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Non-intrusive and semi-intrusive uncertainty quantification of a multiscale in-stent restenosis model
No full textThe In-Stent Restenosis 2D model is a full y coupled multiscale simulation of post-stenting tissue growth, in which the most costly submodel is the blood flow simulation. This paper presents uncertainty estimations of the response of this model, as obtained by both non-intrusive and semi-intrusive uncertainty quantification. A surrogate model based on Gaussian process regression for non-intrusive uncertainty quantification takes the whole model as a black-box and maps directly the three uncertain inputs to the quantity of interest, the neointimal area. The corresponding uncertain estimates matched the results from quasi-Monte Carlo simulations well. In the semi-intrusive uncertainty quantification, the most expensive submodel is replaced with a surrogate model. We developed a surrogate model for the blood flow simulation by using a convolutional neural network. The semi-intrusive method with the new surrogate model offered efficient estimates of uncertainty and sensitivity while keeping a relatively high accuracy. It outperformed the results obtained with earlier surrogate models. It also achieved the estimates comparable to the non-intrusive method with a similar efficiency. Presented results on uncertainty propagation with non-intrusive and semi-intrusive metamodelling methods allow us to draw some conclusions on the advantages and limitations of these methods.</p
Early life stress and behavior problems in early childhood: Investigating the contributions of child temperament and executive functions to resilience
No full textThis preregistered study examined whether child temperament and executive functions moderated the longitudinal association between early life stress (ELS) and behavior problems. In a Dutch population-based cohort (n = 2803), parents reported on multiple stressors (age 0–6 years), child temperament (age 5), and executive functions (age 4), and teachers rated child internalizing and externalizing problems (age 7). Results showed that greater ELS was related to higher levels of internalizing and externalizing problems, with betas reflecting small effects. Lower surgency buffered the positive association of ELS with externalizing problems, while better shifting capacities weakened the positive association between ELS and internalizing problems. Other child characteristics did not act as moderators. Findings underscore the importance of examining multiple protective factors simultaneously
Study protocol for a randomised controlled trial evaluating the clinical effect of antibiotic prophylaxis in children with recurrent respiratory tract infections
No full textIntroduction Respiratory tract infections (RTIs) affect children all over the world and are associated with significant morbidity and mortality. In particular, recurrent RTIs cause a high burden of disease and lead to frequent doctor visits. Children with recurrent RTIs generally have no significant alterations or deficits in systemic immunity. In an attempt to treat the assumed bacterial component involved, they are often treated with prolonged courses of prophylactic antibiotics taken on a daily basis. Despite its common use, there is no evidence that this is beneficial. Studies assessing the clinical effectiveness of antibiotic prophylaxis as well as potential adverse effects and antibiotic resistance development, are therefore urgently needed. Methods and analysis We present a protocol for a randomised double-blind placebo-controlled trial comparing co-trimoxazole with placebo treatment in children with recurrent RTIs. A total of 158 children (aged 6 months-10 years) with recurrent RTIs without significant comorbidity will be enrolled from a minimum of 10 Dutch hospitals. One group receives co-trimoxazole 18 mg/kg two times per day (36 mg/kg/day) and the other group receives a placebo two times per day for a period of 3 months. The main objective is to determine whether antibiotic prophylaxis is more effective than placebo to prevent/reduce respiratory symptoms in children with recurrent RTIs. Respiratory symptoms will be scored by parents on a daily basis in both study arms by the use of a mobile phone application. Our primary outcome will be the number of days with at least two respiratory symptoms during the treatment. Ethics and dissemination Ethics approval was obtained from the Medical Ethics Research Committee Zuidwest Holland/LDD. A manuscript with the study results will be submitted to a peer-reviewed journal. All participants will be informed about the study results. The results of the study will inform clinical guidelines regarding the prophylactic treatment of children with recurrent RTIs. Trial registration number NL7044.</p
Prospective Evaluation of a Circulating Tumor Cell Sensitivity Profile to Predict Response to Cisplatin Chemotherapy in Metastatic Breast Cancer Patients
No full textBackground: Cisplatin (cDDP) has regained interest for metastatic breast cancer (MBC) patients, given the platinum sensitivity in subtypes and better manageable toxicity. Here, the primary aim was to determine whether molecular characteristics of circulating tumor cells (CTCs) could identify patients responding to cDDP and to describe the outcomes to cDDP monotherapy in a large group of MBC patients pretreated with anthracycline- and taxane-based treatments. Methods: Based on cell line data, a CTC-cDDP-sensitivity profile was generated. Applying an A’Herns single-stage phase II design, further investigation was considered worthwhile if 5/10 patients with a favorable profile responded to cDDP. Patients received 70mg/m2 cDDP every three weeks, CTCs were enumerated and the CTC-cDDP-sensitivity profile was determined. In total, 65 heavily pretreated MBC patients (77% received ≥2 lines of previous chemotherapy for MBC) were eligible for the per-protocol analysis. Primary endpoint was response rate, secondary endpoints included best observed response, progression-free survival (PFS) and overall survival (OS). Results: The best observed response during cDDP therapy was a partial response in 7% and stable disease in 56% of the patients. None of the patients with a favorable CTC-cDDP-sensitivity profile had a response. The median baseline CTC count was 8 (range 0-3254). Patients with <5 CTCs had a better PFS and OS than patients with ≥5 CTCs (median PFS 4.5 months (95%CI 2.38-6.62) vs. 2.1 months [(95%CI 1.34-2.80)(p=0.009)] and median OS 13.1 months (95%CI 9.89-16.33) vs. 5.6 months [(95%CI 3.60-7.64)(p=0.003)]. No other factors than CTC count were associated with outcome to cDDP therapy, including triple-negative breast cancer versus ER-positive tumors. Conclusions: The CTC-cDDP-sensitivity profile was unable to select patients responding to cDDP monotherapy. In an unselected group of heavily pretreated MBC patients, cDDP yields outcomes comparable to other chemotherapeutic regimens for heavily pretreated MBC patients. CTC count was the only factor associated with outcome in these patients. Clinical Trial Registration: (https://www.trialregister.nl/trial/3885, identifier NTR4046).</p
Human visceral leishmaniasis in Central-Western Brazil
No full textIn this ecological study, we investigated spatial patterns of human visceral leishmaniasis (VL) incidence, its correlation with socioeconomic aspects, environmental indices (obtained through remote sensing) and canine VL during 2011–2016 in the municipality of Rondonópolis, a relevant endemic area for VL in Central-Western Brazil. Human VL cases were georeferenced and point patterns were analyzed by univariate Ripley's K function and Kernel density estimation (KDE). Poisson-based scan statistics were used to investigate spatial and spatiotemporal clusters of human VL incidence at the neighborhood level. Socioeconomic and environmental characteristics were compared between neighborhoods within and outside spatial human VL clusters. Also, we assessed the correlation between smoothed human VL incidence and canine VL seropositivity rates within and between neighborhoods. Human VL cases were clustered up to 2000 m; four hotspots were identified by KDE in peripheral areas. Spatial and spatiotemporal low-risk clusters for human VL were identified in central and southern areas. Neighborhoods within spatial low-risk cluster presented higher mean income, literacy rate, sanitary sewage service coverage and lower altitude, compared to the rest of the municipality. A positive correlation was found between the occurrence of human and canine VL. On the northern outskirts, high human VL incidence was spatially correlated with high canine VL seropositivity in surrounding neighborhoods. In conclusion, human VL demonstrated a heterogeneous, aggregated and peripheral spatial pattern. This distribution was correlated with intra-urban socioeconomic differences and canine VL seropositivity at the neighborhood level.</p
Comparable infection level and tropism of measles virus and canine distemper virus in organotypic brain slice cultures obtained from natural host species
No full textMeasles virus (MV) and canine distemper virus (CDV) are closely related members of the family Paramyxoviridae, genus Morbillivirus. MV infection of humans and non-human primates (NHPs) results in a self-limiting disease, which rarely involves central nervous system (CNS) com-plications. In contrast, infection of carnivores with CDV usually results in severe disease, in which CNS complications are common and the case-fatality rate is high. To compare the neurovirulence and neurotropism of MV and CDV, we established a short-term organotypic brain slice culture system of the olfactory bulb, hippocampus, or cortex obtained from NHPs, dogs, and ferrets. Slices were inoculated ex vivo with wild-type-based recombinant CDV or MV expressing a fluorescent reporter protein. The infection level of both morbilliviruses was determined at different times post-infection. We observed equivalent infection levels and identified microglia as main target cells in CDV-inoculated carnivore and MV-inoculated NHP brain tissue slices. Neurons were also susceptible to MV infection in NHP brain slice cultures. Our findings suggest that MV and CDV have comparable neurotropism and intrinsic capacity to infect CNS-resident cells of their natural host species.</p
The Role of Edema in Subacute Lesion Progression After Treatment of Acute Ischemic Stroke
No full textBackground: Ischemic lesions commonly continue to progress even days after treatment, and this lesion growth is associated with unfavorable functional outcome in acute ischemic stroke patients. The aim of this study is to elucidate the role of edema in subacute lesion progression and its influence on unfavorable functional outcome by quantifying net water uptake. Methods: We included all 187 patients from the MR CLEAN trial who had high quality follow-up non-contrast CT at 24 h and 1 week. Using a CT densitometry-based method to calculate the net water uptake, we differentiated total ischemic lesion volume (TILV) into edema volume (EV) and edema-corrected infarct volume (ecIV). We calculated these volumes at 24 h and 1 week after stroke and determined their progression in the subacute period. We assessed the effect of 24-h lesion characteristics on EV and ecIV progression. We evaluated the influence of edema and edema-corrected infarct progression on favorable functional outcome after 90 days (modified Rankin Scale: 0–2) after correcting for potential confounders. Lastly, we compared these volumes between subgroups of patients with and without successful recanalization using the Mann–Whitney U-test. Results: Median TILV increased from 37 (IQR: 18–81) ml to 68 (IQR: 30–130) ml between 24 h and 1 week after stroke, while the net water uptake increased from 22 (IQR: 16–26)% to 27 (IQR: 22–32)%. The TILV progression of 20 (8.8–40) ml was mostly caused by ecIV with a median increase of 12 (2.4–21) ml vs. 6.5 (2.7–15) ml of EV progression. Larger TILV, EV, and ecIV volumes at 24 h were all associated with more edema and lesion progression. Edema progression was associated with unfavorable functional outcome [aOR: 0.53 (0.28–0.94) per 10 ml; p-value: 0.05], while edema-corrected infarct progression showed a similar, non-significant association [aOR: 0.80 (0.62–0.99); p-value: 0.06]. Lastly, edema progression was larger in patients without successful recanalization, whereas ecIV progression was comparable between the subgroups. Conclusion: EV increases in evolving ischemic lesions in the period between 1 day and 1 week after acute ischemic stroke. This progression is larger in patients without successful recanalization and is associated with unfavorable functional outcome. However, the extent of edema cannot explain the total expansion of ischemic lesions since edema-corrected infarct progression is larger than the edema progression.</p
A case series of familial ARID1B variants illustrating variable expression and suggestions to update the ACMG criteria
No full textARID1B is one of the most frequently mutated genes in intellectual disability (~1%). Most variants are readily classified, since they are de novo and are predicted to lead to loss of function, and therefore classified as pathogenic according to the American College of Medical Genetics and Genomics (ACMG) guidelines for the interpretation of sequence variants. However, familial loss-of-function variants can also occur and can be challenging to interpret. Such variants may be pathogenic with variable expression, causing only a mild phenotype in a parent. Alternatively, since some regions of the ARID1B gene seem to be lacking pathogenic variants, loss-of-function variants in those regions may not lead to ARID1B haploinsufficiency and may therefore be benign. We describe 12 families with potential loss-of-function variants, which were either familial or with unknown inheritance and were in regions where pathogenic variants have not been described or are otherwise challenging to interpret. We performed detailed clinical and DNA methylation studies, which allowed us to confidently classify most variants. In five families we observed transmission of pathogenic variants, confirming their highly variable expression. Our findings provide further evidence for an alternative translational start site and we suggest updates for the ACMG guidelines for the interpretation of sequence variants to incorporate DNA methylation studies and facial analyses.</p
Antenatal Membranous Nephropathy and Type 2 (Axonal) Charcot-Marie-Tooth With Mutations in the Metallo-Membrane Endopeptidase Gene
No full textStabilization demands of walking modulate the vestibular contributions to gait
No full textStable walking relies critically on motor responses to signals of head motion provided by the vestibular system, which are phase-dependent and modulated differently within each muscle. It is unclear, however, whether these vestibular contributions also vary according to the stability of the walking task. Here we investigate how vestibular signals influence muscles relevant for gait stability (medial gastrocnemius, gluteus medius and erector spinae)—as well as their net effect on ground reaction forces—while humans walked normally, with mediolateral stabilization, wide and narrow steps. We estimated local dynamic stability of trunk kinematics together with coherence of electrical vestibular stimulation (EVS) with muscle activity and mediolateral ground reaction forces. Walking with external stabilization increased local dynamic stability and decreased coherence between EVS and all muscles/forces compared to normal walking. Wide-base walking also decreased vestibulomotor coherence, though local dynamic stability did not differ. Conversely, narrow-base walking increased local dynamic stability, but produced muscle-specific increases and decreases in coherence that resulted in a net increase in vestibulomotor coherence with ground reaction forces. Overall, our results show that while vestibular contributions may vary with gait stability, they more critically depend on the stabilization demands (i.e. control effort) needed to maintain a stable walking pattern.</p