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The lacrimal gland (LG) is responsible for most tear production. Defective tear synthesis and secretion in the LG cause dry eye disease. This is a prevalent disease worldwide that causes eye irritation, and in severe cases, it can lead to eye damage. Understanding LG development is important for creating curative treatments for dry eye disease. Yet, cellular and signaling events during development remain partially uncharacterized. This review compiles an updated model of cell signaling, morphology, and cell lineage specification at each stage of LG development. These aspects of development are described together during presumptive bud formation, bud elongation, and branching. This review takes an innovative approach by further describing fetal and postnatal maturation in this model. Major signaling pathways in LG development are described and their recent characterization too. This review also highlights gaps in knowledge regarding cell heterogeneity, progenitor cells, and interspecies compatibility. In conclusion, this review describes cellular and signaling dynamics that coincide at each stage of LG development. Lastly, development and in vitro modeling are discussed to be of importance for guiding research to better understand LG physiology.

The full text of this thesis is not available due to privacy or embargo reasons.

This position paper provides a comprehensive guide for optimal follow-up of patients with acute pulmonary embolism (PE), covering multiple relevant aspects of patient counselling. It serves as a practical guide to treating patients with acute PE complementary to the formal 2019 European Society of Cardiology guidelines developed with the European Respiratory Society. We propose a holistic approach considering the whole spectrum of serious adverse events that patients with acute PE may encounter on the short and long run. We underline the relevance of assessment of modifiable risk factors for bleeding, of acquired thrombophilia and limited cancer screening (unprovoked PE) as well as a dedicated surveillance for the potential development of chronic thromboembolic pulmonary hypertension as part of routine practice; routine testing for genetic thrombophilia should be avoided. We advocate the use of outcome measures for functional outcome and quality of life to quantify the impact of the PE diagnosis and identify patients with the post-PE syndrome early. Counselling patients on maintaining a healthy lifestyle mitigates the risk of the post-PE syndrome and improves cardiovascular prognosis. Therefore, we consider it important to discuss when and how to resume sporting activities soon after diagnosing PE. Additional patient-relevant topics that require Focused counselling are travel and birth control.

Item does not contain fulltext, PURPOSE: Watchful waiting (WW) can be considered for patients with metastatic clear-cell renal cell carcinoma (mccRCC) with good or intermediate prognosis, especially those with <2 International Metastatic RCC Database Consortium criteria and ≤2 metastatic sites [referred to as watch and wait ("W&W") criteria]. The IMaging PAtients for Cancer drug SelecTion-Renal Cell Carcinoma study objective was to assess the predictive value of [18F]FDG PET/CT and [89Zr]Zr-DFO-girentuximab PET/CT for WW duration in patients with mccRCC. EXPERIMENTAL DESIGN: Between February 2015 and March 2018, 48 patients were enrolled, including 40 evaluable patients with good (n = 14) and intermediate (n = 26) prognosis. Baseline contrast-enhanced CT, [18F]FDG and [89Zr]Zr-DFO-girentuximab PET/CT were performed. Primary endpoint was the time to disease progression warranting systemic treatment. Maximum standardized uptake values (SUVmax) were measured using lesions on CT images coregistered to PET/CT. High and low uptake groups were defined on the basis of median geometric mean SUVmax of RECIST-measurable lesions across patients. RESULTS: The median WW time was 16.1 months [95% confidence interval (CI): 9.0-31.7]. The median WW period was shorter in patients with high [18F]FDG tumor uptake than those with low uptake (9.0 vs. 36.2 months; HR, 5.6; 95% CI: 2.4-14.7; P < 0.001). Patients with high [89Zr]Zr-DFO-girentuximab tumor uptake had a median WW period of 9.3 versus 21.3 months with low uptake (HR, 1.7; 95% CI: 0.9-3.3; P = 0.13). Patients with "W&W criteria" had a longer median WW period of 21.3 compared with patients without: 9.3 months (HR, 1.9; 95% CI: 0.9-3.9; Pone-sided = 0.034). Adding [18F]FDG uptake to the "W&W criteria" improved the prediction of WW duration (P < 0.001); whereas [89Zr]Zr-DFO-girentuximab did not (P = 0.53). CONCLUSIONS: In patients with good- or intermediate-risk mccRCC, low [18F]FDG uptake is associated with prolonged WW. This study shows the predictive value of

Item does not contain fulltext, INTRODUCTION: Chemoradiotherapy (CRT) is the standard of care in inoperable non-small-cell lung cancer (NSCLC) patients, favoring concurrent (cCRT) over sequential CRT (seqCRT), with adjuvant immunotherapy in responders. Elderly and frail NSCLC patients have generally been excluded from trials in the past. In elderly patients however, the higher treatment related morbidity of cCRT, may outweigh the possible lower tumor control of seqCRT. For elderly patients with locally advanced NSCLC real-world data is essential to be able to balance treatment toxicity and treatment outcome. The aim of this study is to analyze acute toxicity and 3-month mortality of curative chemoradiation (CRT) in patients with stage III NSCLC and to analyze whether cCRT for elderly stage III NSCLC patients is safe. METHODS: The Dutch Lung Cancer Audit-Radiotherapy (DLCA-R) is a national lung cancer audit that started in 2013 for patients treated with curative intent radiotherapy. All Dutch patients treated for stage III NSCLC between 2015 and 2018 with seqCRT or cCRT for (primary or recurrent) stage III lung cancer are included in this population-based study. Information was collected on patient, tumor- and treatment characteristics and the incidence and severity of acute non-hematological toxicity (CTCAE-4 version 4.03) and mortality within 3 months after the end of radiotherapy. To evaluate the association between prognostic factors and outcome (acute toxicity and mortality within 3 months), an univariable and multivariable analysis was performed. The definition of cCRT was:radiotherapy started within 30 days after the start of chemotherapy. RESULTS: Out of all 20 Dutch departments of radiation oncology, 19 centers participated in the registry. A total of 2942 NSCLC stage III patients were treated with CRT. Of these 67.2% (n = 1977) were treated with cCRT (median age 66 years) and 32.8% (n = 965) were treated with seqCRT (median age 69 years). Good performance status (WHO 0-1) was scored in 88

01 februari 2023, Item does not contain fulltext, BACKGROUND: Venous thromboembolism (VTE) is a frequent complication in patients with ovarian cancer after major surgery. Based on limited data, international guidelines recommend extended thromboprophylaxis for up to 28 days. OBJECTIVES: To assess the incidence of VTE and bleeding within 30 days following major surgery in patients with ovarian cancer and to evaluate the association between VTE and thromboprophylaxis duration. METHODS: This was a single-center, retrospective, "before-after" cohort study in patients with ovarian cancer undergoing major surgery. Before July 2019, the local protocol mandated a standard course of thromboprophylaxis during hospital stay only. From July 2019 onward, patients received extended thromboprophylaxis for 28 days. The cumulative incidences of VTE and major bleeding within 30 days after surgery were estimated using the Kaplan-Meier method, with 95% confidence intervals (CIs). Cox regression analysis was performed to evaluate the association between thromboprophylaxis duration and VTE incidence. RESULTS: Between January 2018 and December 2020, 250 women were included, of which 118 (47.2%) received extended and 132 (52.8%) standard thromboprophylaxis. During follow-up, 12 patients developed VTE (cumulative incidence, 4.8%; 95% CI, 2.1-7.4) and 2 major bleeding (cumulative incidence 0.8%; 95% CI, 0.0-1.9). Compared with standard thromboprophylaxis, VTE incidence was numerically lower with extended duration of thromboprophylaxis (5/118 [4.2%] vs 7/132 [5.3%]) but not significantly different (hazard ratio, 0.80; 95% CI, 0.25-2.52). The risk of major bleeding was similar in both groups (1/118 [0.8%] vs 1/132 [0.8%]; hazard ratio, 1.12; 95% CI, 0.07-17.89). CONCLUSIONS: The cumulative VTE incidence in patients with ovarian cancer following major surgery was considerable. Extended thromboprophylaxis was safe and associated with a numerically lower risk of VTE but not significantly different.

Item does not contain fulltext, BACKGROUND: The incidence of superficial vein thrombosis (SVT) of the legs and the subsequent risk of venous thromboembolism during pregnancy and the post-partum period is unknown. To better understand the clinical course of SVT during these times, we aimed to estimate the incidence rate of SVT during pregnancy and in the post-partum period, as well as the risk of subsequent venous thromboembolism. METHODS: In this nationwide cohort study, we collected data on all pregnant women who delivered between Jan 1, 1997, and Dec 31, 2017, in Denmark were extracted from the Danish Medical Birth Register, the Danish National Patient Registry, and the Danish National Prescription Registry. Data on ethnicity were not available. Incidence rates per 1000 person-years were calculated for each trimester and the antepartum and post-partum period. Among women with a pregnancy-related SVT, risk of subsequent venous thromboembolism within the same pregnancy or post-partum period were calculated and compared with a matched cohort of pregnant women without SVT using Cox proportional hazards analysis. FINDINGS: During 1 276 046 deliveries, 710 diagnoses of lower extremity SVT occurred from conception up to 12 weeks postpartum (0·6 per 1000 person-years [95% CI 0·5-0·6]). The incidence rates of SVT per 1000 person-years were 0·1 (95% CI 0·1-0·2) during the during the first trimester, 0·2 (0·2-0·3) during the second trimester, and 0·5 (0·5-0·6) during the third trimester. The incidence rate was 1·6 per 1000 person-years (95% CI 1·4-1·7) during the post-partum period. Of the 211 women with antepartum SVT included in the analysis, 22 (10·4%) were diagnosed with venous thromboembolism, compared with 25 (0·1%) in women without SVT (hazard ratio 83·3 [95% CI 46·3-149·7]). INTERPRETATION: The incidence rate of SVT during pregnancy and the post-partum period was low. However, if SVT during pregnancy was diagnosed, the risk of developing venous thromboembolism during the same pregnancy was high. Th

Item does not contain fulltext, BACKGROUND: Cerebral amyloid angiopathy (CAA) is a disease caused by the accumulation of the amyloid-beta protein and is a major cause of intracerebral hemorrhage (ICH) and vascular dementia in the elderly. The presence of the amyloid-beta protein in the vessel wall may induce a chronic state of cerebral inflammation by activating astrocytes, microglia, and pro-inflammatory substances. Minocycline, an antibiotic of the tetracycline family, is known to modulate inflammation, gelatinase activity, and angiogenesis. These processes are suggested to be key mechanisms in CAA pathology. Our aim is to show the target engagement of minocycline and investigate in a double-blind placebo-controlled randomized clinical trial whether treatment with minocycline for 3 months can decrease markers of neuroinflammation and of the gelatinase pathway in cerebrospinal fluid (CSF) in CAA patients. METHODS: The BATMAN study population consists of 60 persons: 30 persons with hereditary Dutch type CAA (D-CAA) and 30 persons with sporadic CAA. They will be randomized for either placebo or minocycline (15 sporadic CAA/15 D-CAA minocycline, 15 sporadic CAA/15 D-CAA placebo). At t = 0 and t = 3 months, we will collect CSF and blood samples, perform a 7-T MRI, and collect demographic characteristics. DISCUSSION: The results of this proof-of-principle study will be used to assess the potential of target engagement of minocycline for CAA. Therefore, our primary outcome measures are markers of neuroinflammation (IL-6, MCP-1, and IBA-1) and of the gelatinase pathway (MMP2/9 and VEGF) in CSF. Secondly, we will look at the progression of hemorrhagic markers on 7-T MRI before and after treatment and investigate serum biomarkers. TRIAL REGISTRATION: ClinicalTrials.gov NCT05680389. Registered on January 11, 2023.

01 juli 2023, Item does not contain fulltext, BACKGROUND: Reliable and safe venous access is crucial for patients using central venous catheters (CVC). However, such CVCs carry a risk for central line-associated bloodstream infections (CLABSIs). Antiseptic barrier caps (ABCs) are a novel tool in the armamentarium for CVC disinfection. Our aim was to review the efficacy and safety of ABCs. METHOD: A literature search was conducted using MedLine, EMBASE, Cochrane library, and CINAHL. Primary aim was to compare CLABSI rates in patients using ABCs versus standard care. Secondary aims included efficacy of ABCs in relevant subgroups (age, ABC brand, clinical setting), safety, compliance, and costs. Fifteen studies were included in the meta-analysis. RESULTS: In total, 391 CLABSIs in 273,993 catheter days occurred in the intervention group versus 620 CLABSIs in 284,912 days in the standard care group, resulting in a risk ratio of 0.65 (95%CI 0.55-0.76; P < .00001). Subgroup analyses showed similar effects, except for nonintensive care unit. In general, ABCs were safe, highly appreciated by patients and caregivers, and cost-effective, while compliance was easy to monitor. In most studies, a substantial risk of bias was observed. CONCLUSION: In conclusion, while available evidence suggests that ABCs are effective, safe, easy in use, and cost-effective. However, due to the poor methodological quality of most available studies, more robust data should justify their use at this point.

Item does not contain fulltext, BACKGROUND: Endovascular treatment for anterior circulation ischaemic stroke is effective and safe within a 6 h window. MR CLEAN-LATE aimed to assess efficacy and safety of endovascular treatment for patients treated in the late window (6-24 h from symptom onset or last seen well) selected on the basis of the presence of collateral flow on CT angiography (CTA). METHODS: MR CLEAN-LATE was a multicentre, open-label, blinded-endpoint, randomised, controlled, phase 3 trial done in 18 stroke intervention centres in the Netherlands. Patients aged 18 years or older with ischaemic stroke, presenting in the late window with an anterior circulation large-vessel occlusion and collateral flow on CTA, and a neurological deficit score of at least 2 on the National Institutes of Health Stroke Scale were included. Patients who were eligible for late-window endovascular treatment were treated according to national guidelines (based on clinical and perfusion imaging criteria derived from the DAWN and DEFUSE-3 trials) and excluded from MR CLEAN-LATE enrolment. Patients were randomly assigned (1:1) to receive endovascular treatment or no endovascular treatment (control), in addition to best medical treatment. Randomisation was web based, with block sizes ranging from eight to 20, and stratified by centre. The primary outcome was the modified Rankin Scale (mRS) score at 90 days after randomisation. Safety outcomes included all-cause mortality at 90 days after randomisation and symptomatic intracranial haemorrhage. All randomly assigned patients who provided deferred consent or died before consent could be obtained comprised the modified intention-to-treat population, in which the primary and safety outcomes were assessed. Analyses were adjusted for predefined confounders. Treatment effect was estimated with ordinal logistic regression and reported as an adjusted common odds ratio (OR) with a 95% CI. This trial was registered with the ISRCTN, ISRCTN19922220. FINDINGS: Between Feb 2, 2018

01 augustus 2023, Item does not contain fulltext, BACKGROUND AND OBJECTIVES: Primary lateral sclerosis (PLS) is a motor neuron disease characterised by loss of the upper motor neurons. Most patients present with slowly progressive spasticity of the legs, which may also spread to the arms or bulbar regions. It is challenging to distinguish between PLS, early-stage amyotrophic lateral sclerosis (ALS) and hereditary spastic paraplegia (HSP). The current diagnostic criteria advise against extensive genetic testing. This recommendation is, however, based on limited data. METHODS: We aim to genetically characterize a PLS cohort using whole exome sequencing (WES) for genes associated with ALS, HSP, ataxia and movement disorders (364 genes) and C9orf72 repeat expansions. Patients fulfilling the definite PLS criteria by Turner et al. and with available DNA samples of sufficient quality were recruited from an on-going, population-based epidemiological study. Genetic variants were classified according to the ACMG criteria and assigned to groups based on disease association. RESULTS: WES was performed in 139 patients and the presence of repeat expansions in C9orf72 was analysed separately in 129 patients. This resulted in 31 variants of which 11 were (likely) pathogenic. (Likely) pathogenic variants resulted in 3 groups based on disease association: ALS-FTD (C9orf72, TBK1), pure HSP (SPAST, SPG7), "ALS-HSP-CMT overlap" (FIG4, NEFL, SPG11). DISCUSSION: In a cohort of 139 PLS patients, genetic analyses resulted in 31 variants (22%) of which 10 (7%) (likely) pathogenic associated with different diseases (predominantly ALS and HSP). Based on these results and the literature, we advise to consider genetic analyses in the diagnostic work-up for PLS.

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Item does not contain fulltext, The aim of this systematic review and meta-analysis was to provide an overview of existing controlled trials focusing on the impact of multiple family therapy (MFT) on mental health problems and family functioning, and to examine the efficacy of MFT. Relevant studies were selected following a screening of 3376 studies identified by a systematic search of seven databases. The following data were extracted: participant characteristics, program characteristics, study characteristics, and information of mental health problems and/or family functioning. A total of 31 peer-reviewed, English, controlled studies evaluating the effect of MFT were included in the systematic review. Sixteen studies presenting 16 trials were included in the meta-analysis. All but one of the studies was at risk of bias, with problems concerning confounding, selection of participants and missing data. The findings confirm that MFT is offered in diverse settings, with studies presenting a variety of therapeutic modalities, focal problems, and populations. Individual studies reported some positive findings, including improvements in mental health, vocational outcomes, and social functioning. The findings of the meta-analysis suggest that MFT is associated with improvements in symptoms of schizophrenia. However, this effect was found not to be significant due to the large amount of heterogeneity. In addition, MFT was associated with small improvements in family functioning. We found little evidence to suggest that MFT successfully alleviates mood and conduct problems. To conclude, more methodologically rigorous research is needed to further examine the potential benefits of MFT, as well as the working mechanisms and core components of MFT.

Wetenschappelijk onderzoek van het IPCC, en de klimaatscenario’s gepubliceerd door het KNMI waarop risico’s kunnen worden ingeschat, laat zien dat Nederland de komende decennia grote gevolgen gaat ondervinden van klimaatverandering. Het wordt het hele jaar door warmer met langere periodes van droogte, natter met verhoogd risico op wateroverlast en de zeespiegel blijft stijgen. Als we alle regio’s in Nederland veilig en aantrekkelijk willen houden dan moet Nederland zich aanpassen aan de gevolgen van extreem weer. Dat betekent dat we niet alleen mitigerende maatregelen moeten nemen om verdere opwarming te helpen voorkomen, maar ook klimaatadaptief moeten worden voor de veranderingen die niet meer te voorkomen zijn. Dit rapport is het resultaat van onderzoek naar hoe klimaatadaptatie in Nederland versneld kan worden. Klimaatadaptatie is een maatschappelijke uitdaging met een primaire rol voor de overheid en noodzaak tot betrokkenheid van, en samenwerking met, private partijen. Dit rapport gaat specifiek over de financiële sector vanwege haar belangrijke maatschappelijke rol en haar invloed op onze samenleving, onder andere doordat de sector projecten en organisaties financiert die bijdragen aan klimaatmitigatie en klimaatadaptatie.

The lacrimal gland (LG) is responsible for most tear production. Defective tear synthesis and secretion in the LG cause dry eye disease. This is a prevalent disease worldwide that causes eye irritation, and in severe cases, it can lead to eye damage. Understanding LG development is important for creating curative treatments for dry eye disease. Yet, cellular and signaling events during development remain partially uncharacterized. This review compiles an updated model of cell signaling, morphology, and cell lineage specification at each stage of LG development. These aspects of development are described together during presumptive bud formation, bud elongation, and branching. This review takes an innovative approach by further describing fetal and postnatal maturation in this model. Major signaling pathways in LG development are described and their recent characterization too. This review also highlights gaps in knowledge regarding cell heterogeneity, progenitor cells, and interspecies compatibility. In conclusion, this review describes cellular and signaling dynamics that coincide at each stage of LG development. Lastly, development and in vitro modeling are discussed to be of importance for guiding research to better understand LG physiology.

Aim: The aim of this study was to examine whether there are associations between child’s externalizing problem behavior and child maltreatment on the one hand and out-of-home placement on the other hand and whether parental intellectual disability moderates these associations. Method: A total of 286 files of juveniles with a supervision order (in Dutch ondertoezichtstelling or OTS) aged 0-18 years were assessed by dichotomously coding the variables ‘child’s externalizing problem behavior’, ‘child maltreatment’, ‘parental intellectual disability’ and ‘out-of-home placement’ using scoring forms. Results: The results of the multiple logistic regression analysis showed that child’s externalizing problem behavior and parental intellectual disability are significant explanatory variables for out-of-home placement. Child maltreatment is not a significant explanatory variable for out-of-home placement. Moreover, the results of the moderation analysis showed a significant interaction effect between child’s externalizing problem behavior and parental intellectual disability on out-of-home placement which means that a child with externalizing problem behavior has a higher risk of being placed out-of-home when parents have an intellectual disability. There is no significant interaction effect for child maltreatment and parental intellectual disability on out-of-home placement. Discussion: In conclusion, to prevent or shorten out-of-home placements as much as possible, prevention and intervention programs should specifically target children with externalizing problem behavior and parents with an intellectual disability. An intervention program which can prevent out-of-home placements is intensive outpatient family treatment (in Dutch intensieve ambulante gezinsbehandeling). Limitations and implications are discussed.

In de benoemde nota’s wordt landschapsgrond gezien als onderdeel en instrument van de brede discussie hoe de samenhang en verbinding tussen natuur en landbouw in de toekomst kan worden vormgegeven, passend bij de gewenste transitie van de landbouw en het landelijk gebied. Tegelijk bestaan er verschillende beelden over landschapsgrond. Sommigen zien het als een aparte categorie in het ruimtelijk beleid, anderen als een verdienmodel, of een instrument om te extensiveren om de doelen vanuit het NPLG te realiseren. Welke meerwaarde heeft landschapsgrond ten opzichte van bestaand instrumentarium en hoe zou je het concept van landschapsgrond kunnen instrumenteren? De positionpapers en publicaties op internet laten zien dat hierover verschillende beelden bestaan. De vraag vanuit het Ministerie van LNV is om deze beelden op een rij te zetten en om op basis daarvan met andere partijen een gezamenlijk beeld te vormen: waar hebben we het over als het gaat over landschapsgrond, hoe het kan bijdragen aan de doelen voor het landelijk gebied, wat zijn de voor- en nadelen, de meerwaarde ten opzichte van bestaand instrumentarium en hoe kan het ingezet worden. Met deze verkenning zetten we de verschillende beelden over landschapsgrond op een rij: WAAROM landschapsgrond, WAT is het (of zou het kunnen zijn), HOE kunnen we het instrumenteren. Tenslotte schetsen we het mogelijke vervolgproces. Deze verkenning is geschreven als basis voor vervolggesprekken.

Item does not contain fulltext, COVID-19 patients have increased risk of pulmonary embolism (PE), but symptoms of both conditions overlap. Because screening algorithms for PE in COVID-19 patients are currently lacking, PE might be underdiagnosed. We evaluated a screening algorithm in which all patients presenting to the ED with suspected or confirmed COVID-19 routinely undergo D-dimer testing, followed by CT pulmonary angiography (CTPA) if D-dimer is ≥ 1.00 mg/L. Consecutive adult patients presenting to the ED of two university hospitals in Amsterdam, The Netherlands, between 01-10-2020 and 31-12-2020, who had a final diagnosis of COVID-19, were retrospectively included. D-dimer and CTPA results were obtained. Of 541 patients with a final diagnosis of COVID-19 presenting to the ED, 25 (4.6%) were excluded because D-dimer was missing, and 71 (13.1%) because they used anticoagulation therapy. Of 445 included patients, 185 (41.6%; 95%CI 37.0-46.3) had a D-dimer ≥ 1.00 mg/L. CTPA was performed in 169 of them, which showed PE in 26 (15.4%; 95%CI 10.3-21.7), resulting in an overall detection rate of 5.8% (95%CI 3.9-8.4) in the complete study group. In patients with and without PE at CTPA, median D-dimer was 9.84 (IQR 3.90-29.38) and 1.64 (IQR 1.17-3.01), respectively (p < 0.001). PE prevalence increased with increasing D-dimer, ranging from 1.2% (95%CI 0.0-6.4) if D-dimer was 1.00-1.99 mg/L, to 48.6% (95%CI 31.4-66.0) if D-dimer was ≥ 5.00 mg/L. In conclusion, by applying this screening algorithm, PE was identified in a considerable proportion of COVID-19 patients. Prospective management studies should assess if this algorithm safely rules-out PE if D-dimer is < 1.00 mg/L.