Trimethylamine N-oxide (TMAO) is a circulating microbiome-derived metabolite implicated in the development of atherosclerosis and cardiovascular disease (CVD). We investigated whether plasma levels... Show moreTrimethylamine N-oxide (TMAO) is a circulating microbiome-derived metabolite implicated in the development of atherosclerosis and cardiovascular disease (CVD). We investigated whether plasma levels of TMAO, its precursors (betaine, carnitine, deoxycarnitine, choline), and TMAO-to-precursor ratios are associated with clinical outcomes, including CVD and mortality. This was followed by an in-depth analysis of their genetic, gut microbial, and dietary determinants. The analyses were conducted in five Dutch prospective cohort studies including 7834 individuals. To further investigate association results, Mendelian Randomization (MR) was also explored. We found only plasma choline levels (hazard ratio [HR] 1.17, [95% CI 1.07; 1.28]) and not TMAO to be associated with CVD risk. Our association analyses uncovered 10 genome-wide significant loci, including novel genomic regions for betaine (6p21.1, 6q25.3), choline (2q34, 5q31.1), and deoxycarnitine (10q21.2, 11p14.2) comprising several metabolic gene associations, for example, CPS1 or PEMT. Furthermore, our analyses uncovered 68 gut microbiota associations, mainly related to TMAO-to-precursors ratios and the Ruminococcaceae family, and 16 associations of food groups and metabolites including fish-TMAO, meat-carnitine, and plant-based food-betaine associations. No significant association was identified by the MR approach. Our analyses provide novel insights into the TMAO pathway, its determinants, and pathophysiological impact on the general population. Show less
Jansma, A.; Bresser, J. de; Schoones, J.W.; Heemst, D. van; Akintola, A.A. 2024
We performed a systematic review and meta-analysis on prospective studies that provided risk estimates for the impact of 3 different MRI markers of small vessel disease (SVD), namely white matter... Show moreWe performed a systematic review and meta-analysis on prospective studies that provided risk estimates for the impact of 3 different MRI markers of small vessel disease (SVD), namely white matter hyperintensities (WMH), cerebral microbleeds (CMB) and lacunes, on cognitive decline in relatively healthy older adults without cognitive deficits at baseline. A total of 23 prospective studies comprising 11,486 participants were included for analysis. Extracted data was pooled, reviewed and meta-analysed separately for global cognition, executive function, memory and attention. The pooled effect size for the association between cerebral SVD and cognitive decline was for global cognition -0.10 [-0.14; -0.05], for executive functioning -0.18 [-0.24; - 0.11], for memory -0.12 [-0.17; -0.07], and for attention -0.17 [-0.23; -0.11]. Results for the association of individual MRI markers of cerebral SVD were statistically significant for WMH and global cognition -0.15 [-0.24; -0.06], WMH and executive function -0.23 [-0.33; -0.13], WMH and memory -0.19 [-0.29; -0.09], WMH and attention -0.24 [-0.39; -0.08], CMB and executive function -0.07 [-0.13; -0.02], CMB and memory -0.11 [-0.21; -0.02] and CMB and attention -0.13 [-0.25; -0.02]. In conclusion, presence of MRI markers of cerebral SVD were found to predict an increased risk of cognitive decline in relatively healthy older adults. While WMH were found to significantly affect all cognitive domains, CMB influenced decline in executive functioning over time as well as (in some studies) decline in memory and attention. Show less
Klei, V.M.G.T.H. van der; Poortvliet, R.K.E.; Bogaerts, J.M.K.; Blom, J.W.; Mooijaart, S.P.; Teh, R.; ... ; Gussekloo, J. 2022
Objectives: Previous findings suggest a vascular foundation underlying apathy, but transdiagnostic and prospective evidence on vascular apathy is scarce. This study examines the association between... Show moreObjectives: Previous findings suggest a vascular foundation underlying apathy, but transdiagnostic and prospective evidence on vascular apathy is scarce. This study examines the association between vascular disease and the presence and development of apathy symptoms in the very old.Methods: Four cohorts of the Towards Understanding Longitudinal International older People Studies (TULIPS)-consortium were included in a two-staged, individual participant data meta-analysis using generalized linear mixed models, Vascular disease was defined as a history of any clinical atherosclerotic pathology (angina pectoris, myocardial infarction, intermittent claudication, transient ischemic attack, stroke or related surgeries) and was related to apathy symptoms as repeatedly measured by the Geriatric Depression Scale (GDS-3A >= 2) over a maximum of 5 years.Results: Of all 1868 participants (median age 85 years old), 53.9% had vascular disease and 44.3% experienced apathy symptoms. Participants with vascular disease had a 76% higher risk of apathy symptoms at baseline (odds ratio (OR) 1.76, 95% confidence interval (CI) 1.32-2.35), irrespective of depressive symptoms and only partially explained by stroke. Conversely, there was no association of vascular disease with the occurrence of apathy symptoms longitudinally, both in those with apathy at baseline (OR 1.00, 95% CI 0.84-1.20) and without (OR 0.96, 95% CI 0.841.09).Conclusions: Vascular disease in the very old is associated with apathy symptoms cross-sectionally, but not proven longitudinally, independent of depressive symptoms. These findings query a vascular cause underlying apathy symptoms. However, the consistency of our cross-sectional findings in direction and magnitude across the TULIPS-consortium do emphasize international relevance of the interplay of vascular factors and apathy in advanced age, which meaning needs further unravelling. Show less
Background: Venous thromboembolism (VTE) is a life-threatening vascular event with environmental and genetic determinants. Recent VTE genome-wide association studies (GWAS) meta-analyses involved... Show moreBackground: Venous thromboembolism (VTE) is a life-threatening vascular event with environmental and genetic determinants. Recent VTE genome-wide association studies (GWAS) meta-analyses involved nearly 30 000 VTE cases and identified up to 40 genetic loci associated with VTE risk, including loci not previously suspected to play a role in hemostasis. The aim of our research was to expand discovery of new genetic loci associated with VTE by using cross-ancestry genomic resources. Methods: We present new cross-ancestry meta-analyzed GWAS results involving up to 81 669 VTE cases from 30 studies, with replication of novel loci in independent populations and loci characterization through in silico genomic interrogations. Results: In our genetic discovery effort that included 55 330 participants with VTE (47 822 European, 6320 African, and 1188 Hispanic ancestry), we identified 48 novel associations, of which 34 were replicated after correction for multiple testing. In our combined discovery-replication analysis (81 669 VTE participants) and ancestry-stratified meta-analyses (European, African, and Hispanic), we identified another 44 novel associations, which are new candidate VTE-associated loci requiring replication. In total, across all GWAS meta-analyses, we identified 135 independent genomic loci significantly associated with VTE risk. A genetic risk score of the significantly associated loci in Europeans identified a 6-fold increase in risk for those in the top 1% of scores compared with those with average scores. We also identified 31 novel transcript associations in transcriptome-wide association studies and 8 novel candidate genes with protein quantitative-trait locus Mendelian randomization analyses. In silico interrogations of hemostasis and hematology traits and a large phenome-wide association analysis of the 135 GWAS loci provided insights to biological pathways contributing to VTE, with some loci contributing to VTE through well-characterized coagulation pathways and others providing new data on the role of hematology traits, particularly platelet function. Many of the replicated loci are outside of known or currently hypothesized pathways to thrombosis. Conclusions: Our cross-ancestry GWAS meta-analyses identified new loci associated with VTE. These findings highlight new pathways to thrombosis and provide novel molecules that may be useful in the development of improved antithrombosis treatments. Show less
BACKGROUND The clinical course of patients with moderate aortic stenosis (AS) remains incompletely defined.OBJECTIVES This study sought to analyze the clinical course of moderate AS and compare it... Show moreBACKGROUND The clinical course of patients with moderate aortic stenosis (AS) remains incompletely defined.OBJECTIVES This study sought to analyze the clinical course of moderate AS and compare it with other stages of the disease.METHODS Multiple electronic databases were searched to identify studies on adult moderate AS. Random-effects models were used to derive pooled estimates. The primary endpoint was all-cause death. The secondary endpoints were cardiac death, heart failure, sudden death, and aortic valve replacement.RESULTS Among a total of 25 studies (12,143 moderate AS patients, 3.7 years of follow-up), pooled rates per 100 person-years were 9.0 (95% CI: 6.9 to 11.7) for all-cause death, 4.9 (95% CI: 3.1 to 7.5) for cardiac death, 3.9 (95% CI: 1.9 to 8.2) for heart failure, 1.1 (95% CI: 0.8 to 1.5) for sudden death, and 7.2 (95% CI: 4.3 to 12.2) for aortic valve replacement. Meta-regression analyses detected that diabetes (P = 0.019), coronary artery disease (P = 0.017), presence of symptoms (P < 0.001), and left ventricle (LV) dysfunction (P = 0.009) were associated with a significant impact on the overall estimate of all-cause death. All-cause mortality was higher in patients with reduced LV ejection fraction (<50%) than with normal LV ejection fraction: 16.5 (95% CI: 5.2 to 52.3) and 4.2 (95% CI: 1.4 to 12.8) per 100 person-years, respectively. Compared with moderate AS, the incidence rate difference of all-cause mortality was-3.9 (95% CI:-6.7 to-1.1) for no or mild AS and +2.2 (95% CI: +0.8 to +3.5) for severe AS patients.CONCLUSIONS Moderate AS appears to be associated with a mortality risk higher than no or mild AS but lower than severe AS, which increases in specific population subsets. The impact of early intervention in moderate AS patients having high-risk features deserves further investigation. (C) 2022 by the American College of Cardiology Foundation. Show less
Background: Coagulation abnormalities and coagulopathy are recognized as consequences of severe acute respiratory syndrome coronavirus 2 infection and the resulting coronavirus disease 2019 (COVID... Show moreBackground: Coagulation abnormalities and coagulopathy are recognized as consequences of severe acute respiratory syndrome coronavirus 2 infection and the resulting coronavirus disease 2019 (COVID-19). Specifically, venous thromboembolism (VTE) has been reported as a frequent complication. By May 27, 2021, at least 93 original studies and 25 meta-analyses investigating VTE incidence in patients with COVID-19 had been published, showing large heterogeneity in reported VTE incidence ranging from 0% to 85%. This large variation complicates interpretation of individual study results as well as comparisons across studies, for example, to investigate changes in incidence over time, compare subgroups, and perform meta-analyses. Objectives: This study sets out to provide an overview of sources of heterogeneity in VTE incidence studies in patients with COVID-19, illustrated using examples. Methods: The original studies of three meta-analyses were screened and a list of sources of heterogeneity that may explain observed heterogeneity across studies was composed. Results: The sources of heterogeneity in VTE incidence were classified as clinical sources and methodologic sources. Clinical sources of heterogeneity include differences between studies regarding patient characteristics that affect baseline VTE risk and protocols used for VTE testing. Methodologic sources of heterogeneity include differences in VTE inclusion types, data quality, and the methods used for data analysis. Conclusions: To appreciate reported estimates of VTE incidence in patients with COVID-19 in relation to its etiology, prevention, and treatment, researchers should unambiguously report about possible clinical and methodological sources of heterogeneity in those estimates. This article provides suggestions for that. Show less
Cushing's syndrome is a rare disease with an endogenous cause of excess cortisol secretion. More evidence substantially links cortisol levels to the pachychoroid spectrum diseases. In this... Show moreCushing's syndrome is a rare disease with an endogenous cause of excess cortisol secretion. More evidence substantially links cortisol levels to the pachychoroid spectrum diseases. In this systematic review and meta-analysis, we summarize available evidence on pachychoroid spectrum diseases in patients with Cushing's syndrome. We performed a systematic literature search in 11 databases on 21 May 2022. Studies were considered eligible if they performed retinal examination of a consecutive group of patients with Cushing's syndrome using optical coherence tomography (OCT) scans. We extracted data on subfoveal choroidal thickness in patients with Cushing's syndrome compared to matched controls. We also extracted data on the prevalence of pachychoroid pigment epitheliopathy (PPE), central serous chorioretinopathy (CSC), and polypoidal choroidal vasculopathy (PCV). We identified six eligible studies with a total of 159 patients with Cushing's syndrome. On average, patients with Cushing's syndrome have 49.5 mu m thicker subfoveal choroidal thickness compared to matched healthy individuals. Pachychoroid spectrum diseases were relatively common in these patients: PPE in 20.8%, CSC in 7.7%, and PCV in 2.8%. We conclude that there should be low threshold to recommend ophthalmic examination to patients with Cushing's syndrome, and that a macular OCT is recommended during this examination. Show less
The purpose of this study was to provide an estimate of the number of current and future patients with polypoidal choroidal vasculopathy (PCV) in Europe. We systematically searched 11 literature... Show moreThe purpose of this study was to provide an estimate of the number of current and future patients with polypoidal choroidal vasculopathy (PCV) in Europe. We systematically searched 11 literature databases on 18 May 2022 for studies on the prevalence of PCV among a consecutive and representative group of patients with suspected neovascular age-related macular degeneration (AMD). Prevalence of PCV in patients with suspected neovascular AMD was summarized and included in a prevalence meta-analysis. We then used current population data and population forecasts by Eurostat and the Office for National Statistics to determine current and future number of patients with neovascular AMD in Europe. Then, we calculated the number of patients with PCV with our calculated estimate of the prevalence of PCV among Europeans suspected with neovascular AMD. A total of five eligible studies were identified which included a total of 1359 patients. All these studies used the gold standard of indocyanine green angiography as a routine part of their diagnostic approach. Among patients undergoing detailed retinal examination for suspected neovascular AMD, our meta-analysis calculated the prevalence of PCV to be 8.3% (95% confidence interval: 6.8-9.8%). Our population estimates find that a total of 217,404 patients with PCV exist in Europe in the year 2022, which constitutes 0.04% of the entire population of Europe. This number is estimated to increase to 287,517 patients in the year 2040. Our estimates are important for different healthcare stakeholders, especially when planning and allocating expensive resources. Show less
Background: The knowledge of factors influencing disease progression in patients with established coronary heart disease (CHD) is still relatively limited. One potential pathway is related to... Show moreBackground: The knowledge of factors influencing disease progression in patients with established coronary heart disease (CHD) is still relatively limited. One potential pathway is related to peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PPARGC1A), a transcription factor linked to energy metabolism which may play a role in the heart function. Thus, its associations with subsequent CHD events remain unclear. We aimed to investigate the effect of three different SNPs in the PPARGC1A gene on the risk of subsequent CHD in a population with established CHD. Methods: We employed an individual-level meta-analysis using 23 studies from the GENetIcs of sUbSequent Coronary Heart Disease (GENIUS-CHD) consortium, which included participants (n = 80,900) with either acute coronary syndrome, stable CHD, or a mixture of both at baseline. Three variants in the PPARGC1A gene (rs8192678, G482S; rs7672915, intron 2; and rs3755863, T528T) were tested for their associations with subsequent events during the follow-up using a Cox proportional hazards model adjusted for age and sex. The primary outcome was subsequent CHD death or myocardial infarction (CHD death/myocardial infarction). Stratified analyses of the participant or study characteristics as well as additional analyses for secondary outcomes of specific cardiovascular disease diagnoses and all-cause death were also performed. Results: Meta-analysis revealed no significant association between any of the three variants in the PPARGC1A gene and the primary outcome of CHD death/myocardial infarction among those with established CHD at baseline: rs8192678, hazard ratio (HR): 1.01, 95% confidence interval (CI) 0.98-1.05 and rs7672915, HR: 0.97, 95% CI 0.94-1.00; rs3755863, HR: 1.02, 95% CI 0.99-1.06. Similarly, no significant associations were observed for any of the secondary outcomes. The results from stratified analyses showed null results, except for significant inverse associations between rs7672915 (intron 2) and the primary outcome among 1) individuals aged >= 65, 2) individuals with renal impairment, and 3) antiplatelet users. Conclusion: We found no clear associations between polymorphisms in the PPARGC1A gene and subsequent CHD events in patients with established CHD at baseline. Show less
Aliasi, M.; Snoep, M.C.; Geloven, N. van; Haak, M.C. 2022
Background Birthweight (BW) is an important prognostic factor in newborns with congenital heart defects (CHD). Objectives To give an overview of the literature on BW z-score in children with... Show moreBackground Birthweight (BW) is an important prognostic factor in newborns with congenital heart defects (CHD). Objectives To give an overview of the literature on BW z-score in children with isolated CHD. Search strategy A systematic search was performed on isolated CHD and BW in PubMed, Embase, Web of Science, COCHRANE Library and Emcare. Selection criteria Neonates with isolated CHD were included if a BW percentile, BW z-score or % small-or-gestational age (SGA) was reported. Data collection and analysis BW z-score and percentage SGA were pooled with random-effect meta-analysis. Quality and risk of bias were assessed using the modified Newcastle Ottawa Scale. Main results Twenty-three articles (27 893 cases) were included. BW z-scores were retrieved from 11 articles, resulting in a pooled z-score of -0.20 (95% CI -0.50 to 0.11). The overall pooled prevalence of SGA <10th percentile was 16.0% (95% CI 11.4-20.5; 14 studies). Subgroup analysis of major CHD showed similar results (BW z-score -0.23 and percentage SGA 16.2%). Conclusions Overall BW in isolated CHD is within range of normality but impaired, with a 1.6-fold higher risk of SGA, irrespective of the type of CHD (major CHD vs all CHD combined). Our findings underline the association between CHD and BW. The use of BW z-scores provides insight into growth of all fetuses with CHD. Show less
Purpose: Intravitreal injections and cataract surgery are two common procedures in the elderly. Posterior capsular rupture (PCR) is a rare but important complication of cataract surgery. We... Show morePurpose: Intravitreal injections and cataract surgery are two common procedures in the elderly. Posterior capsular rupture (PCR) is a rare but important complication of cataract surgery. We systematically reviewed the literature on previous intravitreal injections as a risk factor of PCR and performed meta-analyses to provide pooled summary risk estimates.Methods: We searched 13 literature databases on 1 June 2021 for studies evaluating the risk of PCR in eyes undergoing cataract surgery with data on previous intravitreal injections. Data extraction was made independently by two authors and discussed afterwards until reaching consensus. Random effects metaanalyses on the pooled odds ratio (OR) of PCR in eyes with previous intravitreal injections were made using MetaXL 5.3.Results: Six studies on 1 051 097 eyes undergoing cataract surgery were eligible for the qualitative and quantitative review. Previous history of intravitreal injections was present in 7034 eyes (majority was anti-VEGF). Our metaanalyses revealed that any previous intravitreal injection was a risk factor for PCR with an OR of 2.30 (95% CI 1.39-3.81). For each previous intravitreal injection, the risk of PCR was OR 1.04 (95% CI 1.01-1.08) (equivalent of relative risk similar to 1.04). In other words, risk of PCR increases by 4% for each previous intravitreal injection.Conclusions: Previous intravitreal injection is a risk factor for PCR and should be taken into account when planning cataract surgery. However, to be regarded as a clinically significant risk of PCR, a substantial number of previous intravitreal injection (e.g. >= 10) should have been administered, considering that the a priori risk of PCR is very low (similar to 1%). Show less
Several studies have analyzed gene expression profiles in the substantia nigra to better understand the pathological mechanisms causing Parkinson's disease (PD). However, the concordance between... Show moreSeveral studies have analyzed gene expression profiles in the substantia nigra to better understand the pathological mechanisms causing Parkinson's disease (PD). However, the concordance between the identified gene signatures in these individual studies was generally low. This might have been caused by a change in cell type composition as loss of dopaminergic neurons in the substantia nigra pars compacta is a hallmark of PD. Through an extensive meta-analysis of nine previously published microarray studies, we demonstrated that a big proportion of the detected differentially expressed genes was indeed caused by cyto-architectural alterations due to the heterogeneity in the neurodegenerative stage and/or technical artefacts. After correcting for cell composition, we identified a common signature that deregulated the previously unreported ammonium transport, as well as known biological processes such as bioenergetic pathways, response to proteotoxic stress, and immune response. By integrating with protein interaction data, we shortlisted a set of key genes, such as LRRK2, PINK1, PRKN, and FBXO7, known to be related to PD, others with compelling evidence for their role in neurodegeneration, such as GSK3 beta, WWOX, and VPC, and novel potential players in the PD pathogenesis. Together, these data show the importance of accounting for cyto-architecture in these analyses and highlight the contribution of multiple cell types and novel processes to PD pathology, providing potential new targets for drug development. Show less
Research links high blood pressure variability (BPV) with stroke and cerebrovascular disease, however, its association with cognition remains unclear. Moreover, it remains uncertain which BP... Show moreResearch links high blood pressure variability (BPV) with stroke and cerebrovascular disease, however, its association with cognition remains unclear. Moreover, it remains uncertain which BP-derived parameter (ie, variability or mean) holds more significance in understanding vascular contributions to cognitive impairment. We searched PubMed, Embase, PsycINFO, and Scopus and performed a meta-analysis of studies that quantified the association between resting BPV with dementia or cognitive impairment in adults. Two authors independently reviewed all titles, abstracts, and full-texts and extracted data, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Meta-Analysis of Observational Studies in Epidemiology guidelines. Study quality was assessed using the (modified) Newcastle-Ottawa Scale. A multilevel meta-analysis was used, which included effect sizes for both BPV and mean BP, with a combined end point of dementia or cognitive impairment as primary outcome. In the primary analysis, 54 effect sizes were extracted from 20 studies, with a total analytical sample of n=7 899 697. Higher systolic BPV (odds ratio [OR], 1.25 [95% CI, 1.16-1.35]), mean systolic pressure (OR, 1.12 [95% CI, 1.02-1.29]), diastolic BPV (OR, 1.20 [95% CI, 1.12-1.29]), and mean diastolic pressure (OR, 1.16 [95% CI, 1.04-1.29]) were associated with dementia and cognitive impairment. A direct comparison showed that mean BP effect sizes were less strong than BPV effect sizes (OR, 0.92 [95% CI, 0.87-0.97], P<0.01), indicating that the relative contribution of BPV exceeded that of mean BP. Methodological and statistical heterogeneity was high. Secondary analyses were less consistent as to whether BPV and mean BP were differentially associated with dementia subtypes and cognitive domains. Future studies are required to investigate BPV as a target for dementia prevention. Show less
Background. Immune checkpoint inhibitors (ICI) have been a breakthrough for selected cancer patients, including those with brain metastases (BMs). Likewise, steroids have been an integral component... Show moreBackground. Immune checkpoint inhibitors (ICI) have been a breakthrough for selected cancer patients, including those with brain metastases (BMs). Likewise, steroids have been an integral component of symptomatic management of BM patients. However, clinical evidence on the interaction between ICI and steroids in BM patients is conflicting and has not adequately been summarized thus far. Hence, the aim of this study was to perform a systematic literature review and meta-analysis on the association between steroid use and overall survival (OS) in BM patients receiving ICI.Methods. A systematic literature search was performed. Pooled effect estimates were calculated using randomeffects models across included studies.Results. After screening 1145 abstracts, 15 observational studies were included. Fourteen studies reported sufficient data for meta-analysis, comprising 1102 BM patients of which 32.1% received steroids. In the steroid group, median OS ranged from 2.9 to 10.2 months. In the nonsteroid group, median OS ranged from 4.9 to 25.1 months. Pooled results demonstrated significantly worse OS (HR = 1.84, 95% CI 1.22-2.77) and systemic progression-free survival (PFS; HR = 2.00, 95% CI 1.37-2.91) in the steroid group. Stratified analysis showed a consistent effect across the melanoma subgroup; not in the lung cancer subgroup. No significant association was shown between steroid use and intracranial PFS (HR = 1.31, 95% Cl 0.42-4.07).Conclusions. Administration of steroids was associated with significantly worse OS and PFS in BM patients receiving ICI. Further research on dose, timing, and duration of steroids is needed to elucidate the cause of this association and optimize outcomes in BM patients receiving ICI. Show less
Jong, Y. de; Ramspek, C.L.; Zoccali, C.; Jager, K.J.; Dekker, F.W.; Diepen, M. van 2021
Over the past few years, a large number of prediction models have been published, often of poor methodological quality. Seemingly objective and straightforward, prediction models provide a risk... Show moreOver the past few years, a large number of prediction models have been published, often of poor methodological quality. Seemingly objective and straightforward, prediction models provide a risk estimate for the outcome of interest, usually based on readily available clinical information. Yet, using models of substandard methodological rigour, especially without external validation, may result in incorrect risk estimates and consequently misclassification. To assess and combat bias in prediction research the prediction model risk of bias assessment tool (PROBAST) was published in 2019. This risk of bias (ROB) tool includes four domains and 20 signalling questions highlighting methodological flaws, and provides guidance in assessing the applicability of the model. In this paper, the PROBAST will be discussed, along with an in-depth review of two commonly encountered pitfalls in prediction modelling that may induce bias: overfitting and composite endpoints. We illustrate the prevalence of potential bias in prediction models with a meta-review of 50 systematic reviews that used the PROBAST to appraise their included studies, thus including 1510 different studies on 2104 prediction models. All domains showed an unclear or high ROB; these results were markedly stable over time, highlighting the urgent need for attention on bias in prediction research. This article aims to do just that by providing (1) the clinician with tools to evaluate the (methodological) quality of a clinical prediction model, (2) the researcher working on a review with methods to appraise the included models, and (3) the researcher developing a model with suggestions to improve model quality. Show less
Hulsker, C.C.C.; Mansori, I. el; Fiocco, M.; Zsiros, J.; Wijnen, M.H.W.; Looijenga, L.H.J.; ... ; Steeg, A.F.W. van der 2021
Simple Summary Germ cell tumours are a heterogeneous group of neoplasms and are predominantly midline tumours occurring from birth to late adulthood. Suboptimal outcomes remain for several groups... Show moreSimple Summary Germ cell tumours are a heterogeneous group of neoplasms and are predominantly midline tumours occurring from birth to late adulthood. Suboptimal outcomes remain for several groups of patients, including adolescents, and patients with extragonadal tumours, high tumour markers at diagnosis or platinum-resistant disease. The aim of our systematic review was to explore survival rates internationally over the past two decades in order to better define future practice and treatment strategies and also to define specific subgroups with inferior outcomes. The results of our systematic review describe the heterogeneous nature of germ cell tumours in different anatomical locations, impacting on stage at presentation, treatment modalities used and survival data. Despite this heterogeneity, subpopulations can be defined which have an inferior survival and where future research and more individualised treatment would help to improve survival. Objective: This systematic review and meta-analysis was performed to explore overall survival (OS) and event free survival (EFS) rates internationally over the past two decades and to define specific subgroups with inferior outcomes which may demand different treatment strategies. Methods: The search focused on malignant extracranial germ cell tumours (GCTs) in the paediatric population. The initial database search identified 12,556 articles; 32 articles were finally included in this review, comprising a total of 5095 patients. Results: The studies were heterogeneous, varying from single institution reports to large prospective trials. Older studies, describing eras where non-platinum-based chemotherapy regimens were used, showed clearly worse outcomes. Survival for stage I-II gonadal disease is excellent. On the other hand, patients with an initial alpha-fetoprotein (AFP) > 10,000 ng/mL or kU/L, age > 11 years and stage IV disease confer a survival disadvantage. For testicular disease in particular, lymphovascular invasion and certain histopathological subtypes, such as embryonal carcinoma (EC) and mixed malignant GCTs, survival is poorer. Survival data for sacrococcygeal and mediastinal GCTs show a heterogeneous distribution across studies in this review, independent of year of publication. Patients > 12 years presenting with a mediastinal GCT pose a subpopulation which fares worse than GCTs in other locations or age groups. This is independent of AFP levels, stage of disease or treatment protocol, and these patients may demand a different treatment strategy. Conclusions: This review describes the heterogeneous nature of GCTs in different anatomical locations, impacting on stage at presentation, treatment modalities used and survival data. Despite this heterogeneity, in line with the current developmental biology-based classification system, subpopulations can be defined which have an inferior EFS and OS and where future research and more individualised treatment would help to improve survival. Show less
The treatment of staphylococcal prosthetic joint infection (PJI) with debridement, antibiotics, and retention of the implant (DAIR) often results in failure. An important evidence gap concerns the... Show moreThe treatment of staphylococcal prosthetic joint infection (PJI) with debridement, antibiotics, and retention of the implant (DAIR) often results in failure. An important evidence gap concerns the treatment with rifampicin for PJI. A systematic review and meta-analysis were conducted to assess the outcome of staphylococcal hip and/or knee PJI after DAIR, focused on the role of rifampicin. Studies published until September 2, 2020 were included. Success rates were stratified for type of joint and type of micro-organism. Sixty-four studies were included. The pooled risk ratio for rifampicin effectiveness was 1.10 (95% confidence interval, 1.00-1.22). The pooled success rate was 69% for Staphylococcus aureus hip PJI, 54% for S aureus knee PJI, 83% for coagulase-negative staphylococci (CNS) hip PJI, and 73% for CNS knee PJI. Success rates for MRSA PJI (58%) were similar to MSSA PJI (60%). The metaanalysis indicates that rifampicin may only prevent a small fraction of all treatment failures. Show less
Low prosocial behavior in childhood has been consistently linked to later psychopathology, with evidence supporting the influence of both genetic and environmental factors on its development.... Show moreLow prosocial behavior in childhood has been consistently linked to later psychopathology, with evidence supporting the influence of both genetic and environmental factors on its development. Although neonatal DNA methylation (DNAm) has been found to prospectively associate with a range of psychological traits in childhood, its potential role in prosocial development has yet to be investigated. This study investigated prospective associations between cord blood DNAm at birth and low prosocial behavior within and across four longitudinal birth cohorts from the Pregnancy And Childhood Epigenetics (PACE) Consortium. We examined (a) developmental trajectories of "chronic-low" versus "typical" prosocial behavior across childhood in a case-control design (N = 2,095), and (b) continuous "low prosocial" scores at comparable cross-cohort time-points (N = 2,121). Meta-analyses were performed to examine differentially methylated positions and regions. At the cohort-specific level, three CpGs were found to associate with chronic low prosocial behavior; however, none of these associations was replicated in another cohort. Meta-analysis revealed no epigenome-wide significant CpGs or regions. Overall, we found no evidence for associations between DNAm patterns at birth and low prosocial behavior across childhood. Findings highlight the importance of employing multi-cohort approaches to replicate epigenetic associations and reduce the risk of false positive discoveries. Show less
Simple SummaryThe standard of care for locally advanced cervical cancer is chemoradiation and brachytherapy. The addition of adjuvant systemic treatment may improve overall survival. A systematic... Show moreSimple SummaryThe standard of care for locally advanced cervical cancer is chemoradiation and brachytherapy. The addition of adjuvant systemic treatment may improve overall survival. A systematic review and meta-analysis were conducted to summarize evidence on survival outcomes, treatment completion and toxicity. Thirty-five articles reporting on 29 different studies were selected from a total of 612 articles published on this topic since 2000. Twelve studies on two different chemotherapy combinations (platinum-pyrimidine antagonist and platinum-taxane) were included for meta-analysis. Both these adjuvant chemotherapy combinations did not yield a survival benefit but did lead to more severe side-effects than chemoradiation only. Therefore, these adjuvant treatment strategies cannot be recommended for unselected patients with locally advanced cervical cancer. Most of the studies on other chemotherapeutic agents did not seem to provide a good balance between efficacy and toxicity either. The evidence on adjuvant immunotherapy for locally advanced cervical cancer is still immature.Background: Standard of care for locally advanced cervical cancer is chemoradiation and brachytherapy. The addition of adjuvant systemic treatment may improve overall survival. A systematic review and meta-analysis was conducted to summarize evidence on survival outcomes, treatment completion and toxicity. Methods: PubMed, EMBASE and Web of Science were systematically searched for relevant prospective and retrospective studies. Two authors independently selected studies, extracted data and assessed study quality. Pooled hazard ratios for survival endpoints were estimated using random effect models. Weighted averages of treatment completion and toxicity rates were calculated and compared by the Fisher exact test. Results: The search returned 612 articles; 35 articles reporting on 29 different studies on adjuvant chemotherapy or immunotherapy were selected for systematic review. Twelve studies on an adjuvant platinum-pyrimidine antagonist or platinum-taxane were included for meta-analysis. The pooled hazard ratios for overall survival were 0.76 (99%CI: 0.43-1.34, p = 0.22) and 0.47 (99%CI: 0.12-1.86, p = 0.16) for the addition of, respectively, a platinum-pyrimidine antagonist or platinum-taxane to chemoradiation and brachytherapy. Completion rates were 82% (95%CI: 76-87%) for platinum-pyrimidine antagonist and 74% (95%CI: 63-85%) for platinum-taxane. Severe acute hematological and gastro-intestinal toxicities were significantly increased by adding adjuvant chemotherapy to chemoradiation and brachytherapy. Conclusions: The addition of adjuvant platinum-pyrimidine antagonist or platinum-taxane after chemoradiation and brachytherapy does not significantly improve overall survival, while acute toxicity is significantly increased. These adjuvant treatment strategies can therefore not be recommended for unselected patients with locally advanced cervical cancer. Show less
