Genome-wide analysis to assess if heavy alcohol consumption modifies the association between SNPs and pancreatic cancer risk.

BACKGROUND: Pancreatic cancer is a leading cause of cancer-related death globally. Risk factors for pancreatic cancer include common genetic variants and potentially heavy alcohol consumption. We assessed if genetic variants modify the association between heavy alcohol consumption and pancreatic cancer risk. METHODS: We conducted a genome-wide interaction analysis of single nucleotide polymorphisms (SNP) by heavy alcohol consumption (more than 3 drinks per day) for pancreatic cancer in European ancestry populations from genome-wide association studies (GWAS). Our analysis included 3,707 cases and 4,167 controls from case-control studies and 1,098 cases and 1,162 controls from cohort studies. Fixed effect meta-analyses were conducted. RESULTS: A potential novel region of association on 10p11.22, lead SNP rs7898449 (Pinteraction = 5.1 x 10-8 in the meta-analysis, Pinteraction = 2.1x10-9 in the case-control studies, Pinteraction = 0.91 cohort studies) was identified. A SNP correlated with this lead SNP is an eQTL for the NRP1 gene. Of the 17 genomic regions with genome-wide significant evidence of association with pancreatic cancer in prior studies, we observed suggestive evidence that heavy alcohol consumption modified the association for one SNP near LINC00673, rs11655237 on 17q25.1 (Pinteraction = 0.004). CONCLUSIONS: We identified a novel genomic region that may be associated with pancreatic cancer risk in conjunction with heavy alcohol consumption located near an eQTL for the NRP1, a protein that plays an important role in the development and progression of pancreatic cancer Impact: This work can provide insight into the etiology of pancreatic cancer particularly in heavy drinkers.

Emerging Fungal Pathogen Rhodotorula Species Isolated From a Patient With a Lung Malignancy.

Rhodotorula is a genus of ubiquitous pigmented yeast found in the environment and as a commensal of human and animal microbiota. Previously considered nonpathogenic, Rhodotorula has emerged as an important cause of nosocomial and opportunistic infections in susceptible patients. While Rhodotorula spp. are common commensals in healthy individuals, the yeast may overgrow in patients with compromised immune systems causing disease. Herein, we provide a detailed presentation of a rare case involving a 79-year-old Caucasian female with a lung malignancy who developed massive cavitations in her lungs. The patient's lung tissue was cultured and grew an unidentified species of the genus Rhodotorula. The patient's health declined rapidly, and she expired due to hypoxemia. Clinicians must recognize patient groups potentially at risk for infection with Rhodotorula spp. Early identification and initiation of appropriate interventions are crucial in reducing mortality associated with this opportunistic fungal infection.

Predischarge death or lung transplantation in tracheostomy and ventilator dependent grade 3 bronchopulmonary dysplasia.

BACKGROUND: Premature infants surviving beyond a postmenstrual age (PMA) of 36 weeks with severe or grade 3 bronchopulmonary dysplasia (sBPD) have significant predischarge mortality. The in-hospital mortality for BPD supported by invasive mechanical ventilation beyond 36 weeks PMA is not well described. The role of lung transplantation in treating severe BPD is uncertain. We studied our experience over 20 years to better define the predischarge mortality of infants with progressive grade 3 BPD and whether lung transplant is a feasible intervention. METHODS: Data were obtained from a retrospective review of medical records from Children's Minnesota over a 20-year period (1997-2016). Inclusion criteria included prematurity <32 weeks PMA, BPD, tracheostomy for chronic respiratory failure, and survival beyond 36 weeks PMA. Collected data included perinatal demographics, in-hospital medications and interventions, level of respiratory support, and outcomes. RESULTS: In all, 2374 infants were identified who survived beyond 36 weeks PMA with a diagnosis of <32 weeks gestation prematurity and BPD. Of these, 143/2374 (6.0%) survived beyond 36 weeks PMA and required invasive mechanical ventilation with subsequent tracheostomy for management. Among these patients, discharge to home with tracheostomy occurred in 127/143 (88.8%), and predischarge death or lung transplantation occurred in 16/143 (11.2%). Deteriorating cardiopulmonary status was associated with pulmonary hypertension, prolonged hypoxemic episodes and the need for deep sedation or neuromuscular relaxation. Three of four patients referred for lung transplantation had >5-year survival, chronic allograft rejection, and mild to moderate developmental delays. CONCLUSIONS: Chronic respiratory failure requiring invasive mechanical ventilation for grade 3 BPD is associated with significant morbidity and mortality. For selected patients and their families, timely referral for lung transplantation is a viable option for end-stage grade 3 BPD. As in other infants receiving solid organ transplants, long-term issues with co-morbidities and special needs persist into childhood.

Identification of pre-diagnostic lipid sets associated with liver cancer risk using untargeted lipidomics and chemical set analysis: A nested case-control study within the ATBC cohort.

In pre-disposed individuals, a reprogramming of the hepatic lipid metabolism may support liver cancer initiation. We conducted a high-resolution mass spectrometry based untargeted lipidomics analysis of pre-diagnostic serum samples from a nested case-control study (219 liver cancer cases and 219 controls) within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. Out of 462 annotated lipids, 158 (34.2%) were associated with liver cancer risk in a conditional logistic regression analysis at a false discovery rate (FDR) <0.05. A chemical set enrichment analysis (ChemRICH) and co-regulatory set analysis suggested that 22/28 lipid classes and 47/83 correlation modules were significantly associated with liver cancer risk (FDR <0.05). Strong positive associations were observed for monounsaturated fatty acids (MUFA), triacylglycerols (TAGs) and phosphatidylcholines (PCs) having MUFA acyl chains. Negative associations were observed for sphingolipids (ceramides and sphingomyelins), lysophosphatidylcholines, cholesterol esters and polyunsaturated fatty acids (PUFA) containing TAGs and PCs. Stearoyl-CoA desaturase enzyme 1 (SCD1), a rate limiting enzyme in fatty acid metabolism and ceramidases seems to be critical in this reprogramming. In conclusion, our study reports pre-diagnostic lipid changes that provide novel insights into hepatic lipid metabolism reprogramming may contribute to a pro-cell growth and anti-apoptotic tissue environment and, in turn, support liver cancer initiation.

Assessing water stress in a high-density apple orchard using trunk circumference variation, sap flow index and stem water potential.

Introduction: Automated plant-based measurements of water stress have the potential to advance precision irrigation in orchard crops. Previous studies have shown correlations between sap flow, line variable differential transform (LVDT) dendrometers and fruit tree drought response. Here we report season-long automated measurement of maximum daily change in trunk diameter using band dendrometers and heated needles to measure a simplified sap flow index (SFI). Methods: Measurements were made on two apple cultivars that were stressed at 7 to 12 day intervals by withholding irrigation until the average stem water potential (ΨStem) dropped below -1.5 MPa, after which irrigation was restored and the drought cycle repeated. Results: Dendrometer measurements of maximum daily trunk shrinkage (MDS) were highly correlated (r² = 0.85) with pressure chamber measurements of stem water potential. The SFI measurements were less correlated with stem water potential but were highly correlated with evaporative demand (r² = 0.82) as determined by the Penman-Monteith equation (ETr). Discussion: The high correlation of SFI to ETr suggests that high-density orchards resemble a continuous surface, unlike orchards with widely spaced trees. The correlations of MDS and SFI to ΨStem were higher during the early season than the late season growth. Band dendrometers are less labor intensive to install than LVDT dendrometers and are non-invasive so are well suited to commercialization.

Genetically inferred birthweight, height, and puberty timing and risk of osteosarcoma.

INTRODUCTION: Several studies have linked increased risk of osteosarcoma with tall stature, high birthweight, and early puberty, although evidence is inconsistent. We used genetic risk scores (GRS) based on established genetic loci for these traits and evaluated associations between genetically inferred birthweight, height, and puberty timing with osteosarcoma. METHODS: Using genotype data from two genome-wide association studies, totaling 1039 cases and 2923 controls of European ancestry, association analyses were conducted using logistic regression for each study and meta-analyzed to estimate pooled odds ratios (ORs) and 95% confidence intervals (CIs). Subgroup analyses were conducted by case diagnosis age, metastasis status, tumor location, tumor histology, and presence of a known pathogenic variant in a cancer susceptibility gene. RESULTS: Genetically inferred higher birthweight was associated with an increased risk of osteosarcoma (OR =1.59, 95% CI 1.07-2.38, P = 0.02). This association was strongest in cases without metastatic disease (OR =2.46, 95% CI 1.44-4.19, P = 9.5 ×10-04). Although there was no overall association between osteosarcoma and genetically inferred taller stature (OR=1.06, 95% CI 0.96-1.17, P = 0.28), the GRS for taller stature was associated with an increased risk of osteosarcoma in 154 cases with a known pathogenic cancer susceptibility gene variant (OR=1.29, 95% CI 1.03-1.63, P = 0.03). There were no significant associations between the GRS for puberty timing and osteosarcoma. CONCLUSION: A genetic propensity to higher birthweight was associated with increased osteosarcoma risk, suggesting that shared genetic factors or biological pathways that affect birthweight may contribute to osteosarcoma pathogenesis.

PyQMC: An all-Python real-space quantum Monte Carlo module in PySCF.

We describe a new open-source Python-based package for high accuracy correlated electron calculations using quantum Monte Carlo (QMC) in real space: PyQMC. PyQMC implements modern versions of QMC algorithms in an accessible format, enabling algorithmic development and easy implementation of complex workflows. Tight integration with the PySCF environment allows for a simple comparison between QMC calculations and other many-body wave function techniques, as well as access to high accuracy trial wave functions.

Evaluating the Utility of Proteomics for the Identification of Circulating Pharmacodynamic Biomarkers of IFNß-1a Biologics.

Proteomics has the potential to identify pharmacodynamic (PD) biomarkers for similarity assessment of proposed biosimilars without relying on clinical efficacy end points. In this study, with 36 healthy participants randomized to therapeutic doses of interferon-beta 1a products (IFNß-1a) or pegylated-IFNß-1a (pegIFNß-1a) approved to treat multiple sclerosis or placebo, we evaluated the utility of a proteomic assay that profiles > 7,000 plasma proteins. IFNß-1a and pegIFNß-1a resulted in 248 and 528 differentially expressed protein analytes, respectively, between treatment and placebo groups over the time course. Thirty-one proteins were prioritized based on a maximal fold change ≥ 2 from baseline, baseline adjusted area under the effect curve (AUEC) and overlap between the 2 products. Of these, the majority had a significant AUEC compared with placebo in response to either product; 8 proteins showed > 4-fold maximal change from baseline. We identified previously reported candidates, beta-2microglobulin and interferon-induced GTP-binding protein (Mx1) with ~ 50% coefficient of variation (CV) for AUEC, and many new candidates (including I-TAC, C1QC, and IP-10) with CVs ranging from 26%-129%. Upstream regulator analysis of differentially expressed proteins predicted activation of IFNß1 signaling as well as other cytokine, enzyme, and transcription signaling networks by both products. Although independent replication is required to confirm present results, our study demonstrates the utility of proteomics for the identification of individual and composite candidate PD biomarkers that may be leveraged to support clinical pharmacology studies for biosimilar approvals, especially when biologics have complex mechanisms of action or do not have previously characterized PD biomarkers.

The Oral Microbiome and Lung Cancer Risk: An Analysis of 3 Prospective Cohort Studies.

BACKGROUND: Previous studies suggested associations between the oral microbiome and lung cancer, but studies were predominantly cross-sectional and underpowered. METHODS: Using a case-cohort design, 1306 incident lung cancer cases were identified in the Agricultural Health Study; National Institutes of Health-AARP Diet and Health Study; and Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Referent subcohorts were randomly selected by strata of age, sex, and smoking history. DNA was extracted from oral wash specimens using the DSP DNA Virus Pathogen kit, the 16S rRNA gene V4 region was amplified and sequenced, and bioinformatics were conducted using QIIME 2. Hazard ratios and 95% confidence intervals were calculated using weighted Cox proportional hazards models. RESULTS: Higher alpha diversity was associated with lower lung cancer risk (Shannon index hazard ratio = 0.90, 95% confidence interval = 0.84 to 0.96). Specific principal component vectors of the microbial communities were also statistically significantly associated with lung cancer risk. After multiple testing adjustment, greater relative abundance of 3 genera and presence of 1 genus were associated with greater lung cancer risk, whereas presence of 3 genera were associated with lower risk. For example, every SD increase in Streptococcus abundance was associated with 1.14 times the risk of lung cancer (95% confidence interval = 1.06 to 1.22). Associations were strongest among squamous cell carcinoma cases and former smokers. CONCLUSIONS: Multiple oral microbial measures were prospectively associated with lung cancer risk in 3 US cohort studies, with associations varying by smoking history and histologic subtype. The oral microbiome may offer new opportunities for lung cancer prevention.

A hybrid lesion of intralobar sequestration with mixed features of CPAM type I and type II unmasked following SARS-CoV-2 infection: Case report and literature review.

Introduction: Hybrid lesions of intralobar sequestration (ILS) associated with congenital pulmonary airway malformation (CPAM) is rare and could be undetected by prenatal ultrasound. Some of the cases are discovered incidentally or following lung infection in late childhood or adulthood. Case presentation: 17-year-old female developed chest pain, non-productive cough, low grade fever, and sore throat several weeks following SARS-CoV-2 infection. CT angiogram revealed a large lobulated cystic mass with celiac arterial supply in the posterior right lower lobe that was diagnostic for pulmonary sequestration. Gradually she recovered from all respiratory symptoms after a course of multiple antibiotic treatment for symptom relief. In order to prevent recurrent infection and malignancy, she underwent right lower lung mass resection approximately 3 months later. Discussion and conclusion: Pathological examination confirmed a hybrid lesion of ILS with mixed features of CPAM type I and type II. The hallmark morphological features of SARS-CoV-2 infection were not identified except for those of superimposed acute and chronic bronchopneumonia, abscesses formation and fibrosis within the lesion. This is the first case report of a hybrid lesion of ILS associated with CPAM type I and type II, unmasked following SARS-CoV-2 infection. By using the term of hybrid lesion to report this case is to efficiently correlate the terminology and nomenclature applied in the literature currently for multidisciplinary communication between radiology, pulmonary, surgery and pathology.

Integrative analysis of multiple case-control studies.

It is often challenging to share detailed individual-level data among studies due to various informatics and privacy constraints. However, it is relatively easy to pool together aggregated summary level data, such as the ones required for standard meta-analyses. Focusing on data generated from case-control studies, we present a flexible inference procedure that integrates individual-level data collected from an "internal" study with summary data borrowed from "external" studies. This procedure is built on a retrospective empirical likelihood framework to account for the sampling bias in case-control studies. It can incorporate summary statistics extracted from various working models adopted by multiple independent or overlapping external studies. It also allows for external studies to be conducted in a population that is different from the internal study population. We show both theoretically and numerically its efficiency advantage over several competing alternatives.

Hepcidin-regulating iron metabolism genes and pancreatic ductal adenocarcinoma: a pathway analysis of genome-wide association studies.

BACKGROUND: Epidemiological studies have suggested positive associations for iron and red meat intake with risk of pancreatic ductal adenocarcinoma (PDAC). Inherited pathogenic variants in genes involved in the hepcidin-regulating iron metabolism pathway are known to cause iron overload and hemochromatosis. OBJECTIVES: The objective of this study was to determine whether common genetic variation in the hepcidin-regulating iron metabolism pathway is associated with PDAC. METHODS: We conducted a pathway analysis of the hepcidin-regulating genes using single nucleotide polymorphism (SNP) summary statistics generated from 4 genome-wide association studies in 2 large consortium studies using the summary data-based adaptive rank truncated product method. Our population consisted of 9253 PDAC cases and 12,525 controls of European descent. Our analysis included 11 hepcidin-regulating genes [bone morphogenetic protein 2 (BMP2), bone morphogenetic protein 6 (BMP6), ferritin heavy chain 1 (FTH1), ferritin light chain (FTL), hepcidin (HAMP), homeostatic iron regulator (HFE), hemojuvelin (HJV), nuclear factor erythroid 2-related factor 2 (NRF2), ferroportin 1 (SLC40A1), transferrin receptor 1 (TFR1), and transferrin receptor 2 (TFR2)] and their surrounding genomic regions (±20 kb) for a total of 412 SNPs. RESULTS: The hepcidin-regulating gene pathway was significantly associated with PDAC (P = 0.002), with the HJV, TFR2, TFR1, BMP6, and HAMP genes contributing the most to the association. CONCLUSIONS: Our results support that genetic susceptibility related to the hepcidin-regulating gene pathway is associated with PDAC risk and suggest a potential role of iron metabolism in pancreatic carcinogenesis. Further studies are needed to evaluate effect modification by intake of iron-rich foods on this association.

Racial/Ethnic Disparities In COVID-19 Exposure Risk, Testing, And Cases At The Subcounty Level In California.

With a population of forty million and substantial geographic variation in sociodemographics and health services, California is an important setting in which to study disparities. Its population (37.5 percent White, 39.1 percent Latino, 5.3 percent Black, and 14.4 percent Asian) experienced 59,258 COVID-19 deaths through April 14, 2021-the most of any state. We analyzed California's racial/ethnic disparities in COVID-19 exposure risks, testing rates, test positivity, and case rates through October 2020, combining data from 15.4 million SARS-CoV-2 tests with subcounty exposure risk estimates from the American Community Survey. We defined "high-exposure-risk" households as those with one or more essential workers and fewer rooms than inhabitants. Latino people in California are 8.1 times more likely to live in high-exposure-risk households than White people (23.6 percent versus 2.9 percent), are overrepresented in cumulative cases (3,784 versus 1,112 per 100,000 people), and are underrepresented in cumulative testing (35,635 versus 48,930 per 100,000 people). These risks and outcomes were worse for Latino people than for members of other racial/ethnic minority groups. Subcounty disparity analyses can inform targeting of interventions and resources, including community-based testing and vaccine access measures. Tracking COVID-19 disparities and developing equity-focused public health programming that mitigates the effects of systemic racism can help improve health outcomes among California's populations of color.

Smoking Modifies Pancreatic Cancer Risk Loci on 2q21.3.

Germline variation and smoking are independently associated with pancreatic ductal adenocarcinoma (PDAC). We conducted genome-wide smoking interaction analysis of PDAC using genotype data from four previous genome-wide association studies in individuals of European ancestry (7,937 cases and 11,774 controls). Examination of expression quantitative trait loci data from the Genotype-Tissue Expression Project followed by colocalization analysis was conducted to determine whether there was support for common SNP(s) underlying the observed associations. Statistical tests were two sided and P < 5 × 10-8 was considered statistically significant. Genome-wide significant evidence of qualitative interaction was identified on chr2q21.3 in intron 5 of the transmembrane protein 163 (TMEM163) and upstream of the cyclin T2 (CCNT2). The most significant SNP using the Empirical Bayes method, in this region that included 45 significantly associated SNPs, was rs1818613 [per allele OR in never smokers 0.87, 95% confidence interval (CI), 0.82-0.93; former smokers 1.00, 95% CI, 0.91-1.07; current smokers 1.25, 95% CI 1.12-1.40, P interaction = 3.08 × 10-9). Examination of the Genotype-Tissue Expression Project data demonstrated an expression quantitative trait locus in this region for TMEM163 and CCNT2 in several tissue types. Colocalization analysis supported a shared SNP, rs842357, in high linkage disequilibrium with rs1818613 (r 2 = 0. 94) driving both the observed interaction and the expression quantitative trait loci signals. Future studies are needed to confirm and understand the differential biologic mechanisms by smoking status that contribute to our PDAC findings. SIGNIFICANCE: This large genome-wide interaction study identifies a susceptibility locus on 2q21.3 that significantly modified PDAC risk by smoking status, providing insight into smoking-associated PDAC, with implications for prevention.

A mixed-model approach for powerful testing of genetic associations with cancer risk incorporating tumor characteristics.

Cancers are routinely classified into subtypes according to various features, including histopathological characteristics and molecular markers. Previous genome-wide association studies have reported heterogeneous associations between loci and cancer subtypes. However, it is not evident what is the optimal modeling strategy for handling correlated tumor features, missing data, and increased degrees-of-freedom in the underlying tests of associations. We propose to test for genetic associations using a mixed-effect two-stage polytomous model score test (MTOP). In the first stage, a standard polytomous model is used to specify all possible subtypes defined by the cross-classification of the tumor characteristics. In the second stage, the subtype-specific case-control odds ratios are specified using a more parsimonious model based on the case-control odds ratio for a baseline subtype, and the case-case parameters associated with tumor markers. Further, to reduce the degrees-of-freedom, we specify case-case parameters for additional exploratory markers using a random-effect model. We use the Expectation-Maximization algorithm to account for missing data on tumor markers. Through simulations across a range of realistic scenarios and data from the Polish Breast Cancer Study (PBCS), we show MTOP outperforms alternative methods for identifying heterogeneous associations between risk loci and tumor subtypes. The proposed methods have been implemented in a user-friendly and high-speed R statistical package called TOP (https://github.com/andrewhaoyu/TOP).

Comparison of Multiple Breath Washout and Spirometry in Children with Primary Ciliary Dyskinesia and Cystic Fibrosis and Healthy Controls.

Rationale: In cystic fibrosis (CF), the lung clearance index (LCI), derived from multiple breath washout (MBW), is more sensitive in detecting early lung disease than FEV1; MBW has been less thoroughly evaluated in young patients with primary ciliary dyskinesia (PCD).Objectives: Our objectives were 1) to evaluate the sensitivity of MBW and spirometry for the detection of mild lung disease in young children with PCD and CF compared with healthy control (HC) subjects and 2) to compare patterns of airway obstruction between disease populations.Methods: We used a multicenter, single-visit, observational study in children with PCD and CF with a forced expiratory volume in 1 second (FEV1) greater than 60% predicted and HC subjects, ages 3-12 years. Nitrogen MBW and spirometry were performed and overread for acceptability. χ2 and Kruskall-Wallis tests compared demographics and lung function measures between groups, linear regression evaluated the effect of disease state, and Spearman's rank correlation coefficient compared the LCI and spirometric measurements.Results: Twenty-five children with PCD, 49 children with CF, and 80 HC children were enrolled, among whom 17 children with PCD (68%), 36 children with CF (73%), and 53 (66%) HC children performed both acceptable spirometry and MBW; these children made up the analytic cohort. The median age was 9.0 years (interquartile range [IQR], 6.8-11.1). The LCI was abnormal (more than 7.8) in 10 of 17 (59%) patients with PCD and 21 of 36 (58%) patients with CF, whereas FEV1 was abnormal in three of 17 (18%) patients with PCD and six of 36 (17%) patients with CF. The LCI was significantly elevated in patients with PCD and CF compared with HC subjects (ratio of geometric mean vs. HC: PCD 1.27; 95% confidence interval [CI], 1.15-1.39; and CF 1.24; 95% CI, 1.15-1.33]). Children with PCD had lower midexpiratory-phase forced expiratory flow % predicted compared with children with CF (62% [IQR, 50-78%] vs. 85% [IQR, 68-99%]; P = 0.05). LCI did not correlate with FEV1.Conclusions: The LCI is more sensitive than FEV1 in detecting lung disease in young patients with PCD, similar to CF. LCI holds promise as a sensitive endpoint for the assessment of early PCD lung disease.

Genome-Wide Association Study Data Reveal Genetic Susceptibility to Chronic Inflammatory Intestinal Diseases and Pancreatic Ductal Adenocarcinoma Risk.

Registry-based epidemiologic studies suggest associations between chronic inflammatory intestinal diseases and pancreatic ductal adenocarcinoma (PDAC). As genetic susceptibility contributes to a large proportion of chronic inflammatory intestinal diseases, we hypothesize that the genomic regions surrounding established genome-wide associated variants for these chronic inflammatory diseases are associated with PDAC. We examined the association between PDAC and genomic regions (±500 kb) surrounding established common susceptibility variants for ulcerative colitis, Crohn's disease, inflammatory bowel disease, celiac disease, chronic pancreatitis, and primary sclerosing cholangitis. We analyzed summary statistics from genome-wide association studies data for 8,384 cases and 11,955 controls of European descent from two large consortium studies using the summary data-based adaptive rank truncated product method to examine the overall association of combined genomic regions for each inflammatory disease group. Combined genomic susceptibility regions for ulcerative colitis, Crohn disease, inflammatory bowel disease, and chronic pancreatitis were associated with PDAC at P values < 0.05 (0.0040, 0.0057, 0.011, and 3.4 × 10-6, respectively). After excluding the 20 PDAC susceptibility regions (±500 kb) previously identified by GWAS, the genomic regions for ulcerative colitis, Crohn disease, and inflammatory bowel disease remained associated with PDAC (P = 0.0029, 0.0057, and 0.0098, respectively). Genomic regions for celiac disease (P = 0.22) and primary sclerosing cholangitis (P = 0.078) were not associated with PDAC. Our results support the hypothesis that genomic regions surrounding variants associated with inflammatory intestinal diseases, particularly, ulcerative colitis, Crohn disease, inflammatory bowel disease, and chronic pancreatitis are associated with PDAC. SIGNIFICANCE: The joint effects of common variants in genomic regions containing susceptibility loci for inflammatory bowel disease and chronic pancreatitis are associated with PDAC and may provide insights to understanding pancreatic cancer etiology.

Lung Injury Associated with E-Cigarette or Vaping Product Use.

In the United States, an epidemic of unusual and severe lung disease associated with the use of e-cigarettes, or vaping, began in spring 2019. By fall 2019, the US Centers for Disease Control and Prevention had received reports of e-cigarette or vaping product use-associated lung injury (EVALI) cases from all state health departments in the continental US, Hawaii, and the US Virgin Islands. According to the cases, a number of young people had developed severe lung disease characterized by marked shortness of breath and cough. Constitutional and gastrointestinal symptoms are common. Clinical laboratory test results in EVALI are often consistent with nonspecific findings of pulmonary/systemic inflammation. Many reported cases of EVALI have required critical care interventions including noninvasive positive airway pressure, cardiotonic pressors, and intubation/mechanical ventilation. The need for extracorporeal membrane oxygenation support has been reported in some cases. The lung disease is diffuse and has multiple pathologies. Patients are often treated with intravenous or oral corticosteroids with clinical improvement, although the natural history of the disease remains unknown. In rare cases, the outcome is fatal. This article reviews the epidemiology, clinical presentation, radiographic appearance, diagnostic approach, and treatment regimens for patients with vaping-induced lung disease as noted in multiple patients and the current literature. [Pediatr Ann. 2020;49(2):e93-e98.].

iCARE: An R package to build, validate and apply absolute risk models.

This report describes an R package, called the Individualized Coherent Absolute Risk Estimator (iCARE) tool, that allows researchers to build and evaluate models for absolute risk and apply them to estimate an individual's risk of developing disease during a specified time interval based on a set of user defined input parameters. An attractive feature of the software is that it gives users flexibility to update models rapidly based on new knowledge on risk factors and tailor models to different populations by specifying three input arguments: a model for relative risk, an age-specific disease incidence rate and the distribution of risk factors for the population of interest. The tool can handle missing information on risk factors for individuals for whom risks are to be predicted using a coherent approach where all estimates are derived from a single model after appropriate model averaging. The software allows single nucleotide polymorphisms (SNPs) to be incorporated into the model using published odds ratios and allele frequencies. The validation component of the software implements the methods for evaluation of model calibration, discrimination and risk-stratification based on independent validation datasets. We provide an illustration of the utility of iCARE for building, validating and applying absolute risk models using breast cancer as an example.