The FAIR Cookbook - the essential resource for and by FAIR doers.

The notion that data should be Findable, Accessible, Interoperable and Reusable, according to the FAIR Principles, has become a global norm for good data stewardship and a prerequisite for reproducibility. Nowadays, FAIR guides data policy actions and professional practices in the public and private sectors. Despite such global endorsements, however, the FAIR Principles are aspirational, remaining elusive at best, and intimidating at worst. To address the lack of practical guidance, and help with capability gaps, we developed the FAIR Cookbook, an open, online resource of hands-on recipes for "FAIR doers" in the Life Sciences. Created by researchers and data managers professionals in academia, (bio)pharmaceutical companies and information service industries, the FAIR Cookbook covers the key steps in a FAIRification journey, the levels and indicators of FAIRness, the maturity model, the technologies, the tools and the standards available, as well as the skills required, and the challenges to achieve and improve data FAIRness. Part of the ELIXIR ecosystem, and recommended by funders, the FAIR Cookbook is open to contributions of new recipes.

Daily distracted consumption patterns and their relationship with BMI.

The rapidly increasing prevalence of overweight and obesity has heightened the need for a better understanding of obesity-related eating patterns and dietary behaviours. Recent work suggests that distracted eating is causally related to increased immediate and later food, pushing the need for a better understanding of the prevalence of distracted consumption and how this relates to body weight. To extract insights in the relationship between demographics, daily consumption settings, and BMI, we performed secondary data analyses on data from 1011 individuals representative of the Dutch population (adults, 507F, BMI 17-50 kg/m2). The most commonly reported distractions were talking to others (32.7%) and watching television (21.7%). Only 18.4% of respondents reported no distractions during meals. To examine how different distractions related to BMI, we performed OLS regression which showed, among other things, that watching tv while eating lunch (η2 = 0.37) and working during dinner were associated with a higher BMI (η2 = 1.63). To examine the robustness of these findings, machine learning techniques were used. A random forest analysis (RMSE = 4.09) showed that next to age and education level, distraction during lunch and snack was amongst the largest predictors of BMI. Multiple linear regression with lasso penalty (RMSE = 4.13) showed that specifically watching tv while eating lunch or snacks was associated with a higher BMI. In conclusion, our analyses confirmed the assumption that people are regularly distracted during their daily meals, with distinct distractors relating to BMI. These findings provide a starting point for evidence-based recommendations on which consumption settings are associated with healthier eating patterns and body weight.

Presenting and sharing clinical data using the eTRIKS Standards Master Tree for tranSMART.

MOTIVATION: Standardization and semantic alignment have been considered one of the major challenges for data integration in clinical research. The inclusion of the CDISC SDTM clinical data standard into the tranSMART i2b2 via a guiding master ontology tree positively impacts and supports the efficacy of data sharing, visualization and exploration across datasets. RESULTS: We present here a schema for the organization of SDTM variables into the tranSMART i2b2 tree along with a script and test dataset to exemplify the mapping strategy. The eTRIKS master tree concept is demonstrated by making use of fictitious data generated for four patients, including 16 SDTM clinical domains. We describe how the usage of correct visit names and data labels can help to integrate multiple readouts per patient and avoid ETL crashes when running a tranSMART loading routine. AVAILABILITY AND IMPLEMENTATION: The eTRIKS Master Tree package and test datasets are publicly available at https://doi.org/10.5281/zenodo.1009098 and a functional demo installation at https://public.etriks.org/transmart/datasetExplorer/ under eTRIKS-Master Tree branch, where the discussed examples can be visualized.

Crystalline silica alters Sulfatase-1 expression in rat lungs which influences hyper-proliferative and fibrogenic effects in human lung epithelial cells.

Lung epithelial cells are the first cell-type to come in contact with hazardous dust materials. Upon deposition, they invoke complex reactions in attempt to eradicate particles from the airways, and repair damage. The cell surface is composed of a heterogeneous network of matrix proteins and proteoglycans, which act as scaffold and control cell-signaling networks. These functions are controlled, in part, by the sulfation patterns of heparin-sulfate proteoglycans (HSPGs), which are enzymatically regulated. Although there is evidence of altered HSPG-sulfation in idiopathic pulmonary fibrosis (IPF), this is not investigated in silicosis. Our previous studies revealed down-regulation of Sulfatase-1 (SULF1) in human bronchial epithelial cells (BECs) by crystalline silica (CS). In this study, CS-induced down-regulation of SULF1, and increases in Sulfated-HSPGs, were determined in human BECs, and in rat lungs. By siRNA and plasmid transfection techniques the effects of SULF1 expression on silica-induced fibrogenic and proliferative gene expression were determined. These studies confirmed down-regulation of SULF1 and subsequent increases in sulfated-HSPGs in vitro. Moreover, short-term exposure of rats to CS resulted in similar changes in vivo. Conversely, effects were reversed after long term CS exposure of rats. SULF1 knockdown, and overexpression alleviated and exacerbated silica-induced decrease in cell viability, respectively. Furthermore, overexpression of SULF1 promoted silica-induced proliferative and fibrogenic gene expression, and collagen production. These findings demonstrate that the HSPG modification enzyme SULF1 and HSPG sulfation are altered by CS in vitro and in vivo. Furthermore, these changes may contribute to CS-induced lung pathogenicity by affecting injury tolerance, hyperproliferation, and fibrotic effects.

Gastrointestinal cancer incidence in type 2 diabetes mellitus; results from a large population-based cohort study in the UK.

BACKGROUND: Patients with type 2 diabetes mellitus (T2DM) have been shown to have higher incidences of liver, pancreatic, and colorectal cancer compared to non-diabetic individuals. Current evidence is conflicting for other gastrointestinal (GI) cancers. Therefore, we aimed to determine incidence rates (IRs) of all GI cancers in patients with and without T2DM. METHODS: A cohort study was performed using the UK Clinical Practice Research Datalink (1988-2012). A cohort of antidiabetic drug users was matched at baseline to a non-diabetic cohort, by age, sex, and practice. Crude IRs and 95% confidence intervals (95% CI) of GI cancers per 100,000 person-years were calculated stratified by age, sex, and calendar year. RESULTS: 333,438 T2DM and 333,438 non-diabetic individuals were analyzed. IRs of liver (IR 26, 95% CI 24-28 vs. 8.9, 95% CI 7.7-10), pancreatic (IR 65, 95% CI 62-69 vs. 31, 95% CI 28-34), and colon cancer (IR 119, 95% CI 114-124 vs. 109, 95% CI 104-114) were significantly higher in the diabetic compared to the non-diabetic cohort, whereas the IR of oesophageal cancer was significantly lower (IR 41, 95% CI 39-44 vs. 47, 95% CI 44-51). Sex-specific IRs of colon cancer remained significantly higher in men with T2DM, and IRs of esophageal cancer remained significantly lower in women with T2DM. CONCLUSION: In this study, T2DM patients were shown to have higher crude IRs of liver, pancreatic and colon cancer, but not of gastric, biliary, and rectal cancer. Moreover, the lower observed IRs of oesophageal cancer in diabetic patients warrants further investigation.

Getting Digital Assets from Public-Private Partnership Research Projects through "The Valley of Death," and Making Them Sustainable.

Projects in public-private partnerships, such as the Innovative Medicines Initiative (IMI), produce data services and platforms (digital assets) to help support the use of medical research data and IT tools. Maintaining these assets beyond the funding period of a project can be a challenge. The reason for that is the need to develop a business model that integrates the perspectives of all different stakeholders involved in the project, and these digital assets might not necessarily be addressing a problem for which there is an addressable market of paying customers. In this manuscript, we review four IMI projects and the digital assets they produced as a means of illustrating the challenges in making digital assets sustainable and the lessons learned. To progress digital assets beyond proof-of-concept into widely adopted tools, there is a need for continuation of multi-stakeholder support tailored to these assets. This would be best done by implementing a structure similar to the accelerators that are in place to help transform startup businesses into growing and thriving businesses. The aim of this article is to highlight the risk of digital asset loss and to provoke discussion on the concept of developing an "accelerator" for digital assets from public-private partnership research projects to increase the chance that digital assets will be sustained and continue to add value long after a project has ended.

Choledochal Malformation in Children: Lessons Learned from a Dutch National Study.

INTRODUCTION: A choledochal malformation (CM) is a rare entity, especially in the Western world. We aimed to determine the incidence of CM in the Netherlands and the outcome of surgery for CM in childhood. METHODS: All pediatric patients who underwent a surgical procedure for type I-IV CM between 1989 and 2014 were entered into the Netherlands Study group on choledochal cyst/malformation. Patients with type V CM were excluded from the present analysis. Symptoms, surgical details, short-term (<30 days) and long-term (>30 days) complications were studied retrospectively. RESULTS: Between January 1989 and December 2014, 91 pediatric patients underwent surgery for CM at a median age of 2.1 years (0.0-17.7 years). All patients underwent resection of the extrahepatic biliary tree with restoration of the continuity via Roux-en-Y hepaticojejunostomy. Twelve patients (12%) were operated laparoscopically. Short-term complications, mainly biliary leakage and cholangitis, occurred in 20 patients (22%), without significant correlations with weight or age at surgery or surgical approach. Long-term postoperative complications were mainly cholangitis (13%) and anastomotic stricture (4%). Eight patients (9%) required radiological intervention or additional surgery. Surgery before 1 year of age (OR 9.3) and laparoscopic surgery (OR 4.4) were associated with more postoperative long-term complications. We did not observe biliary malignancies during treatment or follow-up. CONCLUSION: Surgery for CM carries a significant short- and long-term morbidity. Given the low incidence, we would suggest that (laparoscopic) hepatobiliary surgery for CM should be performed in specialized pediatric surgical centers with a wide experience in laparoscopy and hepatobiliary surgery.

Unique clinical conditions associated with different acinar regions of fibrosis in long-term surviving pediatric liver grafts.

In the majority of long-term survivors after PLTx, graft fibrosis has been identified. Recently, subtypes of graft fibrosis have been described based on their predominant acinar localization. We aimed to evaluate whether the development of portal, perisinusoidal, and centrilobular distribution of graft fibrosis is related to patient or transplantation-related parameters. We reviewed the histological features in protocol liver biopsies taken at 1 and 5 years after PLTx of 47 children on a tacrolimus-based immunosuppressive regimen. Fibrosis was assessed according to the LAFSc. The prevalence of portal fibrosis increased from 31% to 62%, sinusoidal from 68% to 79%, and centrilobular from 76% to 85%. The presence of portal fibrosis was associated with total bilirubin and γGT levels (each P<.02) and tended to be associated with biliary complications (P=.06). Sinusoidal fibrosis was associated with prior rejection episodes (P<.02) and centrilobular fibrosis with the presence of HLA mismatches (P=.02). In conclusion, using the LAFSc, we found a high incidence of progressive fibrosis in the 1-year and 5-year protocol biopsies after PLTx. Progression of fibrosis was observed in all acinar compartments, and each of the three locations is associated with different clinical conditions.

The timing of surgery of antenatally diagnosed choledochal malformations: A descriptive analysis of a 26-year nationwide cohort.

INTRODUCTION: Choledochal malformations (CMs) are increasingly diagnosed antenatally. There is a dilemma between early surgery to prevent CM-related symptoms and postponing surgery to reduce complications. We aimed to identify the optimal timing of surgery in asymptomatic neonates with antenatally diagnosed CM and to identify predictors for development of symptoms. METHODS: Using the Netherlands Study group on CHoledochal Cyst/malformation (NeSCHoc) we retrospectively collected demographic, biochemical and surgical data from all Dutch patients with an antenatally detected CM. RESULTS: Between 1989 and 2014, antenatally suspected CM was confirmed in 17 patients at a median age of 10days (1day-2months). Four patients developed symptoms directly after birth (24%). Thirteen patients (76%) remained asymptomatic. Two of these progressed to symptoms before surgical intervention at 0.7 and 2.1months resp. Postoperatively, four patients developed short-term complications and three developed long-term complications. Patients <5.6kg (the series median) showed more short-term complications (66%) when compared to patients >5.6kg (0%, p=0.02). CONCLUSION: When not symptomatic within the first days of life, the majority of children with antenatally detected CM remains asymptomatic. Surgery might safely be delayed to the age of 6months or a weight of 6kg. Postponing surgery in the clinically and biochemical asymptomatic patient might decrease the complication rate. LEVELS OF EVIDENCE: Level III.

Trends in breast cancer incidence among women with type-2 diabetes in British general practice.

AIMS: To quantify breast cancer incidence in women with type-2 diabetes and assess age-standardized trends in invasive breast cancer incidence over time and by age groups. METHODS: A population-based cohort study was conducted using the British general practice database (Clinical Practice Research Datalink) using data from 1989 to 2012. All adult women prescribed anti-hyperglycemic medication were selected and matched (1:1) on age and clinical practice to a reference cohort without diabetes. RESULTS: During approximately 1.6 million person years (py), 2371 breast cancer cases were diagnosed in the diabetes cohort (n=147,998) and 2252 in the reference cohort (n=147,998). Incidence of breast cancer, overall or by age groups, among women with diabetes remained stable over time. The (overall) age-standardized breast cancer IR per 100,000 py of the diabetes cohort (150, 95%CI:143-157) resembled that observed in the reference cohort (148, 95%CI:141-156); with an incidence rate ratio (IRR) of 1.01 (95%CI:0.94-1.08, p>0.05). CONCLUSIONS: Currently, around 2880 women with type-2 diabetes are diagnosed with breast cancer per year in the United Kingdom. However, breast cancer incidence remained stable in the last 10 years and seems to be comparable in women with and without diabetes.

Insulin glargine use and breast cancer risk: Associations with cumulative exposure.

BACKGROUND: This study was aimed to assess the risk of breast cancer associated with exposure to insulin glargine in women with type 2 diabetes and evaluate whether the pattern of risk concurs with the hypothesized trend of an increase in risk with longer duration of use, taking into account previous cumulative exposure to other types of insulin. METHODS: We performed a restrospective cohort study (2002-2013) in the Clinical Practice Research Datalink among adult female patients with a first ever insulin prescription (n = 12 468). Time-dependent exposure measures were used to assess associations with duration of use of: (1) other insulin types before glargine was first prescribed (i.e. among switchers); and (2) of glargine during follow-up. Analyses were performed separately for insulin-naïve glargine users and patients switched to glargine. Cox proportional hazards models were used to derive p-trends, hazard ratios (HR) and 95% confidence intervals (CI) for breast cancer associated with glargine use. RESULTS: During 66 151 person years, 186 breast cancer cases occurred; 76 in glargine users (3.0/1000 years) and 110 in users of other insulins (2.7/1000 years). Among insulin-naïve women, no association with cumulative glargine use was observed (p-trend = 0.91), even after ≥5 years (HR = 1.06, 95% CI 0.48-2.33). Among switchers, a linear trend with years of prior exposure to other insulins was found (p-trend = 0.02). An increased risk was observed in glargine users with extensive (>3 years) past exposure to other insulins (HR = 3.17, 95% CI 1.28-7.84). A non-significant trend with cumulative glargine exposure was found among switchers (p-trend = 0.24). CONCLUSIONS: Exposure to glargine was not associated with an increased breast cancer risk in insulin-naïve patients. Exposure to other insulins prior to the start of glargine appears to be relevant when studying breast cancer risk associated with glargine use.

Intraoperative frozen section analysis of the proximal bile ducts in hilar cholangiocarcinoma is of limited value.

Frozen section analysis (FS) during cancer surgery is widely used to assess resection margins. However, in hilar cholangiocarcinoma (HCCA), FS may be less reliable because of the specific growth characteristics of the tumor. The aim of this study was to determine the accuracy and consequences of intraoperative FS of the proximal bile duct margins in HCCA. Between 1990 and 2014, 67 patients underwent combined extrahepatic bile duct resection and partial liver resection for HCCA with the use of FS. Sensitivity and specificity of FS was 68% and 97%, respectively. Seventeen of 67 patients (25%) displayed a positive bile duct margin at FS. The false-negative rate was 16% (eight patients). Ten patients (15%) with a positive bile duct margin underwent an additional resection in an attempt to achieve negative margins, which succeeded in three patients (4%). However, only one of these three patients did not have concomitant lymph node metastases, which are associated with a poor prognosis by itself. The use of FS of the proximal bile duct is of limited clinical value because of the relatively low sensitivity, high risk of false-negative results, and the low rate of secondary obtained tumor-free resection margins. Supported by the literature, a new approach to the use of FS in HCCA should be adopted, reserving the technique only for cases in which a substantial additional resection is possible.

Immune Homeostasis in Epithelial Cells: Evidence and Role of Inflammasome Signaling Reviewed.

The epithelium regulates the interaction between the noxious xenogenous, as well as the microbial environment and the immune system, not only by providing a barrier but also by expressing a number of immunoregulatory membrane receptors, and intracellular danger sensors and their downstream effectors. Amongst these are a number of inflammasome sensor subtypes, which have been initially characterized in myeloid cells and described to be activated upon assembly into multiprotein complexes by microbial and environmental triggers. This review compiles a vast amount of literature that supports a pivotal role for inflammasomes in the various epithelial barriers of the human body as essential factors maintaining immune signaling and homeostasis.

Strong Upregulation of AIM2 and IFI16 Inflammasomes in the Mucosa of Patients with Active Inflammatory Bowel Disease.

BACKGROUND: Inflammatory bowel disease (IBD) is characterized by a chronic inflammation of the gut, partly driven by defects in the innate immune system. Considering the central role of inflammasome signaling in innate immunity, we studied inflammasome components in IBD mucosa. METHODS: Expression of genes encoding inflammasome sensor subunits was investigated in colonic mucosal biopsies from 2 cohorts of patients with IBD and controls. RESULTS: A significant upregulation (>2-fold change in expression, false discovery rate <0.05) of the PYHIN inflammasomes AIM2 and IFI16 in active IBD versus controls was found. Also IFI16 was significantly increased in inactive IBD versus controls. Moreover, responders to anti-tumor necrosis factor therapy showed decreased expression of these inflammasomes although IFI16 remained significantly increased in responders showing endoscopic healing versus controls. AIM2 was mainly expressed in epithelial cells, whereas IFI16 was expressed in both lymphocytes and epithelial cells. Functional activation of predominant AIM2/IFI16-mediated inflammasomes in active IBD colon was shown by the presence of the downstream effectors CASP1 and HMGB-1 in inflamed mucosa. CONCLUSIONS: Our results highlight the importance of PYHIN inflammasome signaling in IBD and also link anti-tumor necrosis factor responsiveness to inflammasome signaling. Together, this points to the potential value of the inflammasome pathway as a new therapeutic target for IBD treatment.

Achievement of developmental milestones in young adults after liver transplantation in childhood.

Little is known about the achievement of developmental milestones (i.e., COL) after pediatric liver transplantation. The aim of this study was to examine the COL of young adults who underwent a liver transplantation during childhood and to compare it to healthy peers. Furthermore, we studied factors possibly related to their COL. COL was assessed using the CLQ, which assesses the achievement of developmental milestones (autonomy, psychosexual, social, and antisocial development) and risk behavior (substance abuse and gambling). Sociodemographic characteristics and clinical data were collected using the prospective institutional liver transplantation database. A total of 39 young adults who underwent a liver transplantation at the UMCG in their childhood completed the CLQ. They achieved fewer milestones with regard to autonomy, psychosexual, and social development compared to healthy peers, and they reported less risk behavior. Neither age at the time of study nor age at the time of transplantation was significantly correlated with any of the COL subscales. Young adults show delay in reaching developmental milestones in every dimension after a liver transplantation during their childhood.

The risk of colorectal cancer in patients with type 2 diabetes: associations with treatment stage and obesity.

OBJECTIVE: To assess the risk of colorectal cancer associated with type 2 diabetes, as compared with a nondiabetic reference population, and to study additional associations between treatment stage and duration of obesity and colorectal cancer risk. RESEARCH DESIGN AND METHODS: We conducted an observational population-based cohort study within the Clinical Practice Research Datalink (1987-2012). All patients (≥18 years) with at least one prescription for an antidiabetic drug (n = 300,039) were matched (1:1) by birth year, sex, and practice to a comparison cohort without diabetes. Cox proportional hazards models were used to derive adjusted hazard ratios (HRs) for colorectal cancer associated with type 2 diabetes. Within the diabetic cohort, associations of colorectal cancer with treatment stages and duration of obesity (BMI ≥30 kg/m(2)) were studied. RESULTS: After a median follow-up of 4.5 years, 2,759 cases of colorectal cancer were observed among the diabetic study population. Type 2 diabetes was associated with a 1.3-fold increased risk of colorectal cancer (HR 1.26 [95% CI 1.18-1.33]). Among diabetic patients, no association was found with treatment stages. A trend of increased colorectal cancer risk was observed with longer duration of obesity. Risk of colorectal cancer was significantly increased for patients with recorded duration of obesity of 4-8 years (HR 1.19 [1.06-1.34]) and >8 years (1.28 [1.11-1.49]). CONCLUSIONS: Type 2 diabetes is associated with a moderately increased risk of colorectal cancer. Among diabetic patients, an increased risk was observed for patients who suffered from obesity for a total duration of 4 years or more.

Liver Transplantation in Groningen, The Netherlands: A Single Center Status Report.

The liver transplantation program of the University Medical Center Groningen in the Netherlands was started in 1979, making it one of the first programs worldwide. During the past 36 years, a total of 1478 liver transplantations have been performed, 459 of which were in children. One of the first patients transplanted in 1979 is still alive and is one of the longest surviving patients after liver transplantation worldwide. During the last decade, an increasing number of donation after circulatory death (DCD) donor livers have been accepted for transplantation. Over 30% of the livers transplanted in Groningen come from DCD donors. These livers have an increased risk of developing biliary complications, such as non-anastomotic biliary strictures (NAS). One of the main research topics in Groningen has been the pathogenesis and prevention of NAS. In an attempt to reduce the incidence of NAS after liver transplantation, machine perfusion technology has been developed as an alternative to the traditional method of static cold storage. Researchers of the Groningen liver transplant team were the first in the world to report a method of ex situ normothermic machine perfusion of human donor livers. The efficacy and safety of various types of machine perfusion are currently studied in both animal models and clinical trials. A second line of research in Groningen focuses on alterations in the blood coagulation system in patients with liver disease and undergoing liver transplantation. Groningen researchers were the first to describe a 'rebalanced state' of the coagulation system in patients with liver disease, making them prone to both bleeding and thrombo-embolic complications. Clinicians and researchers at the Groningen liver transplant program will continue to collaborate with a shared focus and the aim to provide innovation and the highest level of care to patients with endstage liver disease.

Health status and quality of life in adult biliary atresia patients surviving with their native livers.

INTRODUCTION: Gaining an insight into the quality of life (QOL) in long-term biliary atresia (BA) survivors is becoming more important. Identifying patients with limitations might make tailor made interventions possible. This is the first study investigating the health status (HS) and QOL in adults surviving BA with their native livers, and comparing them with healthy peers. METHODS: BA patients surviving with their native liver were identified in the Netherlands Study Group on Biliary Atresia Registry database. The RAND-36 and the World Health Organization Quality of Life assessment instrument-100 (WHOQOL-100) were used to measure HS and QOL, respectively. Correlation between the RAND-36 and WHOQOL-100 was also assessed. Hospital Anxiety and Depression Scale (HADS) and the Impact Event Scale (IES) were also completed. RESULTS: In total, 25 (83%) of the 30 eligible patients after Kasai portoenterostomy completed the questionnaires (median age 23.2 years). A lower perceived level of general health in HS was found as compared with the reference group and a higher score on the social domain was reported in QOL. Correlations between HS and QOL questionnaires were moderate to good. For the group, overall HADS and IES scores were good, though individual patients did score above the cutoff of both the questionnaires. CONCLUSION: Adult BA patients surviving with their native liver have similar HS and QOL as compared with their healthy peers. RAND-36 and WHOQOL-100 questionnaires are not interchangeable, but complementary to assess the patients' outcomes. The overall scores did not point to increased levels of anxiety and depression. However, on an individual level, three and six patients had a score above the cutoff of the HADS subscales demonstrating clinically relevant levels of anxiety and depression, respectively.

Controversies in Choledochal Malformations: A Survey among Dutch Pediatric Surgeons.

BACKGROUND: Choledochal malformation (CM) is a rare medical condition of which 80% are diagnosed in pediatric patients. There are several important controversies regarding diagnostic workup, management, and follow-up in these pediatric patients. To assess preferences and practices of Dutch pediatric surgeons regarding the diagnostic procedures, management, and follow-up of children with CM we conducted an electronic survey. METHODS: A questionnaire was sent to all the pediatric surgeons working in the academic centers and the only community hospital with a pediatric surgery service. The questionnaire included, items regarding incidence, diagnostic workup, interval between diagnosis and surgery, surgical techniques, and follow-up. We also assessed whether personal exposure influenced the preferences and practices. RESULTS: Overall 22 out of the 31 (71%) Dutch pediatric surgeons returned the questionnaire. Total 15 out of 22 (68%) encountered CM up to 2 times/y, whereas 7 out of 22 (32%) encountered it more than 2 times/y. Indications for surgery were significantly different between surgeons who encountered CM > 2 time/y versus those who did not: 6/6 (100%) of surgeons encountering CM > 2 times/y considered the presence of an asymptomatic CM an indication for surgery versus 5/14 (36%) of the pediatric surgeons who encountered a CM up to 2 times/y (p = 0.01). Overall 12 out of the 22 (55%) respondents preferred surgery between 6 months and 2 years of age. The amount of exposure did not differ in preferred age at surgery or surgical technique. In the symptomatic child 10/22 (45%) of respondents preferred surgery within 3 months. Overall 7/22 (32%) favored laparoscopic resection. Hepaticojejunostomy with Roux-en-Y reconstruction was the preferred reconstruction for all the respondents. One-third stated that they never performed a parenchyma resection. Follow-up was limited to 10 years in almost half of the respondents. CONCLUSION: Dutch pediatric surgeons demonstrate a wide variety of opinions regarding diagnostic workup, treatment, and follow-up of CM. While most surgeons encounter CM up to 2 times/y, there is an association between exposure and several of the outcome parameters. Some of the answers are not in line with the expert opinion. This demonstrates that there is a need for evidence-based (inter)national guidelines regarding the diagnostic approach, management, and follow-up.

Indications for distinct pathogenic mechanisms of asbestos and silica through gene expression profiling of the response of lung epithelial cells.

Occupational and environmental exposures to airborne asbestos and silica are associated with the development of lung fibrosis in the forms of asbestosis and silicosis, respectively. However, both diseases display distinct pathologic presentations, likely associated with differences in gene expression induced by different mineral structures, composition and bio-persistent properties. We hypothesized that effects of mineral exposure in the airway epithelium may dictate deviating molecular events that may explain the different pathologies of asbestosis versus silicosis. Using robust gene expression-profiling in conjunction with in-depth pathway analysis, we assessed early (24 h) alterations in gene expression associated with crocidolite asbestos or cristobalite silica exposures in primary human bronchial epithelial cells (NHBEs). Observations were confirmed in an immortalized line (BEAS-2B) by QRT-PCR and protein assays. Utilization of overall gene expression, unsupervised hierarchical cluster analysis and integrated pathway analysis revealed gene alterations that were common to both minerals or unique to either mineral. Our findings reveal that both minerals had potent effects on genes governing cell adhesion/migration, inflammation, and cellular stress, key features of fibrosis. Asbestos exposure was most specifically associated with aberrant cell proliferation and carcinogenesis, whereas silica exposure was highly associated with additional inflammatory responses, as well as pattern recognition, and fibrogenesis. These findings illustrate the use of gene-profiling as a means to determine early molecular events that may dictate pathological processes induced by exogenous cellular insults. In addition, it is a useful approach for predicting the pathogenicity of potentially harmful materials.