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Cardiogenic shock is associated with a high risk for morbidity and mortality. The impact of gender on treatment and outcomes is poorly defined. This study aimed to evaluate whether gender influences the clinical management and outcomes of patients with prehospital cardiogenic shock. Consecutive adult patients with cardiogenic shock who were transferred to hospital by emergency medical services (EMS) between January 1, 2015 and June 30, 2019 in Victoria, Australia were included. Data were obtained from individually linked ambulance, hospital, and state death index datasets. The primary outcome assessed was 30-day mortality, stratified by patient gender. Propensity score matching was performed for risk adjustment. Over the study period a total of 3,465 patients were identified and 1,389 patients (40.1%) were women. Propensity score matching yielded 1,330 matched pairs with no differences observed in baseline characteristics, including age, initial vital signs, pre-existing co-morbidities, etiology of shock, and prehospital interventions. In the matched cohort, women had higher rates of 30-day mortality (44.7% vs 39.2%, p = 0.009), underwent less coronary angiography (18.3% vs 27.2%, p0.001), and revascularization with percutaneous coronary intervention (8.9% vs 14.2%, p0.001), compared with men. In conclusion, in this large population-based study, women with cardiogenic shock who were transferred by EMS to hospital had significantly worse survival outcomes and reduced rates of invasive cardiac interventions compared to men. These data underscore the urgent need for targeted public health measures to redress gender differences in outcomes and variation with clinical care for patients with cardiogenic shock.

This study aimed to determine incidences, diagnoses, and outcomes of patients with chest pain attended by paramedics using a large population-based sample.Consecutive emergency medical services (EMS) attendances for non-traumatic chest pain in Victoria, Australia from January 2015 to June 2019 were included. Data were individually linked to emergency, hospital admission and mortality records.During the study period (representing 22,186,930 person-years), chest pain was the reason for contacting EMS in 257,017 of 2,736,570 attendances (9.4%). Overall incidence of chest pain attendances was 1,158 (per 100,000 person-years) with a higher incidence observed with increasing age, among females, among Aboriginal and Torres Strait Islanders, in regional settings, and in socially disadvantaged areas. The most common diagnoses were non-specific pain (46%; 30-day mortality 0.5%), non-ST elevation myocardial infarction (5.3%; mortality 1.3%), pneumonia (3.8%; mortality 3.9%), stable coronary syndromes (3.5%; mortality 0.8%), unstable angina (3.3%; mortality 1.3%), and ST-elevation myocardial infarction (2.8%; mortality 7.0%), while pulmonary embolism (0.7%; mortality 3.2%) and aortic pathologies (0.2%; mortality 22.2%) were rare.Chest pain accounts for one in ten ambulance calls, and underlying causes are diverse. Almost half of patients are discharged from hospital with a diagnosis of non-specific pain and low rates of mortality.

International audience; BackgroundAntenatal betamethasone is recommended before preterm delivery to accelerate fetal lung maturation. However, reports of growth and neurodevelopmental dose-related side-effects suggest that the current dose (12 mg plus 12 mg, 24 h apart) might be too high. We therefore investigated whether a half dose would be non-inferior to the current full dose for preventing respiratory distress syndrome.MethodsWe designed a randomised, multicentre, double-blind, placebo-controlled, non-inferiority trial in 37 level 3 referral perinatal centres in France. Eligible participants were pregnant women aged 18 years or older with a singleton fetus at risk of preterm delivery and already treated with the first injection of antenatal betamethasone (11·4 mg) before 32 weeks’ gestation. We used a computer-generated code producing permuted blocks of varying sizes to randomly assign (1:1) women to receive either a placebo (half-dose group) or a second 11·4 mg betamethasone injection (full-dose group) 24 h later. Randomisation was stratified by gestational age (before or after 28 weeks). Participants, clinicians, and study staff were masked to the treatment allocation. The primary outcome was the need for exogenous intratracheal surfactant within 48 h after birth. Non-inferiority would be shown if the higher limit of the 95% CI for the between-group difference between the half-dose and full-dose groups in the primary endpoint was less than 4 percentage points (corresponding to a maximum relative risk of 1·20). Four interim analyses monitoring the primary and the secondary safety outcomes were done during the study period, using a sequential data analysis method that provided futility and non-inferiority stopping rules and checked for type I and II errors. Interim analyses were done in the intention-to-treat population. This trial was registered with ClinicalTrials.gov, NCT02897076.FindingsBetween Jan 2, 2017, and Oct 9, 2019, 3244 women were randomly assigned to the half-dose (n=1620 [49·9%]) or the full-dose group (n=1624 [50·1%]); 48 women withdrew consent, 30 fetuses were stillborn, 16 neonates were lost to follow-up, and 9 neonates died before evaluation, so that 3141 neonates remained for analysis. In the intention-to-treat analysis, the primary outcome occurred in 313 (20·0%) of 1567 neonates in the half-dose group and 276 (17·5%) of 1574 neonates in the full-dose group (risk difference 2·4%, 95% CI –0·3 to 5·2); thus non-inferiority was not shown. The per-protocol analysis also did not show non-inferiority (risk difference 2·2%, 95% CI –0·6 to 5·1). No between-group differences appeared in the rates of neonatal death, grade 3–4 intraventricular haemorrhage, stage ≥2 necrotising enterocolitis, severe retinopathy of prematurity, or bronchopulmonary dysplasia.InterpretationBecause non-inferiority of the half-dose compared with the full-dose regimen was not shown, our results do not support practice changes towards antenatal betamethasone dose reduction.

INTRODUCTION: This study describes the parental perspective of the management and care experience of patients experiencing a pregnancy complicated by a fetal diagnosis to inform more supportive patient-centered care. METHODS: We conducted a prospective multicenter qualitative patient experience study at three metropolitan children’s hospitals’ advanced fetal care centers: the Cincinnati, Colorado, and Midwest Fetal Care Centers. Data were collected from pregnant patients who experienced the management of a pregnancy complicated by a fetal anomaly. Clinical journey data were obtained using qualitative research methods in post-birth semistructured interviews. We assembled a generalizable patient journey map to identify the general clinical encounters, and present common participant experiences from diagnosis to post-birth discharge. RESULTS: Fifteen families were interviewed; four experienced a loss (27%). Common experiences of trust, education, surrounding support, consistency, and abandonment emerged across all centers. Participant trust in their care team was gained through strong referrals, institutional reputation, and transparent outcomes. Unconditional care team support and continual reassurance was paramount to maintaining participant trust throughout their care journey. Participants appreciated both active and passive educational techniques at clinical touch points. A consistent point of contact assured participants. All families mentioned they felt close to their fetal care team; however, several mentioned that the post-birth transition of care created feelings of abandonment. CONCLUSIONS: When a family understands the clinical information and feels supported, they are empowered and confident in their ability to navigate their circumstances. Listening to the parental perspective is important to delivering sensitive fetal care.

International audience; OBJECTIVE: To better understand the physiology of pain in pelvic pain pathological conditions, such as endometriosis, in which alterations of uterine innervation have been highlighted, we performed an anatomic and functional mapping of the macro- and microinnervation of the human uterus. Our aim was to provide a 3-dimensional reconstruction model of uterine innervation. DESIGN: This was an experimental study. We dissected the pelvises of 4 human female fetuses into serial sections, and treated them with hematoxylin and eosin staining before immunostaining. SETTING: Academic Research Unit. PATIENTS: None. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Detection of nerves (S100 +) and characterization of the types of nerves. The slices obtained were aligned to construct a 3-dimensional model. RESULTS: A 3-dimensional model of uterine innervation was constructed. The nerve fibers appeared to have a centripetal path from the uterine serosa to the endometrium. Within the myometrium, innervation was dense. Endometrial innervation was sparse but present in the functional layer of the endometrium. Overall innervation was richest in the supravaginal cervix and rarer in the body of the uterus. Innervation was rich particularly laterally to the cervix next to the parametrium and paracervix. Four types of nerve fibers were identified: autonomic sympathetic (TH+), parasympathetic (VIP+), and sensitive (NPY+, CGRP1+ and VIP+). They were found in the 3 portions and the 3 layers of the uterus. CONCLUSIONS: We constructed a 3-dimensional model of the human uterine innervation. This model could provide a solid base for studying uterine innervation in pathologic situations, in order to find new therapeutic approaches.

To assess whether outcomes following percutaneous coronary intervention (PCI) versus coronary artery bypass grafting (CABG) for left main coronary artery (LMCA) disease differ between men and women.Current guidelines recommend either PCI or CABG for patients with unprotected LMCA disease and low-to-intermediate anatomical complexity. However, it is unclear whether these guidelines apply to women, who are underrepresented in clinical trials.An electronic search was performed to identify studies reporting sex-specific outcomes after PCI versus CABG in patients with LMCA disease. Trial level hazard ratios (HRs) and 95% confidence intervals (CIs) were pooled by random-effects modelling.Eight (8) studies met inclusion criteria, comprising 13,066 patients (24.3% women). In both sexes, there was no difference between PCI and CABG with respect to the primary composite endpoint of death, myocardial infarction or stroke (HR in women: 1.03, 95% CI 0.76-1.40; HR in men: 1.04, 95% CI 0.92-1.17). However, both sexes were more likely to require repeat revascularisation after PCI. There was no interaction between sex and treatment effect for the primary composite endpoint nor for the individual outcomes of death, stroke and repeat revascularisation. However, in women the risk of myocardial infarction was higher after PCI compared with CABG (HR 1.84, 95% CI 1.06-3.18), with a trend toward the opposite in men (HR 0.78, 95% CI 0.54-1.13; p-interaction=0.01).Percutaneous coronary intervention and CABG have a comparable risk of the composite outcome of death, stroke or myocardial infarction in patients undergoing revascularisation for LMCA disease, with no significant interaction between sex and treatment effect.

ImportanceThe administration of a high fraction of oxygen following return of spontaneous circulation in out-of-hospital cardiac arrest may increase reperfusion brain injury.ObjectiveTo determine whether targeting a lower oxygen saturation in the early phase of postresuscitation care for out-of-hospital cardiac arrest improves survival at hospital discharge.Design, Setting, and ParticipantsThis multicenter, parallel-group, randomized clinical trial included unconscious adults with return of spontaneous circulation and a peripheral oxygen saturation (Spo2) of at least 95% while receiving 100% oxygen. The trial was conducted in 2 emergency medical services and 15 hospitals in Victoria and South Australia, Australia, between December 11, 2017, and August 11, 2020, with data collection from ambulance and hospital medical records (final follow-up date, August 25, 2021). The trial enrolled 428 of a planned 1416 patients.InterventionsPatients were randomized by paramedics to receive oxygen titration to achieve an oxygen saturation of either 90% to 94% (intervention; n = 216) or 98% to 100% (standard care; n = 212) until arrival in the intensive care unit.Main Outcomes and MeasuresThe primary outcome was survival to hospital discharge. There were 9 secondary outcomes collected, including hypoxic episodes (Spo2 ResultsThe trial was stopped early due to the COVID-19 pandemic. Of the 428 patients who were randomized, 425 were included in the primary analysis (median age, 65.5 years; 100 [23.5%] women) and all completed the trial. Overall, 82 of 214 patients (38.3%) in the intervention group survived to hospital discharge compared with 101 of 211 (47.9%) in the standard care group (difference, −9.6% [95% CI, −18.9% to −0.2%]; unadjusted odds ratio, 0.68 [95% CI, 0.46-1.00]; P = .05). Of the 9 prespecified secondary outcomes collected during hospital stay, 8 showed no significant difference. A hypoxic episode prior to intensive care was observed in 31.3% (n = 67) of participants in the intervention group and 16.1% (n = 34) in the standard care group (difference, 15.2% [95% CI, 7.2%-23.1%]; OR, 2.37 [95% CI, 1.49-3.79]; P Conclusions and RelevanceAmong patients achieving return of spontaneous circulation after out-of-hospital cardiac arrest, targeting an oxygen saturation of 90% to 94%, compared with 98% to 100%, until admission to the intensive care unit did not significantly improve survival to hospital discharge. Although the trial is limited by early termination due to the COVID-19 pandemic, the findings do not support use of an oxygen saturation target of 90% to 94% in the out-of-hospital setting after resuscitation from cardiac arrest.Trial RegistrationClinicalTrials.gov Identifier: NCT03138005

Tourette Syndrome (TS) is a complex neurodevelopmental disorder characterized by vocal and motor tics lasting more than a year. It is highly polygenic in nature with both rare and common previously associated variants. Epidemiological studies have shown TS to be correlated with other phenotypes, but large-scale phenome wide analyses in biobank level data have not been performed to date. In this study, we used the summary statistics from the latest meta-analysis of TS to calculate the polygenic risk score (PRS) of individuals in the UK Biobank data and applied a Phenome Wide Association Study (PheWAS) approach to determine the association of disease risk with a wide range of phenotypes. A total of 57 traits were found to be significantly associated with TS polygenic risk, including multiple psychosocial factors and mental health conditions such as anxiety disorder and depression. Additional associations were observed with complex non-psychiatric disorders such as Type 2 diabetes, heart palpitations, and respiratory conditions. Cross-disorder comparisons of phenotypic associations with genetic risk for other childhood-onset disorders (e.g.: attention deficit hyperactivity disorder [ADHD], autism spectrum disorder [ASD], and obsessive-compulsive disorder [OCD]) indicated an overlap in associations between TS and these disorders. ADHD and ASD had a similar direction of effect with TS while OCD had an opposite direction of effect for all traits except mental health factors. Sex-specific PheWAS analysis identified differences in the associations with TS genetic risk between males and females. Type 2 diabetes and heart palpitations were significantly associated with TS risk in males but not in females, whereas diseases of the respiratory system were associated with TS risk in females but not in males. This analysis provides further evidence of shared genetic and phenotypic architecture of different complex disorders. Tourette Syndrome (TS) is a complex neurodevelopmental disorder characterized by vocal and motor tics lasting more than a year. It is highly polygenic in nature with both rare and common previously associated variants. Epidemiological studies have shown TS to be correlated with other phenotypes, but large-scale phenome wide analyses in biobank level data have not been performed to date. In this study, we used the summary statistics from the latest meta-analysis of TS to calculate the polygenic risk score (PRS) of individuals in the UK Biobank data and applied a Phenome Wide Association Study (PheWAS) approach to determine the association of disease risk with a wide range of phenotypes. A total of 57 traits were found to be significantly associated with TS polygenic risk, including multiple psychosocial factors and mental health conditions such as anxiety disorder and depression. Additional associations were observed with complex non-psychiatric disorders such as Type 2 diabetes, heart palpitations, and respiratory conditions. Cross-disorder comparisons of phenotypic associations with genetic risk for other childhood-onset disorders (e.g.: attention deficit hyperactivity disorder [ADHD], autism spectrum disorder [ASD], and obsessive-compulsive disorder [OCD]) indicated an overlap in associations between TS and these disorders. ADHD and ASD had a similar direction of effect with TS while OCD had an opposite direction of effect for all traits except mental health factors. Sex-specific PheWAS analysis identified differences in the associations with TS genetic risk between males and females. Type 2 diabetes and heart palpitations were significantly associated with TS risk in males but not in females, whereas diseases of the respiratory system were associated with TS risk in females but not in males. This analysis provides further evidence of shared genetic and phenotypic architecture of different complex disorders.

This study sought to assess the association between cardiac surgery availability and percutaneous coronary intervention (PCI) volume with clinical outcomes of cardiogenic shock (CS) complicating acute coronary syndrome (ACS).CS remains a grave complication of ACS with high mortality rates despite timely reperfusion and improved heart failure therapies.The study analyzed data from consecutive patients with CS complicating ACS who underwent PCI and were prospectively enrolled in the VCOR (Victorian Cardiac Outcomes Registry) from 26 hospitals in Victoria. We compared patients treated at cardiac surgical centers (CSCs) versus non-CSCs as well as the annual CS PCI volume (stratified into tiers of 10, 10-25, and25 cases) for in-hospital major adverse cardiac and cerebrovascular events (MACCE) and long-term mortality.Of 1,179 patients with CS, the mean age of patients was 65 years; males comprised 74%, and 22% had diabetes mellitus. Cardiac arrest occurred in 38% of patients, while 90% presented with ST-segment elevation myocardial infarction and 26% received intra-aortic balloon pump support. Overall, in-hospital and long-term mortality were 42% and 51%, respectively. There was no difference among patients treated non-CSCs compared with a CSCs for in-hospital MACCE and mortality (both P0.05). Similarly, there was no association between tiers of annual CS PCI volume with in-hospital MACCE and mortality (both P0.05).Comparable short- and long-term mortality rates among patients with ACS complicated by CS treated by PCI irrespective of cardiac surgery availability and CS PCI volume support the emergent treatment of these gravely ill patients at their presenting PCI-capable hospital.

Purpose In a search for potentially modifiable factors to improve long-term outcome among kidney transplant recipients (KTR), we hypothesized that boron exposure is associated with improved long-term outcome in KTR. Methods We determined 24 h urinary boron excretion using inductively coupled plasma mass spectrometry as a measure of boron exposure in 693 stable KTR (57% male, mean age 53y), enrolled in the TransplantLines Food and Nutrition Biobank and Cohort Study. Dietary intake was assessed using validated food-frequency questionnaires. Results Linear regression analyses showed that dietary intake of fruit, wine and nuts were key determinants of boron excretion. In addition, boron excretion was negatively correlated with homocysteine and inflammatory parameters. In total, 73 (32%), 47 (20%) and 30 (13%) KTR died among the lowest, middle and highest tertiles of 24 h urinary boron excretion, respectively (Plog-rank P Conclusion Boron may be an overlooked target to improve long-term survival among KTR and potentially other patients, likely through pathways other than inflammation or the methionine-homocysteine cycle that were previously suggested. Interventional trials are warranted to confirm the potential of dietary boron supplementation in KTR and other patient populations.

OBJECTIVE: To identify barriers to and facilitators of return to learning (RTL) for female secondary school students following a sport-related concussion (SRC), and to identify critical junctures on the injury-to-recovery continuum that can be targeted to enhance the RTL process. DESIGN: A grounded theory approach using in-depth qualitative interviews. SETTING: Secondary schools within the York Region District School Board in Ontario. PARTICIPANTS: Ten female secondary school students who presented to a sports medicine physician with an SRC in 2015 or 2016. Five of the students received a Green Folder intervention containing an RTL strategy, while 5 students received no RTL intervention following their SRC. METHODS: In-depth interviews were conducted in person or by telephone. All interviews were audiorecorded and transcribed. The transcriptions were analyzed, coded, and examined for common themes by 2 independent reviewers. MAIN FINDINGS: Barriers to RTL included a lack of a graduated RTL process, students’ own internal stress, poor communication of expectations, lack of concussion education, and inadequate support from teachers. Facilitators of RTL included academic accommodations and having a primary contact person within the school system. Owing to inconsistent implementation, the impact of the Green Folder intervention as a facilitator of RTL remains unknown. CONCLUSION: Results of this study support existing findings in the realm of concussion research. A novel finding includes the importance of a primary contact person as a facilitator of RTL. This person could help to overcome some of the identified barriers to RTL and improve outcomes by assisting with academic accommodations, providing reassurance regarding these accommodations, improving education among teachers and students, and enhancing communication between stakeholders.

Aims Enforced suspension and reduction of in-person cardiac rehabilitation (CR) services during the coronavirus disease-19 (COVID-19) pandemic restrictions required rapid implementation of remote delivery methods, thus enabling a cohort comparison of in-person vs. remote-delivered CR participants. This study aimed to examine the health-related quality of life (HRQL) outcomes and patient experiences comparing these delivery modes. Methods and results Participants across four metropolitan CR sites receiving in-person (December 2019 to March 2020) or remote-delivered (April to October 2020) programmes were assessed for HRQL (Short Form-12) at CR entry and completion. A General Linear Model was used to adjust for baseline group differences and qualitative interviews to explore patient experiences. Participants (n = 194) had a mean age of 65.94 (SD 10.45) years, 80.9% males. Diagnoses included elective percutaneous coronary intervention (40.2%), myocardial infarction (33.5%), and coronary artery bypass grafting (26.3%). Remote-delivered CR wait times were shorter than in-person [median 14 (interquartile range, IQR 10–21) vs. 25 (IQR 16–38) days, P < 0.001], but participation by ethnic minorities was lower (13.6% vs. 35.2%, P < 0.001). Remote-delivered CR participants had equivalent benefits to in-person in all HRQL domains but more improvements than in-person in Mental Health, both domain [mean difference (MD) 3.56, 95% confidence interval (CI) 1.28, 5.82] and composite (MD 2.37, 95% CI 0.15, 4.58). From qualitative interviews (n = 16), patients valued in-person CR for direct exercise supervision and group interactions, and remote-delivered for convenience and flexibility (negotiable contact times). Conclusion Remote-delivered CR implemented during COVID-19 had equivalent, sometimes better, HRQL outcomes than in-person, and shorter wait times. Participation by minority groups in remote-delivered modes are lower. Further research is needed to evaluate other patient outcomes.

The aim of this study was to validate the 29-item Patient-Reported Outcomes Measurement Information System version 2.0 (PROMIS-29v2) health-related quality-of-life (HRQL) questionnaire for use in patients with coronary heart disease (CHD) participating in remotely delivered cardiac rehabilitation (CR).Patients commencing remote CR across four sites in New South Wales, Australia, answered the PROMIS-29v2 and 12-item Short Form Health Survey version 2.0 (SF-12v2) questionnaires at CR entry and completion (6 wk). The data were analyzed for validity, reliability, and responsiveness to change.Patients (N = 89) had a mean age of 66.9 ± 9.3 yr; 83% were male and were referred to CR for elective percutaneous coronary intervention (PCI) (42%), myocardial infarction (36%), and coronary artery bypass grafting (22%). Internal consistency reliability was adequate, with the Cronbach α ranging from 0.78-0.98. Convergent validity between the PROMIS-29v2 and SF-12v2 summary scores showed significantly strong correlations for physical ( r = 0.62) and moderate for mental ( r = 0.36) health. Discriminant validity was confirmed for sex (women reported lower physical and mental health) and referral diagnosis (patients who had elective PCI reported better physical health). Effect size (ES) comparisons confirmed responsiveness to change from CR entry to completion in physical health (ES = 0.51) and demonstrated evidence of more responsiveness than SF-12v2 for mental health (ES = 0.70).The PROMIS-29v2 is reliable, valid, and responsive to changes in patients with CHD attending remotely delivered CR and allows for baseline HRQL assessment, between-diagnosis comparisons, and evaluation of changes over time.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons., Dutch Research Council (NWO); VENI Scheme Grant; VIDI Grant; Prinses Beatrix Spierfonds; Neuromuscular Fellowship Grant; Medical Research Council (MRC); Clinical Infrastructure Award; Epidemiology Unit; Integrative Epidemiology Unit; Canadian Institutes of Health Research; IWT; National Institute on Aging; National Health and Medical Research Council (NHMRC); Enabling Grant; NHMRC/Australian Research Council Strategic Award; NHMRC; NHMRC Centre of Research Excellence Grant; National Health and Medical Research Council of Australia (NHMRC) Research Fellowship; United Kingdom, Medical Research Council; Economic and Social Research Council; European Union (EU); Horizon 2020; European Community's Health Seventh Framework Programme; EuroMOTOR; European Research Council (ERC); Research and Innovation Programme; EScORIAL; ALS Foundation Netherlands; Alzheimer’s Society PhD Studentship; ARSla Funding; Biogen; University of Bristol; Motor Neurone Disease Association (MNDA); NIHR Maudsley Biomedical Research Centre; Dutch Ministry of Education, Culture, and Science; Netherlands Organization for Scientific Research (NWO; BRAINSCAPES); Gravitation Program; ALS Liga België; National Lottery of Belgium; KU Leuven Opening the Future Fund; KU Leuven Funds, “Een Hart voor ALS”, “Laeversfonds voor ALS Onderzoek” and the “Valéry Perrier Race against ALS Fund”; E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders; ALS Liga België; “Live now” Charity Foundation; Moscow ALS palliative Care Service; Canadian Institutes of Health; Research Australia; Ice Bucket Challenge Grant; NIH Intramural Research Programs; FightMND Mid-Career Fellowship; NIHR Senior Investigator; Sheffield NIHR Biomedical Research Centre; Motor Neurone Disease Association; National Institute for Health Research (NIHR) Biomedical Research Centre; Maudsley NHS Foundation Trust; King’s College London; NIHR Senior Investigator Award; Netherlands Organization for Health Research and Development; Vici Scheme; Netherlands Organization for Health Research and Development STRENGTH Project; PPP Allowance

Sexting has become part of the repertoire of adolescents' sexual behaviors, especially among those who identify as gender and sexually diverse. Whereas body dissatisfaction increases during adolescence and is associated with negative sexuality outcomes, little research has examined how body appreciation may contribute to adolescents' sexting. The present study examined associations between body appreciation and sexting behaviors, and whether these differed by gender and sexual orientation, using path analysis in a sample of 2904 adolescents (M

BACKGROUND: Sebaceous carcinoma (SC) is a rare malignant tumour whereby, comprehensive long-term data are scarce. This study aimed to assess the outcome of patients treated with resection for SC.METHODS: Patients treated at four tertiary centres were included. Cumulative incidence curves were calculated for recurrences.RESULTS: A total of 100 patients (57 males, 57%) were included with 103 SCs. The median age was 72 (range, 15-95) years with a median follow-up of 52 (interquartile range [IQR], 24-93) months. Most SCs were located (peri)ocular (49.5%). Of all SCs, 17 locally recurred (16.5%) with a median time to recurrence of 19 (IQR, 8-29) months. The cumulative incidence probability for recurrence was statistically higher for (peri)ocular tumours (p = 0.005), and for positive resection margins (p = 0.001). Two patients presented with lymph node metastases and additional seven patients (8.7%) developed lymph node metastases during follow-up with a median time to metastases of 8 (IQR, 0.5-28) months. Three patients had concurrent in-transit metastases and one patient also developed liver and bone metastases during follow-up.CONCLUSION: SC is a rare, yet locally aggressive tumour. Positive resection margins and (peri)ocular SCs are more frequently associated with local recurrence. SC infrequently presents with locoregional or distant metastases.

Background: Creatinine is the most widely used test to estimate the glomerular filtration rate (GFR), but muscle mass as key determinant of creatinine next to renal function may confound such estimates. We explored effects of 24-h height-indexed creatinine excretion rate (CER index) on GFR estimated with creatinine (eGFRCr), muscle mass-independent cystatin C (eGFRCys), and the combination of creatinine and cystatin C (eGFRCr-Cys) and predicted probabilities of discordant classification given age, sex, and CER index. Methods: We included 8076 adults enrolled in the PREVEND study. Discordant classification was defined as not having eGFRCr 2 when eGFRCys was 2. Baseline effects of age and sex on CER index were quantified with linear models using generalized least squares. Baseline effects of CER index on eGFR were quantified with quantile regression and logistic regression. Effects of annual changes in CER index on trajectories of eGFR were quantified with linear mixed-effects models. Missing observations in covariates were multiply imputed. Results: Mean (SD) CER index was 8.0 (1.7) and 6.1 (1.3) mmol/24 h per meter in male and female participants, respectively (Pdifference Cr and eGFRCys disagreed by 24.7 mL/min/1.73 m2 (and 30.1 mL/min/1.73 m2 when creatinine was not corrected for race). Percentages (95% CI) of discordant classification in male and female participants aged 60 years and older with low muscle mass were 18.5% (14.8–22.1%) and 15.2% (11.4–18.5%), respectively. For a 70-year-old male participant who lost muscle during follow-up, eGFRCr and eGFRCys disagreed by 1.5, 5.0, 8.5, and 12.0 mL/min/1.73 m2 (and 6.7, 10.7, 13.5, and 15.9 mL/min/1.73 m2 when creatinine was not corrected for race) at baseline, 5 years, 10 years, and 15 years of follow-up, respectively. Conclusions: Low muscle mass may cause considerable overestimation of single measurements of eGFRCr. Muscle wasting may cause spurious overestimation of repeatedly measured eGFRCr. Implementing muscle mass-independent markers for estimating renal function, like cystatin C as superior alternative to creatinine, is crucial to accurately assess renal function in settings of low muscle mass or muscle wasting. This would also eliminate the negative consequences of current race-based approaches.

Nonalcoholic fatty liver disease (NAFLD) is a major health problem with complex pathogenesis. Although sex differences in NAFLD pathogenesis have been reported, the mechanisms underlying such differences remain understudied. Interleukin (IL)22 is a pleiotropic cytokine with both protective and/or pathogenic effects during liver injury. IL22 was shown to be hepatoprotective in NAFLD-related liver injury. However, these studies relied primarily on exogenous administration of IL22 and did not examine the sex-dependent effect of IL22. Here, we sought to characterize the role of endogenous IL22-receptor signaling during NAFLD-induced liver injury in males and females.We used immunofluorescence, flow cytometry, histopathologic assessment, and gene expression analysis to examine IL22 production and characterize the intrahepatic immune landscape in human subjects with NAFLD (n = 20; 11 men and 9 women) and in an in vivo Western high-fat diet-induced NAFLD model in IL22RA knock out mice and their wild-type littermates.Examination of publicly available data sets from 2 cohorts with NAFLD showed increased hepatic IL22 gene expression in females compared with males. Furthermore, our immunofluorescence analysis of liver sections from NAFLD subjects (n = 20) showed increased infiltration of IL22-producing cells in females. Similarly, IL22-producing cells were increased in wild-type female mice with NAFLD and the hepatic IL22/IL22 binding protein messenger RNA ratio correlated with expression of anti-apoptosis genes. The lack of endogenous IL22-receptor signaling (IL22RA knockout) led to exacerbated liver damage, inflammation, apoptosis, and liver fibrosis in female, but not male, mice with NAFLD.Our data suggest a sex-dependent hepatoprotective antiapoptotic effect of IL22-receptor signaling during NAFLD-related liver injury in females.

Background Subglottic stenosis (SGS) and tracheal stenosis (TS) are characterized by a narrowing of the airways. The goal of this study was to describe the characteristics and prognosis of nontraumatic and nontumoral SGS or TS. Research Question What are the inflammatory etiologies of SGS and TS, and what are their characteristics and prognosis? Study Design and Methods This multicenter, observational retrospective study was performed in patients with SGS or TS that was neither traumatic nor tumoral. Results Eighty-one patients were included, 33 (41%) with granulomatosis with polyangiitis (GPA) and 21 (26%) with relapsing polychondritis (RP). GPA-related stenoses exhibited circumferential subglottic narrowing in 85% of cases, without calcifications. In contrast, RP-related stenoses displayed anterior involvement in 76%, in a longer distance from vocal cords (4 cm), with calcifications in 62%, and extension to bronchi in 86%. Other diagnoses included bullous dermatoses (n = 3), amyloidosis (n = 3), sarcoidosis (n = 2), and Crohn’s disease (n = 2); the remaining stenoses (n = 15) were idiopathic. SGS/TS was the initial manifestation of the disease in 66% of cases, with a median interval from stenosis to disease diagnosis of 12 months (interquartile range, 0-48 months). Despite the use of glucocorticoids in 80%, combined with methotrexate in 49%, endoscopic procedures were required in 68% of patients. Relapses of stenoses occurred in 76% without any difference between causes (82% in GPA, 67% in RP, and 75% in idiopathic SGS/TS). Three patients died due to the stenosis, two of RP and one of GPA. Interpretation These data show that GPA and RP are the two main inflammatory diseases presenting with SGS/TS. GPA-related stenoses are mostly subglottic and circumferential, whereas RP-related stenoses are mostly tracheal, anterior, and calcified with a frequent extension to bronchi. Relapses of stenoses are common, and relapse rates do not differ between causes. Diagnosis and management of SGS/TS require a multidisciplinary approach.

Since the beginning of the COVID-19 pandemic, an increase in pornography use has been reported based on cross-sectional findings, raising concerns about associated adverse outcomes, such as problematic pornography use (PPU). The aims of the present study were to document potential changes in adolescents’ pornography use frequency, motivations, and PPU before and during the COVID-19 pandemic. As part of an ongoing study on adolescents’ sexual health, we used a large sample (NTime 1 = 1771; 47.6% girls, Mage = 15.42 years, SD = 0.59) to examine changes from baseline (before the COVID-19 pandemic) to one year later (during the COVID-19 pandemic) in adolescents’ self-reported pornography use frequency, motivations, and PPU, using latent change models and examining potential gender differences. No significant changes were observed in adolescents’ pornography use frequency and pornography use motivations, and no gender differences were present in these trends. Although statistically significant, slight decrease was observed in boys’ PPU levels, and a statistically significant, slight increase was observed in girls’ PPU levels, these changes were very small, providing no practical or clinical relevance. In sum, despite previous propositions, concerns, and cross-sectional findings, longitudinal results suggest that adolescents’ pornography use characteristics were rather stable between November 2019 and June 2021, and the COVID-19 pandemic and related lockdowns might not have led to general increases in adolescents’ pornography use as it was expected. Supplementary Information The online version contains supplementary material available at 10.1007/s10508-021-02282-4.

Background Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent, paralleling the obesity epidemic. Ketone bodies are produced in the liver, but it is currently uncertain whether circulating ketone bodies are increased in the context of NAFLD. We investigated the association between NAFLD and circulating ketone bodies and determined the extent to which NAFLD and circulating ketone bodies are associated with all-cause mortality.Methods Plasma ketone bodies were measured by nuclear magnetic resonance spectroscopy in participants of the general population-based PREVEND study. A fatty liver index (FLI) >= 60 was regarded as a proxy of NAFLD. Associations of an elevated FLI and ketone bodies with all-cause mortality were investigated using Cox regression analyses.Results The study included 6,297 participants aged 54 +/- 12 years, of whom 1,970 (31%) had elevated FLI. Participants with elevated FLI had higher total ketone bodies (194 [153-259] vs 170 [133-243] mu mol/L; P < .001) than participants without elevated FLI. During 7.9 [7.8-8.9] years of follow-up, 387 (6%) participants died. An elevated FLI was independently associated with an increased risk of mortality (HR: 1.34 [1.06-1.70]; P = .02). Higher total ketone bodies were also associated with an increased mortality risk (HR per doubling: 1.29 [1.12-1.49]; P < .001). Mediation analysis suggested that the association of elevated FLI with all-cause mortality was in part mediated by ketone bodies (proportion mediated: 10%, P < .001).Conclusion Circulating ketone bodies were increased in participants with suspected NAFLD. Both suspected NAFLD and higher circulating ketone bodies are associated with an increased risk of all-cause mortality.

RATIONALE: People with cystic fibrosis (CF) experience acute worsening of respiratory symptoms and lung function known as pulmonary exacerbations. Treatment with intravenous antimicrobials is common; however, there is scant evidence to support a standard treatment duration. OBJECTIVES: To test differing durations of intravenous antimicrobials for CF exacerbations. METHODS: STOP2 (Standardized Treatment of Pulmonary Exacerbations 2) was a multicenter, randomized, controlled clinical trial in exacerbations among adults with CF. After 7–10 days of treatment, participants exhibiting predefined lung function and symptom improvements were randomized to 10 or 14 days’ total antimicrobial duration; all others were randomized to 14 or 21 days’ duration. MEASUREMENTS AND MAIN RESULTS: The primary outcome was percent predicted FEV(1) (ppFEV(1)) change from treatment initiation to 2 weeks after cessation. Among early responders, noninferiority of 10 days to 14 days was tested; superiority of 21 days compared with 14 days was compared for the others. Symptoms, weight, and adverse events were secondary. Among 982 randomized people, 277 met improvement criteria and were randomized to 10 or 14 days of treatment; the remaining 705 received 21 or 14 days of treatment. Mean ppFEV(1) change was 12.8 and 13.4 for 10 and 14 days, respectively, a ‒0.65 difference (95% CI [‒3.3 to 2.0]), excluding the predefined noninferiority margin. The 21- and 14-day arms experienced 3.3 and 3.4 mean ppFEV(1) changes, a difference of ‒0.10 (‒1.3 to 1.1). Secondary endpoints and sensitivity analyses were supportive. CONCLUSIONS: Among adults with CF with early treatment improvement during exacerbation, ppFEV(1) after 10 days of intravenous antimicrobials is not inferior to 14 days. For those with less improvement after one week, 21 days is not superior to 14 days. Clinical trial registered with www.clinicaltrials.gov (NCT02781610).

Positive views of adolescents' sexuality have only begun to garner interest in the last two decades. Despite great strides in this emerging area, progress is limited by the paucity of valid and reliable measures among this population. The goal of this study was to validate the widely used adult five-item Global Measure of Sexual Satisfaction (GMSEX) in a large sample of sexually active adolescents. A total of 1,036 adolescents (516 girls, 49.8%) aged between 14 and 17 years (

Positive body image refers to individuals' ability to conceptualize their bodies with love, respect, and appreciation. The study of positive body image is relatively new, and instruments used to investigate this multi-faceted construct have received limited use in non-English speaking countries. Thus, the aim of this investigation is to consider four measures that are associated with positive body image across eight different countries. Participants (n = 6272) completed the Body Appreciation Scale-2, the Body Areas Satisfaction Scale, the Physical Appearance Comparison Scale, and the Weight Bias Internalization Scale. Multi-group confirmatory factor analyses (MG-CFAs) and item-response theory (IRT) models were used to examine the measurement invariance of these surveys. Our results generally suggest that positive body image, weight bias, and appearance comparison can be assessed using brief assessments and that these four instruments can be used in different countries, but care should be taken to consider individuals' gender, BMI, and socio-economic position. ispartof: BODY IMAGE vol:35 pages:320-332 ispartof: location:Netherlands status: published

The short- and long-term implications of identifying totally occluded culprit coronary arteries (TOCCA) in patients presenting with non-ST-elevation myocardial infarction (NSTEMI) have not been well studied. This study compares clinical characteristics, short- and long-term outcomes of patients with NSTEMI identified with TOCCA to that of patients with non-TOCCA undergoing percutaneous coronary intervention (PCI). We analyzed data from patients with NSTEMI undergoing single-vessel PCI within the Melbourne Interventional Group multi-center registry between 2005 and 2017. Those with TOCCA were compared to those with non-TOCCA. The primary endpoint was 30-day major adverse cardiac events (MACE). Secondary endpoints included 12-month MACE and long-term mortality. A total of 6,829 patients with NSTEMI had single-vessel PCI of which 954 (14%) had TOCCA. Most TOCCA were non-left anterior descending (right coronary artery 39% versus circumflex 33% versus left anterior descending 26%; p

BACKGROUND: Data on the patient characteristics and health outcomes of Indigenous Australians having revascularisation for treatment of coronary artery disease are scarce. The aim of this study was to assess differences in patient characteristics, presentations, and outcomes among Indigenous and non-Indigenous Australians having percutaneous coronary intervention (PCI) in urban and larger regional centres in Victoria, Australia. METHODS: In this multicentre, prospective, observational cohort study, data were prospectively collected from six government-funded tertiary hospitals in the state of Victoria, Australia. The Melbourne Interventional Group PCI registry was used to identify patients having PCI at Victorian metropolitan and large regional hospitals between Jan 1, 2005, and Dec 31, 2018. The primary outcome was long-term mortality. Secondary outcomes were 30 day mortality and 30 day major adverse cardiovascular events (MACE), defined as a composite endpoint of death, myocardial infarction, and target-vessel revascularisation. Regression analyses, adjusted for clinically relevant covariates and geographical and socioeconomic indices, were used to establish the influence of Indigenous status on these study outcomes. FINDINGS: 41 146 patient procedures were entered into the registry, of whom 179 (0·4%) were recorded as identifying as Indigenous Australian, 39 855 (96·9%) were not Indigenous Australian, and 1112 (2·7%) had incomplete data regarding ethnicity and were excluded. Compared with their non-Indigenous counterparts, Indigenous patients were younger, more often women, and more likely to have comorbidities. Indigenous Australians were also more likely to live in a regional community and areas of socioeconomic disadvantage. Procedural success and complication rates were similar for Indigenous and non-Indigenous patients having PCI. At 30 day follow-up, Indigenous Australians were more likely to be taking optimal medical therapy, although overall follow-up rates were lower and prevalence of persistent smoking was higher. Multivariable analysis showed that Indigenous status was independently associated with increased risk of long-term mortality (hazard ratio 2·49, 95% CI 1·79-3·48; p

Background Fetal Growth restriction (FGR) is the pathological failure of a fetus to reach its biologically determined growth potential. Detection of FGR fetuses is a universally agreed key objective of antenatal care. Antenatal detection of FGR has undeniable benefits, juggling between intensive fetal surveillance and optimized timing of delivery; it reduces adverse perinatal outcomes by up to four-fold. However, FGR is still widely underdiagnosed. We aimed to identify the prevalence of FGR diagnosis in our wards and study the impact of the 2013 published French guidelines on the detection rate of FGR. The secondary objective aimed to highlight the factors of suboptimal screening in the population of non-diagnosed FGR fetuses and emphasize the screening method that led to antenatal diagnosis of FGR. Materials and methods We conducted a retrospective study at a single tertiary maternity center in Lyon-France, the Femme Mere Enfant Hospital, including the exhaustive population of FGR born after 24 + 0 weeks of gestation from 1 January 2011 to 31 December 2017. FGR was defined combining the neonatal and antenatal consensus-based definitions for early and late FGR in absence of congenital anomalies, excluding small for gestational age fetuses. For all FGR fetuses, we compared the antenatal detection rate of FGR during 2011-2013 to 2015-2017, since the French guidelines were published in December 2013. When FGR fetuses underwent an antenatal diagnosis of FGR, we retrospectively collected the characteristics that led to the diagnosis. When fetuses were not diagnosed as FGR, we retrospectively reviewed the implementation of the recommended screening method, enabling to evaluate whether screening was optimal or not. Statistical analysis was performed in July 2018, and statistical significance was regarded as a p-value Results Over the seven-year period, and among 31,052 newborns, 1020 (3.3%) infants were identified as FGR and met the inclusion criteria. The detection rate of FGR was similar before and after publication of the French Guidelines related to FGR in 2013. Indeed, 50.8% (201/395) FGR were diagnosed between 2011 and 2013 versus 52.6% (245/465) between 2015 and 2017 (p = .59). In the population of non-diagnosed FGR infants, screening was suboptimal in 80%. Symphysis-fundal height (SFH) was not measured in 10.7%, with no difference before and after 2014 (7.3 versus 11.8% p = .11). Ultrasound examination for fetal biometry had not been prescribed in spite of abnormal SFH in 47.7% of undiagnosed FGR infants. Diagnosis has been missed in 11.5% of infants because of misinterpretation of the estimated fetal weight's centile. Conclusion FGR is widely underdiagnosed. However, the limited performances can partially be explained by the regular misuse of screening method in clinical practice. Despite the systematic third trimester ultrasound screening, the detection rate of FGR was similar to the one reported in the medical literature. The timing of routine third trimester ultrasound in low-risk women may be rethought.

Objective: Hypertension is a major risk factor for cardiovascular disease, kidney disease, and premature death. Increased levels of creatine kinase are associated with development of hypertension. However, it is unknown if creatine, a substrate of CK, is associated with the development of hypertension. We therefore, aimed to investigate the association between plasma creatine concentration and incident hypertension. Methods: We measured fasting plasma creatine concentrations by nuclear magnetic resonance spectroscopy in participants of the population-based PREVEND study. The study outcome was incident hypertension, defined as either a SBP of at least 140mmHg, a DBP of at least 90mmHg, or the new usage of antihypertensive drugs. Participants with hypertension at baseline were excluded. Results: We included 3135 participants (46% men) aged 49=10years. Mean plasma creatine concentrations were 36.2=17.5mmol/l, with higher concentrations in women than in men (42.2=17.6 versus 29.2=17.6mmol/l; P, Journal of Hypertension, 40 (2)