New insights into the kinetics and variability of egg excretion in controlled human hookworm infections

Four healthy volunteers were infected with 50 Necator americanus infective larvae (L3) in a controlled human hookworm infection trial and followed for 52 weeks. The kinetics of fecal egg counts in volunteers was assessed with Bayesian multilevel analysis, which revealed an increase between weeks 7 and 13, followed by an egg density plateau of about 1000 eggs/g of feces. Variation in egg counts was minimal between same-day measurements but varied considerably between days, particularly during the plateau phase. These analyses pave the way for the controlled human hookworm model to accelerate drug and vaccine efficacy studies

Modelling metastatic colonization of cholangiocarcinoma organoids in decellularized lung and lymph nodes

Cholangiocarcinoma (CCA) is a type of liver cancer with an aggressive phenotype and dismal outcome in patients. The metastasis of CCA cancer cells to distant organs, commonly lung and lymph nodes, drastically reduces overall survival. However, mechanistic insight how CCA invades these metastatic sites is still lacking. This is partly because currently available models fail to mimic the complexity of tissue-specific environments for metastatic CCA. To create an in vitro model in which interactions between epithelial tumor cells and their surrounding extracellular matrix (ECM) can be studied in a metastatic setting, we combined patient-derived CCA organoids (CCAOs) (n=3) with decellularized human lung (n=3) and decellularized human lymph node (n=13). Decellularization resulted in removal of cells while preserving ECM structure and retaining important characteristics of the tissue origin. Proteomic analyses showed a tissue-specific ECM protein signature reflecting tissue functioning aspects. The macro and micro-scale mechanical properties, as determined by rheology and micro-indentation, revealed the local heterogeneity of the ECM. When growing CCAOs in decellularized lung and lymph nodes genes related to metastatic processes, including epithelial-to-mesenchymal transition and cancer stem cell plasticity, were significantly influenced by the ECM in an organ-specific manner. Furthermore, CCAOs exhibit significant differences in migration and proliferation dynamics dependent on the original patient tumor and donor of the target organ. In conclusion, CCA metastatic outgrowth is dictated both by the tumor itself as well as by the ECM of the target organ. Convergence of CCAOs with the ECM of its metastatic organs provide a new platform for mechanistic study of cancer metastasis

Candidate gene resequencing in a large bicuspid aortic valve-associated thoracic aortic aneurysm cohort: SMAD6 as an important contributor

Bicuspid aortic valve (BAV) is the most common congenital heart defect. Although many BAV patients remain asymptomatic, at least 20% develop thoracic aortic aneurysm (TAA). Historically, BAV-related TAA was considered as a hemodynamic consequence of the valve defect. Multiple lines of evidence currently suggest that genetic determinants contribute to the pathogenesis of both BAV and TAA in affected individuals. Despite high heritability, only very few genes have been linked to BAV or BAV/TAA, such as NOTCH1, SMAD6, and MAT2A. Moreover, they only explain a minority of patients. Other candidate genes have been suggested based on the presence of BAV in knockout mouse models (e.g., GATA5, NOS3) or in syndromic (e.g., TGFBR1/2, TGFB2/3) or non-syndromic (e.g., ACTA2) TAA forms. We hypothesized that rare genetic variants in these genes may be enriched in patients presenting with both BAV and TAA. We performed targeted resequencing of 22 candidate genes using Haloplex target enrichment in a strictly defined BAV/TAA cohort (n = 441; BAV in addition to an aortic root or ascendens diameter = 4.0 cm in adults, or a Z-score = 3 in children) and in a collection of healthy controls with normal echocardiographic evaluation (n = 183). After additional burden analysis against the Exome Aggregation Consortium database, the strongest candidate susceptibility gene was SMAD6 (p = 0.002), with 2.5% (n = 11) of BAV/TAA patients harboring causal variants, including two nonsense, one in-frame deletion and two frameshift mutations. All six missense mutations were located in the functionally important MH1 and MH2 domains. In conclusion, we report a significant contribution of SMAD6 mutations to the etiology of the BAV/TAA phenotype

Follow-up of contacts of middle east respiratory syndrome coronavirus–infected returning travelers, the Netherlands, 2014

Notification of 2 imported cases of infection with Middle East respiratory syndrome coronavirus in the Netherlands triggered comprehensive monitoring of contacts. Observed low rates of virus transmission and the psychological effect of contact monitoring indicate that thoughtful assessment of close contacts is prudent and must be guided by clinical and epidemiologic risk factors

Sex difference and intra-operative tidal volume: Insights from the LAS VEGAS study

BACKGROUND: One key element of lung-protective ventilation is the use of a low tidal volume (VT). A sex difference in use of low tidal volume ventilation (LTVV) has been described in critically ill ICU patients.OBJECTIVES: The aim of this study was to determine whether a sex difference in use of LTVV also exists in operating room patients, and if present what factors drive this difference.DESIGN, PATIENTS AND SETTING: This is a posthoc analysis of LAS VEGAS, a 1-week worldwide observational study in adults requiring intra-operative ventilation during general anaesthesia for surgery in 146 hospitals in 29 countries.MAIN OUTCOME MEASURES: Women and men were compared with respect to use of LTVV, defined as VT of 8 ml kg-1 or less predicted bodyweight (PBW). A VT was deemed 'default' if the set VT was a round number. A mediation analysis assessed which factors may explain the sex difference in use of LTVV during intra-operative ventilation.RESULTS: This analysis includes 9864 patients, of whom 5425 (55%) were women. A default VT was often set, both in women and men; mode VT was 500 ml. Median [IQR] VT was higher in women than in men (8.6 [7.7 to 9.6] vs. 7.6 [6.8 to 8.4] ml kg-1 PBW, P < 0.001). Compared with men, women were twice as likely not to receive LTVV [68.8 vs. 36.0%; relative risk ratio 2.1 (95% CI 1.9 to 2.1), P < 0.001]. In the mediation analysis, patients' height and actual body weight (ABW) explained 81 and 18% of the sex difference in use of LTVV, respectively; it was not explained by the use of a default VT.CONCLUSION: In this worldwide cohort of patients receiving intra-operative ventilation during general anaesthesia for surgery, women received a higher VT than men during intra-operative ventilation. The risk for a female not to receive LTVV during surgery was double that of males. Height and ABW were the two mediators of the sex difference in use of LTVV.TRIAL REGISTRATION: The study was registered at Clinicaltrials.gov, NCT01601223

The physical activity scale for individuals with physical disabilities: Test-retest reliability and comparison with an accelerometer

BACKGROUND: The objective was to determine the test-retest reliability and criterion validity of the Physical Activity Scale for Individuals with Physical Disabilities (PASIPD). METHODS: Forty-five non-wheelchair dependent subjects were recruited from three Dutch rehabilitation centers. Subjects' diagnoses were: stroke, spinal cord injury, whiplash, and neurological-, orthopedic- or back disorders. The PASIPD is a 7-d recall physical activity questionnaire that was completed twice, 1 wk apart. During this week, physical activity was also measured with an Actigraph accelerometer. RESULTS: The test-retest reliability Spearman correlation of the PASIPD was 0.77. The criterion validity Spearman correlation was 0.30 when compared to the accelerometer. CONCLUSIONS: The PASIPD had test-retest reliability and criterion validity that is comparable to well established self-report physical activity questionnaires from the general population

Low-back and shoulder complaints among workers with pushing and pulling tasks

Objectives Low-back and shoulder complaints were examined in relation to self-reported and objectively assessed exposure to work-related pushing and pulling. Methods Workers from several companies (eg, nursing homes and flower auctions) with pushing and pulling tasks and, as reference, workers without physically demanding tasks were invited to participate. Altogether 829 workers initially received a questionnaire, of whom 459 responded both initially and after I year of follow-up. Initially, self-reported exposure to pushing and pulling was assessed by questionnaire. Furthermore, a representative sample of 131 workers was observed at work using TRAC (task recording and analysis on computer) to assess exposure to pushing and pulling objectively. For exposure to pushing and pulling, the workers were classified into a reference group and medium and high exposure groups. Initially and in the follow-up, the 12-month prevalence of low-back and shoulder complaints was assessed. Complaints reported in the follow-up were separately used as dependent variables to calculate prevalence rate ratios (PR) in a Cox's proportional hazard regression analysis. Results The adjusted PR values were not significant for low-back complaints. For shoulder complaints, both the medium and high exposure groups showed significant adjusted PR values for self-reported exposure and observed duration of pushing and pulling when compared with the reference group (PR range 2.18-4.86). For the observed frequency of pushing and pulling, only the medium exposure group showed a significant PR, of 3.95. Conclusions The findings suggest a rather strong relationship between pushing and pulling and shoulder complaints. The evidence for a relationship between pushing and pulling and low-back complaints is limite

Breast magnetic resonance imaging as a problem solving tool in women recalled at biennial screening mammography:A population-based study in the Netherlands

PURPOSE: Problem solving magnetic resonance imaging (MRI) is used to exclude malignancy in women with equivocal findings on conventional imaging. However, recommendations on its use for women recalled after screening are lacking. This study evaluates the impact of problem solving MRI on diagnostic workup among women recalled from the Dutch screening program, as well as time trends and inter-hospital variation in its use. METHODS: Women who were recalled at screening mammography in the South of the Netherlands (2008–2017) were included. Two-year follow-up data were collected. Diagnostic-workup and accuracy of problem solving MRI were evaluated and time trends and inter-hospital variation in its use were examined. RESULTS: In the study period 16,175 women were recalled, of whom 906 underwent problem solving MRI. Almost half of the women (45.4%) who underwent problem solving MRI were referred back to the screening program without further workup. The sensitivity, specificity, and positive and negative predictive values of problem solving MRI were 98.2%, 70.0%, 31.1%, and 99.6%, respectively. The percentage of recalled women receiving problem solving MRI fluctuated over time (4.7%–7.2%) and significantly varied among hospitals (2.2%–7.0%). CONCLUSION: The use of problem solving MRI may exclude malignancy in recalled women. The use of problem solving MRI varied over time and among hospitals, which indicates the need for guidelines on problem solving MRI

Classic infantile Pompe patients approaching adulthood : a cohort study on consequences for the brain

AIM: To examine the long-term consequences of glycogen storage in the central nervous system (CNS) for classic infantile Pompe disease using enzyme replacement therapy. METHOD: Using neuropsychological tests and brain magnetic resonance imaging (MRI), we prospectively assessed a cohort of 11 classic infantile Pompe patients aged up to 17 years. RESULTS: From approximately age 2 years onwards, brain MRI showed involvement of the periventricular white matter and centrum semiovale. After 8 years of age, additional white-matter abnormalities occurred in the corpus callosum, internal and external capsule, and subcortical areas. From 11 years of age, white-matter abnormalities were also found in the brainstem. Although there seemed to be a characteristic pattern of involvement over time, there were considerable variations between patients, reflected by variations in neuropsychological development. Cognitive development ranged from stable and normal to declines that lead to intellectual disabilities. INTERPRETATION: As treatment enables patients with classic infantile Pompe disease to reach adulthood, white-matter abnormalities are becoming increasingly evident, affecting the neuropsychological development. Therefore, we advise follow-up programs are expanded to capture CNS involvement in larger, international patient cohorts, to incorporate our findings in the counselling of parents before the start of treatment, and to include the brain as an additional target in the development of next-generation therapeutic strategies for classic infantile Pompe disease. WHAT THIS PAPER ADDS: In our long-term survivors treated intravenously with enzyme replacement therapy, we found slowly progressive symmetric white-matter abnormalities. Cognitive development varied from stable and normal to declines towards intellectual disabilities