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Background: Microbiota alterations are common in patients hospitalised for severe infections, and preclinical models have shown that anaerobic butyrate-producing gut bacteria protect against systemic infections. However, the relationship between microbiota disruptions and increased susceptibility to severe infections in humans remains unclear. We investigated the relationship between gut microbiota and the risk of future infection-related hospitalisation in two large population-based cohorts., Methods: In this observational microbiome study, gut microbiota were characterised using 16S rRNA gene sequencing in independent population-based cohorts from the Netherlands (HELIUS study; derivation cohort) and Finland (FINRISK 2002 study; validation cohort). HELIUS was conducted in Amsterdam, Netherlands, and included adults (aged 18-70 years at inclusion) who were randomly sampled from the municipality register of Amsterdam. FINRISK 2002 was conducted in six regions in Finland and is a population survey that included a random sample of adults (aged 25-74 years). In both cohorts, participants completed questionnaires, underwent a physical examination, and provided a faecal sample at inclusion (Jan 3, 2013, to Nov 27, 2015, for HELIUS participants and Jan 21 to April 19, 2002, for FINRISK participants. For inclusion in our study, a faecal sample needed to be provided and successfully sequenced, and national registry data needed to be available. Primary predictor variables were microbiota composition, diversity, and relative abundance of butyrate-producing bacteria. Our primary outcome was hospitalisation or mortality due to any infectious disease during 5-7-year follow-up after faecal sample collection, based on national registry data. We examined associations between microbiota and infection risk using microbial ecology and Cox proportional hazards., Findings: We profiled gut microbiota from 10 699 participants (4248 [39·7%] from the derivation cohort and 6451 [60·3%] from the validation cohort). 602 (5·6%) participants (152 [3·6%] from the derivation cohort; 450 [7·0%] from the validation cohort) were hospitalised or died due to infections during follow-up. Gut microbiota composition of these participants differed from those without hospitalisation for infections (derivation p=0·041; validation p=0·0002). Specifically, higher relative abundance of butyrate-producing bacteria was associated with a reduced risk of hospitalisation for infections (derivation cohort cause-specific hazard ratio 0·75 [95% CI 0·60-0·94] per 10% increase in butyrate producers, p=0·013; validation cohort 0·86 [0·77-0·96] per 10% increase, p=0·0077). These associations remained unchanged following adjustment for demographics, lifestyle, antibiotic exposure, and comorbidities., Interpretation: Gut microbiota composition, specifically colonisation with butyrate-producing bacteria, was associated with protection against hospitalisation for infectious diseases in the general population across two independent European cohorts. Further studies should investigate whether modulation of the microbiome can reduce the risk of severe infections., Funding: Amsterdam UMC, Porticus, National Institutes of Health, Netherlands Organisation for Health Research and Development (ZonMw), and Leducq Foundation., Competing Interests: Declaration of interests DM owns stock in and is a consultant for Biomesense. AHMvdZ reports grants from Health Hjolland, GSK, Boehringer Ingelheim, and Vertx; consulting fees from Boehringer Ingelheim and AstraZeneca; and honoraria from GSK, all outside the submitted work; and is a chair of the data safety monitoring board of a study on bronchopulmonary dysplasia in neonates. B-JvdB is the chair of the cardiovasular theme of HELIUS, the Netherlands Society of Hypertension, and Amsterdam Cardiovascular Sciences; and participates on the committee of the Dutch Cardiovascular Alliance. RK is on the Scientific Advisory Board of Gencirq, Cybele, DayTwo, Biomesense, and Micronoma; owns stock in Gencirq, Cybele, Biomesense, Micronoma, and Biota; is a consultant for DayTwo and Biomesense; and is a cofounder of Micronoma and Biota. MN is on the Scientific Advisory Board of Caelus Pharmaceuticals. TN reports grants from the Finnish Research Council, Emil Aaltonen Foundation, Sigrid Jusélius Foundation, and Finnish Foundation for Cardiovascular Research; and honoraria from Servier Finland and AstraZeneca. WJW reports grants from ZonMw/NWO and EU (Eurostars); and ad hoc consultancy for AstraZeneca and Shionogi, outside the submitted work. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The aetiology of idiopathic nephrotic syndrome (INS) remains partially unknown. Viral infections have been associated with INS onset. Since we observed fewer first onset INS cases during the Covid-19 pandemic, we hypothesised that lower INS incidence was the result of lockdown measures. Therefore, the aim of this study was to evaluate the incidence of childhood INS before and during the COVID-19 pandemic in two independent European INS cohorts., Methods: Children with new INS in the Netherlands (2018-2021) and Paris area (2018-2021) were included. We estimated incidences using census data for each region. Incidences were compared using two proportion Z-tests., Results: A total of 128 and 324 cases of first onset INS were reported in the Netherlands and Paris area, respectively, corresponding to an annual incidence of 1.21 and 2.58 per 100,000 children/year. Boys and young children (< 7 years) were more frequently affected. Incidence before and during the pandemic did not differ. When schools were closed, incidence was lower in both regions: 0.53 vs. 1.31 (p = 0.017) in the Netherlands and 0.94 vs. 2.63 (p = 0.049) in the Paris area. During peaks of hospital admissions for Covid-19, no cases were reported in the Netherlands or Paris area., Conclusions: Incidence of INS before and during the Covid-19 pandemic was not different, but when schools were closed during lockdown, incidence was significantly lower. Interestingly, incidences of other respiratory viral infections were also reduced as was air pollution. Together, these results argue for a link between INS onset and viral infections and/or environmental factors. A higher resolution version of the Graphical abstract is available as Supplementary information., (© 2023. The Author(s).)

Chronic kidney disease (CKD) has been recognized as a highly prevalent risk factor for both the severity of coronavirus disease 2019 (COVID-19) and COVID-19 associated adverse outcomes. In this multicenter observational cohort study, we aim to determine mortality and readmission rates of patients hospitalized for COVID-19 across varying CKD stages. We performed a multicenter cohort study among COVID-19 patients included in the Dutch COVIDPredict cohort. The cohort consists of hospitalized patients from March 2020 until July 2021 with PCR-confirmed SARS-CoV-2 infection or a highly suspected CT scan-based infection with a CORADS score ≥ 4. A total of 4151 hospitalized COVID-19 patients were included of who 389 had a history of CKD before admission. After adjusting for all confounding covariables, in patients with CKD stage 3a, stage 3b, stage 4 and patients with KTX (kidney transplantation), odds ratios of death and readmission compared to patients without CKD ranged from 1.96 to 8.94. We demonstrate an evident increased 12-week mortality and readmission rate in patients with chronic kidney disease. Besides justified concerns for kidney transplant patients, clinicians should also be aware of more severe COVID-19 outcomes and increased vulnerability in CKD patients., (© 2022. The Author(s).)

Objectives: Plasma ferritin levels above 4,420 ng/mL have been proposed as a diagnostic marker for macrophage activation-like syndrome in sepsis and used for selection of sepsis patients for anti-inflammatory therapy. We here sought to determine the frequency, presentation, outcome, and host response aberrations of macrophage activation-like syndrome, as defined by admission ferritin levels above 4,420 ng/mL, in critically ill patients with community-acquired pneumonia., Design: A prospective observational cohort study., Setting: ICUs in two tertiary hospitals in the Netherlands., Patients: One hundred fifty-three patients admitted with community-acquired pneumonia., Measurements and Main Results: Patients were stratified in community-acquired pneumonia-macrophage activation-like syndrome (n = 15; 9.8%) and community-acquired pneumonia-control groups (n = 138; 90.2%) based on an admission plasma ferritin level above or below 4,420 ng/mL, respectively. Community-acquired pneumonia-macrophage activation-like syndrome patients presented with a higher disease severity and had a higher ICU mortality (46.7% vs 12.3% in community-acquired pneumonia-controls; p = 0.002). Twenty-three plasma biomarkers indicative of dysregulation of key host response pathways implicated in sepsis pathogenesis (systemic inflammation, cytokine responses, endothelial cell activation, and barrier function, coagulation activation) were more disturbed in community-acquired pneumonia-macrophage activation-like syndrome patients. Hematologic malignancies were overrepresented in community-acquired pneumonia-macrophage activation-like syndrome patients (33.3% vs 5.1% in community-acquired pneumonia-controls; p = 0.001). In a subgroup analysis excluding patients with hematologic malignancies (n = 141), differences in mortality were not present anymore, but the exaggerated host response abnormalities in community-acquired pneumonia-macrophage activation-like syndrome patients remained., Conclusions: Macrophage activation-like syndrome in critically ill patients with community-acquired pneumonia occurs more often in patients with hematologic malignancies and is associated with deregulation of multiple host response pathways., Competing Interests: Dr. Brands received funding from the Netherlands Organization for Health Research and Development (ZonMW number 50-53000-98-139). Dr. Peters-Sengers received funding from the Dutch Kidney Foundation (Kolff Grant Nr. 19OK009). Dr. van Engelen received funding from the Amsterdam Medical Center PhD Scholarship. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Purpose: Sepsis is the most frequent cause of acute kidney injury (AKI). The "Acute Disease Quality Initiative Workgroup" recently proposed new definitions for AKI, classifying it as transient or persistent. We investigated the incidence, mortality, and host response aberrations associated with transient and persistent AKI in sepsis patients., Methods: A total of 1545 patients admitted with sepsis to 2 intensive care units in the Netherlands were stratified according to the presence (defined by any urine or creatinine RIFLE criterion within the first 48 h) and evolution of AKI (with persistent defined as remaining > 48 h). We determined 30-day mortality by logistic regression adjusting for confounding variables and analyzed 16 plasma biomarkers reflecting pathways involved in sepsis pathogenesis (n = 866) and blood leukocyte transcriptomes (n = 392)., Results: AKI occurred in 37.7% of patients, of which 18.4% was transient and 81.6% persistent. On admission, patients with persistent AKI had higher disease severity scores and more frequently had severe (injury or failure) RIFLE AKI stages than transient AKI patients. Persistent AKI, but not transient AKI, was associated with increased mortality by day 30 and up to 1 year. Persistent AKI was associated with enhanced and sustained inflammatory and procoagulant responses during the first 4 days, and a more severe loss of vascular integrity compared with transient AKI. Baseline blood gene expression showed minimal differences with respect to the presence or evolution of AKI., Conclusion: Persistent AKI is independently associated with sepsis mortality, as well as with sustained inflammatory and procoagulant responses, and loss of vascular integrity as compared with transient AKI.

Objectives: Contradictory results have been reported regarding the association between polycystic ovary syndrome (PCOS) and cardiovascular disease (CVD). We assessed the cardiometabolic phenotype and prevalence of CVD in middle-aged women with PCOS, compared with age-matched controls from the general population, and estimated 10-year CVD risk and cardiovascular health score., Design: A cross-sectional study., Participants: 200 women aged >45 with PCOS, and 200 age-matched controls., Measurements: Anthropometrics, insulin, lipid levels, prevalence of metabolic syndrome and type II diabetes. Ten-year Framingham risk score and the cardiovascular health score were calculated, and carotid intima-media thickness (cIMT) was measured., Results: Mean age was 50.5 years (SD = 5.5) in women with PCOS and 51.0 years (SD = 5.2) in controls. Increased waist circumference, body mass index and hypertension were more often observed in women with PCOS (P < .001). In women with PCOS, the prevalence of type II diabetes and metabolic syndrome was not significantly increased and lipid levels were not different from controls. cIMT was lower in women with PCOS (P < .001). Calculated cardiovascular health and 10-year CVD risk were similar in women with PCOS and controls., Conclusions: Middle-aged women with PCOS exhibit only a moderately unfavourable cardiometabolic profile compared to age-matched controls, even though they present with an increased BMI and waist circumference. Furthermore, we found no evidence for increased (10-year) CVD risk or more severe atherosclerosis compared with controls from the general population. Long-term follow-up of women with PCOS is necessary to provide a definitive answer concerning long-term risk for CVD., (© 2019 The Authors. Clinical Endocrinology published by John Wiley & Sons Ltd.)

Background: Delayed graft function (DGF) is a common complication after kidney transplantation in the era of accepting an equal number of brain- and circulatory-death donor kidneys in the Netherlands. To identify those cases with an increased risk of developing DGF, various multivariable algorithms have been proposed. The objective was to validate the reproducibility of four predictive algorithms by Irish et al. (A risk prediction model for delayed graft function in the current era of deceased donor renal transplantation. Am J Transplant 2010;10:2279-2286) (USA), Jeldres et al. (Prediction of delayed graft function after renal transplantation. Can Urol Assoc J 2009;3:377-382) (Canada), Chapal et al. (A useful scoring system for the prediction and management of delayed graft function following kidney transplantation from cadaveric donors. Kidney Int 2014;86:1130-1139) (France) and Zaza et al. (Predictive model for delayed graft function based on easily available pre-renal transplant variables. Intern Emerg Med 2015;10:135-141) (Italy) according to a novel framework for external validation., Methods: We conducted a prospective observational study with data from the Dutch Organ Transplantation Registry (NOTR). Renal transplant recipients from all eight Dutch academic medical centers between 2002 and 2012 who received a deceased allograft were included (N = 3333). The four prediction algorithms were reconstructed from donor, recipient and transplantation data. Their predictive value for DGF was validated by c-statistics, calibration statistics and net benefit analysis. Case-mix (un)relatedness was investigated with a membership model and mean and standard deviation of the linear predictor., Results: The prevalence of DGF was 37%. Despite a significantly different case-mix, the US algorithm by Irish was best reproducible, with a c-index of 0.761 (range 0.756 - 0.762), and well-calibrated over the complete range of predicted probabilities of having DGF. The US model had a net benefit of 0.242 at a threshold probability of 0.25, compared with 0.089 net benefit for the same threshold in the original study, equivalent to correctly identifying DGF in 24 cases per 100 patients (true positive results) without an increase in the number of false-positive results., Conclusions: The US model by Irish et al. was generalizable and best transportable to Dutch recipients with a deceased donor kidney. The algorithm detects an increased risk of DGF after allocation and enables us to improve individual patient management.

Objectives: To assess the incidence of head injury and predictors of complication across the care continuum., Design: Retrospective cohort study using data from a research network. We calculated the incidence of overall head injury in a longitudinal cohort covering 1-year interval (31 369 patient-years), and the incidence of complicated head injury in a longitudinal cohort covering 10 years interval (220 352 patient-ears). Incidence rates were calculated per 1000 patient-years with 95% CI using the Mid-P exact test. We calculated ORs to assess potential risk factors for a complicated head injury., Setting: A practice-based research network covering a population of >30 000 patients., Participants: All patients listed in practices within the research network during the years 2005-2014., Main Outcome Measures: Incidence of (complicated) head injury and predictors for clinical complications., Results: The incidence of overall head injury was 22.1 per 1000 person-years and the incidence of a complicated course following head injury was 0.16 per 1000 person-years. The following determinants were risk factors for a complicated course: high energy trauma, bicycle accident, traffic accident in general, use of anticoagulants, alcohol intoxication, age above 60 years and low Glasgow Coma Scale at initial presentation. A complicated course was very unlikely when the patients' first encounter with a healthcare professional was in primary care (OR 0.03, 95% CI 0.01 to 0.07)., Conclusions: Complication after head injury are rarely seen in general practice. Patients who do experience complications are often easily identifiable as requiring specialist care. A more reserved referral policy for general practice may be desirable, suggesting that current guidelines are too defensive., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objectives: The main objective of this article is to demonstrate the usefulness of dynamic modeling for an economic assessment of technology in health care. Specifically, this approach is applied to assess the impact of the use of hearing aids in Dutch health care., Methods: The population is divided into different health classes between which, over time, transitions occur. Transition probabilities are derived from exogenous data. The transitions are associated with economic and societal costs and benefits. People who are satisfied with their hearing aids experience benefits. These benefits are expressed by quality-adjusted life-years (QALYs). Costs are made during transitions (mainly the fitting of hearing aids). A cohort analysis is carried out, starting with people in a particular age group. The starting point is a fixed number of people within this age group, who are followed during their whole lifetime., Results: Costs per QALY ratios are calculated for two health programs. The Fitting Hearing Aid Program describes the present situation in the Netherlands; the Post-purchase Counseling Hearing Aid Program is a hypothetical addition to the first program, where an intervention based on a Dutch study is undertaken to improve satisfaction with hearing aids. Future benefits and costs are discounted at a rate of 5%., Conclusions: The dynamic modeling approach provides a more realistic picture than a static approach. Particularly, the cost-effectiveness of the Fitting Hearing Aid Program is compared with the Post-purchase Counseling Hearing Aid Program.