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Background Age-related changes in frailty have been documented in the literature. However, the evidence regarding changes in frailty prior to death is scarce. Understanding patterns of frailty progression as individuals approach death could inform care and potentially lead to interventions to improve individual’s well-being at the end of life. In this paper, we estimate the progression of frailty in the years prior to death. Methods Using data from 8,317 deceased participants of the Survey of Health, Ageing, and Retirement in Europe, we derived a 56-item Frailty Index. In a coordinated analysis of repeated measures of the frailty index in 14 countries, we fitted growth curve models to estimate trajectories of frailty as a function of distance to death controlling both the level and rate of frailty progression for age, sex, years to death and dementia diagnosis. Results Across all countries, frailty before death progressed linearly. In 12 of the 14 countries included in our analyses, women had higher levels of frailty close to the time of death, although they progressed at a slower rate than men (e.g. Switzerland (-0.008, SE = 0.003) and Spain (-0.004, SE = 0.002)). Older age at the time of death and incident dementia were associated with higher levels and increased rate of change in frailty, whilst higher education was associated with lower levels of frailty in the year preceding death (e.g. Denmark (0.000, SE = 0.001)). Conclusion The progression of frailty before death was linear. Our results suggest that interventions aimed at slowing frailty progression may need to be different for men and women. Further longitudinal research on individual patterns and changes of frailty is warranted to support the development of personalized care pathways at the end of life.

Keenan A Ramsey,1 Suey SY Yeung,1 Anna GM Rojer,1 Noémie Gensous,2 Evans A Asamane,3 Justin Avery Aunger,3 Dmitriy Bondarev,4 Andrea Cabbia,5 Paul Doody,3 Barbara Iadarola,6,7 Belina Rodrigues,8,9 Muhammad R Tahir,10 Victor Kallen,10 Paola Pazienza,6,7 Nadine Correia Santos,8,9 Sarianna Sipilä,4 Janice L Thompson,3 Carel GM Meskers,1,11 Marijke C Trappenburg,12,13 Anna C Whittaker,15 Andrea B Maier1,14,16,17 1Department of Human Movement Sciences, @AgeAmsterdam, Amsterdam Movement Sciences, Vrije Universiteit, Faculty of Behavioural and Human Movement Sciences, Amsterdam, the Netherlands; 2Department of Experimental, Diagnostic, and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy; 3School of Sport, Exercise & Rehabilitation Sciences, University of Birmingham, Birmingham, UK; 4Gerontology Research Center & Faculty of Sport and Health Sciences, University of Jyväskylä, Jyväskylä, Finland; 5Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, the Netherlands; 6Personal Genomics s.r.l., Verona, Italy; 7Department of Biotechnology, University of Verona, Verona, Italy; 8Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal; 9ICVS/3B’s, PT Government Associate Laboratory, Guimarães, Portugal; 10Department of Microbiology and System Biology, The Netherlands Organization for Applied Scientific Research, Zeist, the Netherlands; 11Department of Rehabilitation Medicine, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands; 12Department of Internal Medicine, Section of Gerontology and Geriatrics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands; 13Department of Internal Medicine, Amstelland Hospital, Amstelveen, the Netherlands; 14Department of Medicine and Aged Care, @Age, The University of Melbourne, The Royal Melbourne Hospital, Parkville, Victoria, Australia; 15Faculty of Health Sciences and Sport, University of Stirling, Scotland, UK; 16Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; 17Centre for Healthy Longevity, @AgeSingapore, National University Health System, SingaporeCorrespondence: Andrea B Maier, Department of Human Movement Sciences, @AgeAmsterdam, Amsterdam Movement Sciences, Vrije Universiteit, Faculty of Behavioural and Human Movement Sciences, Van der Boechorststraat 7, Amsterdam, 1081 BT, the Netherlands, Tel +31 20 59 82000, Email a.b.maier@vu.nlPurpose: Evidence-based guidelines on nutrition and physical activity are used to increase knowledge in order to promote a healthy lifestyle. However, actual knowledge of guidelines is limited and whether it is associated with health outcomes is unclear.Participants and Methods: This inception cohort study aimed to investigate the association of knowledge of nutrition and physical activity guidelines with objective measures of physical function and physical activity in community-dwelling older adults attending a public engagement event in Amsterdam, The Netherlands. Knowledge of nutrition and physical activity according to Dutch guidelines was assessed using customized questionnaires. Gait speed and handgrip strength were proxies of physical function and the Minnesota Leisure Time Physical Activity Questionnaire was used to assess physical activity in minutes/week. Linear regression analysis, stratified by gender and adjusted for age, was used to study the association between continuous and categorical knowledge scores with outcomes.Results: In 106 older adults (mean age=70.1 SD=6.6, years) who were highly educated, well-functioning, and generally healthy, there were distinct knowledge gaps in nutrition and physical activity which did not correlate with one another (R2=0.013, p=0.245). Knowledge of nutrition or physical activity guidelines was not associated with physical function or physical activity. However, before age-adjustment nutrition knowledge was positively associated with HGS in males (B= 0.64 (95% CI: 0.05, 1.22)) and having knowledge above the median was associated with faster gait speed in females (B=0.10 (95% CI: 0.01, 0.19)).Conclusion: Our findings may represent a ceiling effect of the impact knowledge has on physical function and activity in the this high performing and educated population and that there may be other determinants of behavior leading to health status such as attitude and perception to consider in future studies.Keywords: health knowledge, attitudes, practice, lifestyle, physical performance, aged

Background: In the Netherlands, treatment with puberty suppression is available to transgender adolescents younger than age 18 years. When gender dysphoria persists testosterone or oestradiol can be added as gender-affirming hormones in young people who go on to transition. We investigated the proportion of people who continued gender-affirming hormone treatment at follow-up after having started puberty suppression and gender-affirming hormone treatment in adolescence. Methods: In this cohort study, we used data from the Amsterdam Cohort of Gender dysphoria (ACOG), which included people who visited the gender identity clinic of the Amsterdam UMC, location Vrije Universiteit Medisch Centrum, Netherlands, for gender dysphoria. People with disorders of sex development were not included in the ACOG. We included people who started medical treatment in adolescence with a gonadotropin-releasing hormone agonist (GnRHa) to suppress puberty before the age of 18 years and used GnRHa for a minimum duration of 3 months before addition of gender-affirming hormones. We linked this data to a nationwide prescription registry supplied by Statistics Netherlands (Centraal Bureau voor de Statistiek) to check for a prescription for gender-affirming hormones at follow-up. The main outcome of this study was a prescription for gender-affirming hormones at the end of data collection (Dec 31, 2018). Data were analysed using Cox regression to identify possible determinants associated with a higher risk of stopping gender-affirming hormone treatment. Findings: 720 people were included, of whom 220 (31%) were assigned male at birth and 500 (69%) were assigned female at birth. At the start of GnRHa treatment, the median age was 14·1 (IQR 13·0–16·3) years for people assigned male at birth and 16·0 (14·1–16·9) years for people assigned female at birth. Median age at end of data collection was 20·2 (17·9–24·8) years for people assigned male at birth and 19·2 (17·8–22·0) years for those assigned female at birth. 704 (98%) people who had started gender-affirming medical treatment in adolescence continued to use gender-affirming hormones at follow-up. Age at first visit, year of first visit, age and puberty stage at start of GnRHa treatment, age at start of gender-affirming hormone treatment, year of start of gender-affirming hormone treatment, and gonadectomy were not associated with discontinuing gender-affirming hormones. Interpretation: Most participants who started gender-affirming hormones in adolescence continued this treatment into adulthood. The continuation of treatment is reassuring considering the worries that people who started treatment in adolescence might discontinue gender-affirming treatment. Funding: None.

purpose Loneliness in adults increases with age. Although loneliness has been found to be associated with psychiatric disorders and dementia, no information is available on prevalence of loneliness in older psychiatric patients. The aims of this study were to examine prevalence of loneliness in older psychiatric outpatients, including gender differences and associations with psychiatric disorders and social isolation. Methods Cross-sectional study in an outpatient clinic for geriatric psychiatry between September 2013 and February 2018. Interviews were done in 181 patients. Results 80% of participants were lonely. Loneliness was associated with having contacts in less social network domains, in women but not in men. There were no associations with DSM-IV-TR-classifications. However, loneliness was associated with higher scores on questionnaires for depression and cognitive function. Intensity of treatment did not differ significantly between lonely and non-lonely participants. Conclusion Loneliness is highly prevalent in older psychiatric outpatients, with men and women equally affected. Loneliness should be assessed in all older psychiatric patients, especially when they show high scores on symptom checklists or have a restricted social network.

Understanding and communicating the risk of pregnancy complications post-living kidney donation is imperative as the majority of living kidney donors (LKD) are women of childbearing age. We aimed to identify all original research articles examining complications in post-donation pregnancies and compared the quality and consistency of related guidelines. We searched Embase, MEDLINE, PubMed, society webpages, and guideline registries for English-language publications published up until December 18, 2020. Ninety-three articles were screened from which 16 studies were identified, with a total of 1399 post-donation pregnancies. The outcome of interest, post-donation pregnancy complications, was not calculable, and only a narrative synthesis of the evidence was possible. The absolute risk of pre-eclampsia increased from similar to 1%-3% pre-donation (lower than the general population) to similar to 4%-10% post-donation (comparable to the general population). The risks of adverse fetal and neonatal outcomes were no different between post-donation and pre-donation pregnancies. Guidelines and consensus statements were consistent in stating the need to inform LKDs of their post-donation pregnancy risk, however, the depth and scope of this guidance were variable. While the absolute risk of pregnancy complications remains low post-donation, a concerted effort is required to better identify and individualize risk in these women, such that consent to donation is truly informed.

Background Employment is important for the quality of life and financial security of patients of working age receiving kidney replacement therapy (KRT). We aimed to examine self-reported work status and general, physical and mental work ability and to determine associations between demographic, disease-related, work-related and macroeconomic factors and employment. Methods Europeans from 37 countries, ages 19–65 years, treated with dialysis or kidney transplantation, filled out the web-based or paper-based cross-sectional EDITH kidney patient survey between November 2017 and January 2019. We performed descriptive analyses and multivariable generalized logistic mixed models. Results Of the 3544 patients, 36.5% were employed and working [25.8% of dialysis patients, 53.9% of kidney transplant recipients (KTRs)]. The mean general work ability was 5.5 out of 10 (dialysis: 4.8, KTRs: 6.5). Non-working patients (all: 4.1, dialysis: 3.9, KTRs: 4.7) scored lower than working patients (all: 7.7, dialysis 7.3, KTRs: 8.0). Working dialysis patients scored lower on physical and mental work ability (7.1 and 8.1) than working KTRs (8.0 and 8.4; P Conclusions Low employment rates and impaired work ability were prevalent among European patients receiving KRT. Demographic, disease-related, work-related and macro-economic factors were associated with employment.

Background: Older adults are particularly prone to the development of poor appetite and undernutrition. Possibly, this is partly due to the aged gut microbiota. We aimed to evaluate the gut microbiota in relation to both poor appetite and undernutrition in community-dwelling older adults. Furthermore, we studied the causal effects of the microbiota on body weight and body composition by transferring faecal microbiota from cohort participants into germ-free mice. Methods: First, we conducted a cross-sectional cohort study of 358 well-phenotyped Dutch community-dwelling older adults from the Longitudinal Aging Study Amsterdam. Data collection included body measurements, a faecal and blood sample, as well as extensive questionnaires on appetite, dietary intake, and nutritional status. Appetite was assessed by the Council of Nutrition Appetite Questionnaire (CNAQ) and undernutrition was defined by either a low body mass index (BMI) (BMI 2 if 2 if ≥70 years) or >5% body weight loss averaged over the last 2 years. Gut microbiota composition was determined with 16S rRNA sequencing. Next, we transferred faecal microbiota from 12 cohort participants with and without low BMI or recent weight loss into a total of 41 germ-free mice to study the potential causal effects of the gut microbiota on host BMI and body composition. Results: The mean age (range) of our cohort was 73 (65–93); 58.4% was male. Seventy-seven participants were undernourished and 21 participants had poor appetite (CNAQ

BackgroundTo explore whether differences between men and women in the sensitivity to (strength of the association) and/or in the exposure to determinants (prevalence) contribute to the difference in physical functioning, with women reporting more limitations.MethodsData of the Doetinchem Cohort Study was used (n = 5856, initial ages 26–70 years), with follow-up measurements every 5 years (up to 20). Physical functioning (subscale SF-36, range:0–100), sex (men or women) and a number of socio-demographic, lifestyle- and health-related determinants were assessed. Mixed-model multivariable analysis was used to investigate differences between men and women in sensitivity (interaction term with sex) and in exposure (change of the sex difference when adjusting) to determinants of physical functioning.ResultsThe physical functioning score among women was 6.55 (95%CI:5.48,7.61) points lower than among men. In general, men and women had similar determinants, but pain was more strongly associated with physical functioning (higher sensitivity), and also more prevalent among women (higher exposure). The higher exposure to low educational level and not having a paid job also contributed to the lower physical functioning score among women. In contrast, current smoking, mental health problems and a low educational level were more strongly associated with a lower physical functioning score among men and lower physical activity and higher BMI were more prevalent among men.ConclusionsAlthough important for physical functioning among both men and women, our findings provide no indications for reducing the difference in physical functioning by promoting a healthy lifestyle but stress the importance of differences in pain, work and education.

BACKGROUND: Health-related Quality of life (HRQoL) in patients with Barrett's esophagus (BE), a premalignant condition, may be influenced by gastroesophageal reflux disease (GERD) symptoms and the risk of developing esophageal adenocarcinoma.METHODS: We aim to investigate HRQoL in non-dysplastic Barrett Esophagus (NDBE) patients, identify factors associated with a negative illness perception of the diagnosis BE and compare outcomes between patients treated in a specialized BE center with non-expert centers. In this multi-center cross-sectional study, HRQoL of NDBE patients were assessed using the Short Form 36, Hospital Anxiety and Depression Scale, Cancer worry Scale, and Reflux Disease Questionnaire. A multivariable, linear regression analysis was conducted to assess factors associated with illness perception (Illness perception scale) of the BE diagnosis. Outcome parameters of patients from expert centers were compared to non-expert centers.RESULTS: A total of 859 NDBE patients (mean age 63.6% and 74.5% male), of which 640 from BE expert centers were included. BE patients scored similar or higher means (i.e. better) on generic HRQoL in comparison with a Dutch norm population. The multivariable regression model showed that cancer worry, GERD symptoms, signs of anxiety and depression, and female gender were associated with a negative illness perception of BE. GERD symptoms were reported in the minority (22.4%) of BE patients. Levels of anxiety symptoms were comparable to a Dutch norm population (mean 3.7 vs. 3.9 p 0.183) and lower for depression symptoms (mean 6.8 vs. 7.6 p < 0.001). Overall, there were no differences found on outcomes between expert centers and non-expert centers.CONCLUSION: NDBE patients scored similar or better on generic HRQoL, anxiety and depression than an age and gender matched norm population. The presence of cancer worry, gastrointestinal symptoms, anxiety and depression, and female gender are factors associated with a negative illness perception of the diagnosis BE.

Contains fulltext : 249039.pdf (Publisher’s version ) (Open Access) Stress initiates a cascade of (neuro)biological, physiological, and behavioral changes, allowing us to respond to a challenging environment. The human response to acute stress can be studied in detail in controlled settings, usually in a laboratory environment. To this end, many studies employ acute stress paradigms to probe stress-related outcomes in healthy and patient populations. Though valuable, these studies in themselves often have relatively limited sample sizes. We established a data-sharing and collaborative interdisciplinary initiative, the STRESS-NL database, which combines (neuro)biological, physiological, and behavioral data across many acute stress studies in order to accelerate our understanding of the human acute stress response in health and disease (www.stressdatabase.eu). Researchers in the stress field from 12 Dutch research groups of 6 Dutch universities created a database to achieve an accurate inventory of (neuro)biological, physiological, and behavioral data from laboratory-based human studies that used acute stress tests. Currently, the STRESS-NL database consists of information on 5529 individual participants (2281 females and 3348 males, age range 6-99 years, mean age 27.7 ± 16 years) stemming from 57 experiments described in 42 independent studies. Studies often did not use the same stress paradigm; outcomes were different and measured at different time points. All studies currently included in the database assessed cortisol levels before, during and after experimental stress, but cortisol measurement will not be a strict requirement for future study inclusion. Here, we report on the creation of the STRESS-NL database and infrastructure to illustrate the potential of accumulating and combining existing data to allow meta-analytical, proof-of-principle analyses. The STRESS-NL database creates a framework that enables human stress research to take new avenues in explorative and hypothesis-driven data analyses with high statistical power. Future steps could be to incorporate new studies beyond the borders of the Netherlands; or build similar databases for experimental stress studies in rodents. In our view, there are major scientific benefits in initiating and maintaining such international efforts. 9 p.

Background: This study aimed to examine the associations of plasma superoxide dismutase (SOD) activity, an indicator of oxidative stress, with disability in activities of daily living (ADL) and objective physical functioning among Chinese older adults. Methods: We used cross-sectional data of 2223 older adults (≥65 years, including 1505 adults≥80 years) from the 2011/2012 main survey of the Chinese Longitudinal Healthy Longevity Survey (CLHLS) and the 2012 biomarker sub-study. Plasma SOD activity was assessed by the T-SOD assay kit based on the hydroxylamine method. Outcomes included ADL disability and disability in three objective physical tasks (standing up from a chair, picking up a book from the floor, and turning around 360°). Logistic regression models were used to examine the associations of plasma SOD activity with outcomes. Results: After controlling for age and sex, compared with participants in the lowest quartile group of SOD activity, those in the highest quartile group had 31% lower odds of ADL disability (odds ratio [OR]: 0.69; 95%CI: 0.48, 0.98); 60% lower odds of disability in standing up from a chair (OR: 0.40; 95%CI: 0.25, 0.63); and 57% lower odds of disability in picking up a book from a floor (OR: 0.43; 95%CI: 0.28, 0.65). The results did not change substantially after controlling for additional covariates. We did not observe statistically significant age and sex differences. Conclusions: Overall, plasma SOD activity was associated with subjectively and objectively measured disability in Chinese older adults, highlighting the potential of SOD activity to serve as a biomarker of physical functioning.

BACKGROUND Although associations between older antiretroviral drug classes and cardiovascular disease in people living with HIV are well described, there is a paucity of data regarding a possible association with integrase strand-transfer inhibitors (INSTIs). We investigated whether exposure to INSTIs was associated with an increased incidence of cardiovascular disease. METHODS RESPOND is a prospective, multicentre, collaboration study between 17 pre-existing European and Australian cohorts and includes more than 32 000 adults living with HIV in clinical care after Jan 1, 2012. Individuals were eligible for inclusion in these analyses if they were older than 18 years, had CD4 cell counts and HIV viral load measurements in the 12 months before or within 3 months after baseline (latest of cohort enrolment or Jan 1, 2012), and had no exposure to INSTIs before baseline. These individuals were subsequently followed up to the earliest of the first cardiovascular disease event (ie, myocardial infarction, stroke, or invasive cardiovascular procedure), last follow-up, or Dec 31, 2019. We used multivariable negative binomial regression to assess associations between cardiovascular disease and INSTI exposure (0 months [no exposure] vs >0 to 6 months, >6 to 12 months, >12 to 24 months, >24 to 36 months, and >36 months), adjusted for cardiovascular risk factors. RESPOND is registered with ClinicalTrials.gov, NCT04090151, and is ongoing. FINDINGS 29 340 people living with HIV were included in these analyses, of whom 7478 (25·5%) were female, 21 818 (74·4%) were male, and 44 (24 to 36 months of exposure). Compared with those with no INSTI exposure, the risk of cardiovascular disease was increased in the first 24 months of INSTI exposure and thereafter decreased to levels similar to those never exposed (>0 to 6 months of exposure: adjusted incidence rate ratio of 1·85 [1·44-2·39]; >6 to 12 months of exposure: 1·19 [0·84-1·68]; >12 to 24 months of exposure: 1·46 [1·13-1·88]; >24 to 36 months of exposure: 0·89 [0·62-1·29]; and >36 months of exposure: 0·96 [0·69-1·33]; p

Objective To evaluate the agreement of hospital physicians and older patients with individualised STOPP/START-based medication optimisation recommendations from a pharmacotherapy team. Methods This study was embedded within a large European, multicentre, cluster randomised controlled trial examining the effect of a structured medication review on drug-related hospital admissions in multimorbid (≥ 3 chronic conditions) older people (≥ 70 years) with polypharmacy (≥ 5 chronic medications), called OPERAM. Data from the Dutch intervention arm of this trial were used for this study. Medication review was performed jointly by a physician and pharmacist (i.e. pharmacotherapy team) supported by a Clinical Decision Support System with integrated STOPP/START criteria. Individualised STOPP/START-based medication optimisation recommendations were discussed with patients and attending hospital physicians. Results 139 patients were included, mean (SD) age 78.3 (5.1) years, 47% male and median (IQR) number of medications at admission 11 (9–14). In total, 371 recommendations were discussed with patients and physicians, overall agreement was 61.6% for STOPP and 60.7% for START recommendations. Highest agreement was found for initiation of osteoporosis agents and discontinuation of proton pump inhibitors (both 74%). Factors associated with higher agreement in multivariate analysis were: female gender (+ 17.1% [3.7; 30.4]), ≥ 1 falls in the past year (+ 15.0% [1.5; 28.5]) and renal impairment i.e. eGFR 30–50 ml/min/1.73 m2; (+ 18.0% [2.0; 34.0]). The main reason for disagreement (40%) was patients’ reluctance to discontinue or initiate medication. Conclusion Better patient and physician education regarding the benefit/risk balance of pharmacotherapy, in addition to more precise and up-to-date medical records to avoid irrelevant recommendations, will likely result in higher adherence with future pharmacotherapy optimisation recommendations. Clinical trial registration Trial Registration Number NCT02986425.

INTRODUCTION: Orthostatic hypotension is a common condition associated with an increased mortality risk. This study investigates this association specifically in geriatric outpatients and additionally focuses on the duration and magnitude of orthostatic hypotension. METHODS: In this observational prospective cohort study with geriatric outpatients from the Amsterdam Ageing cohort, we differentiated orthostatic hypotension in early orthostatic hypotension (EOH) and delayed/prolonged orthostatic hypotension (DPOH). The magnitude of drop in both SBP and DBP after either 1 or 3 min was quantified. Mortality data was obtained from the Dutch municipal register. Cox proportional hazard models were used to determine the association between orthostatic hypotension and mortality, adjusted for sex and age (model 1), additionally adjusted for orthostatic hypotension-inducing drugs + SBP (model 2) and the presence of cardiovascular disease and diabetes (model 3). Stratified analyses in patients with geriatric deficits were performed. RESULTS: We included 1240 patients (mean age 79.4 ± 6.9 years, 52.6% women). Prevalence of orthostatic hypotension was 443 (34.9%); 148 (11.9%) patients had EOH and 285 (23%) DPOH. DPOH was associated with a higher mortality risk [hazard ratio, 95% CI 1.69 (1.28-2.22)] whereas EOH was not associated with mortality risk. This association did not differ in patients with geriatric deficits. Furthermore, the magnitude of drop in both SBP and DBP was associated with a higher mortality risk. CONCLUSION: The presence of DPOH and the magnitude of both systolic and diastolic orthostatic hypotension are related to an increased mortality risk in geriatric outpatients. Whether the duration of orthostatic hypotension and magnitude of the drop in blood pressure is causally related to mortality risk or whether it is a sign of decreased resilience remains to be elucidated.

The use of valve-in-valve transcatheter aortic valve implantation (ViV-TAVI) is increasing, but studies evaluating clinical outcomes in these patients are scarce. Also, there are limited data to guide the choice of valve type in ViV-TAVI. Therefore, this CENTER-study evaluated clinical outcomes in patients with ViV-TAVI compared to patients with native valve TAVI (NV-TAVI). In addition, we compared outcomes in patients with ViV-TAVI treated with self-expandable versus balloon-expandable valves. A total of 256 patients with ViV-TAVI and 11333 patients with NV-TAVI were matched 1:2 using propensity score matching, resulting in 256 patients with ViV-TAVI and 512 patients with NV-TAVI. Mean age was 81 +/- 7 years, 58% were female, and the Society of Thoracic Surgeons Predicted Risk of Mortality was 6.3% (4.0% to 12.8%). Mortality rates were comparable between ViV-TAVI and NV-TAVI patients at 30 days (4.1% vs 5.9%, p = 0.30) and 1 year (14.2% vs 17.3%, p = 0.34). Stroke rates were also similar at 30 days (2.8% vs 1.8%, p = 0.38) and 1 year (4.9% vs 4.3%, p = 0.74). Permanent pacemakers were less frequently implanted in patients with ViV-TAVI (8.8% vs 15.0%, relative risk 0.59, 95% confidence interval [CI] 0.37 to 0.92, p = 0.02). Patients with ViV-TAVI were treated with self-expandable valves (n = 162) and balloon-expandable valves (n = 94). Thirty-day major bleeding was less frequent in patients with self-expandable valves (3% vs 13%, odds ratio 5.12, 95% CI 1.42 to 18.52, p = 0.01). Thirty-day mortality was numerically lower in patients with self-expandable valves (3% vs 7%, odds ratio 3.35, 95% CI 0.77 to 14.51, p = 0.11). In conclusion, ViV-TAVI seems a safe and effective treatment for failing bioprosthetic valves with low mortality and stroke rates comparable to NV-TAVI for both valve types. (C) 2022 The Author(s). Published by Elsevier Inc.

Background: Over the past decade, antiretroviral therapy (ART) regimens that include integrase strand inhibitors (INSTIs) have become the most commonly used for people with HIV starting ART. Although trials and observational studies have compared virological failure on INSTI-based with other regimens, few data are available on mortality in people with HIV treated with INSTIs in routine care. Therefore, we compared all-cause mortality between different INSTI-based and non-INSTI-based regimens in adults with HIV starting ART from 2013 to 2018. Methods: This cohort study used data on people with HIV in Europe and North America from the Antiretroviral Therapy Cohort Collaboration (ART-CC) and UK Collaborative HIV Cohort (UK CHIC). We studied the most common third antiretroviral drugs (additional to nucleoside reverse transcriptase inhibitor) used from 2013 to 2018: rilpivirine, darunavir, raltegravir, elvitegravir, dolutegravir, efavirenz, and others. Adjusted hazard ratios (aHRs; adjusted for clinical and demographic characteristics, comorbid conditions, and other drugs in the regimen) for mortality were estimated using Cox models stratified by ART start year and cohort, with multiple imputation of missing data. Findings: 62 500 ART-naive people with HIV starting ART (12 422 [19·9%] women; median age 38 [IQR 30-48]) were included in the study. 1243 (2·0%) died during 188 952 person-years of follow-up (median 3·0 years [IQR 1·6-4·4]). There was little evidence that mortality rates differed between regimens with dolutegravir, elvitegravir, rilpivirine, darunavir, or efavirenz as the third drug. However, mortality was higher for raltegravir compared with dolutegravir (aHR 1·49, 95% CI 1·15-1·94), elvitegravir (1·86, 1·43-2·42), rilpivirine (1·99, 1·49-2·66), darunavir (1·62, 1·33-1·98), and efavirenz (2·12, 1·60-2·81) regimens. Results were similar for analyses making different assumptions about missing data and consistent across the time periods 2013-15 and 2016-18. Rates of virological suppression were higher for dolutegravir than other third drugs. Interpretation: This large study of patients starting ART since the introduction of INSTIs found little evidence that mortality rates differed between most first-line ART regimens; however, raltegravir-based regimens were associated with higher mortality. Although unmeasured confounding cannot be excluded as an explanation for our findings, virological benefits of first-line INSTIs-based ART might not translate to differences in mortality. We would like to thank our funders (US National Institute on Alcohol Abuse and Alcoholism and UK Medical Research Council) and all patients and the clinical teams associated with the participating cohort studies. The antiretroviral therapy cohort collaboration is funded by the US National Institute on Alcohol Abuse and Alcoholism (U01-AA026209). UK Collaborative HIV Cohort is funded by the UK Medical Research Council (grant numbers G0000199, G0600337, G0900274, and M004236/1). JACS is funded by National Institute for Health Research Senior Investigator award (NF-SI-0611-10168). AT is funded by the Wellcome Trust under a Sir Henry Wellcome Postdoctoral Fellowship (222770/Z/21/Z). Funding for the individual antiretroviral therapy cohort collaboration cohorts included in this analysis was from Alberta Health, Gilead, National Agency for AIDS Research (France REcherche Nord&Sud Sida-hiv Hépatites), the French Ministry of Health, the Austrian Agency for Health and Food Safety, Stichting HIV Monitoring, the Dutch Ministry of Health, Welfare and Sport through the Centre for Infectious Disease Control of the National Institute for Public Health and the Environment, the TP-HIV by the German Centre for Infection Research (NCT02149004), Instituto de Salud Carlos III (through the Red Temática de Investigación Cooperativa en Sida [RD06/006, RD12/0017/0018, and RD16/0002/0006]) as part of the Plan Nacional I + D + i. Other funders of the individual cohorts participating data for this analysis are ISCIII-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional, ViiV Healthcare, Preben og Anna Simonsens Fond, ANRS-Maladies infectieuses émergentes, Institut National de la Santé et de la Recherche Médicale (INSERM), Bristol Myers Squibb, Janssen, Merck, the US National Institute on Alcohol Abuse and Alcoholism (U01-AA026230), the Spanish Ministry of Health, the Swiss National Science Foundation (grant 33CS30_134277), Centers for AIDS Research Network of Integrated Clinical Systems (1R24 AI067039-1, P30-AI-027757), the US Department of Veterans Affairs, the US National Institute on Alcohol Abuse and Alcoholism (U01-AA026224, U01-AA026209, U24-AA020794), the Veterans Health Administration Office of Research and Development, and the US National Institute of Allergy and Infectious Diseases (Tennessee Center for AIDS Research P30 AI110527). Sí

BACKGROUND: Vestibular migraine is a form of migraine where one of the main features is recurrent attacks of vertigo. These episodes are often associated with other features of migraine, including headache and sensitivity to light or sound. These unpredictable and severe attacks of vertigo can lead to a considerable reduction in quality of life. The condition is estimated to affect just under 1% of the population, although many people remain undiagnosed. A number of interventions have been used, or proposed to be used, as prophylaxis for this condition, to help reduce the frequency of the attacks. Many of these interventions include dietary, lifestyle or behavioural changes, rather than medication. OBJECTIVES: To assess the benefits and harms of non-pharmacological treatments used for prophylaxis of vestibular migraine.SEARCH METHODS: The Cochrane ENT Information Specialist searched the Cochrane ENT Register; Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE; Ovid Embase; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 23 September 2022.SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs in adults with definite or probable vestibular migraine comparing dietary modifications, sleep improvement techniques, vitamin and mineral supplements, herbal supplements, talking therapies, mind-body interventions or vestibular rehabilitation with either placebo or no treatment. We excluded studies with a cross-over design, unless data from the first phase of the study could be identified. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were: 1) improvement in vertigo (assessed as a dichotomous outcome - improved or not improved), 2) change in vertigo (assessed as a continuous outcome, with a score on a numerical scale) and 3) serious adverse events. Our secondary outcomes were: 4) disease-specific health-related quality of life, 5) improvement in headache, 6) improvement in other migrainous symptoms and 7) other adverse effects. We considered outcomes reported at three time points: < 3 months, 3 to < 6 months, > 6 to 12 months. We used GRADE to assess the certainty of evidence for each outcome. MAIN RESULTS: We included three studies in this review with a total of 319 participants. Each study addressed a different comparison and these are outlined below. We did not identify any evidence for the remaining comparisons of interest in this review. Dietary interventions (probiotics) versus placebo We identified one study with 218 participants (85% female). The use of a probiotic supplement was compared to a placebo and participants were followed up for two years. Some data were reported on the change in vertigo frequency and severity over the duration of the study. However, there were no data regarding improvement of vertigo or serious adverse events. Cognitive behavioural therapy (CBT) versus no intervention One study compared CBT to no treatment in 61 participants (72% female). Participants were followed up for eight weeks. Data were reported on the change in vertigo over the course of the study, but no information was reported on the proportion of people whose vertigo improved, or on the occurrence of serious adverse events. Vestibular rehabilitation versus no intervention The third study compared the use of vestibular rehabilitation to no treatment in a group of 40 participants (90% female) and participants were followed up for six months. Again, this study reported some data on change in the frequency of vertigo during the study, but no information on the proportion of participants who experienced an improvement in vertigo or the number who experienced serious adverse events. We are unable to draw meaningful conclusions from the numerical results of these studies, as the data for each comparison of interest come from single, small studies and the certainty of the evidence was low or very low. AUTHORS' CONCLUSIONS: There is a paucity of evidence for non-pharmacological interventions that may be used for prophylaxis of vestibular migraine. Only a limited number of interventions have been assessed by comparing them to no intervention or a placebo treatment, and the evidence from these studies is all of low or very low certainty. We are therefore unsure whether any of these interventions may be effective at reducing the symptoms of vestibular migraine and we are also unsure whether they have the potential to cause harm.

Prenatal nutrition may significantly impact brain aging. Results from the Dutch Famine Birth Cohort indicated that prenatal undernutrition is negatively associated with cognition, brain volumes, perfusion and structural brain aging in late life, predominantly in men. This study investigates the association between prenatal undernutrition and late-life functional brain network connectivity. In an exploratory resting-state functional magnetic resonance imaging study of 112 participants from the Dutch Famine Birth Cohort, we investigated whether the within- and between-network functional connectivity of the default mode network, salience network and central executive network differ at age 68 in men (N = 49) and women (N = 63) either exposed or unexposed to undernutrition in early gestation. Additionally, we explored sex-specific effects. Compared to unexposed participants, exposed participants revealed multiple clusters of different functional connectivity within and between the three networks studied. Sex-specific analyses suggested a pattern of network desegregation fitting with brain aging in men and a more diffuse pattern of group differences in women. This study demonstrates that associations between prenatal undernutrition and brain network functional connectivity extend late into life.

Contains fulltext : 246722.pdf (Publisher’s version ) (Open Access) Objectives: This study aims to provide insight into (i) how the combination of paid work and family care is longitudinally associated with gender-related differences in depressive symptoms and (ii) the role of work characteristics in this association. Methods: Data were derived from STREAM, a Dutch prospective cohort study of older workers aged 45-64 years. Respondents were included if they were employed in at least one measurement between 2015 and 2017 (N=12 447). Mixed-models were applied to disentangle between-person (BP) and within-person (WP) effects of family caregiving on depressive symptoms. Analyses were stratified by gender. Work characteristics (social support, autonomy, emotional and mental workload) were separately added to the multivariable models. Results: For older employees, family caregiving was positively associated with depressive symptoms between and within persons for both women [BP B=0.80, 95% confidence interval (CI) 0.52-1.08; WP B=0.32, 95% CI 0.08-0.56] and men (BP B=0.75, 95% CI 0.45-1.05; WP B=0.25, 95% CI 0.01-0.48). Social support at work reduced the adverse effect of family care on depressive symptoms for women (BP) and men (BP and WP). Emotional workload partly explained the effect of family care for both women and men (BP). Conclusions: The longitudinal association between family care and mental health was similar for male and female employees. Resources at work (ie, social support) could protect caregiving employees against depressive symptoms. More research is needed regarding the relative impact of the care context compared to the work context of working family caregivers. 10 p.

Background Young people who have psychiatric problems are more likely than their peers to endure difficulties during their sexual and gender identity development. Aim This study aims to examine the communication between mental health care providers and their patients about the topics of relations, sexuality and gender identity, including a description of professionals’ attitudes toward these topics and the factors that contribute to and inhibit communication. Methods Study participants (n = 242, response rate = 31%) were a representative sample of a large multicenter cohort of 768 mental health care professionals (eg, medical doctors, psychiatrists, psychologists, group counselors, parent counselors) of 7 institutions and 5 solo practices in the Netherlands, who completed a survey on communication about sexuality and gender identity with their young patients (age 12–21 years). Outcomes Sexuality and gender identity are infrequently discussed by mental health care providers with their young patients or their patients’ parents. Results Of the study sample, 99.5 % valued sexuality as an important topic to discuss with their patients. However, only 17.1% of the professionals reported that they discussed sexuality-related issues with the majority (>75%) of their patients (adolescents: 19.9%, parents: 14.4%) Additionally, only 2.3 % of the participants discussed gender nonconformity regularly with patients. Information about sexual side effects of prescribed medication was infrequently (20.3%) provided: antidepressants (40.0%), antipsychotics (34.0%), benzodiazepines (5.1%) and stimulants (2.4%). The most frequently cited reasons for not discussing these topics were a lack of awareness, own feelings of discomfort, and the patients’ supposed feelings of shame. There was no gender differences observed. Clinical implications Recommendations for professionals include to be aware of these topics, initiating age-appropriate conversation and use inclusive language. Strengths and limitations The present study included a diverse and representative group of mental health care professionals. Frequency of sexual communication was based on self-report, which brings a risk of bias. Conclusion Despite a recognized need to engage in age-appropriate communication about sexuality and gender identity in youth mental health care, mental health providers seem to remain hesitant to discuss such topics.

Objective: The aim of this study was to explore the changes in nutritional status before dialysis initiation and to identify modifiable risk factors of nutritional status decline in older adults with advanced renal disease.& nbsp;Design and Methods: The European Quality Study on treatment in advanced chronic kidney disease (EQUAL) is a prospective, observational cohort study involving six European countries. We included 1,103 adults > 65 years with incident estimated glomerular filtration rate < 20 mL/min/1.73 m(2) not on dialysis, attending nephrology care. Nutritional status was assessed with the 7-point Subjective Global Assessment tool (7-p SGA), patient-reported outcomes with RAND-36 and the Dialysis Symptom Index. Logistic regression was used to estimate the associations between potential risk factors and SGA decline.& nbsp;Results: The majority of the patients had a normal nutritional status at baseline, 28% were moderately malnourished (SGA = 2 points). The proportion of patients with low SGA (

Background Patients with hematological cancers (HC) are at high risk of infections, in particular community-acquired pneumonia (CAP). Recent data on incidence and predictors of CAP among patients with HC are scarce. Methods We performed a cohort study (2016–2019) in 2 hospitals in the Netherlands among adults with HC to calculate incidence rates (IRs) of CAP. In addition, we performed a nested case-control study to identify predictors of CAP. Results We identified 275 CAP cases during 6264 patient-years of follow-up. The IR of CAP was 4390/100 000 patient-years of follow-up. Compared with the general population, IR ratios ranged from 5.4 to 55.3 for the different HCs. The case fatality and intensive care unit (ICU) admission rates were 5.5% and 9.8%, respectively. Predictors for CAP in patients with HC were male sex, anemia, lymphocytopenia, chronic kidney disease, cardiovascular disease, autologous and allogeneic stem cell transplantation, treatment with immunosuppressive medication for graft-vs-host disease, treatment with rituximab in the past year, and treatment with immunomodulators (lenalidomide, thalidomide, pomalidomide and/or methotrexate) in the past month. Independent predictors of a severe disease course (death or ICU admission) included neutropenia (odds ratio, 4.14 [95% confidence interval, 1.63–10.2]), pneumococcal pneumonia (10.24 [3.48–30.1]), chronic obstructive pulmonary disease (6.90 [2.07–23.0]), and the use of antibacterial prophylaxis (2.53 [1.05–6.08]). Conclusions The burden of CAP in patients with HC is high, with significant morbidity and mortality rates. Therefore, vaccination against respiratory pathogens early in the disease course is recommended, in particular before starting certain immunosuppressive therapies.

Objective: This study was undertaken to compare the rate of change in cognition between glucocerebrosidase (GBA) mutation carriers and noncarriers with and without subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson disease. Methods: Clinical and genetic data from 12 datasets were examined. Global cognition was assessed using the Mattis Dementia Rating Scale (MDRS). Subjects were examined for mutations in GBA and categorized as GBA carriers with or without DBS (GBA+DBS+, GBA+DBS-), and noncarriers with or without DBS (GBA-DBS+, GBA-DBS-). GBA mutation carriers were subcategorized according to mutation severity (risk variant, mild, severe). Linear mixed modeling was used to compare rate of change in MDRS scores over time among the groups according to GBA and DBS status and then according to GBA severity and DBS status. Results: Data were available for 366 subjects (58 GBA+DBS+, 82 GBA+DBS-, 98 GBA-DBS+, and 128 GBA-DBS- subjects), who were longitudinally followed (range = 36–60 months after surgery). Using the MDRS, GBA+DBS+ subjects declined on average 2.02 points/yr more than GBA-DBS- subjects (95% confidence interval [CI] = −2.35 to −1.69), 1.71 points/yr more than GBA+DBS- subjects (95% CI = −2.14 to −1.28), and 1.49 points/yr more than GBA-DBS+ subjects (95% CI = −1.80 to −1.18). Interpretation: Although not randomized, this composite analysis suggests that the combined effects of GBA mutations and STN-DBS negatively impact cognition. We advise that DBS candidates be screened for GBA mutations as part of the presurgical decision-making process. We advise that GBA mutation carriers be counseled regarding potential risks associated with STN-DBS so that alternative options may be considered. ANN NEUROL 2022;91:424–435.

Background: Older people with subjective memory complaints (SMC) and Instrumental Activities of Daily Living impairments (IADL-I) have an increased risk of developing dementia. Previous reports suggest that the predictive value of SMC and IADL-I may differ between sexes, leaving possible consequences for personalized risk prediction and prognosis. However, none of these studies addressed the competing risk of death, which may substantially differ between sexes. Objective: We investigated sex-differences in the association between IADL-I, SMC, and incident dementia and mortality as competing risk. Methods: 3,409 community-dwelling older people without dementia (mean age 74.3±2.5), were followed for 6.7 years (median). Baseline SMC were assessed using the 15-item Geriatric Depression Scale memory question, and IADL-I using the Academic Medical Center Linear Disability Score. Potential sex-differences in the predictive value of SMC and IADL-I were assessed using Cox regression models with an interaction term for sex. Results: HRs for isolated SMC and SMC + IADL-I and risk of dementia were higher in women (HR: 2.02, 95% CI = 0.91–4.46, p = 0.08; HR:2.85, 95% CI = 1.65–4.91, p

Objective: To determine long-term outcomes of a randomized trial (BIOPEX) comparing biological mesh and primary perineal closure in rectal cancer patients after extralevator abdominoperineal resection and preoperative radiotherapy, with a primary focus on symptomatic perineal hernia. Summary Background Data: BIOPEX is the only randomized trial in this field, which was negative on its primary endpoint (30-day wound healing). Methods: This was a posthoc secondary analysis of patients randomized in the BIOPEX trial to either biological mesh closure (n = 50; 2 dropouts) or primary perineal closure (n = 54; 1 dropout). Patients were followed for 5 years. Actuarial 5-year probabilities were determined by the Kaplan-Meier statistic. Results: Actuarial 5-year symptomatic perineal hernia rates were 7% (95% CI, 0-30) after biological mesh closure versus 30% (95% CI, 10-49) after primary closure (P = 0.006). One patient (2%) in the biomesh group underwent elective perineal hernia repair, compared to 7 patients (13%) in the primary closure group (P = 0.062). Reoperations for small bowel obstruction were necessary in 1/48 patients (2%) and 5/53 patients (9%), respectively (P = 0.208). No significant differences were found for chronic perineal wound problems, locoregional recurrence, overall survival, and main domains of quality of life and functional outcome. Conclusions: Symptomatic perineal hernia rate at 5-year follow-up after abdominoperineal resection for rectal cancer was significantly lower after biological mesh closure. Biological mesh closure did not improve quality of life or functional outcomes.

Introduction Excess visceral fat increases the risk of type 2 diabetes and cardiovascular disease and is influenced by sex hormones. Our aim was to investigate changes in visceral fat and the ratio of visceral fat to total body fat (VAT/TBF) and their associations with changes in lipids and insulin resistance after 1 year of hormone therapy in trans persons. Methods In 179 trans women and 162 trans men, changes in total body and visceral fat estimated with dual-energy X-ray absorptiometry before and after 1 year of hormone therapy were related to lipids and insulin resistance [homeostatic model assessment of insulin resistance (HOMA-IR)] with linear regression analysis. Results In trans women, total body fat increased by 4.0 kg (95% CI 3.4, 4.7), while the amount of visceral fat did not change (−2 grams; 95% CI −15, 11), albeit with a large range from −318 to 281, resulting in a decrease in the VAT/TBF ratio of 17% (95% CI 15, 19). In trans men, total body fat decreased with 2.8 kg (95% CI 2.2, 3.5), while the amount of visceral fat did not change (3 g; 95% CI −10, 16; range −372, 311), increasing the VAT/TBF ratio by 14% (95% CI 10, 17). In both groups, VAT/TBF was not associated with changes in blood lipids or HOMA-IR. Conclusions Hormone therapy in trans women and trans men resulted in changes in VAT/TBF, mainly due to changes in total body fat and were unrelated to changes in cardiometabolic risk factors, which suggests that any unfavorable cardiometabolic effects of hormone therapy are not mediated by changes in visceral fat or VAT/TBF.

Background Coronavirus Disease 2019 (COVID-19) reached the Netherlands in February 2020. To minimize the spread of the virus, the Dutch government announced an “intelligent lockdown”. Older individuals were urged to socially isolate completely, because they are at risk of a severe disease course. Although isolation reduces the medical impact of the virus, the non-medical impact should also be considered. Aim To investigate the impact of COVID-19 pandemic and associated restrictive measures on the six dimensions of Positive Health in community-dwelling older individuals living in the Netherlands, and to identify differences within subgroups. Methods In May/June 2020, community-dwelling older individuals aged ≥ 65 years completed an online survey based on Huber’s model of Positive Health. Positive Health was measured regarding the appreciation of the six dimensions (categorized as poor/satisfactory/excellent) and a comparison with a year before (categorized as decreased/unchanged/increased) using frequencies (%) and a chi-square test. Results 834 older individuals participated (51% women, 38% aged ≥ 76 years, 35% living alone, 16% self-rated poor health). Most respondents assessed their bodily functions, mental well-being and daily functioning as satisfactory, their meaningfulness and quality of life (QoL) as excellent, and their social participation as poor. 12% of the respondents reported a deterioration of 4–6 dimensions and 73% in 1–3 dimensions, compared to the past year. Deterioration was most frequently experienced in the dimension social participation (73%), the dimension mental well-being was most frequently improved (37%) and quality of life was in 71% rated as unchanged. Women more often observed a deterioration of 4–6 dimensions than men (15% vs. 8%, p = 0.001), and individuals with self-rated poor health more often than individuals with self-rated good health (22% vs. 10%, p Conclusion The COVID-19 pandemic and associated restrictive measures had a substantial impact on all six dimensions of Positive Health in community-dwelling older individuals, especially in women, respondents living alone and respondents with self-rated poor general health.

Introduction: Dementia prevalence in older women is higher than that in men. The purpose of the present study was to investigate whether there is a female disadvantage in cognitive functioning at adult age and/or whether a female disadvantage develops with age. Methods: Data of 5,135 women and 4,756 men from the Longitudinal Aging Study Amsterdam (LASA) and the Doetinchem Cohort Study (DCS) were used. In the LASA, memory, processing speed, fluid intelligence, and global cognitive function were measured every 3–4 years since 1992 in persons aged 55+ years for up to 23 years. In the DCS, memory, processing speed, cognitive flexibility, and global cognitive function were measured every 5 years since 1995 in persons aged 45+ years for up to 20 years. Sex differences in cognitive aging were analyzed using linear mixed models and also examined by the 10-year birth cohort or level of education. Results: Women had a better memory, processing speed, flexibility, and, in the DCS only, global cognitive function than men (p’s < 0.01). However, women showed up to 10% faster decline in these cognitive domains, except for flexibility, where women showed 9% slower decline. In the LASA, women scored poorer on fluid intelligence (p < 0.01), but their decline was 10% slower than that in men. Female advantage was larger in later born cohorts; adjustment for the educational level increased the female advantage. Conclusion: Women have better memory and processing speed than men at middle age. This female advantage becomes smaller with aging and has increased in more recent birth cohorts.

Background: Longitudinal studies including parental distress when examining adverse health outcomes in adolescents with type 1 diabetes are lacking. This study examined whether parental depression and anxiety predict adolescent emotional distress and glycated hemoglobin A1c (HbA1c) 1 year later and whether a relation between parental distress and HbA1c is mediated by the level of parental involvement in diabetes care and by treatment behaviors.Methods: Longitudinal path modeling was applied to data from 154 adolescents and parents from diabetes centers participating in the Longitudinal study of Emotional problems in Adolescents with type 1 diabetes and their Parents/caregivers (Diabetes LEAP). At baseline and 1-year follow-up, participants completed measures of depression and anxiety. HbA1c was extracted from medical charts. Responsibility and treatment behavior questionnaires were completed by adolescents at baseline.Results: Baseline parental depressive and anxiety symptoms were not associated with 1-year adolescent depressive symptoms, anxiety symptoms, and HbA1c. Responsibility division and treatment behaviors did not mediate associations between parental emotional distress and 1-year HbA1c.Conclusions: Parental depressive and anxiety symptoms did not predict adolescent health outcomes 1 year later. Future studies may determine whether the link is present in case of mood/anxiety disorders or severe diabetes-specific distress, or whether adolescents are resilient in the face of parental distress.Impact: Adolescents with T1D are a vulnerable group in terms of psychological and health outcomes. Whether parental emotional distress (i.e., depressive and anxiety symptoms) is prospectively associated with adolescent emotional distress and/or HbA1c has been understudied. Our results show that parental distress was not related to adolescent distress or HbA1c 1 year later. Responsibility division and treatment behaviors did not mediate associations between parental emotional distress and 1-year HbA1c. Future studies could determine whether these links are present in case of mood/anxiety disorders or severe diabetes-specific distress, or whether adolescents are resilient in the face of parental distress.

We aimed to assess the validity of an announced telephone pill count in people with type 2 diabetes or cardiovascular disease by comparing this method to a home-visit pill count. We also assessed whether a second telephone pill count improved accuracy. People aged ≥35 years using oral type 2 diabetes or cardiovascular disease medication were included. Thirty-four participants completed a telephone pill count followed by a home-visit pill count, and a subsample of this population (n = 11) completed a second telephone pill count. Scatterplots were used for a visual representation of the number of pills counted with both methods, intraclass correlation coefficients for agreement, and Bland-Altman plots for absolute differences and outliers. A total of 203 pill counts were conducted. The study population consisted of 53% men, with a mean age of 69.6 (±9.2) years and an average of 6.1 (±2.8) medication prescriptions per participant. Scatterplots showed that pills counted with both methods were mostly scattered around the y = x equation. Agreement between the first telephone pill count and home-visit pill count was high, with intraclass correlation coefficients of 0.96 (medication count level) and 0.98 (individual level). No learning effects were observed in the subsample (n = 11), the intraclass correlation coefficient for the first telephone pill count was 0.88 versus 0.89 for the second telephone pill count. Bland-Altman plots indicated high agreement between the two methods. An announced telephone pill count is considered a valid alternative for a home-visit pill count in people with type 2 diabetes or cardiovascular disease. A single pill count appears sufficient.

Background: In the treatment of type 2 diabetes, GLP-1 receptor agonists lower blood glucose concentrations, body weight, and have cardiovascular benefits. The efficacy and side effects of GLP-1 receptor agonists vary between people. Human pharmacogenomic studies of this inter-individual variation can provide both biological insight into drug action and provide biomarkers to inform clinical decision making. We therefore aimed to identify genetic variants associated with glycaemic response to GLP-1 receptor agonist treatment. Methods: In this genome-wide analysis we included adults (aged ≥18 years) with type 2 diabetes treated with GLP-1 receptor agonists with baseline HbA 1c of 7% or more (53 mmol/mol) from four prospective observational cohorts (DIRECT, PRIBA, PROMASTER, and GoDARTS) and two randomised clinical trials (HARMONY phase 3 and AWARD). The primary endpoint was HbA 1c reduction at 6 months after starting GLP-1 receptor agonists. We evaluated variants in GLP1R, then did a genome-wide association study and gene-based burden tests. Findings: 4571 adults were included in our analysis, of these, 3339 (73%) were White European, 449 (10%) Hispanic, 312 (7%) American Indian or Alaskan Native, and 471 (10%) were other, and around 2140 (47%) of the participants were women. Variation in HbA 1c reduction with GLP-1 receptor agonists treatment was associated with rs6923761G→A (Gly168Ser) in the GLP1R (0·08% [95% CI 0·04–0·12] or 0·9 mmol/mol lower reduction in HbA 1c per serine, p=6·0 × 10 −5) and low frequency variants in ARRB1 (optimal sequence kernel association test p=6·7 × 10 −8), largely driven by rs140226575G→A (Thr370Met; 0·25% [SE 0·06] or 2·7 mmol/mol [SE 0·7] greater HbA 1c reduction per methionine, p=5·2 × 10 −6). A similar effect size for the ARRB1 Thr370Met was seen in Hispanic and American Indian or Alaska Native populations who have a higher frequency of this variant (6–11%) than in White European populations. Combining these two genes identified 4% of the population who had a 30% greater reduction in HbA 1c than the 9% of the population with the worse response. Interpretation: This genome-wide pharmacogenomic study of GLP-1 receptor agonists provides novel biological and clinical insights. Clinically, when genotype is routinely available at the point of prescribing, individuals with ARRB1 variants might benefit from earlier initiation of GLP-1 receptor agonists.

We identify biomarkers for disease progression in three type 2 diabetes cohorts encompassing 2,973 individuals across three molecular classes, metabolites, lipids and proteins. Homocitrulline, isoleucine and 2-aminoadipic acid, eight triacylglycerol species, and lowered sphingomyelin 42:2;2 levels are predictive of faster progression towards insulin requirement. Of ~1,300 proteins examined in two cohorts, levels of GDF15/MIC-1, IL-18Ra, CRELD1, NogoR, FAS, and ENPP7 are associated with faster progression, whilst SMAC/DIABLO, SPOCK1 and HEMK2 predict lower progression rates. In an external replication, proteins and lipids are associated with diabetes incidence and prevalence. NogoR/RTN4R injection improved glucose tolerance in high fat-fed male mice but impaired it in male db/db mice. High NogoR levels led to islet cell apoptosis, and IL-18R antagonised inflammatory IL-18 signalling towards nuclear factor kappa-B in vitro. This comprehensive, multi-disciplinary approach thus identifies biomarkers with potential prognostic utility, provides evidence for possible disease mechanisms, and identifies potential therapeutic avenues to slow diabetes progression.

Introduction: Gait speed is a simple and safe measure with strong predictive value for negative health outcomes in clinical practice, yet in-laboratory gait speed seems not representative for daily-life gait speed. This study aimed to investigate the interrelation between and robustness of in-laboratory and daily-life gait speed measures over 12 months in 61- to 70-year-old adults. Methods: Gait speed was assessed in laboratory through standardized stopwatch tests and in daily life by 7 days of trunk accelerometry in the PreventIT cohort, at baseline, and after 6 and 12 months. The interrelation was investigated using Pearson’s correlations between gait speed measures at each time point. For robustness, changes over time and variance components were assessed by ANOVA and measurement agreement over time by Bland-Altman analyses. Results: Included were 189 participants (median age 67 years [interquartile range: 64–68], 52.2% females). In-laboratory and daily-life gait speed measures showed low correlations (Pearson’s r = 0.045–0.455) at each time point. Moreover, both in-laboratory and daily-life gait speed measures appeared robust over time, with comparable and smaller within-subject than between-subject variance (range 0.001–0.095 m/s and 0.032–0.397 m/s, respectively) and minimal differences between measurements over time (Bland-Altman) with wide limits of agreement (standard deviation of mean difference range: 0.12–0.34 m/s). Discussion/Conclusion: In-laboratory and daily-life gait speed measures show robust assessments of gait speed over 12 months and are distinct constructs in this population of high-functioning adults. This suggests that (a combination of) both measures may have added value in predicting health outcomes.

Objectives To examine whether (a) as people age, accumulation of negative events increases (“sensitizing”) or decreases (“steeling”) the detrimental effects of subsequent events on depressive symptoms, and (b) how particular psychosocial factors are associated with the strength of these steeling or sensitizing effects. Method We used data from 6 measurement waves from 2,069 adults aged 55–84 (M = 68.0) at baseline in the Longitudinal Aging Study Amsterdam, the Netherlands. We included 18 different life events across the life course. Using hybrid multilevel models, we tested whether the effects of proximate life events ( Results Cumulative and proximate life events were independently associated with more depressive symptoms. Interaction effects indicated that the more cumulative life events, the weaker the effects of recent life events, suggesting a “steeling” effect. Unexpectedly, 3-way interaction effects showed that higher mastery and lower neuroticism were associated with weaker steeling effects. These effects were predominantly attributable to within-person changes rather than to fixed between-person differences. Results from analyses with event severity scores were similar. Conclusions As a population, older adults appear to become more resilient against new stressors as they accumulate experience in dealing with negative life events. Findings on mastery tentatively suggest that accepting limits to one’s own control over life circumstances may foster a steeling effect.

This qualitative study aimed to explore the experienced influence of HIV on the quality of life (QoL) of people with HIV (PHIV) and key populations without but are vulnerable to HIV in the Netherlands. We conducted and thematically analyzed interviews with 29 PHIV and 13 participants from key populations without HIV (i.e., men who have sex with men). PHIV and key populations shared positive meaningful experiences regarding HIV, i.e., feeling grateful for ART, life, and the availability of PrEP, being loved and supported in the light of HIV, and providing support to the community. Negative predominant experiences regarding HIV were described by both PHIV and key populations as the negative effects of ART, challenges with regards to disclosing HIV, social stigmatization, and self-stigma. It remains important to support HIV community organizations in their efforts to reduce social stigmatization and to continue improving biomedical interventions for HIV.

Background General Practitioners (GPs) are central in the care of Dutch older people and in a good position to have Advance Care Planning (ACP) conversations. Interview studies reveal that the doctor-patient relationship is important when initiating ACP conversations and can also be influenced by ACP conversations. We aimed to examine the association between having an ACP conversation and the patient feeling the GP knows him or her and the patient trusting the GP and vice versa. Methods Implementation of ACP in primary care was evaluated in a pre-and post design. Questionnaires before implementation of ACP and 14 months later were sent to patients aged 75 years or older within 10 GP-practices and 2 care homes. Multivariable logistic regression was used to model the relationship between ACP conversations during implementation and the patient-GP relationship before implementation. Odds ratios were adjusted for potential confounders. Generalized ordered logistic regression was used to model the relationship between the changes in patient-GP relationship before and after implementation and ACP conversations during implementation. Results Four hundred fifty-eight patients filled out the pre- and post-test questionnaire. There was no association between the GP knowing the patient and trust in the pre-test and having an ACP conversation during the implementation. For people who had had an ACP conversation at the end of the implementation period their trust remained more often the same or was higher after implementation (trust to provide good care OR 2.93; trust to follow their wishes OR 2.59), compared to patients who did not have an ACP conversation. A reduction in trust was less likely to happen to patients who had an ACP conversation compared to patients who did not have an ACP conversation. Conclusions Although we have not found evidence for trust as a prerequisite for ACP conversations, this paper shows that ACP conversations can be beneficial for the doctor—patient relationship.

STUDY DESIGN: Cross-sectional study.OBJECTIVES: The aims of this study were (1) to validate the two recently developed SCI-specific REE equations; (2) to develop new prediction equations to predict REE in a general population with SCI.SETTING: University, the Netherlands.METHODS: Forty-eight community-dwelling men and women with SCI were recruited (age: 18-75 years, time since injury: ≥12 months). Body composition was measured by dual-energy X-ray absorptiometry (DXA), single-frequency bioelectrical impedance analysis (SF-BIA) and skinfold thickness. REE was measured by indirect calorimetry. Personal and lesion characteristics were collected. SCI-specific REE equations by Chun et al. [1] and by Nightingale and Gorgey [2] were validated. New equations for predicting REE were developed using multivariate regression analysis.RESULTS: Prediction equations by Chun et al. [1] and by Nightingale and Gorgey [2] significantly underestimated REE (Chun et al.: -11%; Nightingale and Gorgey: -11%). New equations were developed for predicting REE in the general population of people with SCI using FFM measured by SF-BIA and Goosey-Tolfrey et al. skinfold equation (R2 = 0.45-0.47; SEE = 200 kcal/day). The new equations showed proportional bias (p CONCLUSIONS: Prediction equations by Chun et al. [1] and by Nightingale and Gorgey [2] significantly underestimated REE and showed large individual variations in a general population with SCI. The newly developed REE equations showed proportional bias and a wide LoA (±23%) which limit the predictive power and accuracy to predict REE in the general population with SCI. Alternative methods for measuring REE need to be investigated.

Background Female older workers generally leave the work force earlier than men. Depressive symptoms are a risk factor of early work exit and are more common in women. To extend working lives, pathways leading to these sex inequalities need to be identified. The aim of this study was to investigate the association of sex and gender with depressive symptoms in older workers, and the role of working conditions in this association. Methods We used data from the Longitudinal Aging Study Amsterdam (2012–2013/2015–2016, n = 313). Our outcome was depressive symptoms, measured by the Center for Epidemiologic Studies Depression Scale. We included biological sex, a gender index ranging from masculine to feminine (consisting of six items measuring gender roles: working hours, income, occupation segregation, education, informal caregiving, time spent on household chores), and working conditions (physical demands, psychosocial demands, cognitive demands, autonomy, task variation, social support) in our models. We examined the differential vulnerability hypothesis, i.e., sex/gender moderates the association between working conditions and depressive symptoms, and the differential exposure hypothesis, i.e., working conditions mediate the association between sex/gender and depressive symptoms. Results Female sex and feminine gender were both associated with more depressive symptoms. The differential vulnerability hypothesis was not supported by our results. We did find that femininity was negatively associated with autonomy and task variation. In turn, these working conditions were associated with fewer depressive symptoms. Thus, autonomy and task variation partially mediated the association between gender and depressive symptoms, supporting the differential exposure hypothesis. Mediation effects for sex inequalities were not significant. Conclusions Older female workers and older feminine workers have more depressive symptoms than their male/masculine counterparts. Autonomy and task variation appeared to be important in – partially – explaining gender differences in depressive symptoms rather than sex differences. By improving these conditions, gender inequality in mental health among older workers can be reduced, so that both genders have similar chances to reach the retirement age in good mental health.

STUDY QUESTION Can transgender women cryopreserve germ cells obtained from their orchiectomy specimen for fertility preservation, after having used puberty suppression and/or hormonal treatment? SUMMARY ANSWER In the vast majority of transgender women, there were still immature germ cells present in the orchiectomy specimen, and in 4.7% of transgender women—who all initiated medical treatment in Tanner stage 4 or higher—mature spermatozoa were found, which would enable cryopreservation of spermatozoa or testicular tissue after having used puberty suppression and/or hormonal treatment. WHAT IS KNOWN ALREADY Gender affirming treatment (i.e. puberty suppression, hormonal treatment, and subsequent orchiectomy) impairs reproductive function in transgender women. Although semen cryopreservation is generally offered during the transition process, this option is not feasible for all transgender women (e.g. due to incomplete spermatogenesis when initiating treatment in early puberty, in case of inability to masturbate, or when temporary cessation of hormonal treatment is too disruptive). Harvesting mature spermatozoa, or testicular tissue harboring immature germ cells, from orchiectomy specimens obtained during genital gender-affirming surgery (gGAS) might give this group a chance of having biological children later in life. Previous studies on spermatogenesis in orchiectomy specimens showed conflicting results, ranging from complete absence of germ cells to full spermatogenesis, and did not involve transgender women who initiated medical treatment in early- or late puberty. STUDY DESIGN, SIZE, DURATION Histological and immunohistochemical analyses were performed on orchiectomy specimens from 214 transgender women who underwent gGAS between 2006 and 2018. Six subgroups were identified, depending on pubertal stage at initiation of medical treatment (Tanner stage 2-3, Tanner stage 4-5, adult), and whether hormonal treatment was continued or temporarily stopped prior to gGAS in each of these groups. PARTICIPANTS/MATERIALS, SETTING, METHODS All transgender women used a combination of estrogens and testosterone suppressing therapy. Orchiectomy specimen sections were stained with Mayer’s hematoxylin and eosin and histologically analyzed to assess the Johnsen score and the ratio of most advanced germ cell types in at least 50 seminiferous tubular cross-sections. Subsequently, immunohistochemistry was used to validate these findings using spermatogonia, spermatocytes or spermatids markers (MAGE-A3/A4, γH2AX, Acrosin, respectively). Possibilities for fertility preservation were defined as: preservation of spermatozoa, preservation of spermatogonial stem cells or no possibilities (in case no germ cells were found). Outcomes were compared between subgroups and logistic regression analyses were used to assess the association between the duration of hormonal treatment and the possibilities for fertility preservation. MAIN RESULTS AND THE ROLE OF CHANCE Mature spermatozoa were encountered in 4.7% of orchiectomy specimens, all from transgender women who had initiated medical treatment in Tanner stage 4 or higher. In 88.3% of the study sample orchiectomy specimens only contained immature germ cells (round spermatids, spermatocytes or spermatogonia, as most advanced germ cell type). In 7.0%, a complete absence of germ cells was observed, all these samples were from transgender women who had initiated medical treatment in adulthood. Cessation of hormonal treatment prior to gGAS did not affect the presence of germ cells or their maturation stage, nor was there an effect of the duration of hormonal treatment prior to gGAS. LIMITATIONS, REASONS FOR CAUTION Since data on serum hormone levels on the day of gGAS were not available, we were unable to verify if the transgender women who were asked to temporarily stop hormonal treatment 4 weeks prior to surgery actually did so, and if people with full spermatogenesis were compliant to treatment. WIDER IMPLICATIONS OF THE FINDINGS There may still be options for fertility preservation in orchiectomy specimens obtained during gGAS since a small percentage of transgender women had full spermatogenesis, which could enable cryopreservation of mature spermatozoa via a testicular sperm extraction procedure. Furthermore, the vast majority still had immature germ cells, which could enable cryopreservation of testicular tissue harboring spermatogonial stem cells. If maturation techniques like in vitro spermatogenesis become available in the future, harvesting germ cells from orchiectomy specimens might be a promising option for those who are otherwise unable to have biological children. STUDY FUNDING/COMPETING INTEREST None. TRIAL REGISTRATION NUMBER N/A.

Objectives The coronavirus disease (COVID‐19) pandemic is an unprecedented event with massive global health and socio‐economic impacts on vulnerable populations, especially people living with HIV. The epidemic has severely affected Thailand’s economy and potentially impacted the financial and psychological wellbeing of Thai HIV‐positive men who have sex with men (MSM). Methods Between 15 June and 10 December 2020, we conducted qualitative interviews with 26 MSM living with HIV in Thailand who participate in an Adam’s Love We Care Study. We intentionally recruited individuals who may have experienced a greater impact of COVID‐19. Interviews explored worry, stigma and stress surrounding COVID‐19, and multiple domains of potential COVID‐19 impact: financial/employment, HIV service delivery and antiretroviral (ART) adherence during the first 10 months of the COVID‐19 pandemic. Results Participants perceived themselves as immunocompromised and susceptible, and feared contracting COVID‐19. Participants worried that contracting COVID‐19 would lead to HIV status disclosure and stigmatization. Participants had considerable worry about job loss as a result of the economic downturn, and some shared challenges associated with relocation and re‐engaging with HIV care. Financial stress and lack of basic necessities caused by job losses were commonly reported. Participants reported optimal ART adherence as a consequence of local HIV service delivery responses, convenient ART refills and Adam’s Love online support interventions. Conclusions Our study highlights that the COVID‐19 pandemic produced high levels of anxiety and concerns about additional stigma among MSM living with HIV. It had a significant negative effect on the daily lives of our participants. These findings indicate a need for the provision of confidential COVID‐19 diagnosis and care, relief programmes, vaccination roll‐out equity, and addressing employment needs of vulnerable populations.

BackgroundThe central nervous system (CNS) is a likely reservoir of human immunodeficiency virus (HIV), vulnerable to viral rebound, inflammation, and clinical changes upon stopping antiretroviral therapy (ART). It is critical to evaluate the CNS safety of studies using analytic treatment interruption (ATI) to assess HIV remission.MethodsThirty participants who started ART during acute HIV infection underwent CNS assessments across 4 ATI remission trials. ART resumption occurred with plasma viral load >1000 copies/mL. CNS measures included paired pre- vs post-ATI measures of mood, cognitive performance, and neurologic examination, with elective cerebrospinal fluid (CSF) sampling, brain diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS).ResultsMedian participant age was 30 years old and 29/30 were male. Participants’ median time on ART before ATI was 3 years, and ATI lasted a median of 35 days. Post-ATI, there were no differences in median mood scores or neurologic findings and cognitive performance improved modestly. During ATI, a low level of CSF HIV-1 RNA was detectable in 6 of 20 participants with plasma viremia, with no group changes in CSF immune activation markers or brain DTI measures. Mild worsening was identified in post-ATI basal ganglia total choline MRS, suggesting an alteration in neuronal membranes.ConclusionNo adverse CNS effects were observed with brief, closely monitored ATI in participants with acutely treated HIV, except an MRS alteration in basal ganglia choline. Further studies are needed to assess CNS ATI safety in HIV remission trials, particularly for studies using higher thresholds to restart ART and longer ATI durations.

Aim To describe the evolution of electroencephalogram (EEG) characteristics in infants with tuberous sclerosis complex (TSC) and the relationship with neurodevelopmental outcome at 24 months. Method Eighty-three infants were enrolled in the EPISTOP trial and underwent serial EEG follow-up until the age of 24 months (males n=45, females n=37, median age at enrolment 28d, interquartile range 14-54d). Maturation of the EEG background and epileptiform discharges were compared between the TSC1 and TSC2 variants and between preventive and conventional groups respectively. Results Children with TSC2 more frequently had a slower posterior dominant rhythm (PDR) at 24 months (51% vs 11%, p=0.002), a higher number of epileptiform foci (median=8 vs 4, p=0.003), and a lower fraction of EEGs without epileptiform discharges (18% vs 61%, p=0.001) at follow-up. A slower PDR at 24 months was significantly associated with lower cognitive (median=70 vs 80, p=0.028) and motor developmental quotients (median=70 vs 79, p=0.008). A higher fraction of EEGs without epileptiform discharges was associated with a lower probability of autism spectrum disorder symptoms (odds ratio=0.092, 95% confidence interval=0.009-0.912, p=0.042) and higher cognitive (p=0.004), language (p=0.002), and motor (p=0.001) developmental quotients at 24 months. Interpretation TSC2 is associated with more abnormal EEG characteristics compared to TSC1, which are predictive for neurodevelopmental outcome.

Aims Focal cortical dysplasia (FCD) type 2 is an epileptogenic malformation of the neocortex associated with somatic mutations in the mammalian target of rapamycin (mTOR) pathway. Histopathologically, FCD 2 is subdivided into FCD 2a and FCD 2b, the only discriminator being the presence of balloon cells (BCs) in FCD 2b. While pro‐epileptogenic immune system activation and inflammatory responses are commonly detected in both subtypes, it is unknown what contextual role BCs play. Methods The present study employed RNA sequencing of surgically resected brain tissue from FCD 2a (n = 11) and FCD 2b (n = 20) patients compared to autopsy control (n = 9) focusing on three immune system processes: adaptive immunity, innate immunity and cytokine production. This analysis was followed by immunohistochemistry on a clinically well‐characterised FCD 2 cohort. Results Differential expression analysis revealed stronger expression of components of innate immunity, adaptive immunity and cytokine production in FCD 2b than in FCD 2a, particularly complement activation and antigen presentation. Immunohistochemical analysis confirmed these findings, with strong expression of leukocyte antigen I and II in FCD 2b as compared to FCD 2a. Moreover, T‐lymphocyte tissue infiltration was elevated in FCD 2b. Expression of markers of immune system activation in FCD 2b was concentrated in subcortical white matter. Lastly, antigen presentation was strongly correlated with BC load in FCD 2b lesions. Conclusion We conclude that, next to mutation‐driven mTOR activation and seizure activity, BCs are crucial drivers of inflammation in FCD 2b. Our findings indicate that therapies targeting inflammation may be beneficial in FCD 2b., Focal cortical dysplasia (FCD) type 2 is an epileptogenic malformation of the neocortex associated with somatic mutations in the mammalian target of rapamycin (mTOR) pathway. Histopathologically, FCD 2 is subdivided into FCD 2a and FCD 2b, the only discriminator being the presence of balloon cells in FCD 2b. We conclude that, next to mutation‐driven mTOR activation and seizure activity, balloon cells are crucial drivers of inflammation in FCD 2b.

Aims We aim to evaluate if the myelin pathology observed in epilepsy‐associated focal cortical dysplasia type 2B (FCD2B) and—histologically indistinguishable—cortical tubers of tuberous sclerosis complex (TSC) is primarily related to the underlying malformation or constitutes a secondary phenomenon due to the toxic microenvironment created by epileptic seizures. We also aim to investigate the possible beneficial effect of the mTOR pathway regulator everolimus on white matter pathology. Methods Primary mixed glial cell cultures derived from epilepsy surgery specimens of one TSC and seven FCD2B patients were grown on polycaprolactone fibre matrices and analysed using immunofluorescence and electron microscopy. Unaffected white matter from three age‐matched epilepsy patients with mild malformations of cortical development (mMCD) and one with FCD3D served as controls. Additionally, TSC2 knock‐out was performed using an oligodendroglial cell line. Myelination capacities of nanofibre grown cells in an inflammatory environment after mTOR‐inhibitor treatment with everolimus were further investigated. Results Reduced oligodendroglial turnover, directly related to a lower myelin content was found in the patients' primary cells. In our culture model of myelination dynamics, primary cells grown under ‘inflammatory condition’ showed decreased myelination, that was repaired by treatment with everolimus. Conclusions Results obtained in patient‐derived primary oligodendroglial and TSC2 knock‐out cells suggest that maturation of oligodendroglia and production of a proper myelin sheath seem to be impaired as a result of mTOR pathway disturbance. Hence, oligodendroglial pathology may reflect a more direct effect of the abnormal genetic programme rather than to be an inactive bystander of chronic epilepsy., Results obtained in patient‐derived primary oligodendroglial and TSC2 knock‐out cells indicate a higher number of oligodendroglial precursor cells, yet a decline in myelin. Interestingly, everolimus repaired myelin formation and normalized proliferative activity.

Aims Tuberous sclerosis complex (TSC) is a genetic disorder associated with dysregulation of the mechanistic target of rapamycin complex 1 (mTORC1) signalling pathway. Neurodevelopmental disorders, frequently present in TSC, are linked to cortical tubers in the brain. We previously reported microRNA‐34a (miR‐34a) among the most upregulated miRs in tubers. Here, we characterised miR‐34a expression in tubers with the focus on the early brain development and assessed the regulation of mTORC1 pathway and corticogenesis by miR‐34a. Methods We analysed the expression of miR‐34a in resected cortical tubers (n = 37) compared with autopsy‐derived control tissue (n = 27). The effect of miR‐34a overexpression on corticogenesis was assessed in mice at E18. The regulation of the mTORC1 pathway and the expression of the bioinformatically predicted target genes were assessed in primary astrocyte cultures from three patients with TSC and in SH‐SY5Y cells following miR‐34a transfection. Results The peak of miR‐34a overexpression in tubers was observed during infancy, concomitant with the presence of pathological markers, particularly in giant cells and dysmorphic neurons. miR‐34a was also strongly expressed in foetal TSC cortex. Overexpression of miR‐34a in mouse embryos decreased the percentage of cells migrated to the cortical plate. The transfection of miR‐34a mimic in TSC astrocytes negatively regulated mTORC1 and decreased the expression of the target genes RAS related (RRAS) and NOTCH1. Conclusions MicroRNA‐34a is most highly overexpressed in tubers during foetal and early postnatal brain development. miR‐34a can negatively regulate mTORC1; however, it may also contribute to abnormal corticogenesis in TSC., MicroRNA‐34a (MiR‐34a) is overexpressed in cortical tubers from children with tuberous sclerosis complex with a peak during infancy. MiR‐34a negatively regulates constitutively activated mechanistic target of rapamycin complex 1 in human astrocytes. MiR‐34a overexpression impairs corticogenesis in the embryonic mouse brain, potentially through targeting genes involved in neuronal migration.

Introduction Understanding the mechanisms underlying the differences in renal decline between men and women may improve sex-specific clinical monitoring and management. To this end, we aimed to compare the slope of renal function decline in older men and women in chronic kidney disease (CKD) Stages 4 and 5, taking into account informative censoring related to the sex-specific risks of mortality and dialysis initiation. Methods The European QUALity Study on treatment in advanced CKD (EQUAL) study is an observational prospective cohort study in Stages 4 and 5 CKD patients ≥65 years not on dialysis. Data on clinical and demographic patient characteristics were collected between April 2012 and December 2018. Estimated glomerular filtration rate (eGFR) was calculated using the CKD Epidemiology Collaboration equation. eGFR trajectory by sex was modelled using linear mixed models, and joint models were applied to deal with informative censoring. Results We included 7801 eGFR measurements in 1682 patients over a total of 2911 years of follow-up. Renal function declined by 14.0% [95% confidence interval (CI) 12.9–15.1%] on average each year. Renal function declined faster in men (16.2%/year, 95% CI 15.9–17.1%) compared with women (9.6%/year, 95% CI 6.3–12.1%), which remained largely unchanged after accounting for various mediators and for informative censoring due to mortality and dialysis initiation. Diabetes was identified as an important determinant of renal decline specifically in women. Conclusion In conclusion, renal function declines faster in men compared with women, which remained similar after adjustment for mediators and despite a higher risk of informative censoring in men. We demonstrate a disproportional negative impact of diabetes specifically in women.

Background according to the revised sarcopenia definition proposed by the European Working Group on Sarcopenia in Older People (EWGSOP2) and revised definition of the Asian Working Group for Sarcopenia (AWGS2019), handgrip strength (HGS) and chair stand test (CST) can be used interchangeably as initial diagnostic measures. Objective to assess the agreement between sarcopenia prevalence, using either HGS or CST, and their association with adverse outcomes in geriatric rehabilitation inpatients. Methods REStORing health of acutely unwell adulTs is an observational, longitudinal cohort of geriatric rehabilitation inpatients. Cohen’s kappa (κ) was used to assess the agreement between sarcopenia prevalence (no, probable and confirmed and severe sarcopenia) according to EWGSOP2 and AWGS2019 using either HGS or CST. Associations between HGS and CST and readmission, institutionalisation and mortality were assessed by binomial regression. Results patients (n = 1,250, 57% females) had a median age of 83.1 years (interquartile range: [77.5–88.3]). There was no agreement between probable sarcopenia prevalence using HGS or CST for EWGSOP2 and AWGS2019, respectively (HGS: 70.9% and 76.2%; CST: 95.5% and 98.4%; κ = 0.08 and 0.02). Agreement between confirmed and severe sarcopenia prevalence using either HGS or CST was strong to almost perfect. HGS was associated with 3-month institutionalisation and 3-month and 1-year mortality, whereas CST was not associated. Conclusions HGS and CST cannot be used interchangeably as diagnostic measures for probable sarcopenia in geriatric rehabilitation inpatients. CST is not useful to predict adverse outcomes in geriatric rehabilitation inpatients.

Objective: To investigate the associations of morbidity burden and frailty with the transitions between functional decline, institutionalization, and mortality. Design: REStORing health of acutely unwell adulTs (RESORT) is an ongoing observational, longitudinal inception cohort and commenced on October 15, 2017. Consented patients were followed for 3 months postdischarge. Setting and Participants: Consecutive geriatric rehabilitation inpatients admitted to geriatric rehabilitation wards. Methods: Patients’ morbidity burden was assessed at admission using the Charlson Comorbidity Index (CCI) and Cumulative Illness Rating Scale (CIRS). Frailty was assessed using the Clinical Frailty Scale (CFS) and modified Frailty Index based on laboratory tests (mFI-lab). A multistate model was applied at 4 time points: 2 weeks preadmission, admission, and discharge from geriatric rehabilitation and 3 months postdischarge, with the following outcomes: functional decline, institutionalization, and mortality. Cox proportional hazards regression was applied to investigate the associations of morbidity burden and frailty with the transitions between outcomes. Results: The 1890 included inpatients had a median age of 83.4 (77.6-88.4) years, and 56.3% were female. A higher CCI score was associated with a greater risk of transitions from preadmission and declined functional performance to mortality [hazard ratio (HR) 1.28, 95% CI 1.03-1.59; HR 1.32, 95% CI 1.04-1.67]. A higher CIRS score was associated with a higher risk of not recovering from functional decline (HR 0.80, 95% CI 0.69-0.93). A higher CFS score was associated with a greater risk of transitions from preadmission and declined functional performance to institutionalization (HR 1.28, 95% CI 1.10-1.49; HR 1.23, 95% CI 1.04-1.44) and mortality (HR 1.12, 95% CI 1.01-1.33; HR 1.11, 95% CI 1.003-1.31). The mFI-lab was not associated with any of the transitions. None of the morbidity measures or frailty assessment tools were associated with the transitions from institutionalization to other outcomes. Conclusions and Implications: This study demonstrates that greater frailty severity, assessed using the CFS, is a significant risk factor for poor clinical outcomes and demonstrates the importance of implementing it in the geriatric rehabilitation setting.

Objectives Neurodegeneration in suspected Alzheimer’s disease can be determined using visual rating or quantitative volumetric assessments. We examined the feasibility of volumetric measurements of gray matter (GMV) and hippocampal volume (HCV) and compared their diagnostic performance with visual rating scales in academic and non-academic memory clinics. Materials and methods We included 231 patients attending local memory clinics (LMC) in the Netherlands and 501 of the academic Amsterdam Dementia Cohort (ADC). MRI scans were acquired using local protocols, including a T1-weighted sequence. Quantification of GMV and HCV was performed using FSL and FreeSurfer. Medial temporal atrophy and global atrophy were assessed with visual rating scales. ROC curves were derived to determine which measure discriminated best between cognitively normal (CN), mild cognitive impairment (MCI), and Alzheimer’s dementia (AD). Results Patients attending LMC (age 70.9 ± 8.9 years; 47% females; 19% CN; 34% MCI; 47% AD) were older, had more cerebrovascular pathology, and had lower GMV and HCV compared to those of the ADC (age 64.9 ± 8.2 years; 42% females; 35% CN, 43% MCI, 22% AD). While visual ratings were feasible in > 95% of scans in both cohorts, quantification was achieved in 94–98% of ADC, but only 68–85% of LMC scans, depending on the software. Visual ratings and volumetric outcomes performed similarly in discriminating CN vs AD in both cohorts. Conclusion In clinical settings, quantification of GM and hippocampal atrophy currently fails in up to one-third of scans, probably due to lack of standardized acquisition protocols. Diagnostic accuracy is similar for volumetric measures and visual rating scales, making the latter suited for clinical practice. Summary statement In a real-life clinical setting, volumetric assessment of MRI scans in dementia patients may require acquisition protocol optimization and does not outperform visual rating scales. Key Points • In a real-life clinical setting, the diagnostic performance of visual rating scales is similar to that of automatic volumetric quantification and may be sufficient to distinguish Alzheimer’s disease groups. • Volumetric assessment of gray matter and hippocampal volumes from MRI scans of patients attending non-academic memory clinics fails in up to 32% of cases. • Clinical MR acquisition protocols should be optimized to improve the output of quantitative software for segmentation of Alzheimer’s disease–specific outcomes.

In the general population with COVID-19, the male sex is an established risk factor for mortality, in part due to a more robust immune response to COVID-19 in women. Because patients on kidney function replacement therapy (KFRT) have an impaired immune response, especially kidney transplant recipients due to their use of immunosuppressants, we examined whether the male sex is still a risk factor for mortality among patients on KFRT with COVID-19. From the European Renal Association COVID-19 Database (ERACODA), we examined patients on KFRT with COVID-19 who presented between February 1st, 2020, and April 30th, 2021. 1204 kidney transplant recipients (male 62.0%, mean age 56.4 years) and 3206 dialysis patients (male 61.8%, mean age 67.7 years) were examined. Three-month mortality in kidney transplant recipients was 16.9% in males and 18.6% in females (p = 0.31) and in dialysis patients 27.1% in males and 21.9% in females (p = 0.001). The adjusted HR for the risk of 3-month mortality in males (vs females) was 0.89 (95% CI 65, 1.23, p = 0.49) in kidney transplant recipients and 1.33 (95% CI 1.13, 1.56, p = 0.001) in dialysis patients (pinteraction = 0.02). In a fully adjusted model, the aHR for the risk of 3-month mortality in kidney transplant recipients (vs. dialysis patients) was 1.39 (95% CI 1.02, 1.89, p = 0.04) in males and 2.04 (95% CI 1.40, 2.97, p interaction = 0.02). In patients on KFRT with COVID-19, the male sex is not a risk factor for mortality among kidney transplant recipients but remains a risk factor among dialysis patients. The use of immunosuppressants in kidney transplant recipients, among other factors, may have narrowed the difference in the immune response to COVID-19 between men and women, and therefore reduced the sex difference in COVID-19 mortality risk.