METHODS: We utilized data from genome-wide association studies within the Pancreatic Cancer Cohort Consortium and Pancreatic Cancer Case-Control Consortium, involving approximately 9,269 cases and 12,530 controls of European descent, to evaluate associations between pancreatic cancer risk and genetically predicted plasma n-6 PUFA levels. Conventional MR analyses were performed using individual-level and summary-level data.
RESULTS: Using genetic instruments, we did not find evidence of associations between genetically predicted plasma n-6 PUFA levels and pancreatic cancer risk [estimates per one SD increase in each PUFA-specific weighted genetic score using summary statistics: linoleic acid odds ratio (OR) = 1.00, 95% confidence interval (CI) = 0.98-1.02; arachidonic acid OR = 1.00, 95% CI = 0.99-1.01; and dihomo-gamma-linolenic acid OR = 0.95, 95% CI = 0.87-1.02]. The OR estimates remained virtually unchanged after adjustment for covariates, using individual-level data or summary statistics, or stratification by age and sex.
CONCLUSIONS: Our results suggest that variations of genetically determined plasma n-6 PUFA levels are not associated with pancreatic cancer risk.
IMPACT: These results suggest that modifying n-6 PUFA levels through food sources or supplementation may not influence risk of pancreatic cancer.
METHODS: We conducted a gene-environment interaction (GxE) analysis including 8,255 cases and 11,900 controls from four pancreatic cancer genome-wide association study (GWAS) datasets (Pancreatic Cancer Cohort Consortium I-III and Pancreatic Cancer Case Control Consortium). Obesity (body mass index ≥30 kg/m2) and diabetes (duration ≥3 years) were the environmental variables of interest. Approximately 870,000 SNPs (minor allele frequency ≥0.005, genotyped in at least one dataset) were analyzed. Case-control (CC), case-only (CO), and joint-effect test methods were used for SNP-level GxE analysis. As a complementary approach, gene-based GxE analysis was also performed. Age, sex, study site, and principal components accounting for population substructure were included as covariates. Meta-analysis was applied to combine individual GWAS summary statistics.
RESULTS: No genome-wide significant interactions (departures from a log-additive odds model) with diabetes or obesity were detected at the SNP level by the CC or CO approaches. The joint-effect test detected numerous genome-wide significant GxE signals in the GWAS main effects top hit regions, but the significance diminished after adjusting for the GWAS top hits. In the gene-based analysis, a significant interaction of diabetes with variants in the FAM63A (family with sequence similarity 63 member A) gene (significance threshold P < 1.25 × 10-6) was observed in the meta-analysis (P GxE = 1.2 ×10-6, P Joint = 4.2 ×10-7).
CONCLUSIONS: This analysis did not find significant GxE interactions at the SNP level but found one significant interaction with diabetes at the gene level. A larger sample size might unveil additional genetic factors via GxE scans.
IMPACT: This study may contribute to discovering the mechanism of diabetes-associated pancreatic cancer.
METHODS AND RESULTS: The primary outcome (risk of cardiac failure, pacemaker syndrome, or syncope related to the Micra system or procedure) was compared between successfully implanted patients from the Micra IDE trial with a primary pacing indication associated with AF or history of AF (AF group) and those without (non-AF group). Among 720 patients successfully implanted with Micra, 228 (31.7%) were in the non-AF group. Reasons for selecting VVI pacing in non-AF patients included an expectation for infrequent pacing (66.2%) and advanced age (27.2%). More patients in the non-AF group had a condition that precluded the use of a transvenous pacemaker (9.6% vs. 4.7%, P = 0.013). Atrial fibrillation patients programmed to VVI received significantly more ventricular pacing compared to non-AF patients (median 67.8% vs. 12.6%; P
OBJECTIVE: The purpose of this study was to describe the natural history of acute elevated Micra vs traditional transvenous lead thresholds.
METHODS: Micra study VVI patients with threshold data (at 0.24 ms) at implant (n = 711) were compared with Capture study patients with de novo transvenous leads at 0.4 ms (n = 538). In both cohorts, high thresholds were defined as >1.0 V and very high as >1.5 V. Change in pacing threshold (0-6 months) with high (1.0 to ≤1.5 V) or very high (>1.5 V) thresholds were compared using the Wilcoxon signed-rank test.
RESULTS: Of the 711 Micra patients, 83 (11.7%) had an implant threshold of >1.0 V at 0.24 ms. Of the 538 Capture patients, 50 (9.3%) had an implant threshold of >1.0 V at 0.40 ms. There were no significant differences in patient characteristics between those with and without an implant threshold of >1.0 V, with the exception of left ventricular ejection fraction in the Capture cohort (high vs low thresholds, 53% vs 58%; P = .011). Patients with an implant threshold of >1.0 V decreased significantly (P < .001) in both cohorts. Micra patients with high and very high thresholds decreased significantly (P < .01) by 1 month, with 87% and 85% having 6-month thresholds lower than the implant value. However, when the capture threshold at implant was >2 V, only 18.2% had a threshold of ≤1 V at 6 months and 45.5% had a capture threshold of >2 V.
CONCLUSIONS: Pacing thresholds in most Micra patients with elevated thresholds decrease after implant. Micra device repositioning may not be necessary if the pacing threshold is ≤2 V.
METHODS: We reviewed results for injuries from the GBD 2017 study. GBD 2017 measured injury-specific mortality and years of life lost (YLLs) using the Cause of Death Ensemble model. To measure non-fatal injuries, GBD 2017 modelled injury-specific incidence and converted this to prevalence and years lived with disability (YLDs). YLLs and YLDs were summed to calculate disability-adjusted life years (DALYs).
FINDINGS: In 1990, there were 4 260 493 (4 085 700 to 4 396 138) injury deaths, which increased to 4 484 722 (4 332 010 to 4 585 554) deaths in 2017, while age-standardised mortality decreased from 1079 (1073 to 1086) to 738 (730 to 745) per 100 000. In 1990, there were 354 064 302 (95% uncertainty interval: 338 174 876 to 371 610 802) new cases of injury globally, which increased to 520 710 288 (493 430 247 to 547 988 635) new cases in 2017. During this time, age-standardised incidence decreased non-significantly from 6824 (6534 to 7147) to 6763 (6412 to 7118) per 100 000. Between 1990 and 2017, age-standardised DALYs decreased from 4947 (4655 to 5233) per 100 000 to 3267 (3058 to 3505).
INTERPRETATION: Injuries are an important cause of health loss globally, though mortality has declined between 1990 and 2017. Future research in injury burden should focus on prevention in high-burden populations, improving data collection and ensuring access to medical care.
METHODS: In this study, we report and discuss the methods used in GBD 2017 for injury morbidity and mortality burden estimation. In summary, these methods included estimating cause-specific mortality for every cause of injury, and then estimating incidence for every cause of injury. Non-fatal disability for each cause is then calculated based on the probabilities of suffering from different types of bodily injury experienced.
RESULTS: GBD 2017 produced morbidity and mortality estimates for 38 causes of injury. Estimates were produced in terms of incidence, prevalence, years lived with disability, cause-specific mortality, years of life lost and disability-adjusted life-years for a 28-year period for 22 age groups, 195 countries and both sexes.
CONCLUSIONS: GBD 2017 demonstrated a complex and sophisticated series of analytical steps using the largest known database of morbidity and mortality data on injuries. GBD 2017 results should be used to help inform injury prevention policy making and resource allocation. We also identify important avenues for improving injury burden estimation in the future.
METHODS: We used results from the Global Burden of Disease (GBD) 2017 study to report incidence, prevalence, years lived with disability, deaths, years of life lost and disability-adjusted life years for all locations in the GBD 2017 hierarchy from 1990 to 2017 for road injuries. Second, we measured mortality-to-incidence ratios by location. Third, we assessed the distribution of the natures of injury (eg, traumatic brain injury) that result from each road injury.
RESULTS: Globally, 1 243 068 (95% uncertainty interval 1 191 889 to 1 276 940) people died from road injuries in 2017 out of 54 192 330 (47 381 583 to 61 645 891) new cases of road injuries. Age-standardised incidence rates of road injuries increased between 1990 and 2017, while mortality rates decreased. Regionally, age-standardised mortality rates decreased in all but two regions, South Asia and Southern Latin America, where rates did not change significantly. Nine of 21 GBD regions experienced significant increases in age-standardised incidence rates, while 10 experienced significant decreases and two experienced no significant change.
CONCLUSIONS: While road injury mortality has improved in recent decades, there are worsening rates of incidence and significant geographical heterogeneity. These findings indicate that more research is needed to better understand how road injuries can be prevented.
OBJECTIVE: To describe cancer burden for 29 cancer groups in 195 countries from 1990 through 2017 to provide data needed for cancer control planning.
EVIDENCE REVIEW: We used the GBD study estimation methods to describe cancer incidence, mortality, years lived with disability, years of life lost, and disability-adjusted life-years (DALYs). Results are presented at the national level as well as by Socio-demographic Index (SDI), a composite indicator of income, educational attainment, and total fertility rate. We also analyzed the influence of the epidemiological vs the demographic transition on cancer incidence.
FINDINGS: In 2017, there were 24.5 million incident cancer cases worldwide (16.8 million without nonmelanoma skin cancer [NMSC]) and 9.6 million cancer deaths. The majority of cancer DALYs came from years of life lost (97%), and only 3% came from years lived with disability. The odds of developing cancer were the lowest in the low SDI quintile (1 in 7) and the highest in the high SDI quintile (1 in 2) for both sexes. In 2017, the most common incident cancers in men were NMSC (4.3 million incident cases); tracheal, bronchus, and lung (TBL) cancer (1.5 million incident cases); and prostate cancer (1.3 million incident cases). The most common causes of cancer deaths and DALYs for men were TBL cancer (1.3 million deaths and 28.4 million DALYs), liver cancer (572 000 deaths and 15.2 million DALYs), and stomach cancer (542 000 deaths and 12.2 million DALYs). For women in 2017, the most common incident cancers were NMSC (3.3 million incident cases), breast cancer (1.9 million incident cases), and colorectal cancer (819 000 incident cases). The leading causes of cancer deaths and DALYs for women were breast cancer (601 000 deaths and 17.4 million DALYs), TBL cancer (596 000 deaths and 12.6 million DALYs), and colorectal cancer (414 000 deaths and 8.3 million DALYs).
CONCLUSIONS AND RELEVANCE: The national epidemiological profiles of cancer burden in the GBD study show large heterogeneities, which are a reflection of different exposures to risk factors, economic settings, lifestyles, and access to care and screening. The GBD study can be used by policy makers and other stakeholders to develop and improve national and local cancer control in order to achieve the global targets and improve equity in cancer care.
Objective: To estimate mortality and morbidity in children and adolescents from 1990 to 2017 by age and sex in 195 countries and territories.
Design, Setting, and Participants: This study examined levels, trends, and spatiotemporal patterns of cause-specific mortality and nonfatal health outcomes using standardized approaches to data processing and statistical analysis. It also describes epidemiologic transitions by evaluating historical associations between disease indicators and the Socio-Demographic Index (SDI), a composite indicator of income, educational attainment, and fertility. Data collected from 1990 to 2017 on children and adolescents from birth through 19 years of age in 195 countries and territories were assessed. Data analysis occurred from January 2018 to August 2018.
Exposures: Being under the age of 20 years between 1990 and 2017.
Main Outcomes and Measures: Death and disability. All-cause and cause-specific deaths, disability-adjusted life years, years of life lost, and years of life lived with disability.
Results: Child and adolescent deaths decreased 51.7% from 13.77 million (95% uncertainty interval [UI], 13.60-13.93 million) in 1990 to 6.64 million (95% UI, 6.44-6.87 million) in 2017, but in 2017, aggregate disability increased 4.7% to a total of 145 million (95% UI, 107-190 million) years lived with disability globally. Progress was uneven, and inequity increased, with low-SDI and low-middle-SDI locations experiencing 82.2% (95% UI, 81.6%-82.9%) of deaths, up from 70.9% (95% UI, 70.4%-71.4%) in 1990. The leading disaggregated causes of disability-adjusted life years in 2017 in the low-SDI quintile were neonatal disorders, lower respiratory infections, diarrhea, malaria, and congenital birth defects, whereas neonatal disorders, congenital birth defects, headache, dermatitis, and anxiety were highest-ranked in the high-SDI quintile.
Conclusions and Relevance: Mortality reductions over this 27-year period mean that children are more likely than ever to reach their 20th birthdays. The concomitant expansion of nonfatal health loss and epidemiological transition in children and adolescents, especially in low-SDI and middle-SDI countries, has the potential to increase already overburdened health systems, will affect the human capital potential of societies, and may influence the trajectory of socioeconomic development. Continued monitoring of child and adolescent health loss is crucial to sustain the progress of the past 27 years.
METHODS: We conducted a large agnostic pathway-based meta-analysis of GWAS data using the summary-based adaptive rank truncated product method to identify gene sets and pathways associated with pancreatic ductal adenocarcinoma (PDAC) in 9040 cases and 12 496 controls. We performed expression quantitative trait loci (eQTL) analysis and functional annotation of the top SNPs in genes contributing to the top associated pathways and gene sets. All statistical tests were two-sided.
RESULTS: We identified 14 pathways and gene sets associated with PDAC at a false discovery rate of less than 0.05. After Bonferroni correction (P ≤ 1.3 × 10-5), the strongest associations were detected in five pathways and gene sets, including maturity-onset diabetes of the young, regulation of beta-cell development, role of epidermal growth factor (EGF) receptor transactivation by G protein-coupled receptors in cardiac hypertrophy pathways, and the Nikolsky breast cancer chr17q11-q21 amplicon and Pujana ATM Pearson correlation coefficient (PCC) network gene sets. We identified and validated rs876493 and three correlating SNPs (PGAP3) and rs3124737 (CASP7) from the Pujana ATM PCC gene set as eQTLs in two normal derived pancreas tissue datasets.
CONCLUSION: Our agnostic pathway and gene set analysis integrated with functional annotation and eQTL analysis provides insight into genes and pathways that may be biologically relevant for risk of PDAC, including those not previously identified.