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Objective: Mepolizumab proved to be an efficacious treatment for eosinophilic granulomatosis with polyangiitis (EGPA) at a dose of 300 mg every 4 weeks in the randomized, controlled MIRRA trial. In a few recently reported studies, successful real‐life experiences with the approved dose for treating severe eosinophilic asthma (100 mg every 4 weeks) were observed. We undertook this study to assess the effectiveness and safety of mepolizumab 100 mg every 4 weeks and 300 mg every 4 weeks in a large European EGPA cohort. Methods: We included all patients with EGPA treated with mepolizumab at the recruiting centers in 2015–2020. Treatment response was evaluated from 3 months to 24 months after initiation of mepolizumab. Complete response to treatment was defined as no disease activity (Birmingham Vasculitis Activity Score [BVAS] = 0) and a prednisolone or prednisone dose (or equivalent) of ≤4 mg/day. Respiratory outcomes included asthma and ear, nose, and throat (ENT) exacerbations. Results: Two hundred three patients, of whom 191 received a stable dose of mepolizumab (158 received 100 mg every 4 weeks and 33 received 300 mg every 4 weeks) were included. Twenty‐five patients (12.3%) had a complete response to treatment at 3 months. Complete response rates increased to 30.4% and 35.7% at 12 months and 24 months, respectively, and rates were comparable between mepolizumab 100 mg every 4 weeks and 300 mg every 4 weeks. Mepolizumab led to a significant reduction in BVAS score, prednisone dose, and eosinophil counts from 3 months to 24 months, with no significant differences observed between 100 mg every 4 weeks and 300 mg every 4 weeks. Eighty‐two patients (40.4%) experienced asthma exacerbations (57 of 158 [36%] who received 100 mg every 4 weeks; 17 of 33 [52%] who received 300 mg every 4 weeks), and 31 patients (15.3%) experienced ENT exacerbations. Forty‐four patients (21.7%) experienced adverse events (AEs), most of which were nonserious AEs (38 of 44). Conclusion: Mepolizumab at both 100 mg every 4 weeks and 300 mg every 4 weeks is effective for the treatment of EGPA. The 2 doses should be compared in the setting of a controlled trial. [ABSTRACT FROM AUTHOR]

Data regarding angiographic characteristics, clinical profile, and inhospital outcomes of patients with coronavirus disease 2019 (COVID-19) referred for coronary angiography (CAG) are scarce. This is an observational study analyzing confirmed patients with COVID-19 referred for CAG from 10 European centers. We included 57 patients (mean age: 66 ± 15 years, 82% male), of whom 18% had previous myocardial infarction (MI) and 29% had renal insufficiency and chronic pulmonary disease. ST-segment elevation myocardial infarction (STEMI) was the most frequent indication for CAG (58%). Coronavirus disease 2019 was confirmed after CAG in 86% and classified as mild in 49%, with 21% fully asymptomatic. A culprit lesion was identified in 79% and high thrombus burden in 42%; 7% had stent thrombosis. At 40 days follow-up, 16 (28%) patients experienced a major adverse cardiovascular event (MACE): 12 deaths (92% noncardiac), 1 MI, 2 stent thrombosis, and 1 stroke. In an European multicenter registry, patients with confirmed COVID-19 infection referred for CAG during the first wave of the severe acute respiratory syndrome coronavirus 2 pandemic presented mostly with STEMI and were predominantly males with comorbidities. Severity of COVID-19 was in general noncritical and 21% were asymptomatic at the time of CAG. Culprit coronary lesions with high thrombus burden were frequently identified, with a rate of stent thrombosis of 7%. The incidence of MACE at 40 days was high (28%), mostly due to noncardiac death. [ABSTRACT FROM AUTHOR]

Background: Undetected ear and hearing problems negatively impact the quality of life of people with intellectual disability. Methods: This multicentre retrospective study describes the outcome of 10 years of ear and hearing screening in athletes with intellectual disability in seven European countries. The screening was conducted by a trained team using a strictly standardised protocol. Results: Of 15,363 screened athletes with intellectual disability, more than half (58.7%) needed referral for ear and/or hearing problems, ranging from 51.7% (<20 years old) to 81.4% (≥60 years old). The most commonly detected conditions were excessive/impacted earwax (40.3%), middle ear problems (30.1%) and hearing loss (27.0%), with significant differences between age groups and countries. Discussion This study demonstrates an increased risk of ear and hearing problems in people with intellectual disability as compared to the general population. Considering the unawareness and impact of these problems, it is highly recommended to organise systematic screening. Follow‐up for diagnostic elaboration, therapeutic management and long‐term guidance should be provided. [ABSTRACT FROM AUTHOR]

Background: To examine the association of job strain with cognitive ability and the influence of life-course job strain on later life cognitive decline.Methods: Data were derived from six waves of the Survey of Health, Aging, and Retirement in Europe. The study sample consists of 13349 participants aged 50 to 98 years at wave 2 and has been followed up for 12-years. Job strain status across working life was assessed using a short demand-control job strain model containing two core dimensions: job demands and job control collected in wave 3. Cognitive abilities concerning episodic memory was assessed by immediate recall and delayed recall tests, executive function was evaluated by verbal fluency test collected in all waves (waves 2-7) except wave 3. Mixed-effects model was used to estimate working life job strain and its cumulative effect on cognitive decline.Results: Both passive and high strain jobs were associated with lower levels of cognitive ability (episodic memory and verbal fluency) in comparison with active job. Long exposure to active- or low strain-job was associated with higher cognitive ability whereas long exposure to passive job or moderate duration of high strain job was associated with lower cognitive ability. The rate of memory decline was positively related to moderate duration of passive job and negatively related to long-term exposure to low strain job.Limitations: Information on working conditions was based on self-reported recollections.Conclusions: Working life variation in job strain status and their duration may explain individual differences in cognitive ability in later life. [ABSTRACT FROM AUTHOR]

Objective: Gynecologic Sarcomas are rare, aggressive tumors. The aim of this study was to explore the incidence and outcomes of gynecologic sarcomas in a large national data registry and to compare them with reports from other countries.Study Design: Records of gynecologic sarcomas diagnosed in Israel (1980-2014) were extracted from the National Cancer Registry and classified according to International Classification of Diseases for Oncology-3 and characterized according to anatomical site, morphology and demographics. Age-standardized incidence rates and 1, 3, 5 and 10-year relative survival rates were calculated for 3 time periods (1980-1994, 1995-2001 and 2005-2014) according to patient age, stage and years of diagnosis.Results: During 1980-2014, 1271 new gynecologic sarcomas were diagnosed in Israel, with incidence slightly increasing in 1980-2004, to an age-standardized incidence rate of 13 per million women. The most common histologic diagnosis was leiomyosarcoma (48%) and the most common anatomical site was the uterus (89%). The age-standardized incidence rate for uterine sarcoma is higher in Israel (10.55 per million) than in England (7.4 per million) and Germany (5.8 per million) respectively. The 5-year overall survival was significantly poorer in patients >70-years, as compared to younger patients (p<0.001) and in those with leiomyosarcoma compared to endometrial stromal sarcoma (p<0.001). The survival rate of patients with leiomyosarcoma in Israel are comparable to survival rates reported by other studies, although substantially lower regarding endometrial stromal sarcoma.Conclusions: Uterine leiomyosarcoma was the most common gynecologic sarcoma found in the Israeli, European and American registries. Older patients and those with leiomyosarcoma have the worst prognoses. Histological and anatomical variations in Israel are comparable with global statistics, but the incidence in Israel seems higher than in Europe. [ABSTRACT FROM AUTHOR]

Objectives: A novel long-acting regimen (LAR) of cabotegravir and rilpivirine for HIV treatment requires dosing every 2 months instead of daily. We assessed what proportion of people living with HIV and physicians would be interested in trying and offering LAR respectively and why.Methods: 688 people living with HIV on treatment, and 120 HIV physicians completed web-based surveys in Germany, Italy, the UK and France during 2019. Balanced description of a hypothetical LAR regarding efficacy, administration and possible side effects were provided. The hypothetical long-acting injections were assumed to be cost-neutral to current daily oral antiretrovirals. Interest of people living with HIV in trying ('very'/'highly') and physicians' willingness to offer ('definitely'/'probably') this LAR in different situations, with perceived benefits/concerns was measured.Results: Of people living with HIV, 65.8% were interested in trying LAR. The majority (~80%-90%) of those with unmet needs felt LAR would help, including those with strong medical needs (malabsorption and interfering gastrointestinal conditions), suboptimal adherence, confidentiality/privacy concerns and emotional burden of daily dosing. Of physicians, percentage willing to offer LAR varied situationally: strong medical need (dysphagia, 93.3%; malabsorption, 91.6%; interfering gastrointestinal issues, 90.0%; central nervous system disorders, 87.5%); suboptimal adherence (84.2%); confidentiality/privacy concerns (hiding medications, 86.6%) and convenience/lifestyle (84.2%). People living with HIV liked LAR for not having to carry pills when travelling (56.3%); physicians liked the increased patient contact (54.2%). Furthermore, 50.0% of people living with HIV perceived LAR would minimise transmission risk and improve their sexual health. The most disliked attribute was scheduling appointments (37.2%) and resource constraints (57.5%) for people living with HIV and physicians, respectively. Physicians estimated 25.7% of their patients would actually switch.Conclusion: Providers and people living with HIV viewed the described LAR as addressing several unmet needs. Alternative treatment routes and especially LAR may improve adherence and quality of life. [ABSTRACT FROM AUTHOR]

Background: There were gaps between guidelines and practice when surgery was the only treatment for aortic stenosis (AS).Objectives: This study analyzed the decision to intervene in patients with severe AS in the EORP VHD (EURObservational Research Programme Valvular Heart Disease) II survey.Methods: Among 2,152 patients with severe AS, 1,271 patients with high-gradient AS who were symptomatic fulfilled a Class I recommendation for intervention according to the 2012 European Society of Cardiology guidelines; the primary end point was the decision for intervention.Results: A decision not to intervene was taken in 262 patients (20.6%). In multivariate analysis, the decision not to intervene was associated with older age (odds ratio [OR]: 1.34 per 10-year increase; 95% CI: 1.11 to 1.61; P = 0.002), New York Heart Association functional classes I and II versus III (OR: 1.63; 95% CI: 1.16 to 2.30; P = 0.005), higher age-adjusted Charlson comorbidity index (OR: 1.09 per 1-point increase; 95% CI: 1.01 to 1.17; P = 0.03), and a lower transaortic mean gradient (OR: 0.81 per 10-mm Hg decrease; 95% CI: 0.71 to 0.92; P < 0.001). During the study period, 346 patients (40.2%, median age 84 years, median EuroSCORE II [European System for Cardiac Operative Risk Evaluation II] 3.1%) underwent transcatheter intervention and 515 (59.8%, median age 69 years, median EuroSCORE II 1.5%) underwent surgery. A decision not to intervene versus intervention was associated with lower 6-month survival (87.4%; 95% CI: 82.0 to 91.3 vs 94.6%; 95% CI: 92.8 to 95.9; P < 0.001).Conclusions: A decision not to intervene was taken in 1 in 5 patients with severe symptomatic AS despite a Class I recommendation for intervention and the decision was particularly associated with older age and combined comorbidities. Transcatheter intervention was extensively used in octogenarians. [ABSTRACT FROM AUTHOR]

Introduction: Chemsex in a European context is the use of any of the following drugs to facilitate sex: crystal methamphetamine, mephedrone and gamma‐hydroxybutyrate (GHB)/gamma‐butyrolactone (GBL) and, to a lesser extent, cocaine and ketamine. This study describes the prevalence of self‐reported recreational drug use and chemsex in HIV‐positive men who have sex with men (MSM) accessing HIV services in four countries. It also examines the problematic impacts and harms of chemsex and access to chemsex‐related services. Methods: This is a cross‐sectional multi‐centre questionnaire study of HIV‐positive MSM accessing nine HIV services in the UK, Spain, Greece and Italy. Results: In all, 1589 HIV‐positive MSM attending HIV services in four countries completed the questionnaire. The median age of participants was 38 years (interquartile range: 32–46 years) and 1525 (96.0%) were taking antiretroviral therapy (ART). In the previous 12 months, 709 (44.6%) had used recreational drugs, 382 (24.0%) reported chemsex and 104 (6.5%) reported injection of chemsex‐associated drugs ('slamsex'). Of the 382 engaging in chemsex, 155 (40.6%) reported unwanted side effects as a result of chemsex and 81 (21.2%) as a result of withdrawal from chemsex. The reported negative impacts from chemsex were on work (25.1%, 96), friends/family (24.3%, 93) and relationships (28.3%, 108). Fifty‐seven (14.9%) accessed chemsex‐related services in the past year, 38 of whom (67%) felt the service met their needs. Discussion: A quarter of participants self‐reported chemsex in the past 12 months. There were high rates of harms from chemsex across all countries, including negative impacts on work, friends/family and relationships. Although a minority of those engaging in chemsex accessed support, most found this useful. [ABSTRACT FROM AUTHOR]

The development of treatment-related adverse events (trAE) correlates favorably with clinical outcomes in multiple studies of patients receiving immune checkpoint inhibitors (ICI); however, this relationship is undefined in patients with hepatocellular carcinoma (HCC). We derived a cohort of 406 patients with unresectable/advanced HCC receiving ICI therapy as part of international clinical trials submitted to the US Food and Drug Administration (FDA) in support of marketing applications. We tested whether the development of clinically significant trAE (i.e. graded ≥2, trAE2) predicted improved overall survival (OS), progression-free survival (PFS), and objective response rates (ORR) following ICI. We established an international consortium of 10 tertiary-care referral centres located in Europe (n = 67), United States (US, n = 248) and Asia (n = 42) to validate this association. In the FDA dataset of 406 patients, 325 (80%) with Barcelona Clinic Liver Cancer (BCLC) stage C HCC mostly treated with ICI monotherapy (n = 258, 64%), trAE2 were reported in 228 patients (56.1%). Development of trAE2 was associated with longer OS (16.7 versus 11.2 months) and PFS (5.5 versus 2.2 months) and persisted as an independent predictor of outcome after adjusting for viral aetiology, gender, Child-Pugh class, BCLC stage, AFP levels, ECOG-PS, ICI regimen (mono/combination therapy) and receipt of corticosteroid therapy. In a multi-institutional cohort of 357 patients with similar characteristics mostly treated with ICI monotherapy (n = 304, 85%), the development of trAE2 was associated with longer OS (23.3 versus 12.1 months) and PFS (9.6 versus 3.9 months). TrAE2 were confirmed predictors of improved OS (HR 0.43; 95% CI:0.25–0.75) and PFS (HR 0.48; 95% CI: 0.31–0.75), with multivariable analyses confirming their association with outcome independent of clinicopathologic features of interest. Additional time-varying multivariable analyses also indicated that trAEs were associated with a decreased risk of progression (HR 0.56, 95% CI: 0.46–0.67) in the FDA dataset and death (HR 0.55; 95% CI: 0.32–0.95) in the multi-institutional dataset. Development of trAE2 correlates with improved outcomes in patients with HCC receiving ICI in clinical trials and in routine practice. Prospective studies aimed at understanding the underlying immunologic foundations of such relationships are warranted to identify predictive biomarkers of toxicity and response. • Treatment-related adverse events (trAEs) may affect immunotherapy outcomes in HCC. • We correlated trAEs with response and survival in independent datasets. • trAEs predict for better response and survival in trials and clinical practice. [ABSTRACT FROM AUTHOR]

Context: Adrenal gland imaging is recommended by the current guidelines for the workup of primary aldosteronism (PA). However, its diagnostic performance has not been established in large, multiethnic cohorts of patients who undergo adrenal vein sampling (AVS) and adrenalectomy.Objective: This work aims to assess the diagnostic accuracy of cross-sectional adrenal imaging.Methods: This international multicenter study took place in tertiary referral centers. A total of 1625 PA patients seeking surgical cure were enrolled in an international study involving 19 centers in North America, Europe, Asia, and Australia. Of these, 1311 (81%) had imaging data available and 369 (23%), who received a final diagnosis of surgically cured unilateral PA, were examined. Patients underwent AVS and imaging by computed tomography and/or magnetic resonance imaging. The accuracy of detection of unilateral PA at imaging was estimated by the area under the receiver operator characteristics curve using cure (biochemical and/or full clinical success) as the reference at follow-up after unilateral adrenalectomy.Results: In the cohort of 1311 patients with imaging data available, 34% and 7% of cases showed no detectable or bilateral nodules, respectively. Imaging did not detect the culprit adrenal in 28% of the surgically cured unilateral PA patients. Moreover, the clinical outcome did not differ significantly between the imaging-positive and imaging-negative patients.Conclusion: Cross-sectional imaging did not identify a lateralized cause of disease in around 40% of PA patients and failed to identify the culprit adrenal in more than one-fourth of patients with unilateral PA. [ABSTRACT FROM AUTHOR]

Objectives: This paper aims to estimate the percentage of European men who have sex with men (MSM) who may benefit from pre-exposure prophylaxis (PrEP), applying the three most widely used HIV risk indices for MSM (MSM Risk Index, Menza score, San Diego Early Test (SDET) score) and drawing on a large-scale multisite bio-behavioural survey (Sialon II).Methods: The Sialon II study was a bio-behavioural survey among MSM implemented in 13 European cities using either time-location sampling or respondent-driven sampling. Biological and behavioural data from 4901 MSM were collected. Only behavioural data of HIV-negative individuals were considered. Three widely used risk indices to assess HIV acquisition risk among MSM were used to estimate individual HIV risk scores and PrEP eligibility criteria.Results: 4219 HIV-negative MSM were considered. Regardless the HIV risk score used and the city, percentages of MSM eligible for PrEP were found to range between 5.19% and 73.84%. Overall, the MSM Risk Index and the Menza score yielded broadly similar percentages, whereas the SDET Index provided estimates constantly lower across all cities. Although all the three scores correlated positively (r>0.6), their concordance was highly variable (0.01Conclusion: Our findings showed the impact of different scoring systems on the estimation of the percentage of MSM who may benefit from PrEP in European cities. Although our primary aim was not to compare the performance of different HIV risk scores, data show that a considerable percentage of MSM in each city should be offered PrEP in order to reduce HIV infections. As PrEP is highly effective at preventing HIV among MSM, our findings provide useful, practical guidance for stakeholders in implementing PrEP at city level to tackle HIV infections in Europe. [ABSTRACT FROM AUTHOR]

The recent advent of remote ventilator telemonitoring has the potential to revolutionize home-assisted ventilation care in the United States and elsewhere. Home ventilation machines (i.e., respiratory assist devices and portable ventilators) can now wirelessly transmit usage and performance data to cloud-based web servers for remote access by participating clinicians. In this Focused Review, we provide an update on available technology, suggest practical applications for clinical care and research, and review supporting literature. Remote monitoring permits early data review, refinement of device settings to optimize ventilatory function, and troubleshooting if a new problem arises after initial setup. Data from home spirometry and noninvasively measured blood gas tensions can complement ventilator data to reflect physiological response. Acknowledging a paucity of published outcome studies, remote telemonitoring may be a cost-effective strategy to reduce emergency room visits, urgent clinic appointments, and hospitalizations. Ongoing clinical trials in Europe aim to expand on the benefit of this rapidly evolving technology. However, several barriers may hinder widespread implementation, especially in the United States. Clinicians must familiarize themselves with each ventilator manufacturer's proprietary software to safely leverage this technology for improving care. Legal and ethical considerations threaten clinician interest. Medical insurance payers must adapt a reimbursement scheme to incentivize clinicians and durable medical equipment companies to perform this time-consuming service. Cohort-level ventilator data will facilitate multicenter clinical trials focused on improving the respiratory care of this vulnerable population. [ABSTRACT FROM AUTHOR]

Background: For care planning and support, under-detection and late diagnosis of Alzheimer's disease (AD) is a great challenge. Models of Patient-Engagement for Alzheimer's Disease (MOPEAD) is an EU-funded project aiming at testing different strategies to improve this situation.Objective: To make a cost-consequence analysis of MOPEAD.Methods: Four screening strategies were tested in five countries (Germany, the Netherlands, Slovenia, Spain, and Sweden): 1) a web-approach; 2) Open-House initiative; 3) in primary care; and 4) by diabetes specialists. Persons-at-risk of AD in all strategies were offered referral to a hospital-based specialist. The primary health-economic outcome was the cost per true-positive case (TP) of AD from the screened population.Results: Of 2,847 screened persons, 1,121 screened positive (39%), 402 were evaluated at memory clinics (14%), and 236 got an AD diagnosis (8%). The cost per TP of those screened was €3,115 with the web-approach, €2,722 with the Open-House, €1,530 in primary care, and €1,190 by diabetes specialists. Sensitivity analyses that more likely reflect the real-world situation confirmed the results. The number-needed-to-screen was 30 with the web-approach, 8 with the Open-House and primary care, and 6 with the diabetes specialists.There were country differences in terms of screening rates, referrals to memory clinics, staff-types involved, and costs per TP.Conclusion: In primary care and by the diabetes specialist, the costs per TP/screened population were lowest, but the capacity of such settings to identify cases with AD-risk must be discussed. Hence new diagnostic strategies such as web-solutions and Open-House initiatives may be valuable after modifications. [ABSTRACT FROM AUTHOR]

Background: 1.5–8% of older adults live in nursing homes (NHs), presenting a high prevalence of frailty and polypharmacy. Aims: To investigate the association of frailty with polypharmacy and drug prescription patterns in a sample of European Nursing Home (NH) residents. Methods: Cross-sectional study based on the data from the Services and Health for Elderly in Long TERm care (SHELTER) study. 4121 NH residents in Europe and Israel. Residents' clinical, cognitive, social, and physical status were evaluated with the InterRAI LTCF tool, which allows comprehensive, standardized evaluation of persons living in NH. Polypharmacy and hyperpolypharmacy were defined as the concurrent use of ≥ 5 and ≥ 10 medications. Frailty was defined according to the FRAIL-NH scale. Results: Of 4121 participants, 46.6% were frail (mean age 84.6 ± 9.2 years; 76.4% female). Polypharmacy and hyperpolypharmacy were associated with a lower likelihood of frailty (Odds Ratio = 0.72; 95% CI = 0.59–0.87 and OR = 0.75; 95% CI = 0.60–0.94, respectively). Patterns of drug prescriptions were different between frail and non-frail residents. Symptomatic drugs (laxatives, paracetamol, and opioids) were more frequently prescribed among frail residents, while preventive drugs (bisphosphonates, vitamin D, and acetylsalicylic acid) were more frequently prescribed among non-frail residents. Conclusions: Frailty is associated with less polypharmacy and with higher prevalence of symptomatic drugs use among NH residents. Further studies are needed to define appropriateness of drug prescription in frail individuals. [ABSTRACT FROM AUTHOR]

Background: Excess bodyweight and related metabolic perturbations have been implicated in kidney cancer aetiology, but the specific molecular mechanisms underlying these relationships are poorly understood. In this study, we sought to identify circulating metabolites that predispose kidney cancer and to evaluate the extent to which they are influenced by body mass index (BMI).Methods and Findings: We assessed the association between circulating levels of 1,416 metabolites and incident kidney cancer using pre-diagnostic blood samples from up to 1,305 kidney cancer case-control pairs from 5 prospective cohort studies. Cases were diagnosed on average 8 years after blood collection. We found 25 metabolites robustly associated with kidney cancer risk. In particular, 14 glycerophospholipids (GPLs) were inversely associated with risk, including 8 phosphatidylcholines (PCs) and 2 plasmalogens. The PC with the strongest association was PC ae C34:3 with an odds ratio (OR) for 1 standard deviation (SD) increment of 0.75 (95% confidence interval [CI]: 0.68 to 0.83, p = 2.6 × 10-8). In contrast, 4 amino acids, including glutamate (OR for 1 SD = 1.39, 95% CI: 1.20 to 1.60, p = 1.6 × 10-5), were positively associated with risk. Adjusting for BMI partly attenuated the risk association for some-but not all-metabolites, whereas other known risk factors of kidney cancer, such as smoking and alcohol consumption, had minimal impact on the observed associations. A mendelian randomisation (MR) analysis of the influence of BMI on the blood metabolome highlighted that some metabolites associated with kidney cancer risk are influenced by BMI. Specifically, elevated BMI appeared to decrease levels of several GPLs that were also found inversely associated with kidney cancer risk (e.g., -0.17 SD change [ßBMI] in 1-(1-enyl-palmitoyl)-2-linoleoyl-GPC (P-16:0/18:2) levels per SD change in BMI, p = 3.4 × 10-5). BMI was also associated with increased levels of glutamate (ßBMI: 0.12, p = 1.5 × 10-3). While our results were robust across the participating studies, they were limited to study participants of European descent, and it will, therefore, be important to evaluate if our findings can be generalised to populations with different genetic backgrounds.Conclusions: This study suggests a potentially important role of the blood metabolome in kidney cancer aetiology by highlighting a wide range of metabolites associated with the risk of developing kidney cancer and the extent to which changes in levels of these metabolites are driven by BMI-the principal modifiable risk factor of kidney cancer. [ABSTRACT FROM AUTHOR]

Background: Traumatic brain injury (TBI) is an important global public health burden, where those injured by high-energy transfer (e.g., road traffic collisions) are assumed to have more severe injury and are prioritised by emergency medical service trauma triage tools. However recent studies suggest an increasing TBI disease burden in older people injured through low-energy falls. We aimed to assess the prevalence of low-energy falls among patients presenting to hospital with TBI, and to compare their characteristics, care pathways, and outcomes to TBI caused by high-energy trauma.Methods and Findings: We conducted a comparative cohort study utilising the CENTER-TBI (Collaborative European NeuroTrauma Effectiveness Research in TBI) Registry, which recorded patient demographics, injury, care pathway, and acute care outcome data in 56 acute trauma receiving hospitals across 18 countries (17 countries in Europe and Israel). Patients presenting with TBI and indications for computed tomography (CT) brain scan between 2014 to 2018 were purposively sampled. The main study outcomes were (i) the prevalence of low-energy falls causing TBI within the overall cohort and (ii) comparisons of TBI patients injured by low-energy falls to TBI patients injured by high-energy transfer-in terms of demographic and injury characteristics, care pathways, and hospital mortality. In total, 22,782 eligible patients were enrolled, and study outcomes were analysed for 21,681 TBI patients with known injury mechanism; 40% (95% CI 39% to 41%) (8,622/21,681) of patients with TBI were injured by low-energy falls. Compared to 13,059 patients injured by high-energy transfer (HE cohort), the those injured through low-energy falls (LE cohort) were older (LE cohort, median 74 [IQR 56 to 84] years, versus HE cohort, median 42 [IQR 25 to 60] years; p < 0.001), more often female (LE cohort, 50% [95% CI 48% to 51%], versus HE cohort, 32% [95% CI 31% to 34%]; p < 0.001), more frequently taking pre-injury anticoagulants or/and platelet aggregation inhibitors (LE cohort, 44% [95% CI 42% to 45%], versus HE cohort, 13% [95% CI 11% to 14%]; p < 0.001), and less often presenting with moderately or severely impaired conscious level (LE cohort, 7.8% [95% CI 5.6% to 9.8%], versus HE cohort, 10% [95% CI 8.7% to 12%]; p < 0.001), but had similar in-hospital mortality (LE cohort, 6.3% [95% CI 4.2% to 8.3%], versus HE cohort, 7.0% [95% CI 5.3% to 8.6%]; p = 0.83). The CT brain scan traumatic abnormality rate was 3% lower in the LE cohort (LE cohort, 29% [95% CI 27% to 31%], versus HE cohort, 32% [95% CI 31% to 34%]; p < 0.001); individuals in the LE cohort were 50% less likely to receive critical care (LE cohort, 12% [95% CI 9.5% to 13%], versus HE cohort, 24% [95% CI 23% to 26%]; p < 0.001) or emergency interventions (LE cohort, 7.5% [95% CI 5.4% to 9.5%], versus HE cohort, 13% [95% CI 12% to 15%]; p < 0.001) than patients injured by high-energy transfer. The purposive sampling strategy and censorship of patient outcomes beyond hospital discharge are the main study limitations.Conclusions: We observed that patients sustaining TBI from low-energy falls are an important component of the TBI disease burden and a distinct demographic cohort; further, our findings suggest that energy transfer may not predict intracranial injury or acute care mortality in patients with TBI presenting to hospital. This suggests that factors beyond energy transfer level may be more relevant to prehospital and emergency department TBI triage in older people. A specific focus to improve prevention and care for patients sustaining TBI from low-energy falls is required. [ABSTRACT FROM AUTHOR]

Background Sepsis is one of the most frequent reasons for acute intensive care unit (ICU) admission of very old patients and mortality rates are high. However, the impact of pre-existing physical and cognitive function on long-term outcome of ICU patients ≥ 80 years old (very old intensive care patients (VIPs)) with sepsis is unclear. Objective To investigate both the short- and long-term mortality of VIPs admitted with sepsis and assess the relation of mortality with pre-existing physical and cognitive function. Design Prospective cohort study. Setting 241 ICUs from 22 European countries in a six-month period between May 2018 and May 2019. Subjects Acutely admitted ICU patients aged ≥80 years with sequential organ failure assessment (SOFA) score ≥ 2. Methods Sepsis was defined according to the sepsis 3.0 criteria. Patients with sepsis as an admission diagnosis were compared with other acutely admitted patients. In addition to patients' characteristics, disease severity, information about comorbidity and polypharmacy and pre-existing physical and cognitive function were collected. Results Out of 3,596 acutely admitted VIPs with SOFA score ≥ 2, a group of 532 patients with sepsis were compared to other admissions. Predictors for 6-month mortality were age (per 5 years): Hazard ratio (HR, 1.16 (95% confidence interval (CI), 1.09–1.25, P  < 0.0001), SOFA (per one-point): HR, 1.16 (95% CI, 1.14–1.17, P  < 0.0001) and frailty (CFS > 4): HR, 1.34 (95% CI, 1.18–1.51, P  < 0.0001). Conclusions There is substantial long-term mortality in VIPs admitted with sepsis. Frailty, age and disease severity were identified as predictors of long-term mortality in VIPs admitted with sepsis. [ABSTRACT FROM AUTHOR]

Background: Given increasing incidence of cognitive impairment and dementia, further understanding of modifiable factors contributing to increased healthspan is crucial. Extensive literature provides evidence that physical activity (PA) delays the onset of cognitive impairment; however, it is unclear whether engaging in PA in older adulthood is sufficient to influence progression through cognitive status categories.Method: Applying a coordinated analysis approach, this project independently analyzed 14 longitudinal studies (NTotal = 52 039; mean baseline age across studies = 69.9-81.73) from North America and Europe using multistate survival models to estimate the impact of engaging in PA on cognitive status transitions (nonimpaired, mildly impaired, severely impaired) and death. Multinomial regression models were fit to estimate life expectancy (LE) based on American PA recommendations. Meta-analyses provided the pooled effect sizes for the role of PA on each transition and estimated LEs.Results: Controlling for baseline age, sex, education, and chronic conditions, analyses revealed that more PA is significantly associated with decreased risk of transitioning from nonimpaired to mildly impaired cognitive functioning and death, as well as substantially longer LE. Results also provided evidence for a protective effect of PA after onset of cognitive impairment (eg, decreased risk of transitioning from mild-to-severe cognitive impairment; increased likelihood of transitioning backward from severe-to-mild cognitive impairment), though between-study heterogeneity suggests a less robust association.Conclusions: These results yield evidence for the importance of engaging in PA in older adulthood for cognitive health, and a rationale for motivating older adults to engage consistently in PA. [ABSTRACT FROM AUTHOR]

Background: Baseline frailty index (FI) values have been shown to predict mortality among older adults, but little is known about the effects of changes in FI on mortality.Methods: In a coordinated approach, we analyzed data from 4 population-based cohorts: the Health and Retirement Study (HRS), the Survey of Health, Ageing and Retirement in Europe (SHARE), the English Longitudinal Survey of Ageing (ELSA), and the Longitudinal Aging Study Amsterdam (LASA), comprising a total of 24 961 respondents (65+), 95 897 observations, up to 9 repeated FI assessments, and up to 23 years of mortality follow-up. The effect of time-varying FI on mortality was modeled with joint regression models for longitudinal and time-to-event data.Results: Differences (of 0.01) in current FI levels (hazard ratio [HR] = 1.04, 95% credible interval [CI] = 1.03-1.05) and baseline FI levels (HR = 1.03, 95% CI = 1.03-1.05) were consistently associated with mortality across studies. Importantly, individuals with steeper FI growth also had a higher mortality risk: An increase in annual FI growth by 0.01 was associated with an increased mortality risk of HR = 1.56 (95% CI = 1.49-1.63) in HRS, HR = 1.24 (95% CI = 1.13-1.35) in SHARE, HR = 1.40 (95% CI = 1.25-1.52) in ELSA, and HR = 1.71 (95% CI = 1.46-2.01) in LASA.Conclusions: FI changes predicted mortality independently of baseline FI differences. Repeated assessment of frailty and individual's frailty trajectory could provide a means to anticipate further health deterioration and mortality and could thus support clinical decision making. [ABSTRACT FROM AUTHOR]

Prehospital care for traumatic brain injury (TBI) is important to prevent secondary brain injury. We aim to compare prehospital care systems within Europe and investigate the association of system characteristics with the stability of patients at hospital arrival. We studied TBI patients who were transported to CENTER-TBI centers, a pan-European, prospective TBI cohort study, by emergency medical services between 2014 and 2017. The association of demographic factors, injury severity, situational factors, and interventions associated with on-scene time was assessed using linear regression. We used mixed effects models to investigate the case mix adjusted variation between countries in prehospital times and interventions. The case mix adjusted impact of on-scene time and interventions on hypoxia (oxygen saturation <90%) and hypotension (systolic blood pressure <100mmHg) at hospital arrival was analyzed with logistic regression. Among 3878 patients, the greatest driver of longer on-scene time was intubation (+8.3 min, 95% CI: 5.6–11.1). Secondary referral was associated with shorter on-scene time (-5.0 min 95% CI: −6.2– −3.8). Between countries, there was a large variation in response (range: 12–25 min), on-scene (range: 16-36 min) and travel time (range: 15–32 min) and in prehospital interventions. These variations were not explained by patient factors such as conscious level or severity of injury (expected OR between countries: 1.8 for intubation, 1.8 for IV fluids, 2.0 for helicopter). On-scene time was not associated with the regional EMS policy (p= 0.58). Hypotension and/or hypoxia were seen in 180 (6%) and 97 (3%) patients in the overall cohort and in 13% and 7% of patients with severe TBI (GCS <8). The largest association with secondary insults at hospital arrival was with major extracranial injury: the OR was 3.6 (95% CI: 2.6–5.0) for hypotension and 4.4 (95% CI: 2.9–6.7) for hypoxia. Hypoxia and hypotension continue to occur in patients who suffer a TBI, and remain relatively common in severe TBI. Substantial variation in prehospital care exists for patients after TBI in Europe, which is only partially explained by patient factors. [ABSTRACT FROM AUTHOR]

Background: Clinical studies with work participation (WP) as an outcome domain pose particular methodological challenges that hamper interpretation, comparison between studies and meta-analyses.Objectives: To develop Points to Consider (PtC) for design, analysis and reporting of studies of patients with inflammatory arthritis that include WP as a primary or secondary outcome domain.Methods: The EULAR Standardised Operating Procedures were followed. A multidisciplinary taskforce with 22 experts including patients with rheumatic diseases, from 10 EULAR countries and Canada, identified methodologic areas of concern. Two systematic literature reviews (SLR) appraised the methodology across these areas. In parallel, two surveys among professional societies and experts outside the taskforce sought for additional methodological areas or existing conducting/reporting recommendations. The taskforce formulated the PtC after presentation of the SLRs and survey results, and discussion. Consensus was obtained through informal voting, with levels of agreement obtained anonymously.Results: Two overarching principles and nine PtC were formulated. The taskforce recommends to align the work-related study objective to the design, duration, and outcome domains/measurement instruments of the study (PtC: 1-3); to identify contextual factors upfront and account for them in analyses (PtC: 4); to account for interdependence of different work outcome domains and for changes in work status over time (PtC: 5-7); to present results as means as well as proportions of patients reaching predefined meaningful categories (PtC: 8) and to explicitly report volumes of productivity loss when costs are an outcome (PtC:9).Conclusion: Adherence to these EULAR PtC will improve the methodological quality of studies evaluating WP. [ABSTRACT FROM AUTHOR]

Objective: Pulmonary vein isolation (PVI) guided by a standardised CLOSE (contiguous optimised lesions) protocol has been shown to increase clinical success after catheter ablation for paroxysmal atrial fibrillation (PAF). This study analysed healthcare utilisation and quality of life (QOL) outcomes from a large multicentre prospective study, measured association between QOL and atrial fibrillation (AF) burden and identified factors associated with lack of QOL improvement.Methods: CLOSE-guided ablation was performed in 329 consecutive patients (age 61.4 years, 60.8% male) with drug-refractory PAF in 17 European centres. QOL was measured at baseline and 12 months post-ablation via Atrial Fibrillation Effect on QualiTy of Life Survey (AFEQT) and EuroQoL EQ-5D-5L questionnaires. All-cause and cardiovascular hospitalisations and cardioversions over 12 months pre-ablation and post-ablation were recorded. Rhythm monitoring included weekly and symptom-driven trans-telephonic monitoring, plus ECG and Holter monitoring at 3, 6 and 12 months. AF burden was defined as the percentage of postblanking tracings with an atrial tachyarrhythmia ≥30 s. Continuous measures across multiple time points were analysed using paired t-tests, and associations between various continuous measures were analysed using independent sample t-tests. Each statistical test used two-sided p values with a significance level of 0.05.Results: Both QOL instruments showed significant 12-month improvements across all domains: AFEQT score increased 25.1-37.5 points and 33.3%-50.8% fewer patients reporting any problem across EuroQoL EQ-5D-5L domains. Overall, AFEQT improvement was highly associated with AF burden (p=0.009 for <10% vs ≥10% burden, p<0.001 for <20% vs ≥20% burden). Cardiovascular hospitalisations were significantly decreased after ablation (42%, p=0.001). Patients without substantial improvement in AFEQT (55/301, 18.2%) had higher AFEQT and CHA2DS2-VASc scores at baseline, and higher AF burden following PVI.Conclusions: QOL improved and healthcare utilisation decreased significantly after ablation with a standardised CLOSE protocol. QOL improvement was significantly associated with impairment at baseline and AF burden after ablation.Trial Registration Number: NCT03062046. [ABSTRACT FROM AUTHOR]

Background: Many surveys have been performed over the years to assess the medical and social requirements of patients with a rare disease, but no studies have focused specifically on patients in Europe or with an inherited metabolic disease (IMD). To obtain a comprehensive overview of the social and psychological status and needs of IMD patients, especially in Europe, the European Reference Network for Hereditary Metabolic Disorders (MetabERN) has performed a dedicated survey among its metabolic patients.Results: A total of 924 patients and caregivers responded to the questionnaire. Most participants were from 25 European countries, with Spain, Italy, and Germany being the most represented; only eight participants were extra-European. The survey showed that most social assistance services, from free educational/development services for those with intellectual disability to transition from childhood to adult care and job placement support, are available for a limited number of patients or are unknown to the majority of patients or their parents/caregivers. Similarly, psychological assistance for the patient or the parent/caregiver is available for a small fraction of respondents, despite the fact that the majority considers this type of support necessary for both the patient and the caregiver. In addition, for most IMD patients local specialised or emergency medical assistance is lacking, although national clinical pathways are defined, and medical professionals of reference are readily available when needed. Lastly, while most national health services in Europe cover all or part of the expenses for medications, medical devices, food supplements, dietary integrators, physiotherapy, and speech therapy, significant gaps in the economic support for healthcare and other expenses still exist.Conclusions: Overall, our survey reveals a widespread lack of social, psychological, and economic support for IMD patients in Europe. More needs to be done to provide daily assistance to IMD patients in order to alleviate the burden on caregivers and to allow patients to become independent and productive adults. Where support is actually available locally or nationally, most IMD patients are not aware of it, so an active dissemination of this information among the metabolic community is essential. [ABSTRACT FROM AUTHOR]

There is increasing evidence for altered brain resting state functional connectivity in adolescents with disruptive behavior. While a considerable body of behavioral research points to differences between reactive and proactive aggression, it remains unknown whether these two subtypes have dissociable effects on connectivity. Additionally, callous-unemotional traits are important specifiers in subtyping aggressive behavior along the affective dimension. Accordingly, we examined associations between two aggression subtypes along with callous-unemotional traits using a seed-to-voxel approach. Six functionally relevant seeds were selected to probe the salience and the default mode network, based on their presumed role in aggression. The resting state sequence was acquired from 207 children and adolescents of both sexes [mean age (standard deviation) = 13.30 (2.60); range = 8.02–18.35] as part of a Europe-based multi-center study. One hundred eighteen individuals exhibiting disruptive behavior (conduct disorder/oppositional defiant disorder) with varying comorbid attention-deficit/hyperactivity disorder (ADHD) symptoms were studied, together with 89 healthy controls. Proactive aggression was associated with increased left amygdala–precuneus coupling, while reactive aggression related to hyper-connectivities of the posterior cingulate cortex (PCC) to the parahippocampus, the left amygdala to the precuneus and to hypo-connectivity between the right anterior insula and the nucleus caudate. Callous-unemotional traits were linked to distinct hyper-connectivities to frontal, parietal, and cingulate areas. Additionally, compared to controls, cases demonstrated reduced connectivity of the PCC and left anterior insula to left frontal areas, the latter only when controlling for ADHD scores. Taken together, this study revealed aggression-subtype-specific patterns involving areas associated with emotion, empathy, morality, and cognitive control. [ABSTRACT FROM AUTHOR]

The evidence-based public health course equips public health professionals with skills and tools for applying evidence-based frameworks and processes in public health practice. To date, training has included participants from all the 50 U.S. states, 2 U.S. territories, and multiple other countries besides the U.S. This study pooled follow-up efforts (5 surveys, with 723 course participants, 2005-2019) to explore the benefits, application, and barriers to applying the evidence-based public health course content. All analyses were completed in 2020. The most common benefits (reported by >80% of all participants) were identifying ways to apply knowledge in their work, acquiring new knowledge, and becoming a better leader who promotes evidence-based approaches. Participants most frequently applied course content to searching the scientific literature (72.9%) and least frequently to writing grants (42.7%). Lack of funds for continued training (35.3%), not having enough time to implement evidence-based public health approaches (33.8%), and not having coworkers trained in evidence-based public health (33.1%) were common barriers to applying the content from the course. Mean scores were calculated for benefits, application, and barriers to explore subgroup differences. European participants generally reported higher benefits from the course (mean difference=0.12, 95% CI=0.00, 0.23) and higher frequency of application of the course content to their job (mean difference=0.17, 95% CI=0.06, 0.28) than U.S. participants. Participants from later cohorts (2012-2019) reported more overall barriers to applying course content in their work (mean difference=0.15, 95% CI=0.05, 0.24). The evidence-based public health course represents an important strategy for increasing the capacity (individual skills) for evidence-based processes within public health practice. Organization-level methods are also needed to scale up and sustain capacity-building efforts. [ABSTRACT FROM AUTHOR]

Background: Physical activity (PA) during childhood is important for preventing future metabolic syndrome (MetS). To examine the relationship between PA and MetS in more detail, accurate measures of PA are needed. Previous studies have only utilized a small part of the information available from accelerometer measured PA. This study investigated the association between measured PA and MetS in children with a new method for data processing and analyses that enable more detailed interpretation of PA intensity level. Methods: The association between PA pattern and risk factors related to MetS was investigated in a cross- sectional sample of children (n = 2592, mean age 10.9 years, 49.4% male) participating in the European multicenter I. Family study. The risk factors examined include body mass index, blood pressure, high-density lipoprotein cholesterol, insulin resistance and a combined risk factor score (MetS score). PA was measured by triaxial accelerometers and raw data was processed using the 10 Hz frequency extended method (FEM). The PA output was divided into an intensity spectrum and the association with MetS risk factors was analyzed by partial least squares regression. Results: PA patterns differed between the European countries investigated, with Swedish children being most active and Italian children least active. Moderate intensity physical activity was associated with lower insulin resistance (R2 = 2.8%), while vigorous intensity physical activity was associated with lower body mass index (R2 = 3.6%), MetS score (R2 = 3.1%) and higher high-density lipoprotein cholesterol (R2 = 2.3%). PA of all intensities was associated with lower systolic- and diastolic blood pressure, although the associations were weaker than for the other risk factors (R2 = 1.5% and R2 = 1.4%). However, the multivariate analysis implies that the entire PA pattern must be considered. The main difference in PA was observed between normal weight and overweight children. Conclusions: The present study suggests a greater importance of more PA corresponding to an intensity of at least brisk walking with inclusion of high-intense exercise, rather than a limited time spent sedentary, in the association to metabolic health in children. The methods of data processing and statistical analysis enabled accurate analysis and interpretation of the health benefits of high intensity PA that have not been shown previously. [ABSTRACT FROM AUTHOR]

Objective: Parent anxiety is associated with offspring internalizing problems (emotional problems related to anxiety and depression). This may reflect causal processes, whereby exposure to parent anxiety directly influences offspring internalizing (and/or vice versa). However, parent-offspring associations could also be attributable to their genetic relatedness. A systematic review and meta-analysis were conducted to investigate whether exposure to parent anxiety is associated with offspring internalizing after controlling for genetic relatedness.Method: A literature search across 5 databases identified 429 unique records. Publications were retained if they used a quasi-experimental design in a general population sample to control for participant relatedness in associations between parent anxiety and offspring internalizing outcomes. Publications were excluded if they involved an experimental exposure or intervention. Studies of prenatal and postnatal anxiety exposure were meta-analyzed separately. Pearson's correlation coefficient estimates (r) were pooled using multilevel random-effects models.Results: Eight publications were retained. Data were drawn from 4 population cohorts, each unique to a quasi-experimental design: adoption, sibling-comparison, children-of-twins or in vitro fertilization. Cohorts were located in northern Europe or America. Families were predominantly of European ancestry. Three publications (Nfamilies >11,700; offspring age range, 0.5-10 years) showed no association between prenatal anxiety exposure and offspring internalizing outcomes after accounting for participant relatedness (r = .04; 95% CI: -.07, .14). Six publications (Nfamilies >12,700; offspring age range, 0.75-22 years) showed a small but significant association between concurrent symptoms in parents and offspring after accounting for participant relatedness (r = .13; 95% CI: .04, .21).Conclusion: Initial literature, derived from homogeneous populations, suggests that prenatal anxiety exposure does not cause offspring internalizing outcomes. However, postnatal anxiety exposure may be causally associated with concurrent offspring internalizing via nongenetic pathways. Longitudinal stability, child-to-parent effects, and the role of moderators and methodological biases require attention. [ABSTRACT FROM AUTHOR]

Objectives: Mexiletine is a long-known drug used for the treatment of arrhythmias and repurposed in the 1980s for patients with nondystrophic myotonia (NDM). Recently, the price of mexiletine in Europe increased significantly after registration as an orphan drug for NDM. This led to international discussions on affordability and willingness to reimburse mexiletine in the absence of background information that would justify such a price. Our objective was to calculate a cost-based price for mexiletine for adult patients with NDM based on detailed information on development costs.Methods: We calculated a fair price based on a cost-based pricing model for commercial mexiletine to treat adults with NDM using a recent European drug-pricing model as a framework to include actual costs incurred. Three scenarios were applied: 1 with minimum estimated costs, 1 with maximum estimated costs, and 1 with costs as if mexiletine was innovative.Results: The calculated fair price of mexiletine per patient per year (PPPY) is €452 for the minimum scenario and €1996 for the maximum scenario. By using hypothetical R&D costs used for innovative drugs, the price would be €6685 PPPY. In Europe, the list price of mexiletine ranges from €30 707-60 730 PPPY, based on 600 mg daily.Conclusions: The current list price for mexiletine in Europe is manifold higher than any scenario of the cost-based models. Accounting for the reduced costs for clinical development in a repurposing scenario, the cost-based pricing model provides a fair commercial price range, which can be used as benchmark for pricing negotiations and/or reimbursement decisions. [ABSTRACT FROM AUTHOR]

Objectives: To model the cost-effectiveness of the TYRX Absorbable Antibacterial Envelope when used in patients at increased risk of cardiac implantable electronic device (CIED) infection in the context of 3 European healthcare systems: Germany, Italy, and England.Methods: A decision tree model with a lifetime horizon was populated using data from the Worldwide Randomized Antibiotic Envelope Infection Prevention Trial, a large multicenter randomized controlled trial. Use of the antibacterial envelope adjunctive to standard of care was compared to standard of care infection prevention alone. Patients in the model were divided into subgroups based on presence of factors known to increase infection risk.Results: The antibacterial envelope had the most favorable cost-effectiveness profile when patients had previously experienced CIED infection, had a history of immunosuppressive therapy, or had a Prevention of Arrhythmia Device Infection Trial (PADIT) score indicating high risk of infection (scores ≥6) at cost-effectiveness thresholds of €50 000 in Germany (assumed in the absence of an official threshold), €40 000 in Italy, and £30 000 in England. Probabilistic sensitivity analysis indicated that the antibacterial envelope was likely to be cost-effective in patients with other risk factors (including replacement of high power CIEDs, generator replacement with lead modification, and PADIT scores indicating intermediate risk of infection) when used with some device types and in some countries.Conclusions: The absorbable antibacterial envelope was associated with cost-effectiveness ratios below European benchmarks in selected patients at increased risk of infection, suggesting the envelope provides value for European healthcare systems by reducing CIED infections. [ABSTRACT FROM AUTHOR]

Background: Abnormal weights, eg, obesity, has shown a strong modifying effect on the association between air pollution exposure and lung function impairment in adults.Research Question: How might weight status modify the effects of long-term air pollution exposure on adolescents' lung function, particularly in areas with pollution levels much lower than the current European Union (EU) air quality standards?Study Design and Methods: In this observational study, we investigated 2,224 adolescents from the German Infant Study on the Influence of Nutrition Intervention Plus Environmental and Genetic Influences on Allergy Development and the Influence of Life Style Factors on the Development of the Immune System and Allergies in East and West Germany birth cohorts. Lung function was measured at age 15 years. Underweight, normal weight, and overweight or obese were defined using percentiles of BMI. Average concentrations of air pollution were modelled at residential addresses at four exposure windows between 0 and 15 years. Multivariate linear regression models were fitted by weight group on lung function with exposure at each window or cumulative exposure since birth.Results: The median air pollution concentrations were half to two-thirds of the EU standards. Significant associations were observed only for individuals who were underweight and overweight or obese. For example, per interquartile range increase in nitrogen dioxide at the 15-year exposure window, FEV1 declined by -2.9% (95% CI, -5.2% to -0.5%) for the underweight group and -3.4% (95% CI, -5.4% to -1.2%) for the overweight or obese group. Similarly, longer exposure to moderate-level air pollution since birth was associated significantly with lung function impairment for groups with abnormal weight.Interpretation: Exposure to low to moderate levels of air pollution was associated with lung function impairment for adolescents with abnormal weight. Longer exposure aggravated the adverse effect. Whether a critical exposure window since birth exists warrants further exploration. [ABSTRACT FROM AUTHOR]

Background: Treatment resistant depression (TRD) characterizes a subgroup of 10-30% of patients with major depressive disorder, and is associated with considerable morbidity and mortality. A consensus treatment for TRD does not exist, which often leads to wide variations in treatment strategies. Real-world studies on treatment patterns and outcomes in TRD patients in Europe are lacking and could help elucidate current treatment strategies and their efficacy.Methods: This non-interventional cohort study of patients with TRD (defined as treatment failure on ≥2 oral antidepressants given at adequate dose and duration) with moderate to severe depression collected real-world data on treatment patterns and outcomes in several European countries. Patients were started on a new treatment for depression according to routine clinical practice.Results: Among 411 patients enrolled, after 6 months, only 16.7% achieved remission and 73.5% showed no response. At Month 12, while 19.2% achieved remission and 69.2% showed no response, 33.3% of those in remission at Month 6 were no longer in remission. Pharmacological treatments employed were heterogenous; 54 different drugs were recorded at baseline, and the top 5 treatment types according to drug classes accounted for 40.0% of patients. Even though remission rates were very low, at Month 12, 60.0% of patients had not changed treatment since enrolment.Conclusions: The heterogeneity of treatments highlights a lack of consensus. Moreover, despite low response rates, patients often remained on treatments for substantial periods of time. These data further support existence of an unmet treatment need for TRD patients in Europe. [ABSTRACT FROM AUTHOR]

Objective: To examine longitudinal and dose-dependent associations of dietary glycemic index (GI), glycemic load (GL), and fiber with body weight and glycemic status during 3-year weight loss maintenance (WLM) in adults at high risk of type 2 diabetes.Research Design and Methods: In this secondary analysis we used pooled data from the PREVention of diabetes through lifestyle Intervention and population studies in Europe and around the World (PREVIEW) randomized controlled trial, which was designed to test the effects of four diet and physical activity interventions. A total of 1,279 participants with overweight or obesity (age 25-70 years and BMI ≥25 kg ⋅ m-2) and prediabetes at baseline were included. We used multiadjusted linear mixed models with repeated measurements to assess longitudinal and dose-dependent associations by merging the participants into one group and dividing them into GI, GL, and fiber tertiles, respectively.Results: In the available-case analysis, each 10-unit increment in GI was associated with a greater regain of weight (0.46 kg ⋅ year-1; 95% CI 0.23, 0.68; P < 0.001) and increase in HbA1c. Each 20-unit increment in GL was associated with a greater regain of weight (0.49 kg ⋅ year-1; 0.24, 0.75; P < 0.001) and increase in HbA1c. The associations of GI and GL with HbA1c were independent of weight change. Compared with those in the lowest tertiles, participants in the highest GI and GL tertiles had significantly greater weight regain and increases in HbA1c. Fiber was inversely associated with increases in waist circumference, but the associations with weight regain and glycemic status did not remain robust in different analyses.Conclusions: Dietary GI and GL were positively associated with weight regain and deteriorating glycemic status. Stronger evidence on the role of fiber is needed. [ABSTRACT FROM AUTHOR]

Background: Emerging resistance to cephalosporins in Neisseria gonorrhoeae (Ng) is a major public health threat, since these are considered antibiotics of last resort. Continuous surveillance is needed to monitor the circulation of resistant strains and those with reduced susceptibility.Objectives: For the purpose of epidemiological surveillance, genomic population analysis was performed on Ng isolates from Amsterdam with a focus on isolates with reduced susceptibility to ceftriaxone.Methods: WGS data were obtained from 318 isolates from Amsterdam, the Netherlands between 2014 and 2019. Isolates were typed according to MLST, Ng Multi-Antigen Sequence Typing (NG-MAST) and Ng Sequence Typing for Antimicrobial Resistance (NG-STAR) schemes and additional resistance markers were identified. Phylogenetic trees were created to identify genetic clusters and to compare Dutch and non-Dutch MLST7827 isolates.Results: MLST7363 and MLST1901 were the predominant strains having reduced susceptibility to ceftriaxone during 2014-16; MLST7827 emerged and dominated during 2017-19. NG-STAR38 and NG-MAST2318/10386 were predominant among MLST7827 isolates. MLST7827 reduced susceptibility isolates carried a non-mosaic 13.001 penA allele with an A501V mutation and porB1b G120K/A121D mutations, which were lacking in susceptible MLST7827 isolates. Phylogenetic analysis of all publicly available MLST7827 isolates showed strong genetic clustering of Dutch and other European MLST7827 isolates.Conclusions: MLST7827 isolates with reduced ceftriaxone susceptibility have emerged during recent years in Amsterdam. Co-occurrence of penA A501V and porB1b G120K/A121D mutations was strongly associated with reduced susceptibility to ceftriaxone. Genetic clustering of Dutch and other European MLST7827 isolates indicates extensive circulation of this strain in Europe. Close monitoring of the spread of this strain having an alarming susceptibility profile is needed. [ABSTRACT FROM AUTHOR]

Background: In Europe, knowledge about the social determinants of health among undocumented migrants is scarce. The canton of Geneva, Switzerland, implemented in 2017-2018 a pilot public policy aiming at regularizing undocumented migrants. We sought to test for associations between self-rated health, proven eligibility for residence status regularization and social and economic integration.Methods: This paper reports data from the first wave of the Parchemins Study, a prospective study whose aim is to investigate the effect of residence status regularization on undocumented migrants' living conditions and health. The convenience sample included undocumented migrants living in Geneva for at least 3 years. We categorized them into those who were in the process of receiving or had just been granted a residence permit (eligible or newly regularized) and those who had not applied or were ineligible for regularization (undocumented). We conducted multivariate regression analyses to determine factors associated with better self-rated health, i.e., with excellent/very good vs. good/fair/poor self-rated health. Among these factors, measures of integration, social support and economic resources were included.Results: Of the 437 participants, 202 (46%) belonged to the eligible or newly regularized group. This group reported better health more frequently than the undocumented group (44.6% versus 28.9%, p-value < .001), but the association was no longer significant after adjustment for social support and economic factors (odds ratio (OR): 1.12; 95% confidence interval (CI): 0.67-1.87). Overall, better health was associated with larger social networks (OR: 1.66; 95% CI: 1.04-2.64). This association remained significant even after adjusting for health-related variables.Conclusion: At the onset of the regularization program, access to regularization was not associated with better self-rated health. Policies aiming at favouring undocumented migrants' inclusion and engagement in social networks may promote better health. Future research should investigate long-term effects of residence status regularization on self-rated health. [ABSTRACT FROM AUTHOR]

Background: The optimal revascularization strategy for the elderly with complex coronary artery disease remains unclear.Objectives: The goal of this study was to investigate 10-year all-cause mortality, life expectancy, 5-year major adverse cardiac or cerebrovascular events (MACCE), and 5-year quality of life (QOL) after percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) in elderly individuals (>70 years old) with 3-vessel disease (3VD) and/or left main disease (LMD).Methods: In the present pre-specified analysis on age of the SYNTAX Extended Survival study, 10-year all-cause death and 5-year MACCE were compared with Kaplan-Meier estimates and Cox proportional hazards models among elderly or nonelderly patients. Life expectancy was estimated by restricted mean survival time within 10 years, and QOL status according to the Seattle Angina Questionnaire up to 5 years was assessed by linear mixed-effects models.Results: Among 1,800 randomized patients, 575 patients (31.9%) were elderly. Ten-year mortality did not differ significantly between PCI and CABG in elderly (44.1% vs. 41.1%; hazard ratio [HR]: 1.08; 95% confidence interval [CI]: 0.84 to 1.40) and nonelderly patients (21.1% vs. 16.6%; HR: 1.30; 95% CI: 1.00 to 1.69; pinteraction = 0.332). Among elderly patients, 5-year MACCE was comparable between PCI and CABG (39.4% vs. 35.1%; HR: 1.18; 95% CI: 0.90 to 1.56), whereas it was significantly higher in PCI over CABG among nonelderly patients (36.3% vs. 23.0%; HR: 1.69; 95% CI: 1.36 to 2.10; pinteraction = 0.043). There were no significant difference in life expectancy (mean difference: 0.2 years in favor of CABG; 95% CI: -0.4 to 0.7) and 5-year QOL status between PCI and CABG among elderly patients.Conclusions: Elderly patients with 3VD and/or LMD had comparable 10-year all-cause death, life expectancy, 5-year MACCE, and 5-year QOL status irrespective of revascularization mode. (Synergy Between PCI With TAXUS and Cardiac Surgery: SYNTAX Extended Survival [SYNTAXES]; NCT03417050) (SYNTAX Study: TAXUS Drug-Eluting Stent Versus Coronary Artery Bypass Surgery for the Treatment of Narrowed Arteries [SYNTAX]; NCT00114972). [ABSTRACT FROM AUTHOR]

Background: Smoking, obesity and alcohol abuse greatly affect mortality and exhibit a distinct time dynamic, with their prevalence and associated mortality rates increasing and (eventually) declining over time. Their combined impact on secular trends in life expectancy is unknown but is relevant for understanding these trends. We therefore estimate the combined impact of smoking, obesity and alcohol on life-expectancy trends in Europe.Methods: We used estimated national age-specific smoking-, obesity- and alcohol-attributable mortality fractions for 30 European countries by sex, 1990-2014, which we aggregated multiplicatively to obtain lifestyle-attributable mortality. We estimated potential gains in life expectancy by eliminating lifestyle-attributable mortality and compared past trends in life expectancy at birth (e0) with and without lifestyle-attributable mortality. We examined all countries combined, by region and individually.Results: Among men, the combined impact of smoking, obesity and alcohol on e0 declined from 6.6 years in 1990 to 5.8 years in 2014, mainly due to declining smoking-attributable mortality. Among women, the combined impact increased from 1.9 to 2.3 years due to mortality increases in all three lifestyle-related factors. The observed increase in e0 over the 1990-2014 period was 5.0 years for men and 4.0 years for women. After excluding lifestyle-attributable mortality, this increase would have been 4.2-4.3 years for both men and women.Conclusion: Without the combined impact of smoking, obesity and alcohol, the increase over time in life expectancy at birth would have been smaller among men but larger among women, resulting in a stable increase in e0, parallel for men and women. [ABSTRACT FROM AUTHOR]

Background: Migrants present high rates of psychosis. A better understanding of this phenomenon is needed. Methods: We conducted a multicentre First-Episode Psychosis (FEP) prospective study over two years (January 2012–December 2013) to evaluate first-generation migrants presenting with FEP at the participating Community Mental Health Centers (CMHCs). Results: 109 FEP migrants were identified. Almost half of them were highly educated, employed and in a stable affective relationship. The average age was 32.8 (± 9.8) years, and the average length of stay in Italy was 8.6 (± 8.8) years. About 2/3 of patients were referred to CMHCs following Emergency Department access or psychiatric admission. Conclusions: Our finding of a "high functioning portrait" of FEP migrants allow us to hypothesize that a high burden of negative psychosocial factors is likely to be needed for the FEP onset. Furtherly, mental health services should implement more appropriate resources and organizational methods to respond to migrants' health needs. [ABSTRACT FROM AUTHOR]

Background: Current techniques for measuring absolute lung volumes rely on bulky and expensive equipment and are complicated to use for the operator and the patient. A novel method for measurement of absolute lung volumes, the MiniBox method, is presented.Research Question: Across a population of patients and healthy participants, do values for total lung capacity (TLC) determined by the novel compact device (MiniBox, PulmOne Advanced Medical Devices, Ltd.) compare favorably with measurements determined by traditional whole body plethysmography?Study Design and Methods: A total of 266 participants (130 men) and respiratory patients were recruited from five global centers (three in Europe and two in the United States). The study population comprised individuals with obstructive (n = 197) and restrictive (n = 33) disorders as well as healthy participants (n = 36). TLC measured by conventional plethysmography (TLCPleth) was compared with TLC measured by the MiniBox (TLCMB).Results: TLC values ranged between 2.7 and 10.9 L. The normalized root mean square difference (NSD) between TLCPleth and TLCMB was 7.0% in healthy participants. In obstructed patients, the NSD was 7.9% in mild obstruction and 9.1% in severe obstruction. In restricted patients, the NSD was 7.8% in mild restriction and 13.9% in moderate and severe restriction. No significant differences were found between TLC values obtained by the two measurement techniques. Also no significant differences were found in results obtained among the five centers.Interpretation: TLC as measured by the novel MiniBox system is not significantly different from TLC measured by conventional whole body plethysmography, thus validating the MiniBox method as a reliable method to measure absolute lung volumes. [ABSTRACT FROM AUTHOR]

Purpose: We compared a restrictive fluid management strategy to usual care among critically ill patients with acute kidney injury (AKI) who had received initial fluid resuscitation.Methods: This multicenter feasibility trial randomized 100 AKI patients 1:1 in seven ICUs in Europe and Australia. Restrictive fluid management included targeting negative or neutral daily fluid balance by minimizing fluid input and/or enhancing urine output with diuretics administered at the discretion of the clinician. Fluid boluses were administered as clinically indicated. The primary endpoint was cumulative fluid balance 72 h from randomization.Results: Mean (SD) cumulative fluid balance at 72 h from randomization was - 1080 mL (2003 mL) in the restrictive fluid management arm and 61 mL (3131 mL) in the usual care arm, mean difference (95% CI) - 1148 mL (- 2200 to - 96) mL, P = 0.033. Median [IQR] duration of AKI was 2 [1-3] and 3 [2-7] days, respectively (median difference - 1.0 [- 3.0 to 0.0], P = 0.071). Altogether, 6 out of 46 (13%) patients in the restrictive fluid management arm and 15 out of 50 (30%) in the usual care arm received renal replacement therapy (RR 0.42; 95% CI 0.16-0.91), P = 0.043. Cumulative fluid balance at 24 h and 7 days was lower in the restrictive fluid management arm. The dose of diuretics was not different between the groups. Adverse events occurred more frequently in the usual care arm.Conclusions: In critically ill patients with AKI, a restrictive fluid management regimen resulted in lower cumulative fluid balance and less adverse events compared to usual care. Larger trials of this intervention are justified. [ABSTRACT FROM AUTHOR]

Background: There are limited data available on regional differences in the diagnosis and management of narcolepsy. In order to better understand worldwide trends in clinical assessment and management of narcolepsy, a survey of health-care providers was conducted by the World Sleep Society Narcolepsy task force.Methods: A total of 146 surveys that included items on the diagnosis and management of narcolepsy were completed by practitioners representing 37 countries.Results: Most of the participants were from Europe, North America, Oceania, Asia and Latin America. A consistent approach to applying the diagnostic criteria of Narcolepsy was documented with the exception of measurement of CSF hypocretin-1, which has limited availability. While the majority of practitioners (58%) reported not using the test, 1% indicated always evaluating CSF hypocretin-1 levels. There was much variability in the availability of currently recommended medications such as sodium oxybate and pitolisant; modafinil and antidepressants were the most commonly used medications. Amphetamines were unavailable in some countries.Conclusion: The results of the study highlight clinical and therapeutic realities confronted by worldwide physicians in the management of narcolepsy. While the diagnostic criteria of narcolepsy rely in part on the quantification of CSF hypocretin-1, few physicians reported having incorporated this test into their routine assessment of the condition. Regional differences in the management of narcolepsy appeared to be related to geographic availability and expense of the therapeutic agents. [ABSTRACT FROM AUTHOR]

In 2018, an upsurge in echovirus 30 (E30) infections was reported in Europe. We conducted a large-scale epidemiologic and evolutionary study of 1,329 E30 strains collected in 22 countries in Europe during 2016-2018. Most E30 cases affected persons 0-4 years of age (29%) and 25-34 years of age (27%). Sequences were divided into 6 genetic clades (G1-G6). Most (53%) sequences belonged to G1, followed by G6 (23%), G2 (17%), G4 (4%), G3 (0.3%), and G5 (0.2%). Each clade encompassed unique individual recombinant forms; G1 and G4 displayed >2 unique recombinant forms. Rapid turnover of new clades and recombinant forms occurred over time. Clades G1 and G6 dominated in 2018, suggesting the E30 upsurge was caused by emergence of 2 distinct clades circulating in Europe. Investigation into the mechanisms behind the rapid turnover of E30 is crucial for clarifying the epidemiology and evolution of these enterovirus infections. [ABSTRACT FROM AUTHOR]

Study Question: Does the presence of single nucleotide polymorphisms (SNPs) in the FSH receptor gene (FSHR) and/or FSH beta subunit-encoding gene (FSHB) influence ovarian response in predicted normal responders treated with rFSH?Summary Answer: The presence of FSHR SNPs (rs6165, rs6166, rs1394205) has a statistically significant impact in ovarian response, although this effect is of minimal clinical relevance in predicted normal responders treated with a fixed dose of 150 IU rFSH.What Is Known Already: Ovarian reserve markers have been a breakthrough in response prediction following ovarian stimulation. However, a significant percentage of patients show a disproportionate lower ovarian response, as compared with their actual ovarian reserve. Studies on pharmacogenetics have demonstrated a relationship between FSHR or FSHB genotyping and drug response, suggesting a potential effect of individual genetic variability on ovarian stimulation. However, evidence from these studies is inconsistent, due to the inclusion of patients with variable ovarian reserve, use of different starting gonadotropin doses, and allowance for dose adjustments during treatment. This highlights the necessity of a well-controlled prospective study in a homogenous population treated with the same fixed protocol.Study Design, Size, Duration: We conducted a multicenter multinational prospective study, including 368 patients from Vietnam, Belgium, and Spain (168 from Europe and 200 from Asia), from November 2016 until June 2019. All patients underwent ovarian stimulation followed by oocyte retrieval in an antagonist protocol with a fixed daily dose of 150 IU rFSH until triggering. Blood sampling and DNA extraction was performed prior to oocyte retrieval, followed by genotyping of four SNPs from FSHR (rs6165, rs6166, rs1394205) and FSHB (rs10835638).Participants/materials, Setting, Methods: Eligible were predicted normal responder women <38 years old undergoing their first or second ovarian stimulation cycle. Laboratory staff and clinicians were blinded to the clinical results and genotyping, respectively. The prevalence of hypo-responders, the number of oocytes retrieved, the follicular output rate (FORT), and the follicle to oocyte index (FOI) were compared between different FSHR and FSHB SNPs genotypes.Main Results and the Role Of Chance: The prevalence of derived allele homozygous SNPs in the FSHR was rs6166 (genotype G/G) 15.8%, rs6165 (genotype G/G) 34.8%, and rs1394205 (genotype A/A) 14.1%, with significant differences between Caucasian and Asian women (P < 0.001). FSHB variant rs10835638 (c.-211 G>T) was very rare (0.5%). Genetic model analysis revealed that the presence of the G allele in FSHR variant rs6166 resulted in less oocytes retrieved when compared to the AA genotype (13.54 ± 0.46 vs 14.81 ± 0.61, estimated mean difference (EMD) -1.47 (95% CI -2.82 to -0.11)). In FSHR variant rs1394205, a significantly lower number of oocytes was retrieved in patients with an A allele when compared to G/G (13.33 ± 0.41 vs 15.06 ± 0.68, EMD -1.69 (95% CI -3.06 to -0.31)). A significantly higher prevalence of hypo-responders was found in patients with the genotype A/G for FSHR variant rs6166 (55.9%, n = 57) when compared to A/A (28.4%, n = 29), ORadj 1.87 (95% CI 1.08-3.24). No significant differences were found regarding the FORT across the genotypes for FSHR variants rs6166, rs6165, or rs1394205. Regarding the FOI, the presence of the G allele for FSHR variant rs6166 resulted in a lower FOI when compared to the A/A genotype, EMD -13.47 (95% CI -22.69 to -4.24). Regarding FSHR variant rs6165, a lower FOI was reported for genotype A/G (79.75 ± 3.35) when compared to genotype A/A (92.08 ± 6.23), EMD -13.81 (95% CI -25.41 to -2.21).Limitations, Reasons For Caution: The study was performed in relatively young women with normal ovarian reserve to eliminate biases related to age-related fertility decline; thus, caution is needed when extrapolating results to older populations. In addition, no analysis was performed for FSHB variant rs10835638 due to the very low prevalence of the genotype T/T (n = 2).Wider Implications Of the Findings: Based on our results, genotyping FSHR SNPs rs6165, rs6166, rs1394205, and FSHB SNP rs10835638 prior to initiating an ovarian stimulation with rFSH in predicted normal responders should not be recommended, taking into account the minimal clinical impact of such information in this population. Future research may focus on other populations and other genes related to folliculogenesis or steroidogenesis.Study Funding/competing Interest(s): This study was supported by an unrestricted grant by Merck Sharp & Dohme (MSD). N.P.P. reports grants and/or personal fees from MSD, Merck Serono, Roche Diagnostics, Ferring International, Besins Healthcare, Gedeon Richter, Theramex, and Institut Biochimique SA (IBSA). N.L.V. and M.T.H. report consultancy and conference fees from Merck, Ferring, and MSD, outside the submitted work. P.D. has received honoraria for lecturing and/or research grants from MSD, Ferring International, and Merck. D.S. reports grants and/or personal fees from MSD, Ferring International, Merck Serono, Cook, and Gedeon Richter. A.R.N., B.A.M., C.S., J.M., L.H.L., P.Q.M.M., H.T., and S.G. report no conflict of interests.Trial Registration Number: NCT03007043. [ABSTRACT FROM AUTHOR]

Study Question: How many twins are born in human populations and how has this changed over recent decades?Summary Answer: Since the 1980s, the global twinning rate has increased by a third, from 9.1 to 12.0 twin deliveries per 1000 deliveries, to about 1.6 million twin pairs each year.What Is Known Already: It was already known that in the 1980s natural twinning rates were low in (East) Asia and South America, at an intermediate level in Europe and North America, and high in many African countries. It was also known that in recent decades, twinning rates have been increasing in the wealthier parts of our world as a result of the rise in medically assisted reproduction (MAR) and delayed childbearing.Study Design, Size, Duration: We have brought together all information on national twinning rates available from statistical offices, demographic research institutes, individual survey data and the medical literature for the 1980-1985 and the 2010-2015 periods.Participants/materials, Setting, Methods: For 165 countries, covering over 99% of the global population, we were able to collect or estimate twinning rates for the 2010-2015 period. For 112 countries, we were also able to obtain twinning rates for 1980-1985.Main Results and the Role Of Chance: Substantial increases in twinning rates were observed in many countries in Europe, North America and Asia. For 74 out of 112 countries the increase was more than 10%. Africa is still the continent with highest twinning rates, but Europe, North America and Oceania are catching up rapidly. Asia and Africa are currently home to 80% of all twin deliveries in the world.Limitations, Reasons For Caution: For some countries, data were derived from reports and papers based on hospital registrations which are less representative for the country as a whole than data based on public administrations and national surveys.Wider Implications Of the Findings: The absolute and relative number of twins for the world as a whole is peaking at an unprecedented level. An important reason for this is the tremendous increase in medically assisted reproduction in recent decades. This is highly relevant, as twin deliveries are associated with higher infant and child mortality rates and increased complications for mother and child during pregnancy and during and after delivery.Study Funding/competing Interest(s): The contribution of CM was partially supported by the European Research Council (ERC) under the European Union's Horizon 2020 Research and Innovation Programme (grant No 681546, FAMSIZEMATTERS), Nuffield College, and the Leverhulme Trust. The contribution of GP was partially supported by the French Agence Nationale de la Recherche (grant No ANR-18-CE36-0007-07). The authors declare no conflict of interest.Trial Registration Number: N/A. [ABSTRACT FROM AUTHOR]

Background: Insufficiently treated pain after paediatric appendectomy and tonsillectomy is frequent. We aimed to identify variables associated with poor patient-reported outcomes.Methods: This analysis derives from the European PAIN OUT infant registry providing information on perioperative pharmacological data and patient-reported outcomes 24 h after surgery. Variables associated with the endpoint 'desire for more pain treatment' were evaluated by elastic net regularisation (odds ratio [95% confidence interval]).Results: Data from children undergoing appendectomy (n=472) and tonsillectomy (n=466) between 2015 and 2019 were analysed. Some 24.8% (appendectomy) and 20.2% (tonsillectomy) wished they had received more pain treatment in the 24 h after surgery. They reported higher composite pain scores (5.2 [4.8-5.5] vs 3.6 [3.5-3.8]), more pain-related interference, and more adverse events than children not desiring more pain treatment, and they received more opioids after surgery (morphine equivalents (81 [60-102] vs 50 [43-56] μg kg-1). Regression analysis revealed that pain-related sleep disturbance (appendectomy odds ratio: 2.8 [1.7-4.6], tonsillectomy 3.7 [2.1-6.5]; P<0.001) and higher pain intensities (1.5-fold increase) increased the probability of desiring more pain treatment. There was an inverse association between the number of different classes of non-opioids administered preventively, and the desire for more analgesics postoperatively. Children not receiving any non-opioid analgesics before the end of a tonsillectomy had a 3.5-fold (2.1-6.5-fold) increase in the probability of desiring more pain treatment, compared with children receiving at least two classes of different non-opioid analgesics.Conclusions: Preventive administration of at least two classes of non-opioid analgesics is a simple strategy and may improve patient-reported outcomes. [ABSTRACT FROM AUTHOR]

Background: Neonates and infants requiring anaesthesia are at risk of physiological instability and complications, but triggers for peri-anaesthetic interventions and associations with subsequent outcome are unknown.Methods: This prospective, observational study recruited patients up to 60 weeks' postmenstrual age undergoing anaesthesia for surgical or diagnostic procedures from 165 centres in 31 European countries between March 2016 and January 2017. The primary aim was to identify thresholds of pre-determined physiological variables that triggered a medical intervention. The secondary aims were to evaluate morbidities, mortality at 30 and 90 days, or both, and associations with critical events.Results: Infants (n=5609) born at mean (standard deviation [sd]) 36.2 (4.4) weeks postmenstrual age (35.7% preterm) underwent 6542 procedures within 63 (48) days of birth. Critical event(s) requiring intervention occurred in 35.2% of cases, mainly hypotension (>30% decrease in blood pressure) or reduced oxygenation (SpO2 <85%). Postmenstrual age influenced the incidence and thresholds for intervention. Risk of critical events was increased by prior neonatal medical conditions, congenital anomalies, or both (relative risk [RR]=1.16; 95% confidence interval [CI], 1.04-1.28) and in those requiring preoperative intensive support (RR=1.27; 95% CI, 1.15-1.41). Additional complications occurred in 16.3% of patients by 30 days, and overall 90-day mortality was 3.2% (95% CI, 2.7-3.7%). Co-occurrence of intraoperative hypotension, hypoxaemia, and anaemia was associated with increased risk of morbidity (RR=3.56; 95% CI, 1.64-7.71) and mortality (RR=19.80; 95% CI, 5.87-66.7).Conclusions: Variability in physiological thresholds that triggered an intervention, and the impact of poor tissue oxygenation on patient's outcome, highlight the need for more standardised perioperative management guidelines for neonates and infants.Clinical Trial Registration: NCT02350348. [ABSTRACT FROM AUTHOR]

Background: Neonates and infants are susceptible to hypoxaemia in the perioperative period. The aim of this study was to analyse interventions related to anaesthesia tracheal intubations in this European cohort and identify their clinical consequences.Methods: We performed a secondary analysis of tracheal intubations of the European multicentre observational trial (NEonate and Children audiT of Anaesthesia pRactice IN Europe [NECTARINE]) in neonates and small infants with difficult tracheal intubation. The primary endpoint was the incidence of difficult intubation and the related complications. The secondary endpoints were the risk factors for severe hypoxaemia attributed to difficult airway management, and 30 and 90 day outcomes.Results: Tracheal intubation was planned in 4683 procedures. Difficult tracheal intubation, defined as two failed attempts of direct laryngoscopy, occurred in 266 children (271 procedures) with an incidence (95% confidence interval [CI]) of 5.8% (95% CI, 5.1-6.5). Bradycardia occurred in 8% of the cases with difficult intubation, whereas a significant decrease in oxygen saturation (SpO2<90% for 60 s) was reported in 40%. No associated risk factors could be identified among co-morbidities, surgical, or anaesthesia management. Using propensity scoring to adjust for confounders, difficult anaesthesia tracheal intubation did not lead to an increase in 30 and 90 day morbidity or mortality.Conclusions: The results of the present study demonstrate a high incidence of difficult tracheal intubation in children less than 60 weeks post-conceptual age commonly resulting in severe hypoxaemia. Reassuringly, the morbidity and mortality at 30 and 90 days was not increased by the occurrence of a difficult intubation event.Clinical Trial Registration: NCT02350348. [ABSTRACT FROM AUTHOR]

Objectives: Our study aimed to compare the clinical severity of lower respiratory tract infections (LRTI's) caused by Influenza and Respiratory Syncytial Virus (RSV). Methods: We conducted a retrospective cohort study of LRTI admissions with positive PCR results for Influenza or RSV from 2017 to 2019 in three teaching hospitals in southern Europe. Data on clinical characteristics, viral agents and disease outcome were collected. Nosocomial infection was excluded. Main outcomes were invasive mechanical ventilation and in-hospital death. Results: A total of 984 patients were included. Median age was 75 years. Influenza A was the most frequently identified virus (56.5%), of which 27.1% were subtype H1N1 and 53.0% H3N2. Influenza B was isolated in 22.3% and RSV in 21.0%. There were 10.5% of patients who died during admission and 8.3% submitted to IMV. Influenza A H1N1 was associated with lower age and less co-morbidity, while the opposite was observed for RSV. Influenza A H1N1 was independently associated with both higher risk of death (adjusted odds ratio 2.0 [1.2–3.4] p = 0.008) and IMV (adjusted odds ratio 5.1 [3.0–8.5] p < 0.001). Conclusion: Influenza A H1N1 was an independent predictor of mortality and IMV. These findings may have implications on hospital resource planning and vaccination policies. [ABSTRACT FROM AUTHOR]

Objective: To describe the radiographic phenotype of axial spondyloarthritis (SpA) according to the presence of HLA-B27.Methods: An international collaboration compared the radiographic phenotype of axial SpA according to HLA-B27 status. Patients with ankylosing spondylitis (AS) and axial psoriatic arthritis (PsA) were collected. Radiographs were read centrally, blinded to clinical details. The symmetry of the sacroiliac joints and lumbar syndesmophytes and the morphology of syndesmophytes (typical marginal versus atypical chunky), together with the modified Stoke Ankylosing Spondylitis Spine Score and the Psoriatic Arthritis Spondylitis Radiographic Index, were recorded.Results: A total of 244 patients with PsA and 198 patients with AS were included. In PsA, 60 patients (25%) were HLA-B27 positive while in AS, 148 patients (75%) were HLA-B27 positive. Patients with HLA-B27 were younger and more often male and had a longer duration of disease. In multivariable logistic regression, HLA-B27 was significantly associated with syndesmophyte symmetry (odds ratio [OR] 3.02 [95% confidence interval (95% CI) 1.38, 6.61]) and marginal syndesmophytes (OR 1.97 [95% CI 1.16, 3.36]) but not with sacroiliac symmetry. Mean radiographic scores were higher for patients with HLA-B27.Conclusion: Patients with axial SpA who are positive for HLA-B27 have more severe radiographic damage, more marginal syndesmophytes, and more frequent syndesmophyte symmetry compared to patients who are negative for HLA-B27. [ABSTRACT FROM AUTHOR]

Background: We investigated whether associations between prevalent diabetes and cancer risk are pertinent to older adults and whether associations differ across subgroups of age, body weight status or levels of physical activity.Methods: We harmonised data from seven prospective cohort studies of older individuals in Europe and the United States participating in the CHANCES consortium. Cox proportional hazard regression was used to estimate the associations of prevalent diabetes with cancer risk (all cancers combined, and for colorectum, prostate and breast). We calculated summary risk estimates across cohorts using pooled analysis and random-effects meta-analysis.Results: A total of 667,916 individuals were included with an overall median (P25-P75) age at recruitment of 62.3 (57-67) years. During a median follow-up time of 10.5 years, 114,404 total cancer cases were ascertained. Diabetes was not associated with the risk of all cancers combined (hazard ratio (HR) = 0.94; 95% confidence interval (CI): 0.86-1.04; I2 = 63.3%). Diabetes was positively associated with colorectal cancer risk in men (HR = 1.17; 95% CI: 1.08-1.26; I2 = 0%) and a similar HR in women (1.13; 95% CI: 0.82-1.56; I2 = 46%), but with a confidence interval including the null. Diabetes was inversely associated with prostate cancer risk (HR = 0.81; 95% CI: 0.77-0.85; I2 = 0%), but not with postmenopausal breast cancer (HR = 0.96; 95% CI: 0.89-1.03; I2 = 0%). In exploratory subgroup analyses, diabetes was inversely associated with prostate cancer risk only in men with overweight or obesity.Conclusions: Prevalent diabetes was positively associated with colorectal cancer risk and inversely associated with prostate cancer risk in older Europeans and Americans. [ABSTRACT FROM AUTHOR]

Background: The European Friedreich's Ataxia Consortium for Translational Studies (EFACTS) investigates the natural history of Friedreich's ataxia. We aimed to assess progression characteristics and to identify patient groups with differential progression rates based on longitudinal 4-year data to inform upcoming clinical trials in Friedreich's ataxia.Methods: EFACTS is a prospective, observational cohort study based on an ongoing and open-ended registry. Patients with genetically confirmed Friedreich's ataxia were seen annually at 11 clinical centres in seven European countries (Austria, Belgium, France, Germany, Italy, Spain, and the UK). Data from baseline to 4-year follow-up were included in the current analysis. Our primary endpoints were the Scale for the Assessment and Rating of Ataxia (SARA) and the activities of daily living (ADL). Linear mixed-effect models were used to analyse annual disease progression for the entire cohort and subgroups defined by age of onset and ambulatory abilities. Power calculations were done for potential trial designs. This study is registered with ClinicalTrials.gov, NCT02069509.Findings: Between Sept 15, 2010, and Nov 20, 2018, of 914 individuals assessed for eligibility, 602 patients were included. Of these, 552 (92%) patients contributed data with at least one follow-up visit. Annual progression rate for SARA was 0·82 points (SE 0·05) in the overall cohort, and higher in patients who were ambulatory (1·12 [0·07]) than non-ambulatory (0·50 [0·07]). ADL worsened by 0·93 (SE 0·05) points per year in the entire cohort, with similar progression rates in patients who were ambulatory (0·94 [0·07]) and non-ambulatory (0·91 [0·08]). Although both SARA and ADL showed slightly greater worsening in patients with typical onset (symptom onset at ≤24 years) than those with late onset (symptom onset ≥25 years), differences in progression slopes were not significant. For a 2-year parallel-group trial, 230 (115 per group) patients would be required to detect a 50% reduction in SARA progression at 80% power: 118 (59 per group) if only individuals who are ambulatory are included. With ADL as the primary outcome, 190 (95 per group) patients with Friedreich's ataxia would be needed, and fewer patients would be required if only individuals with early-onset are included.Interpretation: Our findings for stage-dependent progression rates have important implications for clinicians and researchers, as they provide reliable outcome measures to monitor disease progression, and enable tailored sample size calculation to guide upcoming clinical trial designs in Friedreich's ataxia.Funding: European Commission, Voyager Therapeutics, and EuroAtaxia. [ABSTRACT FROM AUTHOR]