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Affection and rejection in close relationships during adolescence are thought to impact adult interpersonal functioning, but few studies focused on how the quality of adolescents' relationships with different people (e.g. parents, peers, and teachers) impacts the daily, micro-level social experiences as well as general, macro-level interpersonal functioning in young adulthood. The present study investigated the associations between: (i) parental, teacher and peer affection and rejection during adolescence and macro-level (over several months) interpersonal functioning as well as different patterns (i.e. mean, variability and inertia) of micro-level (daily social experiences) during young adulthood; (ii) macro-level interpersonal functioning and the patterns of micro-level social experiences during young adulthood. The sample consisted of N = 122 (43% female) youth. At 11.2 ± 0.4 and 16.0 ± 0.6 years old, self- and other-reported parental, peer and teacher affection and rejection were assessed. At 23.7 ± 0.6 years old, participants reported daily social experiences and interpersonal functioning across six months. The results suggested that: (i) higher teacher-reported peer rejection was associated with lower macro-level interpersonal functioning, higher means and higher variability in negative social experiences during adulthood; (ii) higher macro-level interpersonal functioning during young adulthood was associated with higher means and lower inertia in positive and lower variability in negative daily social experiences. These findings indicate that the affection and rejection during adolescence impact interpersonal functioning at macro- and micro-level during adulthood. The present study also shows distinct associations between macro-level interpersonal functioning and dynamics in daily social experiences. ispartof: Journal Of Youth And Adolescence vol:51 issue:11 pages:2130-2145 ispartof: location:United States status: published more...

Background: In patients with atrial fibrillation who survive an anticoagulation-associated intracerebral haemorrhage, a decision must be made as to whether restarting or permanently avoiding anticoagulation is the best long-term strategy to prevent recurrent stroke and other vascular events. In APACHE-AF, we aimed to estimate the rates of non-fatal stroke or vascular death in such patients when treated with apixaban compared with when anticoagulation was avoided, to inform the design of a larger trial. Methods: APACHE-AF was a prospective, randomised, open-label, phase 2 trial with masked endpoint assessment, done at 16 hospitals in the Netherlands. Patients who survived intracerebral haemorrhage while treated with anticoagulation for atrial fibrillation were eligible for inclusion 7–90 days after the haemorrhage. Participants also had a CHA2DS2-VASc score of at least 2 and a score on the modified Rankin scale (mRS) of 4 or less. Participants were randomly assigned (1:1) to receive oral apixaban (5 mg twice daily or a reduced dose of 2·5 mg twice daily) or to avoid anticoagulation (oral antiplatelet agents could be prescribed at the discretion of the treating physician) by a central computerised randomisation system, stratified by the intention to start or withhold antiplatelet therapy in participants randomised to avoiding anticoagulation, and minimised for age and intracerebral haemorrhage location. The primary outcome was a composite of non-fatal stroke or vascular death, whichever came first, during a minimum follow-up of 6 months, analysed using Cox proportional hazards modelling in the intention-to-treat population. APACHE-AF is registered with ClinicalTrials.gov (NCT02565693) and the Netherlands Trial Register (NL4395), and the trial is closed to enrolment at all participating sites. Findings: Between Jan 15, 2015, and July 6, 2020, we recruited 101 patients (median age 78 years [IQR 73–83]; 55 [54%] were men and 46 [46%] were women; 100 [99%] were White and one [1%] was Black) a median of 46 days (IQR 21–74) after intracerebral haemorrhage. 50 were assigned to apixaban and 51 to avoid anticoagulation (of whom 26 [51%] started antiplatelet therapy). None were lost to follow-up. Over a median follow-up of 1·9 years (IQR 1·0–3·1; 222 person-years), non-fatal stroke or vascular death occurred in 13 (26%) participants allocated to apixaban (annual event rate 12·6% [95% CI 6·7–21·5]) and in 12 (24%) allocated to avoid anticoagulation (11·9% [95% CI 6·2–20·8]; adjusted hazard ratio 1·05 [95% CI 0·48–2·31]; p=0·90). Serious adverse events that were not outcome events occurred in 29 (58%) of 50 participants assigned to apixaban and 29 (57%) of 51 assigned to avoid anticoagulation. Interpretation: Patients with atrial fibrillation who had an intracerebral haemorrhage while taking anticoagulants have a high subsequent annual risk of non-fatal stroke or vascular death, whether allocated to apixaban or to avoid anticoagulation. Our data underline the need for randomised controlled trials large enough to allow identification of subgroups in whom restarting anticoagulation might be either beneficial or hazardous. Funding: Dutch Heart Foundation (grant 2012T077). more...

Supplemental Digital Content is available in the text., Background and Purpose: Optimal blood pressure (BP) management in the acute phase of ischemic stroke remains an unresolved issue. It is uncertain whether guidelines for BP management during and after intravenous alteplase can be extrapolated to endovascular treatment (EVT) for stroke due to large artery occlusion in the anterior circulation. We evaluated the associations between systolic BP (SBP) in the first 6 hours following EVT and functional outcome as well as symptomatic intracranial hemorrhage. Methods: Patients of 8 MR CLEAN (Multicenter Randomized Controlled Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) Registry centers, with available data on SBP in the 6 hours following EVT, were analyzed. We evaluated maximum, minimum, and mean SBP. Study outcomes were functional outcome (modified Rankin Scale) at 90 days and symptomatic intracranial hemorrhage. We used multivariable ordinal and binary regression analysis to adjust for important prognostic factors and studied possible effect modification by successful reperfusion. Results: Post-EVT SBP data were available for 1161/1796 patients. Higher maximum SBP (per 10 mm Hg increments) was associated with worse functional outcome (adjusted common odds ratio, 0.93 [95% CI, 0.88–0.98]) and a higher rate of symptomatic intracranial hemorrhage (adjusted odds ratio, 1.17 [95% CI, 1.02–1.36]). The association between minimum SBP and functional outcome was nonlinear with an inflection point at 124 mm Hg. Minimum SBP lower and higher than the inflection point were associated with worse functional outcomes (adjusted common odds ratio, 0.85 per 10 mm Hg decrements [95% CI, 0.76–0.95] and adjusted common odds ratio, 0.81 per 10 mm Hg increments [95% CI, 0.71–0.92]). No association between mean SBP and functional outcome was observed. Successful reperfusion did not modify the relation of SBP with any of the outcomes. Conclusions: Maximum SBP in the first 6 hours following EVT is positively associated with worse functional outcome and an increased risk of symptomatic intracranial hemorrhage. Both lower and higher minimum SBP are associated with worse outcomes. A randomized trial to evaluate whether modifying post-intervention SBP results in better outcomes after EVT for ischemic stroke seems justified. more...

Background and Purpose: The benefit of endovascular treatment (EVT) for posterior circulation stroke (PCS) remains uncertain, and little is known on treatment outcomes in clinical practice. This study evaluates outcomes of a large PCS cohort treated with EVT in clinical practice. Simultaneous to this observational study, several intervention centers participated in the BASICS trial (Basilar Artery International Cooperation Study), which tested the efficacy of EVT for basilar artery occlusion in a randomized setting. We additionally compared characteristics and outcomes of patients treated outside BASICS in trial centers to those from nontrial centers. Methods: We included patients with PCS from the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands Registry: a prospective, multicenter, observational study of patients who underwent EVT in the Netherlands between 2014 and 2018. Primary outcome was a score of 0 to 3 on the modified Rankin Scale at 90 days. Secondary outcomes included reperfusion status and symptomatic intracranial hemorrhage. For outcome comparison between patients treated in trial versus nontrial centers, we used ordinal logistic regression analysis. Results: We included 264 patients of whom 135 (51%) had received intravenous thrombolysis. The basilar artery was most often involved (77%). Favorable outcome (modified Rankin Scale score 0–3) was observed in 115/252 (46%) patients, and 109/252 (43%) patients died. Successful reperfusion was achieved in 178/238 (75%), and symptomatic intracranial hemorrhage occurred in 9/264 (3%). The 154 nontrial patients receiving EVT in BASICS trial centers had similar characteristics and outcomes as the 110 patients treated in nontrial centers (modified Rankin Scale adjusted cOR: 0.77 [95% CI, 0.5–1.2]). Conclusions: Our study shows that high rates of favorable clinical outcome and successful reperfusion can be achieved with EVT for PCS, despite high mortality. Characteristics and outcomes of patients treated in trial versus nontrial centers were similar indicating that our cohort is representative of clinical practice in the Netherlands. Randomized studies using modern treatment approaches are needed for further insight in the benefit of EVT for PCS. more...

Background: Basal cell carcinoma (BCC) is the most frequently diagnosed malignancy worldwide and an ever increasing annual incidence is observed. However, nationwide registries of BCCs are very rare, and often extrapolation of the data has been necessary to estimate the absolute number of diagnoses. As of September 2016, all histopathologically confirmed BCCs are registered in the Netherlands, due to developments in automatic notification and import in the Netherlands Cancer Registry. This offers the unique possibility to assess the nationwide population-based incidence of first and multiple BCCs. Objectives: To assess the nationwide incidence and trends of first and multiple BCCs in the Netherlands and to predict incidence rates up to 2029. Methods: All patients with histopathologically confirmed BCC between 2001 and 2019 were selected from the population-based Netherlands Cancer Registry. Age-standardized incidence rates were calculated and trends were analysed with use of the estimated annual percentage change. Prediction of BCC incidence rates up to 2029 was based on a regression model. Results: In total, 601 806 patients were diagnosed with a first BCC over the period 2001–2019. The age-standardized incidence rates for both men and women with a first BCC increased over these years, from 157 to 304 and from 124 to 274 per 100 000 person-years, respectively. For male and female patients aged 30–39 years, decreases in annual incidences of −3·6% and −3·0%, respectively, were found in recent years. For patients aged 50 years or older an ever increasing trend was found. One-quarter of the patients with a first primary BCC developed one or more subsequent BCCs within 3 years. Increases in incidence of 30·4% (male) and 25·3% (female) are expected in the next 10 years. Conclusions: BCC incidence has doubled over the past two decades. Trends have seemed to stabilize in recent years for patients aged < 50 years. This might be a first sign of a decreasing trend. The incidence continues to rise in patients aged 50 years and older. In the next decade a further increase in BCC incidence is expected. more...

Supplemental Digital Content is available in the text., Background and Purpose: Blinded outcome assessment in trials with prospective randomized open blinded end point design is challenging. Unblinding can result in misclassified outcomes and biased treatment effect estimates. An outcome adjudication committee assures blinded outcome assessment, but the added value for trials with prospective randomized open blinded end point design and subjective outcomes is unknown. We aimed to assess the degree of misclassification of modified Rankin Scale (mRS) scores by a central assessor and its impact on treatment effect estimates in a stroke trial with prospective randomized open blinded end point design. Methods: We used data from the MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands). The primary outcome was the mRS at 90 days. Standardized, algorithm-based telephone interviews to assess the mRS were conducted from a central location by an experienced research nurse, unaware but not formally blinded to treatment allocation (central assessor). Masked reports of these interviews were adjudicated by a blinded outcome committee. Misclassification was defined as an incorrect classification of the mRS by the central assessor. The effect of endovascular treatment on the mRS was assessed with multivariable ordinal logistic regression. Results: In MR CLEAN, 53/500 (10.6%) of the mRS scores were misclassified. The degree and direction of misclassification did not differ between treatment arms (P=0.59). Benefit of endovascular treatment was shown on the mRS when scored by the central assessor (adjusted common odds ratio, 1.60 [95% CI, 1.16–2.21]) and the outcome adjudication committee (adjusted common odds ratio, 1.67 [95% CI, 1.21–2.20]). Conclusions: Misclassification by the central assessor was small, randomly distributed over treatment arms, and did not affect treatment effect estimates. This study suggests that the added value of a blinded outcome adjudication committee is limited in a stroke trial with prospective randomized open blinded end point design applying standardized, algorithm-based outcome assessment by a central assessor, who is unaware but not formally blinded to treatment allocation. Registration: URL: https://www.isrctn.com; Unique identifier: ISRCTN10888758. more...

ImportanceThe longer-term effects of therapies for the treatment of critically ill patients with COVID-19 are unknown.ObjectiveTo determine the effect of multiple interventions for critically ill adults with COVID-19 on longer-term outcomes.Design, Setting, and ParticipantsPrespecified secondary analysis of an ongoing adaptive platform trial (REMAP-CAP) testing interventions within multiple therapeutic domains in which 4869 critically ill adult patients with COVID-19 were enrolled between March 9, 2020, and June 22, 2021, from 197 sites in 14 countries. The final 180-day follow-up was completed on March 2, 2022.InterventionsPatients were randomized to receive 1 or more interventions within 6 treatment domains: immune modulators (n = 2274), convalescent plasma (n = 2011), antiplatelet therapy (n = 1557), anticoagulation (n = 1033), antivirals (n = 726), and corticosteroids (n = 401).Main Outcomes and MeasuresThe main outcome was survival through day 180, analyzed using a bayesian piecewise exponential model. A hazard ratio (HR) less than 1 represented improved survival (superiority), while an HR greater than 1 represented worsened survival (harm); futility was represented by a relative improvement less than 20% in outcome, shown by an HR greater than 0.83.ResultsAmong 4869 randomized patients (mean age, 59.3 years; 1537 [32.1%] women), 4107 (84.3%) had known vital status and 2590 (63.1%) were alive at day 180. IL-6 receptor antagonists had a greater than 99.9% probability of improving 6-month survival (adjusted HR, 0.74 [95% credible interval {CrI}, 0.61-0.90]) and antiplatelet agents had a 95% probability of improving 6-month survival (adjusted HR, 0.85 [95% CrI, 0.71-1.03]) compared with the control, while the probability of trial-defined statistical futility (HR >0.83) was high for therapeutic anticoagulation (99.9%; HR, 1.13 [95% CrI, 0.93-1.42]), convalescent plasma (99.2%; HR, 0.99 [95% CrI, 0.86-1.14]), and lopinavir-ritonavir (96.6%; HR, 1.06 [95% CrI, 0.82-1.38]) and the probabilities of harm from hydroxychloroquine (96.9%; HR, 1.51 [95% CrI, 0.98-2.29]) and the combination of lopinavir-ritonavir and hydroxychloroquine (96.8%; HR, 1.61 [95% CrI, 0.97-2.67]) were high. The corticosteroid domain was stopped early prior to reaching a predefined statistical trigger; there was a 57.1% to 61.6% probability of improving 6-month survival across varying hydrocortisone dosing strategies.Conclusions and RelevanceAmong critically ill patients with COVID-19 randomized to receive 1 or more therapeutic interventions, treatment with an IL-6 receptor antagonist had a greater than 99.9% probability of improved 180-day mortality compared with patients randomized to the control, and treatment with an antiplatelet had a 95.0% probability of improved 180-day mortality compared with patients randomized to the control. Overall, when considered with previously reported short-term results, the findings indicate that initial in-hospital treatment effects were consistent for most therapies through 6 months. more...

Symptoms of psychopathology lie on a continuum ranging from mental health to psychiatric disorders. Although much research has focused on progression along this continuum, for most individuals, subthreshold symptoms do not escalate into full-blown disorders. This study investigated how the stability of psychopathological symptoms (attractor strength) varies across severity levels (homebase). Data were retrieved from the TRAILS TRANS-ID study, where 122 at-risk young adults (mean age 23.6 years old, 57% males) monitored their mental states daily for a period of six months (± 183 observations per participant). We estimated each individual’s homebase and attractor strength using generalized additive mixed models. Regression analyses showed no association between homebases and attractor strengths (linear model: B = 0.02, p = 0.47, R2 2 more...

Previous studies showed that postmenopausal women are more likely to have poorly controlled hypertension than men of the same age. Whether this is caused by inadequate treatment or poor response to antihypertensive agents remains unknown. The aim of this study is to analyze treatment response to the most potent renin angiotensin aldosterone system (RAAS) inhibitor perindopril in different age categories in women and men. Individual patient data were used from the combined European Trial on Reduction of Cardiac Events With Perindopril (EUROPA), Perindopril Protection Against Recurrent Stroke Study (PROGRESS), and Action in Diabetes and Vascular disease: Preterax and Diamicron-MR Controlled Evaluation (ADVANCE) trials, which include patients with vascular disease (n = 29,463). We studied the relative and absolute changes in systolic blood pressure (SBP) and diastolic blood pressure (DBP) during a 4-week run-in phase in which all patients were treated with the perindopril-based treatment in different age categories. In total, 8366 women and 21,097 men were included in the analysis. Women greater than 65 years of age showed a significantly smaller blood pressure reduction after perindopril treatment (2.8 mmHg [95% confidence interval {CI} = 0.1–5.5] less reduction compared to women ≤45 years, p = 0.039). In men, the SBP reduction after perindopril in patients greater than 55–65 and greater than 65 years was lower compared to the age category less than or equal to 45 years (adjusted mean difference >55–65: 2.8 mmHg [95% CI = 1.8–3.7], p 65: 3.7 mmHg [95% CI = 2.7–4.7], p more...

Abstract Understanding the cardiac-coronary interaction is fundamental to developing treatment strategies for ischemic heart disease. We sought to examine the impact of afterload reduction following isosorbide dinitrate (ISDN) administration on LV properties and coronary hemodynamics to further our understanding of the cardiac-coronary interaction. Novel methodology enabled real-time simultaneous acquisition and analysis of coronary and LV hemodynamics in vivo using coronary pressure-flow wires (used to derive coronary wave energies) and LV pressure-volume loop assessment. ISDN administration resulted in afterload reduction, reduced myocardial demand, and increased mechanical efficiency (all Pr=0.6) following ISDN. In the presence of minimal microvascular resistance, coronary blood flow velocity exhibited an inverse relationship with LV elastance. In summary this study demonstrated a reduction in myocardial demand with ISDN, an inverse relationship between coronary blood flow velocity and LV contraction-relaxation and a direct correlation between FCW and arterial elastance. Graphical abstract The pressure volume-loop and corresponding parameters b The pressure volume loop before (solid line) and after (broken line) Isosorbide dintrate more...

BACKGROUND: Patients with symptomatic carotid stenosis are at high risk for recurrent stroke. The decision for carotid endarterectomy currently mainly relies on degree of stenosis (cutoff value >50% or 70%). Nevertheless, also, patients with mild-to-moderate stenosis still have a considerable recurrent stroke risk. Increasing evidence suggests that carotid plaque composition rather than degree of stenosis determines plaque vulnerability; however, it remains unclear whether this also provides additional information to improve clinical decision making. OBJECTIVES: The PARISK (Plaque At RISK) study aimed to improve the identification of patients at increased risk of recurrent ischemic stroke using multimodality carotid imaging. METHODS: The authors included 244 patients (71% men; mean age, 68 years) with a recent symptomatic mild-to-moderate carotid stenosis in a prospective multicenter cohort study. Magnetic resonance imaging (carotid and brain) and computed tomography angiography (carotid) were performed at baseline and after 2 years. The clinical endpoint was a recurrent ipsilateral ischemic stroke or transient ischemic attack (TIA). Cox proportional hazards models were used to assess whether intraplaque hemorrhage (IPH), ulceration, proportion of calcifications, and total plaque volume in ipsilateral carotid plaques were associated with the endpoint. Next, the authors investigated the predictive performance of these imaging biomarkers by adding these markers (separately and simultaneously) to the ECST (European Carotid Surgery Trial) risk score. RESULTS: During 5.1 years follow-up, 37 patients reached the clinical endpoint. IPH presence and total plaque volume were associated with recurrent ipsilateral ischemic stroke or TIA (HR: 2.12 [95% CI: 1.02-4.44] for IPH; HR: 1.07 [95% CI: 1.00-1.15] for total plaque volume per 100 µL increase). Ulcerations and proportion of calcifications were not statistically significant determinants. Addition of IPH and total plaque volume to the ECST risk score improved the model performance (C-statistics increased from 0.67 to 0.75-0.78). CONCLUSIONS: IPH and total plaque volume are independent risk factors for recurrent ipsilateral ischemic stroke or TIA in patients with mild-to-moderate carotid stenosis. These plaque characteristics improve current decision making. Validation studies to implement plaque characteristics in clinical scoring tools are needed. (PARISK: Validation of Imaging Techniques [PARISK]; NCT01208025). more...

Conflicting data about inflammatory bowel disease [IBD] and immunosuppressants are risk factors for severe COVID-19 confuse patients and healthcare providers. Clinical reports with longer follow-up are lacking. A retrospective search was performed for severe COVID-19 (hospital admission and/or mortality) one year after the SARS-CoV-2 outbreak in an IBD cohort from one of the most affected Dutch regions. Cohort characteristics were explored by value-based healthcare data, including immunotherapy. COVID-19 cases were detected by ICD-10 codes and further examined for IBD determinants (including medication) and COVID-19 characteristics (intensive care admission, respiratory support, treatment, mortality). The national mortality register was consulted, ensuring detection of patients that died without admission. Results were compared with regional and national general population registries. The IBD cohort consisted of 1453 patients (51% Crohn’s disease, 54% women, 39.9% using immunotherapy), including children. Biologics use increased during the study. Eight cases (0.55%) had severe COVID-19: seven were hospitalized (0.48%, 95% confidence interval [CI] 0.21–1.04), and two died (0.14%, CI 0.002–0.55). Six patients had comorbidity, one used immunotherapy, and four had no medication. Both deceased patients were older than 80 years, had severe comorbidity, but used no immunotherapy. Hospitalization occurred significantly more in the IBD cohort than regionally (0.18%, CI 0.17–0.19, p = 0.015), but not significantly more than nationally (0.28%, CI 0.279–0.284). Mortality was equal in IBD patients, regionally (0.11%, CI 0.10–0.12) and nationally (0.13%, CI 0.125–0.128). Neither IBD nor immunosuppressants are associated with increased risks of severe COVID-19 in an observational study with one-year follow-up. more...

Despite the growing knowledge on the (epi)genetic background of facioscapulohumeral muscular dystrophy (FSHD), the substantial variability in disease severity that exists between FSHD patients is not fully understood. We hypothesized that smoking and alcohol consumption are disease modifiers in FSHD and contribute to the variability in disease severity, because they are both associated with higher levels of oxidative stress in muscle tissue. Oxidative stress is known to influence FSHD muscle tissue. One hundred and ninety-eight genetically confirmed FSHD patients completed a questionnaire from which the number of packyears of smoking and the lifetime cumulative alcohol units consumed were calculated. Disease severity was determined by the FSDH evaluation score. Multiple linear regression analyses showed that both the number of packyears and the amount of alcohol consumption did not influence disease severity (respectively B = 0.025, ΔR2=0.006, p = 0.231; and B = 0.000, ΔR2=0.004, p = 0.406). Although smoking and excessive alcohol consumption are unhealthy habits which should be discouraged, these results show that smoking and alcohol consumption have no clinically meaningful modifying effect on disease severity in FSHD patients. However, prospective data should show whether alcohol consumption and smoking influence disease progression rate. more...

Contains fulltext : 234060.pdf (Publisher’s version ) (Open Access) Prematurity and perinatal stress, such as intrauterine growth restriction (IUGR) and chorioamnionitis, are pathological processes creating an impaired intrauterine environment. These intrauterine factors are associated with the development of proteinuria, hypertension, and chronic kidney disease (CKD) later in life. Initially, this was thought to be secondary to oligonephropathy, subsequent glomerular hypertrophy, and hyperfiltration, leading to glomerulosclerosis, a further decrease in nephron number, and finally CKD. Nowadays, there is increasing evidence that prematurity and perinatal stress affect not only nephron endowment but also the maturation of podocytes and vasculogenesis. IUGR is associated with podocyte damage and an aggravated course of nephrotic syndrome. Moreover, preterm birth and IUGR are known to cause upregulation of the postnatal renin-angiotensin system, resulting in hypertension. Chorioamnionitis causes damage to the glomeruli, thereby predisposing to the development of glomerulosclerosis. This review aims to summarize current knowledge on the influence of prematurity, IUGR, and chorioamnionitis on the development of different glomerular structures. After summarizing human and experimental data on low nephron number in general, a specific focus on the current understanding of podocyte and glomerular capillary formation in relation to prematurity and different causes of perinatal stress is presented. more...

Summary Background A rapid, blood-based triage test that allows targeted investigation for tuberculosis at the point of care could shorten the time to tuberculosis treatment and reduce mortality. We aimed to test the performance of a host blood transcriptomic signature (RISK11) in diagnosing tuberculosis and predicting progression to active pulmonary disease (prognosis) in people with HIV in a community setting. Methods In this prospective diagnostic and prognostic accuracy study, adults (aged 18–59 years) with HIV were recruited from five communities in South Africa. Individuals with a history of tuberculosis or household exposure to multidrug-resistant tuberculosis within the past 3 years, comorbid risk factors for tuberculosis, or any condition that would interfere with the study were excluded. RISK11 status was assessed at baseline by real-time PCR; participants and study staff were masked to the result. Participants underwent active surveillance for microbiologically confirmed tuberculosis by providing spontaneously expectorated sputum samples at baseline, if symptomatic during 15 months of follow-up, and at 15 months (the end of the study). The coprimary outcomes were the prevalence and cumulative incidence of tuberculosis disease confirmed by a positive Xpert MTB/RIF, Xpert Ultra, or Mycobacteria Growth Indicator Tube culture, or a combination of such, on at least two separate sputum samples collected within any 30-day period. Findings Between March 22, 2017, and May 15, 2018, 963 participants were assessed for eligibility and 861 were enrolled. Among 820 participants with valid RISK11 results, eight (1%) had prevalent tuberculosis at baseline: seven (2·5%; 95% CI 1·2–5·0) of 285 RISK11-positive participants and one (0·2%; 0·0–1·1) of 535 RISK11-negative participants. The relative risk (RR) of prevalent tuberculosis was 13·1 times (95% CI 2·1–81·6) greater in RISK11-positive participants than in RISK11-negative participants. RISK11 had a diagnostic area under the receiver operating characteristic curve (AUC) of 88·2% (95% CI 77·6–96·7), and a sensitivity of 87·5% (58·3–100·0) and specificity of 65·8% (62·5–69·0) at a predefined score threshold (60%). Of those with RISK11 results, eight had primary endpoint incident tuberculosis during 15 months of follow-up. Tuberculosis incidence was 2·5 per 100 person-years (95% CI 0·7–4·4) in the RISK11-positive group and 0·2 per 100 person-years (0·0–0·5) in the RISK11-negative group. The probability of primary endpoint incident tuberculosis was greater in the RISK11-positive group than in the RISK11-negative group (cumulative incidence ratio 16·0 [95% CI 2·0–129·5]). RISK11 had a prognostic AUC of 80·0% (95% CI 70·6–86·9), and a sensitivity of 88·6% (43·5–98·7) and a specificity of 68·9% (65·3–72·3) for incident tuberculosis at the 60% threshold. Interpretation RISK11 identified prevalent tuberculosis and predicted risk of progression to incident tuberculosis within 15 months in ambulant people living with HIV. RISK11's performance approached, but did not meet, WHO's target product profile benchmarks for screening and prognostic tests for tuberculosis. Funding Bill & Melinda Gates Foundation and the South African Medical Research Council. more...

Cementoblastomas are rare odontogenic tumors developing in close proximity to the roots of teeth. Due to their striking morphologic resemblance to osteoblastomas of the peripheral skeleton, we set out to determine whether cementoblastomas harbor the same FOS rearrangements with overexpression of c-FOS as has recently been described for osteoblastomas. In total, 16 cementoblastomas were analyzed for FOS expression by immunohistochemistry and for FOS rearrangements by fluorescence in situ hybridization (FISH). We observed strong and diffuse staining of c-FOS in 71% of cementoblastomas and identified a FOS rearrangement in all cases (n=3) applicable for FISH. In the remaining cases, FISH failed due to decalcification. Cementoblastomas harbor similar FOS rearrangements and show overexpression of c-FOS like osteoblastomas, suggesting that both entities might represent parts of the spectrum of the same disease. more...

ObjectiveDespite regular colonoscopy surveillance, colorectal cancers still occur in patients with Lynch syndrome. Thus, detection of all relevant precancerous lesions remains very important. The present study investigates Linked Colour imaging (LCI), an image-enhancing technique, as compared with high-definition white light endoscopy (HD-WLE) for the detection of polyps in this patient group.DesignThis prospective, randomised controlled trial was performed by 22 experienced endoscopists from eight centres in six countries. Consecutive Lynch syndrome patients ≥18 years undergoing surveillance colonoscopy were randomised (1:1) and stratified by centre for inspection with either LCI or HD-WLE. Primary outcome was the polyp detection rate (PDR).ResultsBetween January 2018 and March 2020, 357 patients were randomised and 332 patients analysed (160 LCI, 172 HD-WLE; 6 excluded due to incomplete colonoscopies and 19 due to insufficient bowel cleanliness). No significant difference was observed in PDR with LCI (44.4%; 95% CI 36.5% to 52.4%) compared with HD-WLE (36.0%; 95% CI 28.9% to 43.7%) (p=0.12). Of the secondary outcome parameters, more adenomas were found on a patient (adenoma detection rate 36.3%; vs 25.6%; p=0.04) and a colonoscopy basis (mean adenomas per colonoscopy 0.65 vs 0.42; p=0.04). The median withdrawal time was not statistically different between LCI and HD-WLE (12 vs 11 min; p=0.16).ConclusionLCI did not improve the PDR compared with HD-WLE in patients with Lynch syndrome undergoing surveillance. The relevance of findings more adenomas by LCI has to be examined further.Trial registration numberNCT03344289. more...

Introduction The addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to interval cytoreductive surgery (CRS) improves recurrence-free (RFS) and overall survival (OS) in patients with FIGO stage III ovarian cancer. We evaluated the effect of HIPEC on patient's health-related quality of life (HRQoL) in the OVHIPEC trial. Materials and methods OVHIPEC was a multicentre, open-label, randomized phase III trial for patients with stage III ovarian cancer. Patients were randomly assigned (1:1) to receive interval CRS with or without HIPEC with cisplatin. HRQoL was assessed using the EORTC QLQ-C30, and the ovarian (QLQ-OV28) and colorectal cancer (QLQ-CR38) modules. HRQoL questionnaires were administered at baseline, after surgery, after end of treatment, and every three months thereafter. HRQoL was a secondary endpoint, with the prespecified focus on the QLQ-C30 summary score and symptom scores on fatigue, neuropathy and gastro-intestinal symptoms. HRQoL was analysed using linear and non-linear mixed effect models. Results In total, 245 patients were randomized. One-hundred-ninety-seven patients (80%) completed at least one questionnaire. No significant difference over time in the QLQ-C30 summary scores was observed between the study arms (p-values for linear and non-linear growth: p > 0.133). The pattern over time for fatigue, neuropathy and gastro-intestinal symptoms did not significantly differ between treatment arms. Conclusion The addition of HIPEC to interval CRS does not negatively impact HRQoL in patients with stage III ovarian cancer who are treated with interval CRS due to the extent of disease. These HRQoL results, together with the improvement in RFS and OS, support the viability of HIPEC as an important treatment option in this patient population. ClinicalTrials.gov number NCT00426257 . EudraCT number 2006-003466-34. more...

Background: Postmastectomy immediate breast reconstruction (IBR) may improve the quality of life (QoL) of breast cancer patients. Guidelines recommend to discuss the option IBR with all patients undergoing mastectomy. However, substantial hospital variation in IBR-rates was previously observed in the Netherlands, influenced by patient, tumour and hospital factors and clinicians’ believes. Information provision about IBR may have a positive effect on receiving IBR and therefore QoL. This study investigated patient-reported QoL of patients treated with mastectomy with and without IBR. Methods: An online survey, encompassing the validated BREAST-Q questionnaire, was distributed to a representative sample of 1218 breast cancer patients treated with mastectomy. BREAST-Q scores were compared between patients who had undergone mastectomy either with or without IBR. Results: A total of 445 patients were included for analyses: 281 patients with and 164 without IBR. Patients who had received IBR showed significantly higher BREAST-Q scores on “psychosocial well-being” (75 versus 67, p < 0.001), “sexual well-being” (62 versus 52, p < 0.001) and “physical well-being” (77 versus 74, p = 0.021) compared to patients without IBR. No statistically significant difference was found for “satisfaction with breasts” (64 versus 62, p = 0.21). Similar results were found after multivariate regression analyses, revealing IBR to be an independent factor for a better patient-reported QoL. Conclusions: Patients diagnosed with breast cancer with IBR following mastectomy report a better QoL on important psychosocial, sexual and physical well-being domains. This further supports the recommendation to discuss the option of IBR with all patients with an indication for mastectomy and to enable shared decision-making. more...

Objective In this retrospective, single-center observational study, we investigated whether discontinuing metformin for at least 48 h prevents metformin-induced [18F]fluorodeoxyglucose (FDG) uptake in all segments of the colon. Methods Patients with type 2 diabetes who were using metformin before undergoing an FDG PET/CT scan were included. Two groups were created: patients who discontinued metformin for less than 48 h ( Results Colonic FDG uptake in the ≥ 48 h group (n = 23) was higher than uptake in the control group (n = 96) in the colon descendens [odds ratio (OR) 14.0; 95% confidence interval (CI) 4.8–40.9; p value: 0.001] and rectosigmoid (OR 11.3; 95% CI 4.0–31.9; p value: 0.001), and there was no difference in the colon ascendens and transversum. Colonic FDG uptake in the n = 25) was higher than uptake in the ≥ 48 h group (n = 23) in the colon transversum (OR 4.8; 95% CI 1.3–18.5; p value: 0.022) and rectosigmoid (p value: 0.023), and there was no difference in the colon ascendens and descendens. Conclusions Discontinuing metformin for 48 h before undergoing an FDG PET/CT still gives a high uptake in the distal parts of the colon when compared with non-diabetic patients who are not using metformin. Discontinuing metformin for 48 h seems to be useful for scanning the more proximal segments of the colon. more...

Objective To investigate the learning curve of robot‐assisted laparoscopy in early‐stage cervical cancer and quantify impact on oncological outcomes. Design Observational cohort study. Setting Tertiary referral centre with one surgical team. Population All women with early‐stage cervical cancer treated consecutively with robot‐assisted laparoscopy between 2007 and 2017. Methods With multivariate risk‐adjusted cumulative sum analysis (RA‐CUSUM), we assessed the learning curve of robot‐assisted laparoscopy of a single surgical team based on cervical cancer recurrence. Subsequently, a survival analysis was conducted comparing oncological outcomes of women treated during different phases of the learning curve. Main outcome measures Surgical proficiency based on recurrence, survival rates in the different learning phases. Results One hundred and sixty‐five women with cervical cancer underwent robot‐assisted laparoscopy, with a median follow up of 57 months (range 3–132 months). The RA‐CUSUM analysis demonstrated two phases of the learning curve: a learning phase of 61 procedures (group 1) and an experienced phase representing the 104 procedures thereafter (group 2). The 5‐year disease‐free survival was 80.2% in group 1 and 91.1% in group 2 (P = 0.040). Both the 5‐year disease‐specific survival and overall survival significantly increased after the learning phase. Conclusion The learning phase of robot‐assisted laparoscopy in early‐stage cervical cancer in this institutional cohort is at least 61 procedures, with higher survival rates in the women treated thereafter. The learning curve of robot‐assisted laparoscopy affects oncological outcomes and warrants more attention in the design of future studies. Tweetable abstract The learning curve of robot‐assisted laparoscopy in early‐stage cervical cancer affects oncological outcomes and warrants more attention., Tweetable abstract The learning curve of robot‐assisted laparoscopy in early‐stage cervical cancer affects oncological outcomes and warrants more attention. more...

Introduction Radiopharmaceuticals may cause adverse events. Knowledge about adverse events from a patient’s perspective could help healthcare professionals to detect, understand, and manage adverse events more efficiently when using radiopharmaceuticals. Researchers need a validated questionnaire that can be used in patients to assess adverse events with radiopharmaceuticals. Objective The aim of this study was to develop, validate the content of, and perform initial testing of a questionnaire assessing patient-reported adverse events of radiopharmaceuticals. Methods Based on existing literature, six professionals drafted and evaluated a first version of the questionnaire. Further content validation was performed using cognitive interviews with six patients undergoing a nuclear medicine examination. After adaptations, the questionnaire was developed into a web-based questionnaire. One hundred patients undergoing nuclear examination tested this version, and the results were used to assess its acceptability and evaluate reported adverse events. Results Questions and answer options were revised in the initial questionnaire to improve clarity. In addition, some questions were removed. The final version consisted of 18 questions. In the test phase, the acceptability of the questionnaire was demonstrated (e.g. 79% of the patients who received the questionnaire completed it, and the median time to complete the questionnaire was 12 min for patients who reported an adverse event). Of the 100 patients (53% men, median age 64 years), 12 reported a total of 22 adverse events. One of these adverse events had a high causal association. Conclusion After validation and testing, the developed questionnaire to study patient-reported adverse events of radiopharmaceuticals is a suitable and valid instrument which can be used in future research. Electronic supplementary material The online version of this article (10.1007/s40264-019-00895-2) contains supplementary material, which is available to authorized users. more...

Development 149(9), dev200198 (2022). doi:10.1242/dev.200198, Published by The Company of Biologists, Cambridge

Background: Whether certain activities can trigger spontaneous intracerebral hemorrhage (ICH) remains unknown. Insights into factors that trigger vessel rupture resulting in ICH improves knowledge on the pathophysiology of ICH. We assessed potential trigger factors and their risk for ICH onset. Methods: We included consecutive patients diagnosed with ICH between July 1, 2013, and December 31, 2019. We interviewed patients on their exposure to 12 potential trigger factors (eg, Valsalva maneuvers) in the (hazard) period soon before onset of ICH and their normal exposure to these trigger factors in the year before the ICH. We used the case-crossover design to calculate relative risks (RR) for potential trigger factors. Results: We interviewed 149 patients (mean age 64, 66% male) with ICH. Sixty-seven (45%) had a lobar hemorrhage, 60 (40%) had a deep hemorrhage, 19 (13%) had a cerebellar hemorrhage, and 3 (2%) had an intraventricular hemorrhage. For ICH in general, there was an increased risk within an hour after caffeine consumption (RR=2.5 [95% CI=1.8–3.6]), within an hour after coffee consumption alone (RR=4.8 [95% CI=3.3–6.9]), within an hour after lifting >25 kg (RR=6.6 [95% CI=2.2–19.9]), within an hour after minor head trauma (RR=10.1 [95% CI=1.7–60.2]), within an hour after sexual activity (RR=30.4 [95% CI=16.8–55.0]), within an hour after straining for defecation (RR=37.6 [95% CI=22.4–63.4]), and within an hour after vigorous exercise (RR=21.8 [95% CI=12.6–37.8]). Within 24 hours after flu-like disease or fever, the risk for ICH was also increased (RR=50.7 [95% CI=27.1–95.1]). Within an hour after Valsalva maneuvers, the RR for deep ICH was 3.5 (95% CI=1.7–6.9) and for lobar ICH the RR was 2.0 (95% CI=0.9–4.2). Conclusions: We identified one infection and several blood pressure related trigger factors for ICH onset, providing new insights into the pathophysiology of vessel rupture resulting in ICH. more...

Sex differences in adverse drug reactions (ADRs) associated with angiotensin-converting enzymeinhibitors (ACEIs) remain poorly understood owing to a lack of sex-specific ADR data from clinicaltrials. 1 Postmarketing pharmacovigilance data, containing structured and detailed ADR information,may play an important role in such analyses. However, these data are often not corrected forprescription numbers and therefore cannot separate sex differences in ADR risk from sex differencesin prescription rates. To investigate whether women report more ACEI-related ADRs than men aftercorrection for sex-specific prescription and describe sex differences in reported ADR types, wecombined data from the global pharmacovigilance database VigiBase and the prescription-correctedDutch pharmacovigilance database Lareb. more...

INTRODUCTION:Local full-thickness resections of the scar (FTRS) after local excision of a T1 colorectal cancer (CRC) with uncertain resection margins is proposed as an alternative strategy to completion surgery (CS), provided that no local intramural residual cancer (LIRC) is found. However, a comparison on long-term oncological outcome between both strategies is missing.METHODS:A large cohort of patients with consecutive T1 CRC between 2000 and 2017 was used. Patients were selected if they underwent a macroscopically complete local excision of a T1 CRC but positive or unassessable (R1/Rx) resection margins at histology and without lymphovascular invasion or poor differentiation. Patients treated with CS or FTRS were compared on the presence of CRC recurrence, a 5-year overall survival, disease-free survival, and metastasis-free survival.RESULTS:Of 3,697 patients with a T1 CRC, 434 met the inclusion criteria (mean age 66 years, 61% men). Three hundred thirty-four patients underwent CS, and 100 patients underwent FTRS. The median follow-up period was 64 months. CRC recurrence was seen in 7 patients who underwent CS (2.2%, 95% CI 0.9%-4.6%) and in 8 patients who underwent FTRS (9.0%, 95% CI 3.9%-17.7%). Disease-free survival was lower in FTRS strategy (96.8% vs 89.9%, P = 0.019), but 5 of the 8 FTRS recurrences could be treated with salvage surgery. The metastasis-free survival (CS 96.8% vs FTRS 92.1%, P = 0.10) and overall survival (CS 95.6% vs FTRS 94.4%, P = 0.55) did not differ significantly between both strategies.DISCUSSION:FTRS after local excision of a T1 CRC with R1/Rx resection margins as a sole risk factor, followed by surveillance and salvage surgery in case of CRC recurrence, could be a valid alternative strategy to CS. more...

Altered stress-reactivity may represent a general risk factor for psychopathology. In a broad at-risk sample, we examined (a) how stress and mild, daily expressions of psychopathology were interrelated over time, (b) whether we could detect subgroups with similar dynamics between stress and daily expressions of psychopathology (i.e., stress-reactivity), and (c) whether stress-reactivity was associated with psychopathology and social functioning. One hundred twenty-two young adults (43.4% women, mean age 23.6) at risk for developing a wide range of psychopathology completed a 6-month daily diary study. We used group iterative multiple model estimation (GIMME) to identify temporal associations between event stress and 11 mild expressions of psychopathology (e.g., feeling down, restlessness) at group, subgroup, and individual levels. Stress was associated with feeling irritated during the same day for >70% of individuals, and with feeling down and worrying during the same day for >50% of individuals. No stable subgroups characterized by similar daily stress-reactivity were identified. Instead, we observed 71 different stress-reactivity patterns in 122 individuals. Average daily event stress, but not overall stress-reactivity (weighted stress-response), was associated with psychopathology severity and social dysfunction. This study showed important similarities, as well as many differences between individuals, in terms of the impact of stress on mild expressions of psychopathology in daily life. Clustering based on similar stress-reactivity did not lead to stable subgroups. Finally, average daily stress levels, but not daily stress-reactivity, were associated with psychopathologic severity and social dysfunction. Findings highlight the importance of considering heterogeneity in stress-reactivity, but also challenges for identifying generalizable processes in doing so. (PsycInfo Database Record (c) 2022 APA, all rights reserved). more...

To investigate how GPs manage women with urinary incontinence (UI) in the Netherlands and to assess whether this is in line with the relevant Dutch GP guideline. Because UI has been an underreported and undertreated problem for decades despite appropriate guidelines being created for general practitioners (GPs). Retrospective cohort study. Routine primary care data for 2017 in the Netherlands. We included the primary care records of women aged 18–75 years with at least one contact registered for UI, and then extracted information about baseline characteristics, diagnosis, treatment, and referral to pelvic physiotherapy or secondary care. In total, 374 records were included for women aged 50.3 ± 15.1 years. GPs diagnosed 31.0%, 15.2%, and 15.0% women with stress, urgency, or mixed UI, respectively; no diagnosis of type was recorded in 40.4% of women. Urinalysis was the most frequently used diagnostic test (42.5%). Education was the most common treatment, offered by 17.9% of GPs; however, no treatment or referral was reported in 15.8% of cases. As many as 28.7% and 21.7% of women were referred to pelvic physiotherapy and secondary care, respectively. Female UI is most probably not managed in line with the relevant Dutch GP guideline. It is also notable that Dutch GPs often fail to report the type of UI, to use available diagnostic approaches, and to provide appropriate education. Moreover, GPs referred to specialists too often, especially for the management of urgency UI.Key pointsUrinary incontinence (UI) has been an underreported and undertreated problem for decades. Despite various guidelines, UI often lies outside the GPs comfort zone.•According to this study: general practitioners do not treat urinary incontinence according to guidelines.•The type of incontinence is frequently not reported and diagnostic approaches are not fully used.•We believe that increased awareness will help improve treatment and avoidable suffering. Urinary incontinence (UI) has been an underreported and undertreated problem for decades. Despite various guidelines, UI often lies outside the GPs comfort zone. •According to this study: general practitioners do not treat urinary incontinence according to guidelines. •The type of incontinence is frequently not reported and diagnostic approaches are not fully used. •We believe that increased awareness will help improve treatment and avoidable suffering. more...

Background and Purpose: Although evidence accumulates that the cerebellum is involved in cerebral amyloid angiopathy (CAA), cerebellar superficial siderosis is not considered to be a disease marker. The objective of this study is to investigate cerebellar superficial siderosis frequency and its relation to hemorrhagic magnetic resonance imaging markers in patients with sporadic and Dutch-type hereditary CAA and patients with deep perforating arteriopathy–related intracerebral hemorrhage. Methods: We recruited patients from 3 prospective 3 Tesla magnetic resonance imaging studies and scored siderosis and hemorrhages. Cerebellar siderosis was identified as hypointense linear signal loss (black) on susceptibility-weighted or T2*-weighted magnetic resonance imaging which follows at least one folia of the cerebellar cortex (including the vermis). Results: We included 50 subjects with Dutch-type hereditary CAA, (mean age 50 years), 45 with sporadic CAA (mean age 72 years), and 43 patients with deep perforating arteriopathy–related intracerebral hemorrhage (mean age 54 years). Cerebellar superficial siderosis was present in 5 out of 50 (10% [95% CI, 2–18]) patients with Dutch-type hereditary CAA, 4/45 (9% [95% CI, 1–17]) patients with sporadic CAA, and 0 out of 43 (0% [95% CI, 0–8]) patients with deep perforating arteriopathy–related intracerebral hemorrhage. Patients with cerebellar superficial siderosis had more supratentorial lobar (median number 9 versus 2, relative risk, 2.9 [95% CI, 2.5–3.4]) and superficial cerebellar macrobleeds (median number 2 versus 0, relative risk, 20.3 [95% CI, 8.6–47.6]) compared with patients without the marker. The frequency of cortical superficial siderosis and superficial cerebellar microbleeds was comparable. Conclusions: We conclude that cerebellar superficial siderosis might be a novel marker for CAA. more...

Background and Objectives: To evaluate the representativeness of Dutch patients participating in the European Organization for Research and Treatment of Cancer EORTC boost-no-boost trial to the target breast cancer patient population. Methods: All female breast cancer patients diagnosed between 1989 and 1996, aged < 70 years, treated with breast-conserving surgery and radiation therapy, were selected from the Netherlands Cancer Registry (NCR) and linked to the EORTC trial database. Baseline characteristics were compared between trial and non-trial participants, for the Dutch population and according to seven participating institutions. Kaplan-Meier curves and multivariable Cox regression were used to explore potential heterogeneity in overall survival between low, medium and high-volume institutes. Results: Overall, 20,880 patients were identified from the NCR: 2,445 of 2,602 (94%) trial participants could be linked, and 18,435 were treated outside the trial. Trial participants had similar age, morphology, topography, laterality and socioeconomic status as non trial participants, but more often stage I (62.7% vs. 56.4%) tumours and less often adjuvant treatment (22.9% vs. 26.5%). Crude 20 year survival ranged from 52.5% to 57.4%, without significant differences in multivariable analyses. Conclusion: This case study showed that participants in the boost-no-boost trial well represented the Dutch target population. Data linkage comes with challenges, but can close the gap between research and clinical practice. (C) 2022 The Author(s). Published by Elsevier Inc. more...

Contains fulltext : 288341.pdf (Publisher’s version ) (Open Access) BACKGROUND: In all giant-cell-rich lesions (GCRL) occurring in bone, a common underlying excessive RANKL expression is held responsible for the osteolytic activity. Apart from giant cell tumour of bone (GCTB), systematic outcome analysis of RANKL inhibition in other GCRL is unavailable. The aim of this study is to assess the efficacy and safety of a 1-year denosumab protocol in giant cell lesions of the jaw (GCLJ). METHODS: A retrospective cohort study was conducted compromising patients treated with a 1-year protocol of monthly subcutaneously administered 120 mg denosumab. Objective tumour response based on histology and imaging was used to calculate objective tumour response rate, progression-free survival (PFS) and time to progression. Type, severity and frequency of adverse events were recorded in a standardised way to assess safety. RESULTS: Twenty patients, predominantly female (90%), were included. Fifty-five per cent of lesions were located in the mandible; most classified as aggressive lesions (90%). Thirty-five per cent (7/20) of cases were either recurrent after prior treatment or progressive, while on other drug treatment. Objective tumour response rate was 100% after 12 months of treatment. Median PFS was 50.4 months (95% CI 38.0-62.8) with a cumulative PFS rate of 22.6% (95% CI 1.8-43.4) at 5 years follow-up. Median time to progression was 38.4 months (95% CI 26.0-50.8). Treatment was well tolerated, and none of the patients had to interrupt therapy for toxicity. CONCLUSION: High-dose denosumab is effective and safe in achieving a complete response in GCLJ within 12 months. The high long-term relapse rate after treatment cessation is the main obstacle for denosumab to become standard treatment for GCLJ. more...

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Background and Purpose: Endovascular treatment for acute ischemic stroke has been proven clinically effective, but evidence of the cost-effectiveness based on real-world data is scarce. The aim of this study was to assess whether endovascular therapy plus usual care is cost-effective in comparison to usual care alone in acute ischemic stroke patients. Methods: An economic evaluation was performed from a societal perspective with a 2-year time horizon. Empirical data on health outcomes and the use of resources following endovascular treatment were gathered parallel to the MR CLEAN trial (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) and its 2-year follow-up study. Incremental cost-effectiveness ratios were calculated as the extra costs per additional patient with functional independence (modified Rankin Scale score 0–2) and the extra cost per quality-adjusted life year gained. Results: The mean costs per patient in the intervention group were $126 494 versus $143 331 in the control group (mean difference, −$16 839 [95% CI, −$38 113 to $5456]). Compared with patients in the control group, more patients in the intervention group achieved functional independence, 37.2% versus 23.9% (absolute difference, 13.3% [95% CI, 4.0%–22.0%]) and they generated more quality-adjusted life years, 0.99 versus 0.83 (mean difference of 0.16 [95% CI, 0.04–0.29]). Endovascular treatment dominated standard treatment with $18 233 saved per extra patient with a good outcome and $105 869 saved per additional quality-adjusted life year. Conclusions: Endovascular treatment added to usual care is clinically effective, and cost saving in comparison to usual care alone in patients with acute ischemic stroke. Registration: URL: https://www.trialregister.nl/trial/695 ; Unique identifier: NL695. URL: https://www.isrctn.com ; Unique identifier: ISRCTN10888758. more...

Surgery for locoregionally advanced head and neck squamous cell carcinoma (HNSCC) results in 30‒50% five-year overall survival. In IMCISION (NCT03003637), a non-randomized phase Ib/IIa trial, 32 HNSCC patients are treated with 2 doses (in weeks 1 and 3) of immune checkpoint blockade (ICB) using nivolumab (NIVO MONO, n = 6, phase Ib arm A) or nivolumab plus a single dose of ipilimumab (COMBO, n = 26, 6 in phase Ib arm B, and 20 in phase IIa) prior to surgery. Primary endpoints are feasibility to resect no later than week 6 (phase Ib) and primary tumor pathological response (phase IIa). Surgery is not delayed or suspended for any patient in phase Ib, meeting the primary endpoint. Grade 3‒4 immune-related adverse events are seen in 2 of 6 (33%) NIVO MONO and 10 of 26 (38%) total COMBO patients. Pathological response, defined as the %-change in primary tumor viable tumor cell percentage from baseline biopsy to on-treatment resection, is evaluable in 17/20 phase IIa patients and 29/32 total trial patients (6/6 NIVO MONO, 23/26 COMBO). We observe a major pathological response (MPR, 90‒100% response) in 35% of patients after COMBO ICB, both in phase IIa (6/17) and in the whole trial (8/23), meeting the phase IIa primary endpoint threshold of 10%. NIVO MONO’s MPR rate is 17% (1/6). None of the MPR patients develop recurrent HSNCC during 24.0 months median postsurgical follow-up. FDG-PET-based total lesion glycolysis identifies MPR patients prior to surgery. A baseline AID/APOBEC-associated mutational profile and an on-treatment decrease in hypoxia RNA signature are observed in MPR patients. Our data indicate that neoadjuvant COMBO ICB is feasible and encouragingly efficacious in HNSCC., Immune checkpoint blockade has become standard care for patients with recurrent metastatic head and neck squamous cell carcinoma (HNSCC). Here the authors present the results of a non-randomized phase Ib/IIa trial, reporting safety and efficacy of neoadjuvant nivolumab monotherapy and nivolumab plus ipilimumab prior to standard-of-care surgery in patients with HNSCC. . more...

Patients with symptomatic carotid stenosis are at high risk for recurrent stroke. The decision for carotid endarterectomy currently mainly relies on degree of stenosis (cutoff value50% or 70%). Nevertheless, also, patients with mild-to-moderate stenosis still have a considerable recurrent stroke risk. Increasing evidence suggests that carotid plaque composition rather than degree of stenosis determines plaque vulnerability; however, it remains unclear whether this also provides additional information to improve clinical decision making.The PARISK (Plaque At RISK) study aimed to improve the identification of patients at increased risk of recurrent ischemic stroke using multimodality carotid imaging.The authors included 244 patients (71% men; mean age, 68 years) with a recent symptomatic mild-to-moderate carotid stenosis in a prospective multicenter cohort study. Magnetic resonance imaging (carotid and brain) and computed tomography angiography (carotid) were performed at baseline and after 2 years. The clinical endpoint was a recurrent ipsilateral ischemic stroke or transient ischemic attack (TIA). Cox proportional hazards models were used to assess whether intraplaque hemorrhage (IPH), ulceration, proportion of calcifications, and total plaque volume in ipsilateral carotid plaques were associated with the endpoint. Next, the authors investigated the predictive performance of these imaging biomarkers by adding these markers (separately and simultaneously) to the ECST (European Carotid Surgery Trial) risk score.During 5.1 years follow-up, 37 patients reached the clinical endpoint. IPH presence and total plaque volume were associated with recurrent ipsilateral ischemic stroke or TIA (HR: 2.12 [95% CI: 1.02-4.44] for IPH; HR: 1.07 [95% CI: 1.00-1.15] for total plaque volume per 100 µL increase). Ulcerations and proportion of calcifications were not statistically significant determinants. Addition of IPH and total plaque volume to the ECST risk score improved the model performance (C-statistics increased from 0.67 to 0.75-0.78).IPH and total plaque volume are independent risk factors for recurrent ipsilateral ischemic stroke or TIA in patients with mild-to-moderate carotid stenosis. These plaque characteristics improve current decision making. Validation studies to implement plaque characteristics in clinical scoring tools are needed. (PARISK: Validation of Imaging Techniques [PARISK]; NCT01208025). more...

Background: The COVID-19 pandemic impacted Dutch society and the healthcare system. Focus switched to care for COVID-19 patients, thereby altering care for non-COVID patients. Non-urgent medical visits were cancelled or postponed and patients were reluctant to visit healthcare services. Objectives: This study aimed to investigate the impact of the COVID-19 pandemic on trends in diagnoses of keratinocyte carcinoma (cutaneous squamous cell carcinoma (cSCC), basal cell carcinoma (BCC)) and to assess the magnitude of diagnostic delays. Methods: The number of cSCC and BCC diagnoses in each month of 2020 was compared to the expected number of diagnoses for these months, using data from the Netherlands Cancer Registry. Expected diagnoses for 2020 were used as a reference to take the yearly increase in keratinocyte carcinoma incidence into account and were calculated by extrapolating the trends observed in 2017–2019. Comparisons were further stratified by age, sex and region. Estimates of diagnostic delays were calculated and corrected for the influence of excess mortality due to the pandemic on keratinocyte carcinoma incidence. Results: The number of cSCC and BCC diagnoses substantially decreased when compared to the number of diagnoses expected from March to May 2020 (cSCC −29%, BCC −50%). These decreases were observed across all age groups, both sexes, and all regions. From June to September the number of cSCC and BCC diagnoses was higher than expected, after which it slightly dropped below expected in October to December. In total, 2020 keratinocyte carcinoma diagnoses continued to trail those expected, with a backlog of around 1150 cSCCs and 11 767 BCCs remaining at the end of the year. Conclusion: Diagnosis of keratinocyte carcinoma was suboptimal during the COVID-19 pandemic, due to diagnostic delays likely resulting from both patient and health system-related delay. Further studies will need to determine the effects of these diagnostic delays on outcomes. more...

Alteplase with EVT versus EVT Alone for Stroke Trials involving Asian patients with acute stroke have suggested that endovascular treatment alone is not inferior to the usual practice of thrombolysis before endovascular treatment. This trial involving European patients did not show noninferiority or superiority of endovascular treatment alone.Background The value of administering intravenous alteplase before endovascular treatment (EVT) for acute ischemic stroke has not been studied extensively, particularly in non-Asian populations. Methods We performed an open-label, multicenter, randomized trial in Europe involving patients with stroke who presented directly to a hospital that was capable of providing EVT and who were eligible for intravenous alteplase and EVT. Patients were randomly assigned in a 1:1 ratio to receive EVT alone or intravenous alteplase followed by EVT (the standard of care). The primary end point was functional outcome on the modified Rankin scale (range, 0 [no disability] to 6 [death]) at 90 days. We assessed the superiority of EVT alone over alteplase plus EVT, as well as noninferiority by a margin of 0.8 for the lower boundary of the 95% confidence interval for the odds ratio of the two trial groups. Death from any cause and symptomatic intracerebral hemorrhage were the main safety end points. Results The analysis included 539 patients. The median score on the modified Rankin scale at 90 days was 3 (interquartile range, 2 to 5) with EVT alone and 2 (interquartile range, 2 to 5) with alteplase plus EVT. The adjusted common odds ratio was 0.84 (95% confidence interval [CI], 0.62 to 1.15; P=0.28), which showed neither superiority nor noninferiority of EVT alone. Mortality was 20.5% with EVT alone and 15.8% with alteplase plus EVT (adjusted odds ratio, 1.39; 95% CI, 0.84 to 2.30). Symptomatic intracerebral hemorrhage occurred in 5.9% and 5.3% of the patients in the respective groups (adjusted odds ratio, 1.30; 95% CI, 0.60 to 2.81). Conclusions In a randomized trial involving European patients, EVT alone was neither superior nor noninferior to intravenous alteplase followed by EVT with regard to disability outcome at 90 days after stroke. The incidence of symptomatic intracerebral hemorrhage was similar in the two groups. (Funded by the Collaboration for New Treatments of Acute Stroke consortium and others; MR CLEAN-NO IV ISRCTN number, .) more...

In the past decade, the leading international cardiology societies have released statements that emphasize the importance of sex-specific reporting of the findings of clinical trials in cardiovascular research. To find out whether this has led to improvement, we compared sex-specific reporting of efficacy and safety outcomes for trials of cardiovascular drug interventions presented at the major clinical trials sessions of the European Society of Cardiology (ESC), American Heart Association (AHA) and the American College of Cardiology (ACC) before and after publication of these statements. We found that sex-specific efficacy and safety outcomes of the most influential cardiovascular intervention trials are still not systematically presented. more...

Contains fulltext : 220736.pdf (Publisher’s version ) (Closed access) Background Amlodipine is a widely used antihypertensive agent for the treatment of paediatric hypertension, but the commercially available tablets are not suitable to treat young patients, who need lower, flexible dosages and a liquid formulation. Objective To determine the pharmacokinetic properties of amlodipine and the acceptability of a standardised, extemporaneous oral solution. Method A newly developed liquid formulation of amlodipine was administered to hypertensive children between the age of 6 months and 11 years. Using a limited sampling strategy, population PK analysis was performed using nonlinear mixed effects modelling. Results Nine children, with a median age of 2.9 years (IQR 1.8-8.4), receiving stable amlodipine therapy in a median dose of 0.15 mg kg(-1) day(-1) (IQR 0.11-0.18), were switched to study medication. The population pharmacokinetic model was able to accurately predict the clearance of amlodipine in the study population. Based on the final model, clearance was reduced by 31.2% (RSE: 10%) in females. Patient reported outcomes on taste from a five-point hedonic scale were available for five patients, who scored the taste from positive to slightly negative. Conclusion The results from the PK study and the acceptability assessment show that the amlodipine oral solution presented in this study offers an appropriate treatment option for young children. more...

Background Pharmacokinetics (PK) are severely altered in critically ill patients due to changes in volume of distribution (Vd) and/or drug clearance (Cl). This affects the target attainment of antibiotics in critically ill children. We aimed to identify gaps in current knowledge and to compare published PK parameters and target attainment of antibiotics in critically ill children to healthy children and critically ill adults. Methods Systematic literature search in PubMed, EMBASE and Web of Science. Articles were labelled as relevant when they included information on PK of antibiotics in critically ill, non-neonatal, pediatric patients. Extracted PK-parameters included Vd, Cl, (trough) concentrations, AUC, probability of target attainment, and elimination half-life. Results 50 relevant articles were identified. Studies focusing on vancomycin were most prevalent (17/50). Other studies included data on penicillins, cephalosporins, carbapenems and aminoglycosides, but data on ceftriaxone, ceftazidime, penicillin and metronidazole could not be found. Critically ill children generally show a higher Cl and larger Vd than healthy children and critically ill adults. Reduced target-attainment was described in critically ill children for multiple antibiotics, including amoxicillin, piperacillin, cefotaxime, vancomycin, gentamicin, teicoplanin, amikacin and daptomycin. 38/50 articles included information on both Vd and Cl, but a dosing advice was given in only 22 articles. Conclusion The majority of studies focus on agents where TDM is applied, while other antibiotics lack data altogether. The larger Vd and higher Cl in critically ill children might warrant a higher dose or extended infusions of antibiotics in this patient population to increase target-attainment. Studies frequently fail to provide a dosing advice for this patient population, even if the necessary information is available. Our study shows gaps in current knowledge and encourages future researchers to provide dosing advice for special populations whenever possible. Electronic supplementary material The online version of this article (10.1007/s40262-019-00813-w) contains supplementary material, which is available to authorized users. more...

Objectives Acute kidney injury (AKI) is common in critically ill children, but current biomarkers are suboptimal. Proenkephalin A 119–159 (PENK) is a promising new biomarker for AKI in adults, but pediatric data is lacking. We determined PENK reference intervals for healthy children, crucial for clinical implementation, and explored concentrations in critically ill infants aged under 1 year. Methods Observational cohort study in healthy infants and critically ill children aged 0–1 years. Reference values were determined using generalized additive models. Plasma PENK concentrations between healthy children and critically ill children with and without AKI, were compared using linear mixed modelling. The performance of PENK as AKI biomarker was compared to cystatin C (CysC) and β-trace protein (BTP) using receiver-operating-characteristic (ROC) analysis. Results PENK concentrations in 100 healthy infants were stable during the first year of life (median 517.3 pmol/L). Median PENK concentrations in 91 critically ill children, were significantly higher in those with AKI (n=40) (KDIGO Stage 1 507.9 pmol/L, Stage 2 704.0 pmol/L, Stage 3 930.5 pmol/L) than non-AKI patients (n=51, 432.2 pmol/L) (p Conclusions PENK reference values are much higher in young infants than adults, but clearly discriminate between children with and without AKI, with comparable or better performance than CysC and BTP. Our results illustrate the importance of establishing age-normalized reference values and indicate PENK as a promising pediatric AKI biomarker. more...

Background and Objective Bodyweight-based dosing of tacrolimus is considered standard care. Currently, at first steady state, a third of pediatric kidney transplant recipients has a tacrolimus pre-dose concentration within the target range. We investigated whether adaptation of the starting dose according to a validated dosing algorithm could increase this proportion. Methods This was a multi-center, single-arm, prospective trial with a planned interim analysis after 16 patients, in which the tacrolimus starting dose was based on bodyweight, cytochrome P450 3A5 genotype, and donor status (living vs. deceased donor). Results At the interim analysis, 31% of children had a tacrolimus pre-dose concentration within the target range. As the original dosing algorithm was poorly predictive of tacrolimus exposure, the clinical trial was terminated prematurely. Next, the original model was improved by including the data of the children included in this trial, thereby doubling the number of children in the model building cohort. Data were best described with a two-compartment model with inter-individual variability, allometric scaling, and inter-occasion variability on clearance. Cytochrome P450 3A5 genotype, hematocrit, and creatinine influenced the tacrolimus clearance. A new starting dose model was developed in which the cytochrome P450 3A5 genotype was incorporated. Both models were successfully internally and externally validated. Conclusions The weight-normalized starting dose of tacrolimus should be higher in patients with a lower bodyweight and in those who are cytochrome P450 3A5 expressers. Electronic supplementary material The online version of this article (10.1007/s40262-019-00831-8) contains supplementary material, which is available to authorized users. more...

Purpose We assessed the recent trends in the administration of adjuvant chemotherapy thereby evaluating the role of the 70-gene signature (70-GS) testing in decision-making in the systemic treatment of patients with lymph node negative (N0) and lymph node positive (N+) breast cancer. Methods Patients with a national guideline directed indication for 70-GS use treated between 2013 and 2016 were selected from the Netherlands Cancer Registry. Time trends in the administration of adjuvant chemotherapy were evaluated within guideline- and age-delineated subgroups. The influence of the 70-GS on chemotherapy use was assessed with logistic regression. Results During the study period, the overall administration of adjuvant chemotherapy decreased from 49 to 23% and 70-GS use increased from 24 to 51%. The 70-GS was not associated with a decreased likelihood for N0 patients to receive chemotherapy (odds ratio [OR] 1.0; 95% confidence interval [CI] 0.86–1.17), as the proportion of N0 patients who received chemotherapy in the absence of 70-GS use decreased during the study period. In patients with N1a disease, 70-GS testing was associated with a decreased likelihood to receive chemotherapy (OR 0.21; 95% CI 0.15–0.29). In patients more...

Purpose The aim of this study is to validate the RayStation Monte Carlo (MC) dose algorithm using animal tissue neck phantoms and a water breast phantom. Methods Three anthropomorphic phantoms were used in a clinical setting to test the RayStation MC dose algorithm. We used two real animal necks that were cut to a workable shape while frozen and then thawed before being CT scanned. Secondly, we made a patient breast phantom using a breast prosthesis filled with water and placed on a flat surface. Dose distributions in the animal and breast phantoms were measured using the MatriXX PT device. Results The measured doses to the neck and breast phantoms compared exceptionally well with doses calculated by the analytical pencil beam (APB) and MC algorithms. The comparisons between APB and MC dose calculations and MatriXX PT measurements yielded an average depth difference for best gamma agreement of more...

Aims: Chondrosarcoma, osteosarcoma and Ewing sarcoma form the majority of malignant primary tumours of bone. High-grade bone sarcomas require intensive treatment due to their rapid and invasive growth pattern and metastasising capabilities. This nationwide study covers overall incidence, treatment and survival patterns of bone sarcomas in a 15-year period (2000-2014) in the total population of the Netherlands.Patients and methods: Data for this study were derived from the Netherlands Cancer Registry, which receives primary notification from the national pathology database. Classification and categorisation was based on the ICD-O-3 classification and the WHO classification 2013 applied according to our clinicopathological expertise. Overall incidence over the 15-year-period was calculated as a rate per 100,000 person-years (using the European Standardised Rate, ESR). Survival was analysed with Kaplan-Meier curves and Cox proportional hazards regression.Results: Incidence for high-grade chondrosarcoma (n = 429) was estimated at 0.15 per 100,000 ESR, and 5-year overall survival at 65.9% (95% confidence interval (CI): 61.0%-70.4%). Incidence for high-grade central osteosarcoma (n = 605) was estimated at 0.25 per 100,000 ESR and 5-year survival at 53.9% (95% CI: 49.7%-58.0%). Ewing sarcoma incidence (n = 334) was estimated at 0.15 per 100,000 ESR and 5-year survival at 59.3% (95% CI: 53.5%-64.6%). For high-grade central osteosarcoma, treatment at a bone tumour centre was associated with better survival (HR 0.593).Conclusions: This study provides comprehensive incidence estimates for all the main primary bone sarcomas over a 15-year time period in a Northern European country with little migration. Centralisation of bone sarcoma care improves the clinical outcome in osteosarcoma. more...

Aims: To determine the variation in radiation therapy boost use in a nationwide study following adjustment of a national guideline in 2011, as well as to address the relationship to patient, tumour and radiation therapy institutional factors.Materials and methods: All invasive breast cancers and non-invasive breast cancers (ductal carcinoma in situ; DCIS) that received external whole-breast radiation between 2011 and 2016 were selected from the Netherlands Cancer Registry. Box plots were used to evaluate variation over time and logistic regression was carried out to address other factors influencing the variation. Funnel plots were constructed, with unadjusted and adjusted data for patient and tumour factors significantly affecting the use of a boost.Results: For breast cancer patients (n = 45,207), the proportion receiving a boost and its range decreased over the years from 37.3-92.7% in 2011 to 28.3-65.4% in 2016. This trend was not observed in DCIS patients (n = 6,844). Young age, large tumours, high grade and the absence of tumour-free resection margins were associated with boost use for both breast cancer and DCIS. For breast cancer, triple-negative tumour subtype and metastatic lymph node involvement were also associated with boost use. Institutional factors did not influence the use of a boost and institutional variation remained substantial after case-mix adjustments.Conclusion: Following adjustment of a nationwide implemented guideline, variation in radiation therapy boost use decreased in patients with breast cancer but not in patients with DCIS. Several tumour and patient characteristics were associated with boost use. Substantial institutional variation could not be explained by differences in patient, tumour or predefined institutional characteristics. (C) 2018 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. more...

PURPOSE:Patients may transfer of hospital for clinical reasons but this may delay time to treatment. The purpose ofthis study is to provide insight in the extent of hospital transfer in breast cancer care; which type of patients transfer and what is the impact on time to treatment.METHODS:We included 41,413 breast cancer patients registered in the Netherlands Cancer Registry between 2014and 2016. We investigated transfer of hospital between diagnosis and first treatment being surgery or neoadjuvant chemotherapy (NAC). Co-variate adjusted characteristics predictive for hospital transfer were determined. To adjust for possible treatment by indication bias we used propensity score matching (PSM). Time to treatment in patients with and without hospital transfer was compared.RESULTS:Among 41,413 patients, 8.5% of all patients transferred to another hospital between diagnosis and firsttreatment; 4.9% before primary surgery and 24.8% before NAC. Especially young (aged CONCLUSIONS:While almost 5% of Dutch patients treated with primary surgery transfer hospital after diagnosis andup to 25% for patients treated with NAC, our findings suggest that especially those treated with primary surgery are at risk for additional treatment delay by hospital transfer. more...

To evaluate the efficacy and long-term outcome of repeat large loop excision of the transformation zone in women with residual or recurrent cervical intraepithelial neoplasia.PALGA (the Dutch Pathology Registry), a database of deidentified cervical cytologic and histologic data, was used to examine women with cervical dysplasia who underwent two or more large loop excision of the transformation zone procedures between January 2005 and June 2015. We obtained cervical cytology and histology results. The main outcome was efficacy of repeated large loop excision of the transformation zone procedure in women with residual or recurrent cervical intraepithelial neoplasia. We also examined subsequent excisional procedures and hysterectomy.We identified 499 women who had undergone two or more large loop excision of the transformation zone procedures. After their second procedure, 60.7% of women had a normal first cervical cytologic sample. The mean duration of follow-up was 68 months (0-163 months). Additional cervical excisional procedures were performed in 33.7% of women. Overall, 1.2% of women developed cervical cancer during follow-up. Moreover, 19.0% of women eventually underwent hysterectomy.One third of the women who undergo two large loop excision of the transformation zone procedures require an additional excisional procedure or hysterectomy. Almost one fifth of these women eventually undergo hysterectomy. more...

Malaltia d'Alzheimer; Biomarcadors; Microdissecció de captura làser Alzheimer's disease; Biomarkers; Laser capture microdissection Enfermedad de Alzheimer; Biomarcadores; Microdisección por captura láser Brain accumulation of amyloid-beta (Aβ) is a crucial feature in Alzheimer´s disease (AD) and cerebral amyloid angiopathy (CAA), although the pathophysiological relationship between these diseases remains unclear. Numerous proteins are associated with Aβ deposited in parenchymal plaques and/or cerebral vessels. We hypothesized that the study of these proteins would increase our understanding of the overlap and biological differences between these two pathologies and may yield new diagnostic tools and specific therapeutic targets. We used a laser capture microdissection approach combined with mass spectrometry in the APP23 transgenic mouse model of cerebral-β-amyloidosis to specifically identify vascular Aβ-associated proteins. We focused on one of the main proteins detected in the Aβ-affected cerebrovasculature: MFG-E8 (milk fat globule-EGF factor 8), also known as lactadherin. We first validated the presence of MFG-E8 in mouse and human brains. Immunofluorescence and immunoblotting studies revealed that MFG-E8 brain levels were higher in APP23 mice than in WT mice. Furthermore, MFG-E8 was strongly detected in Aβ-positive vessels in human postmortem CAA brains, whereas MFG-E8 was not present in parenchymal Aβ deposits. Levels of MFG-E8 were additionally analysed in serum and cerebrospinal fluid (CSF) from patients diagnosed with CAA, patients with AD and control subjects. Whereas no differences were found in MFG-E8 serum levels between groups, MFG-E8 concentration was significantly lower in the CSF of CAA patients compared to controls and AD patients. Finally, in human vascular smooth muscle cells MFG-E8 was protective against the toxic effects of the treatment with the Aβ40 peptide containing the Dutch mutation. In summary, our study shows that MFG-E8 is highly associated with CAA pathology and highlights MFG-E8 as a new CSF biomarker that could potentially be used to differentiate cerebrovascular Aβ pathology from parenchymal Aβ deposition. This work was funded by the Instituto de Salud Carlos III (ISCIII), (PI20/00465), co-financed by the European Regional Development Fund (FEDER). The Neurovascular Research Laboratory is part of the INVICTUS + network, ISCIII, Spain (RD16/0019/0021). P.M. held a predoctoral fellowship from the Vall d’Hebron Research Institute. MMV is supported by the BIONIC project (no. 733050822, which has been made possible by ZonMW as part of ‘Memorabel’, the research and innovation program for dementia, as part of the Dutch national ‘Deltaplan for Dementia’:the CAFÉ project (the National Institutes of Health, USA, grant number 5R01NS104147-02), and a grant from the Selfridges Group Foundation (NR170024). The BIONIC project is a consortium of Radboudumc, LUMC, ADX Neurosciences, and Rhode Island University. more...