse gliomas. The GliMR COST action wants to raise awareness about the state of the art of advanced MRI techniques in gliomas and their possible clinical translation. This review describes current methods, limits, and applications of advanced MRI for the preoperative assessment of glioma, summarizing the level of clinical validation of different techniques. In this second part, we review magnetic resonance spectroscopy (MRS), chemical exchange saturation transfer (CEST), susceptibility-weighted imaging (SWI), MRI-PET, MR elastography (MRE), and MR-based radiomics applications. The first part of this review addresses dynamic susceptibility contrast (DSC) and dynamic contrast-enhanced (DCE) MRI, arterial spin labeling (ASL), diffusion-weighted MRI, vessel imaging, and magnetic resonance fingerprinting (MRF). Evidence Level: 3. Technical Efficacy: Stage 2.

Background: In the past, deprivation has been mostly captured through simple and univariate measures such as low income or poor educational attainment in research on health and social inequalities in Belgium. This paper presents a shift towards a more complex, multidimensional measure of deprivation at the aggregate level and describes the development of the first Belgian Indices of Multiple Deprivation (BIMDs) for the years 2001 and 2011.Methods: The BIMDs are constructed at the level of the smallest administrative unit in Belgium, the statistical sector. They are a combination of six domains of deprivation: income, employment, education, housing, crime and health. Each domain is built on a suite of relevant indicators representing individuals that suffer from a certain deprivation in an area. The indicators are combined to create the domain deprivation scores, and these scores are then weighted to create the overall BIMDs scores. The domain and BIMDs scores can be ranked and assigned to deciles from 1 (the most deprived) to 10 (the least deprived).Results: We show geographical variations in the distribution of the most and least deprived statistical sectors in terms of individual domains and overall BIMDs, and we identify hotspots of deprivation. The majority of the most deprived statistical sectors are located in Wallonia, whereas most of the least deprived statistical sectors are in Flanders.Conclusion: The BIMDs offer a new tool for researches and policy makers for analyzing patterns of deprivation and identifying areas that would benefit from special initiatives and programs. This study was conducted as part of the ELLIS project (Monitoring and Mitigating Environmental Health Inequalities), funded by the Belgian Federal Science Policy (B2/191/P3/ELLIS). This work was produced using data from Statbel (Directorate-general Statistics – Statistics Belgium) – Demobel (adaptation of the National Register), Census 1991, 2001, 2011, and IPCAL. Computational resources have been provided by the supercomputing facilities of the Universit´e catholique de Louvain (CISM/UCL) and the Consortium des Equipements ´ de Calcul Intensif en F´ed´eration Wallonie Bruxelles (CECI) ´ funded by the Fond de la Recherche Scientifique de Belgique (F.R.S.-FNRS) under convention 2.5020.11 and by the Walloon Region. The authors want to thank Statbel and particularly Patrick Lusyne and Clo¨e Ost for preparing and making pseudonymized data available for research, the centre for Demographic Research (DEMO) of UCLouvain for allowing us to access the data, the CISM team for managing the statistical servers, and the Federal Police Belgium – DRI – Business Police Accounting for providing us with data on crime.

Background: Elexacaftor–tezacaftor–ivacaftor has been shown to be safe and efficacious in people with cystic fibrosis and at least one F508del allele. Our aim was to identify a novel cystic fibrosis transmembrane conductance regulator (CFTR) modulator combination capable of further increasing CFTR-mediated chloride transport, with the potential for once-daily dosing. Methods: We conducted two phase 2 clinical trials to assess the safety and efficacy of a once-daily combination of vanzacaftor–tezacaftor–deutivacaftor in participants with cystic fibrosis who were aged 18 years or older. A phase 2 randomised, double-blind, active-controlled study (VX18-561-101; April 17, 2019, to Aug 20, 2020) was carried out to compare deutivacaftor monotherapy with ivacaftor monotherapy in participants with CFTR gating mutations, following a 4-week ivacaftor monotherapy run-in period. Participants were randomly assigned to receive either ivacaftor 150 mg every 12 h, deutivacaftor 25 mg once daily, deutivacaftor 50 mg once daily, deutivacaftor 150 mg once daily, or deutivacaftor 250 mg once daily in a 1:1:2:2:2 ratio. The primary endpoint was absolute change in ppFEV1 from baseline at week 12. A phase 2 randomised, double-blind, controlled, proof-of-concept study of vanzacaftor–tezacaftor–deutivacaftor (VX18-121-101; April 30, 2019, to Dec 10, 2019) was conducted in participants with cystic fibrosis and heterozygous for F508del and a minimal function mutation (F/MF genotypes) or homozygous for F508del (F/F genotype). Participants with F/MF genotypes were randomly assigned 1:2:2:1 to receive either 5 mg, 10 mg, or 20 mg of vanzacaftor in combination with tezacaftor–deutivacaftor or a triple placebo for 4 weeks, and participants with the F/F genotype were randomly assigned 2:1 to receive either vanzacaftor (20 mg)–tezacaftor–deutivacaftor or tezacaftor–ivacaftor active control for 4 weeks, following a 4-week tezacaftor–ivacaftor run-in period. Primary endpoints for part 1 and part 2 were safety and tolerability and absolute change in ppFEV1 from baseline to day 29. Secondary efficacy endpoints were absolute change from baseline at day 29 in sweat chloride concentrations and Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score. These clinical trials are registered with ClinicalTrials.gov, NCT03911713 and NCT03912233, and are complete. Findings: In study VX18-561-101, participants treated with deutivacaftor 150 mg once daily (n=23) or deutivacaftor 250 mg once daily (n=24) had mean absolute changes in ppFEV1 of 3·1 percentage points (95% CI –0·8 to 7·0) and 2·7 percentage points (–1·0 to 6·5) from baseline at week 12, respectively, versus –0·8 percentage points (–6·2 to 4·7) with ivacaftor 150 mg every 12 h (n=11); the deutivacaftor safety profile was consistent with the established safety profile of ivacaftor 150 mg every 12 h. In study VX18-121-101, participants with F/MF genotypes treated with vanzacaftor (5 mg)–tezacaftor–deutivacaftor (n=9), vanzacaftor (10 mg)–tezacaftor–deutivacaftor (n=19), vanzacaftor (20 mg)–tezacaftor–deutivacaftor (n=20), and placebo (n=10) had mean changes relative to baseline at day 29 in ppFEV1 of 4·6 percentage points (−1·3 to 10·6), 14·2 percentage points (10·0 to 18·4), 9·8 percentage points (5·7 to 13·8), and 1·9 percentage points (−4·1 to 8·0), respectively, in sweat chloride concentration of −42·8 mmol/L (–51·7 to –34·0), −45·8 mmol/L (95% CI –51·9 to –39·7), −49·5 mmol/L (–55·9 to –43·1), and 2·3 mmol/L (−7·0 to 11·6), respectively, and in CFQ-R respiratory domain score of 17·6 points (3·5 to 31·6), 21·2 points (11·9 to 30·6), 29·8 points (21·0 to 38·7), and 3·3 points (−10·1 to 16·6), respectively. Participants with the F/F genotype treated with vanzacaftor (20 mg)–tezacaftor–deutivacaftor (n=18) and tezacaftor–ivacaftor (n=10) had mean changes relative to baseline (taking tezacaftor–ivacaftor) at day 29 in ppFEV1 of 15·9 percentage points (11·3 to 20·6) and −0·1 percentage points (−6·4 to 6·1), respectively, in sweat chloride concentration of −45·5 mmol/L (−49·7 to −41·3) and −2·6 mmol/L (−8·2 to 3·1), respectively, and in CFQ-R respiratory domain score of 19·4 points (95% CI 10·5 to 28·3) and −5·0 points (−16·9 to 7·0), respectively. The most common adverse events overall were cough, increased sputum, and headache. One participant in the vanzacaftor–tezacaftor–deutivacaftor group had a serious adverse event of infective pulmonary exacerbation and another participant had a serious rash event that led to treatment discontinuation. For most participants, adverse events were mild or moderate in severity. Interpretation: Once-daily dosing with vanzacaftor–tezacaftor–deutivacaftor was safe and well tolerated and improved lung function, respiratory symptoms, and CFTR function. These results support the continued investigation of vanzacaftor–tezacaftor–deutivacaftor in phase 3 clinical trials compared with elexacaftor–tezacaftor–ivacaftor. Funding: Vertex Pharmaceuticals.

Preoperative clinical magnetic resonance imaging (MRI) protocols for gliomas, brain tumors with dismal outcomes due to their infiltrative properties, still rely on conventional structural MRI, which does not deliver information on tumor genotype and is limited in the delineation of diffuse gliomas. The GliMR COST action wants to raise awareness about the state of the art of advanced MRI techniques in gliomas and their possible clinical translation or lack thereof. This review describes current methods, limits, and applications of advanced MRI for the preoperative assessment of glioma, summarizing the level of clinical validation of different techniques. In this first part, we discuss dynamic susceptibility contrast and dynamic contrast-enhanced MRI, arterial spin labeling, diffusion-weighted MRI, vessel imaging, and magnetic resonance fingerprinting. The second part of this review addresses magnetic resonance spectroscopy, chemical exchange saturation transfer, susceptibility-weighted imaging, MRI-PET, MR elastography, and MR-based radiomics applications.Evidence Level: 3Technical Efficacy: Stage 2

Objective: To describe the spectrum of Leber congenital amaurosis (LCA) and cone-rod dystrophy (CORD) associated with the GUCY2D gene and to identify potential end points and optimal patient selection for future therapeutic trials.Design: International, multicenter, retrospective cohort study.Subjects: Eighty-two patients with GUCY2D-associated LCA or CORD from 54 families.Methods: Medical records were reviewed for medical history, best-corrected visual acuity (BCVA), ophthalmoscopy, visual fields, full-field electroretinography, and retinal imaging (fundus photography, spectral -domain OCT [SD-OCT], fundus autofluorescence).Main Outcomes Measures: Age of onset, evolution of BCVA, genotype-phenotype correlations, anatomic characteristics on funduscopy, and multimodal imaging.Results: Fourteen patients with autosomal recessive LCA and 68 with autosomal dominant CORD were included. The median follow-up times were 5.2 years (interquartile range [IQR] 2.6-8.8 years) for LCA and 7.2 years (IQR 2.2-14.2 years) for CORD. Generally, LCA presented in the first year of life. The BCVA in patients with LCA ranged from no light perception to 1.00 logarithm of the minimum angle of resolution (logMAR) and remained relatively stable during follow-up. Imaging for LCA was limited but showed little to no structural degeneration. In patients with CORD, progressive vision loss started around the second decade of life. The BCVA declined annually by 0.022 logMAR (P < 0.001) with no difference between patients with the c.2513G>A and the c.2512C>T GUCY2D variants (P = 0.798). At the age of 40 years, the probability of being blind or severely visually impaired was 32%. The integrity of the ellipsoid zone (EZ) and that of the external limiting membrane (ELM) on SD-OCT correlated signifi-cantly with BCVA (Spearman r = 0.744, P = 0.001, and r = 0.712, P < 0.001, respectively) in those with CORD.Conclusions: Leber congenital amaurosis associated with GUCY2D caused severe congenital visual impairment with relatively intact macular anatomy on funduscopy and available imaging, suggesting long pres-ervation of photoreceptors. Despite large variability, GUCY2D-associated CORD generally presented during adolescence, with a progressive loss of vision, and culminated in severe visual impairment during mid-to-late adulthood. The integrity of the ELM and EZ may be suitable structural end points for therapeutic studies of GUCY2D-associated CORD. Ophthalmology Retina 2022;6:711-722 (c) 2022 by the American Academy of Ophthalmology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).

Objectives International guidelines recommend additional salt supplementation during infancy in classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. The influence of corticoid medication and growth has not been assessed. Aim To investigate the current use of salt supplementation, fludrocortisone (FC) and hydrocortisone (HC) dosage as well as weight, height, BMI and blood pressure (BP) in CAH children aged 0–3 years. Methods Retrospective multicentre analysis using data from the I-CAH registry. Salt-treated (ST) and non-salt-treated (NST) children were compared regarding FC and HC dosage, weight, height and BP at 0, 3, 6, 9, 12, 18, 24, 30, and 36 months. Results We analysed 2483 visits of 331 patients born after year 2000 in 13 countries (male, n = 145) with 203 ST patients (61%). NST children had significantly higher FC dosages at 1.5–4.5 months and higher HC dosages until 1.5 months of age. No differences in weight, length and BP between subgroups were observed. Children of the whole cohort showed increased BMI-SDS during the study period and about half of the reported BP readings were >P95. Conclusion In children treated with additional salt supplementation, FC and HC dosages are lower during the first months of life but without differences in weight, length and BP until 3 years of age compared to NST children. All children showed an increase in BMI-SDS and a high rate of BP readings >P95 until 3 years, indicating the start of weight gain and negative effects on blood pressure already in very early life.

STUDY QUESTION Does ovarian stimulation with the addition of tamoxifen or letrozole affect the number of cumulus-oocyte complexes (COCs) retrieved compared to standard ovarian stimulation in women with breast cancer who undergo fertility preservation? SUMMARY ANSWER Alternative ovarian stimulation protocols with tamoxifen or letrozole did not affect the number of COCs retrieved at follicle aspiration in women with breast cancer. WHAT IS KNOWN ALREADY Alternative ovarian stimulation protocols have been introduced for women with breast cancer who opt for fertility preservation by means of banking of oocytes or embryos. How these ovarian stimulation protocols compare to standard ovarian stimulation in terms of COC yield is unknown. STUDY DESIGN, SIZE, DURATION This multicentre, open-label randomized controlled superiority trial was carried out in 10 hospitals in the Netherlands and 1 hospital in Belgium between January 2014 and December 2018. We randomly assigned women with breast cancer, aged 18–43 years, who opted for banking of oocytes or embryos to one of three study arms; ovarian stimulation plus tamoxifen, ovarian stimulation plus letrozole or standard ovarian stimulation. Standard ovarian stimulation included GnRH antagonist, recombinant FSH and GnRH agonist trigger. Randomization was performed with a web-based system in a 1:1:1 ratio, stratified for oral contraception usage at start of ovarian stimulation, positive estrogen receptor (ER) status and positive lymph nodes. Patients and caregivers were not blinded to the assigned treatment. The primary outcome was number of COCs retrieved at follicle aspiration. PARTICIPANTS/MATERIALS, SETTING, METHODS During the study period, 162 women were randomly assigned to one of three interventions. Fifty-four underwent ovarian stimulation plus tamoxifen, 53 ovarian stimulation plus letrozole and 55 standard ovarian stimulation. Analysis was according to intention-to-treat principle. MAIN RESULTS AND THE ROLE OF CHANCE No differences among groups were observed in the mean (±SD) number of COCs retrieved: 12.5 (10.4) after ovarian stimulation plus tamoxifen, 14.2 (9.4) after ovarian stimulation plus letrozole and 13.6 (11.6) after standard ovarian stimulation (mean difference −1.13, 95% CI −5.70 to 3.43 for tamoxifen versus standard ovarian stimulation and 0.58, 95% CI −4.03 to 5.20 for letrozole versus standard ovarian stimulation). After adjusting for oral contraception usage at the start of ovarian stimulation, positive ER status and positive lymph nodes, the mean difference was −1.11 (95% CI −5.58 to 3.35) after ovarian stimulation plus tamoxifen versus standard ovarian stimulation and 0.30 (95% CI −4.19 to 4.78) after ovarian stimulation plus letrozole versus standard ovarian stimulation. There were also no differences in the number of oocytes or embryos banked. There was one serious adverse event after standard ovarian stimulation: one woman was admitted to the hospital because of ovarian hyperstimulation syndrome. LIMITATIONS, REASONS FOR CAUTION The available literature on which we based our hypothesis, power analysis and sample size calculation was scarce and studies were of low quality. Our study did not have sufficient power to perform subgroup analysis on follicular, luteal or random start of ovarian stimulation. WIDER IMPLICATIONS OF THE FINDINGS Our study showed that adding tamoxifen or letrozole to a standard ovarian stimulation protocol in women with breast cancer does not impact the effectiveness of fertility preservation and paves the way for high-quality long-term follow-up on breast cancer treatment outcomes and women’s future pregnancy outcomes. Our study also highlights the need for high-quality studies for all women opting for fertility preservation, as alternative ovarian stimulation protocols have been introduced to clinical practice without proper evidence. STUDY FUNDING/COMPETING INTEREST(S) The study was supported by a grant (2011.WO23.C129) of ‘Stichting Pink Ribbon’, a breast cancer fundraising charity organization in the Netherlands. M.G., C.B.L. and R.S. declared that the Center for Reproductive Medicine, Amsterdam UMC (location VUMC) has received unconditional research and educational grants from Guerbet, Merck and Ferring, not related to the presented work. C.B.L. declared a speakers fee for Inmed and Yingming. S.C.L. reports grants and non-financial support from Agendia, grants, non-financial support and other from AstraZeneca, grants from Eurocept-pharmaceuticals, grants and non-financial support from Genentech/Roche and Novartis, grants from Pfizer, grants and non-financial support from Tesaro and Immunomedics, other from Cergentis, IBM, Bayer, and Daiichi-Sankyo, outside the submitted work; In addition, S.C.L. has a patent UN23A01/P-EP pending that is unrelated to the present work. J.M.J.S. reported payments and travel grants from Merck and Ferring. C.C.M.B. reports her role as unpaid president of the National guideline committee on Fertility Preservation in women with cancer. K.F. received unrestricted grants from Merck Serono, Good Life and Ferring not related to present work. K.F. declared paid lectures for Ferring. D.S. declared former employment from Merck Sharp & Dohme (MSD). K.F. declared paid lectures for Ferring. D.S. reports grants from MSD, Gedeon Richter and Ferring paid to his institution; consulting fee payments from MSD and Merck Serono paid to his institution; speaker honoraria from MSD, Gedeon Richter, Ferring Pharmaceuticals and Merck Serono paid to his institution. D.S. has also received travel and meeting support from MSD, Gedeon Richter, Ferring Pharmaceuticals and Merck Serono. No payments are related to present work. TRIAL REGISTRATION NUMBER NTR4108. TRIAL REGISTRATION DATE 6 August 2013. DATE OF FIRST PATIENT’S ENROLMENT 30 January 2014.

ObjectiveTo examine trends in end-of-life communication with people with cancer in general practice.MethodsMortality follow-back survey among general practitioners (GPs) in representative epidemiological surveillance networks in Belgium (BE), the Netherlands (NL) and Spain (ES) in 2009–2010 (ES: 2010–2011) and 2013–2014. Using a standardised form, GPs registered all deceased adult patients in their practice and reported for five end-of-life care topics whether they had been discussed with the patient. Non-sudden cancer deaths were included (n=2306; BE: 1233; NL: 729; ES: 344).ResultsA statistically significant increase was found between 2009/2010 and 2014 in the prevalence of communication about diagnosis (from 84% to 94%) and options for end-of-life care (from 73% to 90%) in BE, and in GPs’ awareness of patients’ preferences for medical treatment and a proxy decision-maker in BE (from 41% and 20% up to 53% and 28%) and the NL (from 62% and 32% up to 70% and 52%). Communication about options for end-of-life care and psychosocial problems decreased in the NL (from 88% and 91% down to 73%) and ES (from 76% and 77% down to 26% and 39%).ConclusionConsiderable change in GP–patient communication seems possible in a relatively short time span, but communication cannot be assumed to increase over time. Increasing specialisation of care and task differentiation may lead to new roles in communication for healthcare providers in primary and secondary care. Improved information sharing between GPs and other healthcare providers may be necessary to ensure that patients have the chance to discuss important end-of-life topics.

Background It is currently unknown whether there are differences in desire for gender affirming medical treatment (GAMT) between binary and non-binary transgender individuals, although the latter seek treatment less prevalently. Aim To investigate differences between binary and non-binary individuals on received GAMT, desire for GAMT, and motives for (not) wanting GAMT, and to explore the association between having an unfulfilled treatment desire and general and sexual well-being. Methods We conducted an online questionnaire in a community sample of 125 transgender men, 72 transgender women, and 62 non-binary transgender individuals (age: M = 30.4, SD = 11.31, range 18-69). Outcome measures Undergone GAMT, GAMT desire, motives for (not) wanting (further) GAMT, Utrecht Gender Dysphoria Scale, Satisfaction With Life Scale, Hospital Anxiety and Depression Scale, Global Measure of Sexual Satisfaction, transgender-specific body image worries, and sexual self-concept discrepancies. Results Binary transgender participants reported having undergone more GAMT procedures than non-binary transgender participants (P < .001 for both gender affirming hormone treatment (GAHT) and gender affirming surgery (GAS)). While binary participants reported a stronger desire for GAHT compared to non-binary participants (X2(1, N = 93) = 32.63, P < .001), the groups did not differ in their desire for GAS (X2(1, N = 247) = 0.68, P = .411). Binary and non-binary participants reported similar reasons for wanting treatment, mostly related to body and/or gender incongruence and gender affirmation. In terms of not wanting treatment, the non-binary group reported their gender identity as the most important reason, while the binary group mostly mentioned possible medical complications. The majority of both groups had an unfulfilled treatment desire (69% of binary participants and 64.5% of non-binary participants), which was related to lower levels of general life satisfaction (P < .001) and sexual satisfaction (P = .005), more anxiety (P = .006) and transgender-specific body image worries (P < .001), and larger sexual self-concept discrepancies (P < .001 for actual and/or ideal, P < .001 for actual and/or ought). Clinical implications Systemic barriers to GAMT (especially GAS) should be removed not only for binary but also for non-binary identifying transgender individuals to decrease the discrepancy between treatment desire and actually seeking treatment. Strengths & limitations This study was the first to systematically investigate differences in treatment desire motives between binary and non-binary transgender individuals, while also showing the possible negative consequences of an unfulfilled treatment desire. Given the online character of the study, results may not generalize to the broader transgender community. Conclusion Similarly to binary transgender individuals, many non-binary transgender individuals have a desire for GAMT, and not being able to receive GAMT has a negative effect on their mental and sexual health. Further efforts should be made to make GAMT accessible for all transgender individuals, regardless of gender identity.

The credibility of threshold-based alarms in anesthesia monitors is low and most of the warnings they produce are not informative. This study aims to show that Machine Learning techniques have a potential to generate meaningful alarms during general anesthesia without putting constraints on the type of procedure. Two distinct approaches were tested – Complication Detection and Anomaly Detection. The former is a generic supervised learning problem and for this a simple feed-forward Neural Network performed best. For the latter, we used an Encoder-Decoder Long Short-Term Memory architecture that does not require a large manually-labeled dataset. We show this approach to be more flexible and in the spirit of Explainable Artificial Intelligence, offering greater potential for future improvement.

AIMS: P-glycoprotein (P-gp) and CYP3A4-interacting drugs influence plasma levels of non-vitamin K antagonist oral anticoagulants (NOACs). However, the clinical relevance is questioned. Therefore, the impact of pharmacokinetically-interacting drugs on the effectiveness and safety of NOACs in patients with atrial fibrillation (AF) was investigated. METHODS: A meta-analysis was performed based on randomized controlled trials and observational studies retrieved from Pubmed and Embase that investigated the impact of concomitantly used P-gp/CYP3A4-interacting drugs on the risk-benefit profile of NOACs in AF patients. RESULTS: Fifteen studies were included, investigating 21 711 and 306 421 NOAC-treated AF patients with and without P-gp/CYP3A4 inhibitor use respectively, while only 1 study included P-gp/CYP3A4 inducers. In NOAC-treated AF patients, concomitant use of P-gp/CYP3A4 inhibitors was associated with significantly higher major bleeding (relative risk [RR] 1.10, 95% confidence interval [CI; 1.01-1.19]) and all-cause mortality risks (RR 1.14, 95%CI [1.05-1.23]) compared to not using P-gp/CYP3A4 inhibitors, while the risks of stroke/systemic embolism (RR 0.88, 95%CI [0.77-1.01]), intracranial bleeding (RR 0.89, 95%CI [0.68-1.15]) and gastrointestinal bleeding (RR 1.09, 95%CI [0.91-1.30]) were not significantly different. Concomitant use of amiodarone with NOACs was associated with lower thromboembolic (RR 0.75, 95%CI [0.61-0.92]), similar major bleeding (RR 0.92, 95%CI [0.80-1.07]) but higher mortality risks (RR 1.21, 95%CI [1.05-1.39]). Coadministration of verapamil or diltiazem was associated with higher major bleeding risks (RR 1.64, 95%CI [1.31-2.06]), but comparable thromboembolic (RR 1.10, 95%CI [0.75-1.61]) and mortality risks (RR 1.01, 95%CI [0.77-1.33]). CONCLUSION: Given the higher bleeding and mortality risks in NOAC-treated AF patients concomitantly using P-gp/CYP3A4 inhibitors, close monitoring is warranted.

Aims TASK-1 (K2P3.1) two-pore domain potassium channels are atrial-specific and significantly upregulated in atrial fibrillation (AF) patients, contributing to AF-related electrical remodelling. Inhibition of TASK-1 in cardiomyocytes of AF patients was shown to counteract AF-related action potential duration shortening. Doxapram was identified as a potent inhibitor of the TASK-1 channel. In the present study, we investigated the antiarrhythmic efficacy of doxapram in a porcine model of AF. Methods and results Doxapram successfully cardioverted pigs with artificially induced episodes of AF. We established a porcine model of persistent AF in domestic pigs via intermittent atrial burst stimulation using implanted pacemakers. All pigs underwent catheter-based electrophysiological investigations prior to and after 14 d of doxapram treatment. Pigs in the treatment group received intravenous administration of doxapram once per day. In doxapram-treated AF pigs, the AF burden was significantly reduced. After 14 d of treatment with doxapram, TASK-1 currents were still similar to values of sinus rhythm animals. Doxapram significantly suppressed AF episodes and normalized cellular electrophysiology by inhibition of the TASK-1 channel. Patch-clamp experiments on human atrial cardiomyocytes, isolated from patients with and without AF could reproduce the TASK-1 inhibitory effect of doxapram. Conclusions Repurposing doxapram might yield a promising new antiarrhythmic drug to treat AF in patients. Translational perspective Pharmacological suppression of atrial TASK 1 potassium currents prolongs atrial refractoriness with no effects on ventricular repolarization, resulting in atrial-specific class III antiarrhythmic effects. In our preclinical pilot study the respiratory stimulant doxapram was successfully administered for cardioversion of acute AF as well as rhythm control of persistent AF in a clinically relevant porcine animal model.

BACKGROUND: At Eurotransplant (ET), kidneys are transferred to "rescue allocation" (RA), whenever the standard allocation (SA) algorithms Eurotransplant Kidney Allocation System (ETKAS) and Eurotransplant Senior Program (ESP) fail. We analyzed the outcome of RA. METHODS: Retrospective patient clinical and demographic characteristics association analyses were performed with graft outcomes for 2422 recipients of a deceased donor renal transplantation (DDRT) after RA versus 25 481 after SA from 71 centers across all ET countries from 2006 to 2018. RESULTS: Numbers of DDRTs after RA increased over the time, especially in Germany. RA played a minor role in ESP versus ETKAS (2.7% versus 10.4%). RA recipients and donors were older compared with SA recipients and donors, cold ischemia times were longer, waiting times were shorter, and the incidence of primary nonfunction was comparable. Among ETKAS recipients, HLA matching was more favorable in SA (mean 3.7 versus 2.5). In multivariate modeling, the incidence of graft loss in ETKAS recipients was reduced in RA compared with SA (subdistribution hazard ratio, 0.80; 95% confidence interval [0.70-0.91], P

Repetitive transcranial magnetic stimulation (rTMS) is a tool that can be used to administer treatment for neuropsychiatric disorders such as major depressive disorder, although the clinical efficacy is still rather modest. Overly general stimulation protocols that consider neither patient-specific depression symptomology nor individualized brain characteristics, such as anatomy or structural and functional connections, may be the cause of the high inter- and intraindividual variability in rTMS clinical responses. Multimodal neuroimaging can provide the necessary insights into individual brain characteristics and can therefore be used to personalize rTMS parameters. Optimal coil positioning should include a three-step process: 1) identify the optimal (indirect) target area based on the exact symptom pattern of the patient; 2) derive the cortical (direct) target location based on functional and/or structural connectomes derived from functional and diffusion magnetic resonance imaging data; and 3) determine the ideal coil position by computational modeling, such that the electric field distribution overlaps with the cortical target. These TMS-induced electric field simulations, derived from anatomical and diffusion magnetic resonance imaging data, can be further applied to compute optimal stimulation intensities. In addition to magnetic resonance imaging, electroencephalography can provide complementary information regarding the ongoing brain oscillations. This information can be used to determine the optimal timing and frequency of the stimuli. The heightened benefits of these personalized stimulation approaches are logically reasoned, but speculative. Randomized clinical trials will be required to compare clinical responses from standard rTMS protocols to personalized protocols. Ultimately, an optimized clinical response may result from precision protocols derived from combinations of personalized stimulation parameters.

As treatments for second relapsed and refractory first relapsed paediatric AML transition from purely palliative to more commonly curative in nature, comparative data is necessary for evaluating the effectiveness of emerging treatment options. Furthermore, little is known about predictors of prognosis following third-line therapy. From 2004 until 2019, 277 of the 869 patients enrolled in NOPHO-DB SHIP consortium trials experienced a first relapse and, of these patients, 98 experienced refractory first relapse and 59 a second relapse. Data on patient and disease characteristics within this cohort of 157 patients was analysed to determine probability of overall survival (pOS) and to identify factors influencing survival. Data on early treatment response and complete remission were not available. One and 5-year pOS were 22 ± 3% and 14 ± 3%, respectively. There was no statistically significant difference in survival between refractory first relapsed and second relapsed AML. Factors influencing prognosis included: late relapse, type of third-line treatment, FLT3 mutational status, and original treatment protocol. These data provide a baseline for evaluating the effectiveness of emerging therapies for the treatment of children with refractory first relapsed and second relapsed paediatric AML and evidence that select patients receiving third-line therapy can be cured.

The Belgian Society for Viruses of Microbes (BSVoM) was founded on 9 June 2022 to capture and enhance the collaborative spirit among the expanding community of microbial virus researchers in Belgium. The sixteen founders are affiliated to fourteen different research entities across academia, industry and government. Its inaugural symposium was held on 23 September 2022 in the Thermotechnical Institute at KU Leuven. The meeting program covered three thematic sessions launched by international keynote speakers: (1) virus-host interactions, (2) viral ecology, evolution and diversity and (3) present and future applications. During the one-day symposium, four invited keynote lectures, ten selected talks and eight student pitches were given along with 41 presented posters. The meeting hosted 155 participants from twelve countries. ispartof: VIRUSES-BASEL vol:15 issue:5 ispartof: location:Switzerland status: published

The aim of this article is to identify and describe clinical practice performance characteristics for bordered foam dressings in the treatment of complex wounds. Our recently published systematic review of outcomes and applied measurement instruments for the use of bordered foam dressings in complex wounds has led to us identifying a range of important clinical and patient-centred issues related to this dressing class. Specifically, here, we focus on an overview of performance criteria in the areas of application, adhesion, exudate management and debridement functions of bordered foam dressings. Our hope is that by highlighting the clinical performance criteria, future testing standards for wound dressings will more closely match our clinical expectations and, thereby, assist clinicians to make better wound treatment choices based on meaningful and clinically relevant dressing product performance standards. complex wounds, complex wound care, treatment, bordered foam dressings, dressing performance.

The radionuclide therapy [177Lu]Lu-PSMA-617 was recently FDA-approved for treatment of metastatic castration-resistant prostate cancer. Salivary gland toxicity is currently considered as the main dose-limiting side effect. However, its uptake and retention mechanisms in the salivary glands remain elusive. Therefore, our aim was to elucidate the uptake patterns of [177Lu]Lu-PSMA-617 in salivary gland tissue and cells by conducting cellular binding and autoradiography experiments. Briefly, A-253 and PC3-PIP cells, and mouse kidney and pig salivary gland tissue, were incubated with 5 nM [177Lu]Lu-PSMA-617 to characterize its binding. Additionally, [177Lu]Lu-PSMA-617 was co-incubated with monosodium glutamate, ionotropic or metabotropic glutamate receptor antagonists. Low, non-specific binding was observed in salivary gland cells and tissues. Monosodium glutamate was able to decrease [177Lu]Lu-PSMA-617 in PC3-PIP cells, mouse kidney and pig salivary gland tissue. Kynurenic acid (ionotropic antagonist) decreased the binding of [177Lu]Lu-PSMA-617 to 29.2 ± 20.6% and 63.4 ± 15.4%, respectively, with similar effects observed on tissues. (RS)-MCPG (metabotropic antagonist) was able to decrease the [177Lu]Lu-PSMA-617 binding on A-253 cells to 68.2 ± 16.8% and pig salivary gland tissue to 53.1 ± 36.8%. To conclude, we showed that the non-specific binding on [177Lu]Lu-PSMA-617 could be reduced by monosodium glutamate, kynurenic acid and (RS)-MCPG.

Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited., Background and objectives: The efficacy of deep brain stimulation of the anterior nucleus of the thalamus (ANT DBS) in patients with drug-resistant epilepsy (DRE) was demonstrated in the double-blind Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy randomized controlled trial. The Medtronic Registry for Epilepsy (MORE) aims to understand the safety and longer-term effectiveness of ANT DBS therapy in routine clinical practice. Methods: MORE is an observational registry collecting prospective and retrospective clinical data. Participants were at least 18 years old, with focal DRE recruited across 25 centers from 13 countries. They were followed for at least 2 years in terms of seizure frequency (SF), responder rate (RR), health-related quality of life (Quality of Life in Epilepsy Inventory 31), depression, and safety outcomes. Results: Of the 191 patients recruited, 170 (mean [SD] age of 35.6 [10.7] years, 43% female) were implanted with DBS therapy and met all eligibility criteria. At baseline, 38% of patients reported cognitive impairment. The median monthly SF decreased by 33.1% from 15.8 at baseline to 8.8 at 2 years (p < 0.0001) with 32.3% RR. In the subgroup of 47 patients who completed 5 years of follow-up, the median monthly SF decreased by 55.1% from 16 at baseline to 7.9 at 5 years (p < 0.0001) with 53.2% RR. High-volume centers (>10 implantations) had 42.8% reduction in median monthly SF by 2 years in comparison with 25.8% in low-volume center. In patients with cognitive impairment, the reduction in median monthly SF was 26.0% by 2 years compared with 36.1% in patients without cognitive impairment. The most frequently reported adverse events were changes (e.g., increased frequency/severity) in seizure (16%), memory impairment (patient-reported complaint, 15%), depressive mood (patient-reported complaint, 13%), and epilepsy (12%). One definite sudden unexpected death in epilepsy case was reported. Discussion: The MORE registry supports the effectiveness and safety of ANT DBS therapy in a real-world setting in the 2 years following implantation. Classification of evidence: This study provides Class IV evidence that ANT DBS reduces the frequency of seizures in patients with drug-resistant focal epilepsy., The MORE registry was sponsored and funded by Medtronic, plc.

PURPOSE Single-agent chemotherapies have limited activity and considerable toxicity in patients with platinum-resistant epithelial ovarian cancer (PROC). Mirvetuximab soravtansine (MIRV) is an antibody-drug conjugate targeting folate receptor α (FRα). SORAYA is a single-arm, phase II study evaluating efficacy and safety of MIRV in patients with PROC. METHODS SORAYA enrolled FRα-high patients with PROC who had received one to three prior therapies, including required bevacizumab. The primary end point was confirmed objective response rate (ORR) by investigator; duration of response was the key secondary end point. RESULTS One hundred six patients were enrolled; 105 were evaluable for efficacy. All patients had received prior bevacizumab, 51% had three prior lines of therapy, and 48% received a prior poly ADP-ribose polymerase inhibitor. Median follow-up was 13.4 months. ORR was 32.4% (95% CI, 23.6 to 42.2), including five complete and 29 partial responses. The median duration of response was 6.9 months (95% CI, 5.6 to 9.7). In patients with one to two priors, the ORR by investigator was 35.3% (95% CI, 22.4 to 49.9) and in patients with three priors was 30.2% (95% CI, 18.3 to 44.3). The ORR by investigator was 38.0% (95% CI, 24.7 to 52.8) in patients with prior poly ADP-ribose polymerase inhibitor exposure and 27.5% (95% CI, 15.9 to 41.7) in those without. The most common treatment-related adverse events (all grade and grade 3-4) were blurred vision (41% and 6%), keratopathy (29% and 9%), and nausea (29% and 0%). Treatment-related adverse events led to dose delays, reductions, and discontinuations in 33%, 20%, and 9% of patients, respectively. CONCLUSION MIRV demonstrated consistent clinically meaningful antitumor activity and favorable tolerability and safety in patients with FRα-high PROC who had received up to three prior therapies, including bevacizumab, representing an important advance for this biomarker-selected population.

Background: Advance care planning supports patients to reflect on and discuss preferences for future treatment and care. Studies of the impact of advance care planning on healthcare use and healthcare costs are scarce. Aim: To determine the impact on healthcare use and costs of an advance care planning intervention across six European countries. Design: Cluster-randomised trial, registered as ISRCTN63110516, of advance care planning conversations supported by certified facilitators. Setting/participants: Patients with advanced lung or colorectal cancer from 23 hospitals in Belgium, Denmark, Italy, the Netherlands, Slovenia and the UK. Data on healthcare use were collected from hospital medical files during 12 months after inclusion. Results: Patients with a good performance status were underrepresented in the intervention group ( pConclusions: Lower care costs as observed in the intervention group were mainly related to patients’ characteristics. A definite impact of the intervention itself could not be established.

X-linked recessive deficiency of TLR7, a MyD88- and IRAK-4-dependent endosomal ssRNA sensor, impairs SARS-CoV-2 recognition and type I IFN production in plasmacytoid dendritic cells (pDCs), thereby underlying hypoxemic COVID-19 pneumonia with high penetrance. We report 22 unvaccinated patients with autosomal recessive MyD88 or IRAK-4 deficiency infected with SARS-CoV-2 (mean age: 10.9 yr; 2 mo to 24 yr), originating from 17 kindreds from eight countries on three continents. 16 patients were hospitalized: six with moderate, four with severe, and six with critical pneumonia, one of whom died. The risk of hypoxemic pneumonia increased with age. The risk of invasive mechanical ventilation was also much greater than in age-matched controls from the general population (OR: 74.7, 95% CI: 26.8-207.8, P < 0.001). The patients' susceptibility to SARS-CoV-2 can be attributed to impaired TLR7-dependent type I IFN production by pDCs, which do not sense SARS-CoV-2 correctly. Patients with inherited MyD88 or IRAK-4 deficiency were long thought to be selectively vulnerable to pyogenic bacteria, but also have a high risk of hypoxemic COVID-19 pneumonia. ispartof: JOURNAL OF EXPERIMENTAL MEDICINE vol:220 issue:5 ispartof: location:United States status: published

BackgroundRecent in vitro studies strongly implicated mast cell-derived proteases as regulators of IL-33 activity by enzymatic cleavage in its central domain. A better understanding of the role of mast cell proteases on IL-33 activity in vivo is needed. We aimed to compare the expression of mast cell proteases in C57BL/6 and BALB/c mice, their role in the cleavage of IL-33 cytokine, and their contribution to allergic airway inflammation.ResultsIn vitro, full-length IL-33 protein was efficiently degraded by mast cell supernatants of BALB/c mice in contrast to the mast cell supernatants from C57BL/6 mice. RNAseq analysis indicated major differences in the gene expression profiles of bone marrow-derived mast cells from C57BL/6 and BALB/c mice. In Alternaria alternata (Alt) - treated C57BL/6 mice the full-length form of IL-33 was mainly present, while in BALB/c mice, the processed shorter form of IL-33 was more prominent. The observed cleavage pattern of IL-33 was associated with a nearly complete lack of mast cells and their proteases in the lungs of C57BL/6 mice. While most inflammatory cells were similarly increased in Alt-treated C57BL/6 and BALB/c mice, C57BL/6 mice had significantly more eosinophils in the bronchoalveolar lavage fluid and IL-5 protein levels in their lungs than BALB/c mice.ConclusionOur study demonstrates that lung mast cells differ in number and protease content between the two tested mouse strains and could affect the processing of IL-33 and inflammatory outcome of Alt -induced airway inflammation. We suggest that mast cells and their proteases play a regulatory role in IL-33-induced lung inflammation by limiting its proinflammatory effect via the IL-33/ST2 signaling pathway.

Clinical History: A 32-year-old female presented at the emergency department with acute right-sided thoracic pain. She also complained of a chronic dry cough. She was an active smoker with 10 packyears. Clinical examination and laboratory results were unremarkable. The patient was hemodynamically stable and afebrile., 32 years, female

This thesis details how young adults with ongoing post-concussion symptoms deal with the omnipresence of screens and social media in their daily lives. Their injuries often induce heightened sensitivities to stimuli, requiring them to commence “cognitive rest,” a treatment contested by experts in the field. While emerging literature endorses such rest during the acute phase of concussion recovery, numerous clinicians still recommend that patients reduce screen exposure (i.e., extend the rest) beyond this period until symptoms resolve. Complex dilemmas arise, however, for young adult screen users whose symptoms persist for weeks, months, and years. Drawing upon Max van Manen’s phenomenology of practice, this thesis delineates these dilemmas. Its central inquiry concerns young adults’ post-injury screen and social media use as they (a) attend to their online identities and obligations (e.g., relational upkeep and schoolwork) and (b) obtain information on the Internet about current concussion management strategies to aid their recoveries. Addressing both (a) and (b), five female participants aged 18-25 shared their lived experiences through semi-structured interviews. These participants experienced screens as simultaneously helpful and harmful, alleviating some of their challenges while aggravating others. They appreciated that screens afforded them social connectedness, distraction from difficulties, and accessible concussion information. Conversely, they confronted technology’s central role in their everyday routines, struggled to integrate their invisible injuries into their social media presences, and concluded that Internet information could supplement (but not supplant) traditional clinical encounters. Underlying their interrelated screen-use dilemmas was the realization that they could use screens as an escape but not fully escape screens.

In the last decade, in vitro embryo production in horses has become an established clinical practice, but blastocyst rates from vitrified equine oocytes remain low. Cryopreservation impairs the oocyte developmental potential, which may be reflected in the messenger RNA (mRNA) profile. Therefore, this study aimed to compare the transcriptome profiles of metaphase II equine oocytes vitrified before and after in vitro maturation. To do so, three groups were analyzed with RNA sequencing: (1) fresh in vitro matured oocytes as a control (FR), (2) oocytes vitrified after in vitro maturation (VMAT), and (3) oocytes vitrified immature, warmed, and in vitro matured (VIM). In comparison with fresh oocytes, VIM resulted in 46 differentially expressed (DE) genes (14 upregulated and 32 downregulated), while VMAT showed 36 DE genes (18 in each category). A comparison of VIM vs. VMAT resulted in 44 DE genes (20 upregulated and 24 downregulated). Pathway analyses highlighted cytoskeleton, spindle formation, and calcium and cation ion transport and homeostasis as the main affected pathways in vitrified oocytes. The vitrification of in vitro matured oocytes presented subtle advantages in terms of the mRNA profile over the vitrification of immature oocytes. Therefore, this study provides a new perspective for understanding the impact of vitrification on equine oocytes and can be the basis for further improvements in the efficiency of equine oocyte vitrification.

Background: Considering the long natural history of prostate cancer (PCa), long-term results of the European Randomised Study of Screening for PCa (ERSPC) are crucial. Objective: To provide an update on the effect of prostate-specific antigen (PSA)-based screening on PCa-specific mortality (PCSM), metastatic disease, and overdiagnosis in the Dutch arm of the ERSPC. Design, setting, and participants: Between 1993 and 2000, a total of 42 376 men, aged 55–74 yr, were randomised to a screening or a control arm. The main analysis was performed with men aged 55–69 yr (n = 34 831). Men in the screening arm were offered PSA-based screening with an interval of 4 yr. Outcome measurements and statistical analysis: Intention-to-screen analyses with Poisson regression were used to calculate rate ratios (RRs) of PCSM and metastatic PCa. Results and limitations: After a median follow-up of 21 yr, the RR of PCSM was 0.73 (95% confidence interval [CI]: 0.61–0.88) favouring screening. The numbers of men needed to invite (NNI) and needed to diagnose (NND) to prevent one PCa death were 246 and 14, respectively. For metastatic PCa, the RR was 0.67 (95% CI: 0.58–0.78) favouring screening. The NNI and NND to prevent one metastasis were 121 and 7, respectively. No statistical difference in PCSM (RR of 1.18 [95% CI: 0.87–1.62]) was observed in men aged ≥70 yr at the time of randomisation. In the screening arm, higher rates of PCSM and metastatic disease were observed in men who were screened only once and in a selected group of men above the screening age cut-off of 74 yr. Conclusions: The current analysis illustrates that with a follow-up of 21 yr, both absolute metastasis and mortality reduction continue to increase, resulting in a more favourable harm-benefit ratio than demonstrated previously. These data do not support starting screening at the age of 70–74 yr and show that repeated screening is essential. Patient summary: Prostate-specific antigen–based prostate cancer screening reduces metastasis and mortality. Longer follow-up shows fewer invitations and diagnoses needed to prevent one death, a positive note towards the issue of overdiagnosis.

COVID-19; Haematology; Nirmatrelvir COVID-19; Hematología; Nirmatrelvir COVID-19; Hematologia; Nirmatrelvir Background Nirmatrelvir/ritonavir treatment decreases the hospitalisation rate in immunocompetent patients with COVID-19, but data on efficacy in patients with haematological malignancy are scarce. Here, we describe the outcome of nirmatrelvir/ritonavir treatment in a large cohort of the latter patients. Methods This is a retrospective cohort study from the multicentre EPICOVIDEHA registry (NCT04733729) on patients with haematological malignancy, who were diagnosed with COVID-19 between January and September 2022. Patients receiving nirmatrelvir/ritonavir were compared to those who did not. A logistic regression was run to determine factors associated with nirmatrelvir/ritonavir administration in our sample. Mortality between treatment groups was assessed with Kaplan–Meier survival plots after matching all the patients with a propensity score. Additionally, a Cox regression was modelled to detect factors associated with mortality in patients receiving nirmatrelvir/ritonavir. Findings A total of 1859 patients were analysed, 117 (6%) were treated with nirmatrelvir/ritonavir, 1742 (94%) were treated otherwise. Of 117 patients receiving nirmatrelvir/ritonavir, 80% had received ≥1 anti-SARS-CoV-2 vaccine dose before COVID-19 onset, 13% of which received a 2nd vaccine booster. 5% were admitted to ICU. Nirmatrelvir/ritonavir treatment was associated with the presence of extrapulmonary symptoms at COVID-19 onset, for example anosmia, fever, rhinitis, or sinusitis (aOR 2.509, 95%CI 1.448–4.347) and 2nd vaccine booster (aOR 3.624, 95%CI 1.619–8.109). Chronic pulmonary disease (aOR 0.261, 95%CI 0.093–0.732) and obesity (aOR 0.105, 95%CI 0.014–0.776) were not associated with nirmatrelvir/ritonavir use. After propensity score matching, day-30 mortality rate in patients treated with nirmatrelvir/ritonavir was 2%, significantly lower than in patients with SARS-CoV-2 directed treatment other than nirmatrelvir/ritonavir (11%, p = 0.036). No factor was observed explaining the mortality difference in patients after nirmatrelvir/ritonavir administration. Interpretation Haematological malignancy patients were more likely to receive nirmatrelvir/ritonavir when reporting extrapulmonary symptoms or 2nd vaccine booster at COVID-19 onset, as opposed to chronic pulmonary disease and obesity. The mortality rate in patients treated with nirmatrelvir/ritonavir was lower than in patients with targeted drugs other than nirmatrelvir/ritonavir. EPICOVIDEHA has received funds from Optics COMMIT (COVID-19 Unmet Medical Needs and Associated Research Extension) COVID-19 RFP program by GILEAD Science, United States (Project 2020-8223).

Muscle atrophy is an extra-pulmonary complication of acute exacerbations (AE) in chronic obstructive pulmonary disease (COPD). The endogenous production and therapeutic application of glucocorticoids (GCs) have been implicated as drivers of muscle loss in AE-COPD. The enzyme 11 beta-hydroxysteroid dehydrogenase 1 (11beta-HSD1) activates GCs and contributes towards GC-induced muscle wasting. To explore the potential of 11betaHSD1 inhibition to prevent muscle wasting here, the objective of this study was to ascertain the contribution of endogenous GC activation and amplification by 11betaHSD1 in skeletal muscle wasting during AE-COPD. Emphysema was induced by intra-tracheal (IT) instillation of elastase to model COPD in WT and 11betaHSD1/KO mice, followed by vehicle or IT-LPS administration to mimic AE. microCT scans were obtained prior and at study endpoint 48h following IT-LPS, to assess emphysema development and muscle mass changes, respectively. Plasma cytokine and GC profiles were determined by ELISA. In vitro myonuclear accretion and cellular response to plasma and GCs were determined in C2C12 and human primary myotubes. Muscle wasting was exacerbated in LPS-11betaHSD1/KO animals compared to WT controls. RT-qPCR and western blot analysis showed elevated catabolic and suppressed anabolic pathways in muscle of LPS-11betaHSD1/KO animals relative to WTs. Plasma corticosterone levels were higher in LPS-11betaHSD1/KO animals, whilst C2C12 myotubes treated with LPS-11betaHSD1/KO plasma or exogenous GCs displayed reduced myonuclear accretion relative to WT counterparts. This study reveals that 11beta-HSD1 inhibition aggravates muscle wasting in a model of AE-COPD, suggesting that therapeutic inhibition of 11beta-HSD1 may not be appropriate to prevent muscle wasting in this setting.