Clark-Baraitser syndrome is a rare autosomal dominant intellectual disability syndrome caused by pathogenic variants in the TRIP12 (Thyroid Hormone Receptor Interactor 12) gene. TRIP12 encodes an... Show moreClark-Baraitser syndrome is a rare autosomal dominant intellectual disability syndrome caused by pathogenic variants in the TRIP12 (Thyroid Hormone Receptor Interactor 12) gene. TRIP12 encodes an E3 ligase in the ubiquitin pathway. The ubiquitin pathway includes activating E1, conjugating E2 and ligating E3 enzymes which regulate the breakdown and sorting of proteins. This enzymatic pathway is crucial for physiological processes. A significant proportion of TRIP12 variants are currently classified as variants of unknown significance (VUS). Episignatures have been shown to represent a powerful diagnostic tool to resolve inconclusive genetic findings for Mendelian disorders and to re-classify VUSs. Here, we show the results of DNA methylation episignature analysis in 32 individuals with pathogenic, likely pathogenic and VUS variants in TRIP12. We identified a specific and sensitive DNA methylation (DNAm) episignature associated with pathogenic TRIP12 variants, establishing its utility as a clinical biomarker for Clark-Baraitser syndrome. In addition, we performed analysis of differentially methylated regions as well as functional correlation of the TRIP12 genome-wide methylation profile with the profiles of 56 additional neurodevelopmental disorders. Show less
Meulenbroek, A.L.; Faes, M.C.; Mil, S.R. van; Buimer, M.G.; Groot, H.G.W. de; Veen, E.J.; ... ; Laan, L. van der 2022
Objective: Chronic limb threatening ischemia is the final stage of peripheral arterial disease. Current treatment is based on revascularization to preserve the leg. In the older, hospitalized... Show moreObjective: Chronic limb threatening ischemia is the final stage of peripheral arterial disease. Current treatment is based on revascularization to preserve the leg. In the older, hospitalized chronic limb threatening ischemia patient, delirium is a frequent and severe complication after revascularization. Delirium leads to an increased length of hospital stay, a higher mortality rate and a decrease in quality of life. Currently, no specific guidelines to prevent delirium in chronic limb threatening ischemia patients exist. We aim to evaluate the effect of a multicomponent, multidisciplinary prehabilitation program on the incidence of delirium in chronic limb threatening ischemia patients >65 years. Design: A prospective observational cohort study to investigate the effects of the program on the incidence of delirium will be performed in a large teaching hospital in the Netherlands. This manuscript describes the design of the study and the content of this specific prehabilitation program. Methods: Chronic limb threatening ischemia patients >65 years that require revascularization will participate in the program. This program focuses on optimizing the patient's overall health and includes delirium risk assessment, nutritional optimization, home-based physical therapy, iron infusion in case of anaemia and a comprehensive geriatric assessment in case of frailty. The primary outcome is the incidence of delirium. Secondary outcomes include quality of life, amputation-free survival, length of hospital stay and mortality. Exclusion criteria are the requirement of acute treatment or patients who are mentally incompetent to understand the procedures of the study or to complete questionnaires. A historical cohort from the same hospital is used as a control group. Discussion: This study will clarify the effect of a prehabilitation program on delirium incidence in chronic limb threatening ischemia patients. New insights will be obtained on optimizing a patient's preoperative mental and physical condition to prevent postoperative complications, including delirium. Trial: This protocol is registered at the Netherlands National Trial Register (NTR) number: NL9380. Show less
Janssen, T.L.; Lodder, P.; Vries, J. de; Hoof-de Lepper, C.C.H.A. van; Gobardhan, P.D.; Ho, G.H.; Laan, L. van der 2020
Background Health-care systems nowadays rely on complementary patient care by informal caregivers. The need for, and burden on, informal caregivers will likely increase in the upcoming years. This... Show moreBackground Health-care systems nowadays rely on complementary patient care by informal caregivers. The need for, and burden on, informal caregivers will likely increase in the upcoming years. This study aimed to examine the burden on caregivers when providing care for elderly patients undergoing major abdominal surgery. Methods A single-centre longitudinal cohort study was conducted between November 2015 and June 2018 in the Amphia hospital in Breda, the Netherlands. Patients aged 70+ undergoing elective surgery for colorectal carcinoma (CRC) or an abdominal aortic aneurysm (AAA) were included in this study. Informal caregiver burden was assessed and compared over time using the Caregiver Strain Index (CSI) at the outpatient clinic visit, at discharge, 2 weeks post-discharge and after 6 and 12 months. The effects of patient- and caregiver-related factors on the experienced caregiver strain were examined. Results CSI scores of 248 caregivers were significantly increased at discharge (3.5 vs 2.6; p < 0.001) and 2 weeks post-discharge (3.3 vs 2.6; p < 0.001). After 12 months, scores dropped below baseline scores (1.8 vs 2.6; p = 0.012). The highest strain was observed 2 weeks post-discharge for AAA patients and at discharge for CRC patients. Older age, physical or cognitive impairment and burden of comorbidity were associated with an increased caregiver strain at baseline. Type of surgery was independently associated with the change in mean CSI scores over time; a bigger change in caregiver burden is observed after open surgery. Conclusion In the early postoperative period, perceived caregiver strain was significantly increased. Psychological support for caregivers may be advisable, with timing of this support depending on diagnosis and patient-related factors. Show less
Karthaus, E.G.; Tong, T.M.L.; Vahl, A.; Hamming, J.F.; Akker, L.H. van den; Akker, P.J. van den; ... ; Vos 2019
Objective: The aim of this was to analyze differences between saccularshaped abdominal aortic aneurysms (SaAAAs) and fusiform abdominal aortic aneurysms (FuAAAs) regarding patient characteristics,... Show moreObjective: The aim of this was to analyze differences between saccularshaped abdominal aortic aneurysms (SaAAAs) and fusiform abdominal aortic aneurysms (FuAAAs) regarding patient characteristics, treatment, and outcome, to advise a threshold for intervention for SaAAAs.Background: Based on the assumption that SaAAAs are more prone to rupture, guidelines suggest early elective treatment. However, little is known about the natural history of SaAAAs and the threshold for intervention is not substantiated.Methods: Observational study including primary repairs of degenerative AAAs in the Netherlands between 2016 and 2018 in which the shape was registered, registered in the Dutch Surgical Aneurysm Audit (DSAA). Patients were stratified by urgency of surgery; elective versus acute (symptomatic/ruptured). Patient characteristics, treatment, and outcome were compared between SaAAAs and FuAAAs.Results: A total of 7659 primary AAA-patients were included, 6.1% (n = 471) SaAAAs and 93.9% (n = 7188) FuAAAs. There were 5945 elective patients (6.5% SaAAA) and 1714 acute (4.8% SaAAA). Acute SaAAApatients were more often female (28.9% vs 17.2%, P = 0.007) compared with acute FuAAA-patients. SaAAAs had smaller diameters than FuAAAs, in elective (53.0mm vs 61 mm, P = 0.000) and acute (68mm vs 75 mm, P = 0.002) patients, even after adjusting for sex. In addition, 25.2% of acute SaAAA-patients presented with diameters <55mm and 8.4% <45 mm, versus 8.1% and 0.6% of acute FuAAA-patients (P = 0.000). Postoperative outcomes did not significantly differ between shapes in both elective and acute patients.Conclusions: SaAAAs become acute at smaller diameters than FuAAAs in DSAA patients. This study therefore supports the current idea that SaAAAs should be electively treated at smaller diameters than FuAAAs. The exact diameter threshold for elective treatment of SaAAAs is difficult to determine, but a diameter of 45mm seems to be an acceptable threshold. Show less
Dulk, A.C. den; Shi, X.; Verhoeven, C.; Dubbeld, J.; Claas, F.H.J.; Wolterbeek, R.; ... ; Roelen, D. 2018
