Moderate Increase In Risk Research Articles

Dietary omega-3 fatty acids and endometrial cancer risk in the Epidemiology of Endometrial Cancer Consortium: An individual-participant meta-analysis

BackgroundLimited data from prospective studies suggest that higher dietary intake of long-chain omega-3 polyunsaturated fatty acids (LCn3PUFA), which hold anti-inflammatory properties, may reduce endometrial cancer risk; particularly among certain subgroups characterized by body mass and tumor pathology. Materials and methodsData from 12 prospective cohort studies participating in the Epidemiology of Endometrial Cancer Consortium were harmonized as nested case-control studies, including 7268 endometrial cancer cases and 26,133 controls. Habitual diet was assessed by food frequency questionnaire, from which fatty acid intakes were estimated. Two-stage individual-participant data mixed effects meta-analysis estimated adjusted odds ratios (OR) and 95% confidence intervals (CI) through logistic regression for associations between study-specific energy-adjusted quartiles of LCn3PUFA and endometrial cancer risk. ResultsWomen with the highest versus lowest estimated dietary intakes of docosahexaenoic acid, the most abundant LCn3PUFA in diet, had a 9% increased endometrial cancer risk (Quartile 4 vs. Quartile 1: OR 1.09, 95% CI: 1.01–1.19; P trend = 0.04). Similar elevated risks were observed for the summary measure of total LCn3PUFA (OR 1.07, 95% CI: 0.99–1.16; P trend = 0.06). Stratified by body mass index, higher intakes of LCn3PUFA were associated with 12–19% increased endometrial cancer risk among overweight/obese women and no increased risk among normal-weight women. Higher associations appeared restricted to White women. The results did not differ by cancer grade. ConclusionHigher dietary intakes of LCn3PUFA are unlikely to reduce endometrial cancer incidence; rather, they may be associated with small to moderate increases in risk in some subgroups of women, particularly overweight/obese women.

Cancer Progress and Priorities: Breast Cancer.

Breast cancer is the most commonly diagnosed invasive cancer among women both globally and within the United States and the number one cause of cancer-related deaths among women globally ([1, 2][1]). Less than 1% of diagnosed breast cancers occur in men ([2][2]) and, therefore, male breast cancer is

Prenatal and early childhood exposure to tetrachloroethylene (PCE) and non-medical use of prescription drugs: A retrospective cohort study in Cape Cod, MA

BackgroundBetween 1968 and 1983, public drinking water supplies of Cape Cod, Massachusetts were contaminated with the chlorinated solvent tetrachloroethylene (PCE). We previously found an affinity for risk-taking behaviors, including the use of illicit drugs, following prenatal and early childhood exposure to PCE. Using newly collected data, we investigated the risk of non-medical use of prescription drugs (NMUPD) following prenatal and early childhood PCE exposure. MethodsParticipants were identified from a retrospective cohort study ("Cape Cod Health Study”) via cross-matching birth certificates and water system data. The original self-administered questionnaire gathered data on demographics, work and medical history, and alcohol and illicit drug use from 618 individuals (363 exposed and 255 unexposed). The follow-up survey added questions on non-medical use of prescription pain relievers, tranquilizers, stimulants and sedatives. A validated leaching and transport model was used to estimate exposure to PCE exposure in drinking water. ResultsThere was a wide distribution of cumulative prenatal and early childhood PCE exposure levels (range: 0.04 g–3722.2 g). PCE exposed subjects had a 1.92-fold increase in risk of any non-medical use of prescription drugs [Adjusted RR: 1.92, (95% CI: 1.31, 2.83)]. Furthermore, the association followed a dose-response relationship where the risk of NMUPD was higher for those exposed to PCE levels greater than or equal the median level versus those exposed to levels less than the median [Adjusted RR: 2.05 (95% CI: 1.34, 3.15) vs. 1.83 (95% CI: 1.20, 2.79) (p-value for trend < 0.01)]. Additionally, we found moderate increases in risk by level of non-medical use (any non-medical use, non-medical use of 1 or more categories of prescription drugs, or 2+ categories) as well as by category of drug for pain relivers, stimulants and tranquilizers. ConclusionWe found that prenatal and early childhood exposure to PCE was associated with a moderate increase in the risk of NMUPD. Exposed subjects had dose-related increased risks of NMUPD of pain relievers, tranquilizers, and stimulants. This study has a number of limitations and is the first to report this association. Additional longitudinal studies of populations exposed to PCE during early life should be conducted to examine its long-term neurotoxic effects.

Shift work and long work hours and their association with chronic health conditions: A systematic review of systematic reviews with meta-analyses.

Previous reviews have demonstrated that shift work and long work hours are associated with increased risk for chronic conditions. However, these reviews did not comprehensively assessed the body of evidence, and some were not conducted in a systematic manner. A better understanding of the health consequences of shift work and long work hours will aid in creating policy and practice recommendations. This review revisits the epidemiologic evidence on the association of shift work and long work hours with chronic conditions with particular emphasis on assessing the quality of the evidence. We conducted a systematic review of systematic reviews with meta-analyses (SR-MA) that assessed the link between shift work or long work hours and chronic conditions (PROSPERO CRD42019122084). We evaluated the risk of bias of each SR-MA using AMSTAR v2 and assessed the overall evidence for each condition using the GRADE approach. We included 48 reviews covering cancers, cardiovascular diseases, metabolic syndrome and related conditions, pregnancy complications, depression, hypertension, and injuries. On average, only 7 of 16 AMSTAR items were fulfilled. Few SR-MAs had a registered protocol and nearly all failed to conduct a comprehensive search. We found moderate grade evidence linking shift work to breast cancer and long work hours to stroke. We found low grade evidence linking both shift work and long work hours with low to moderate increase in risk for some pregnancy complications and cardiovascular diseases. Low grade evidence also link long work hours and depression. Moderate grade evidence suggest that shift work and long work hours increase the risk of breast cancer and stroke, but the evidence is unclear on other chronic conditions. There is a need for high-quality studies to address this gap. Stakeholders should be made aware of these increased risks, and additional screening and prevention should be considered, particularly for workers susceptible to breast cancer and stroke.

Risk of gastrointestinal cancer in a symptomatic cohort after a complete colonoscopy: Role of faecal immunochemical test.

BACKGROUNDFaecal immunochemical test (FIT) has been recommended to assess symptomatic patients for colorectal cancer (CRC) detection. Nevertheless, some conditions could theoretically favour blood originating in proximal areas of the gastrointestinal tract passing through the colon unmetabolized. A positive FIT result could be related to other gastrointestinal cancers (GIC).AIMTo assess the risk of GIC detection and related death in FIT-positive symptomatic patients (threshold 10 μg Hb/g faeces) without CRC.METHODSPost hoc cohort analysis performed within two prospective diagnostic test studies evaluating the diagnostic accuracy of different FIT analytical systems for CRC and significant colonic lesion detection. Ambulatory patients with gastrointestinal symptoms referred consecutively for colonoscopy from primary and secondary healthcare, underwent a quantitative FIT before undergoing a complete colonoscopy. Patients without CRC were divided into two groups (positive and negative FIT) using the threshold of 10 μg Hb/g of faeces and data from follow-up were retrieved from electronic medical records of the public hospitals involved in the research. We determined the cumulative risk of GIC, CRC and upper GIC. Hazard rate (HR) was calculated adjusted by age, sex and presence of significant colonic lesion.RESULTSWe included 2709 patients without CRC and a complete baseline colonoscopy, 730 (26.9%) with FIT ≥ 10 µgr Hb/gr. During a mean time of 45.5 ± 20.0 mo, a GIC was detected in 57 (2.1%) patients: An upper GIC in 35 (1.3%) and a CRC in 14 (0.5%). Thirty-six patients (1.3%) died due to GIC: 22 (0.8%) due to an upper GIC and 9 (0.3%) due to CRC. FIT-positive subjects showed a higher CRC risk (HR 3.8, 95%CI: 1.2-11.9) with no differences in GIC (HR 1.5, 95%CI: 0.8-2.7) or upper GIC risk (HR 1.0, 95%CI: 0.5-2.2). Patients with a positive FIT had only an increased risk of CRC-related death (HR 10.8, 95%CI: 2.1-57.1) and GIC-related death (HR 2.2, 95%CI: 1.1-4.3), with no differences in upper GIC-related death (HR 1.4, 95%CI: 0.6-3.3). An upper GIC was detected in 22 (0.8%) patients during the first year. Two variables were independently associated: anaemia (OR 5.6, 95%CI: 2.2-13.9) and age ≥ 70 years (OR 2.7, 95%CI: 1.1-7.0).CONCLUSIONSymptomatic patients without CRC have a moderate risk increase in upper GIC, regardless of the FIT result. Patients with a positive FIT have an increased risk of post-colonoscopy CRC.

Group sequential adaptive designs in series of time-to-event randomised trials in rare diseases: A simulation study.

In rare diseases, fully powered large trials may not be doable in a reasonable time frame even with international collaborations. In a previous work, we proposed an approach based on a series of smaller parallel group two-arm randomised controlled trials (RCT) performed over a long research horizon. Within the series of trials, the treatment selected after each trial becomes the control treatment of the next one. We concluded that running more trials with smaller sample sizes and relaxed α-levels leads in the long term and under reasonable assumptions to larger survival benefits with a moderate increase of risk as compared to traditional designs based on larger but fewer trials designed to meet stringent evidence criteria. We now extend this quantitative framework with more 'flexible' designs including interim analyses for futility and/or efficacy, and three-arm adaptive designs with treatment selection at interim. In the simulation study, we considered different disease severities, accrual rates, and hypotheses of how treatments improve over time. For each design, we estimated the long-term survival benefit as the relative difference in hazard rates between the end and the start of the research horizon, and the risk defined as the probability of selecting at the end of the research horizon a treatment inferior to the initial control. We assessed the impact of the α-level and the choice of the stopping rule on the operating characteristics. We also compared the performance of series based on two- vs. three-arm trials. We show that relaxing α-levels within the limit of 0.1 is associated with larger survival gains and moderate increase of risk which remains within acceptable ranges. Including an interim analysis with a futility rule is associated with an additional survival gain and a better risk control as compared to series with no interim analysis, when the α-level is below or equal to 0.1, whereas the benefit of including an interim analysis is rather small for higher α-levels. Including an interim analysis for efficacy yields almost no additional gain. Series based on three-arm trials are associated with a systematic improvement in terms of survival gain and risk control as compared to series of two-arm trials.

Diagnostic Accuracy of Clinical Biomarkers for Preoperative Prediction of Lymph Node Metastasis in Endometrial Carcinoma: A Systematic Review and Meta-Analysis.

In endometrial carcinoma (EC), preoperative classification is based on histopathological criteria, with only moderate diagnostic performance for the risk of lymph node metastasis (LNM). So far, existing molecular classification systems have not been evaluated for prediction of LNM. Optimized use of clinical biomarkers as recommended by international guidelines might be a first step to improve tailored treatment, awaiting future molecular biomarkers. To determine the diagnostic accuracy of preoperative clinical biomarkers for the prediction of LNM in endometrial cancer. A systematic review was performed according to the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines. Studies identified in MEDLINE and EMBASE were selected by two independent reviewers. Included biomarkers were based on recommended guidelines (cancer antigen 125 [Ca-125], lymphadenopathy on magnetic resonance imaging, computed tomography, and 18F-fluorodeoxyglucose positron emission tomography/computed tomography [18FDG PET-CT]) or obtained by physical examination (body mass index, cervical cytology, blood cell counts). Pooled sensitivity, specificity, area under the curve (AUC), and likelihood ratios were calculated with bivariate random-effects meta-analysis. Likelihood ratios were classified into small (0.5-1.0 or 1-2.0), moderate (0.2-0.5 or 2.0-5.0) or large (0.1-0.2 or ≥ 5.0) impact. Eighty-three studies, comprising 18,205 patients, were included. Elevated Ca-125 and thrombocytosis were associated with a moderate increase in risk of LNM; lymphadenopathy on imaging with a large increase. Normal Ca-125, cytology, and no lymphadenopathy on 18FDG PET-CT were associated with a moderate decrease. AUCs were above 0.75 for these biomarkers. Other biomarkers had an AUC <0.75 and incurred only small impact. Ca-125, thrombocytosis, and imaging had a large and moderate impact on risk of LNM and could improve preoperative risk stratification. Routine lymphadenectomy in clinical early-stage endometrial carcinoma does not improve outcome and is associated with 15%-20% surgery-related morbidity, underlining the need for improved preoperative risk stratification. New molecular classification systems are emerging but have not yet been evaluated for the prediction of lymph node metastasis. This article provides a robust overview of diagnostic performance of all clinical biomarkers recommended by international guidelines. Based on these, at least measurement of cancer antigen 125 serum level, assessment of thrombocytosis, and imaging focused on lymphadenopathy should complement current preoperative risk stratification in order to better stratify these patients by risk.

Abstract P256: Stability of Obesity and Metabolic Health and the Risk of Cardiovascular Disease

Introduction: Metabolic syndrome (MetSyn) reportedly confers higher risk of cardiovascular disease (CVD) than its individual components. Although typically defined as a binary exposure, each of its component factors can vary over time. Little is known about whether CVD risk differs according to MetSyn stability. Methods: We defined longitudinal states of obesity and metabolic health among 2,952 Framingham Offspring Study participants for whom we had sufficient data to define MetSyn at ≥4 exams between Exams 2 (1979-1983) and 9 (2011-2014). Obesity was defined as BMI ≥30 kg/m 2 , high triglycerides as ≥150 mg/dL/taking lipid-lowering medication, low HDL as &lt;40 mg/dL for males/ &lt;50 mg/dL for females; high blood pressure as systolic blood pressure ≥130 mm Hg/diastolic blood pressure ≥85 mm Hg/taking antihypertensive medication, and high blood glucose as ≥100 mg/dL/taking antidiabetic medication. Metabolic health was defined as having &lt;2 metabolic conditions. Obesity and metabolic health were classified as unstable if there was a change from one state to the other in ≥33% of observations occurring before a CVD event or end of follow-up, stable obese/metabolically unhealthy if not unstable and &gt;50% of observations were classified as stable obese/metabolically unhealthy, or stable non-obese/metabolically healthy otherwise. CVD was defined as any of the following coronary death, myocardial infarction, coronary insufficiency, angina pectoris, stroke, transient ischemic attack, intermittent claudication, or congestive heart failure. We estimated hazard ratios (HRs) and 95% confidence intervals (95% CIs) using Cox proportional hazards regression with age as the time scale. Results: We classified 332 participants (11.3%) as having unstable metabolic health, and 130 (4.4%) as having unstable obesity. We observed 1,206 events in 75,673 person-years of follow-up (median 30 years). Participants classified as stable metabolically unhealthy had the highest CVD risk (HR 1.77, 95% CI 1.47, 2.13, compared to stable metabolically healthy). Stable obesity was associated with a 48% (95% CI 24, 80) increase in CVD risk relative to stable non-obese. Unstable metabolic health and obesity were associated with moderate increases in risk compared to stable metabolically healthy and stable non-obese (HRs: 1.32, 95% CI 1.03, 1.71 and 1.25, 95% CI 0.88, 1.77, respectively). There was no interaction between obesity- and metabolic health stability (p interaction =0.23). Conclusions: In our sample, stability of obesity and of metabolic health influenced CVD risk, with the highest risk of CVD observed among stable metabolically unhealthy participants. Instability of both obesity and metabolic health convey a risk intermediate between the stable obese/metabolically healthy and stable non-obese/metabolically unhealthy conditions.

Exenatide modulates tumor-endothelial cell interactions in human ovarian cancer cells.

Diabetes and cancer are prevalent diseases whose incidence is increasing globally. Diabetic women have a moderate risk increase in ovarian cancer, suggested to be due to an interaction between these two disorders. Furthermore, patients manifesting both diseases have associated worse prognosis, reduced survival and shorter relapse-free survival. According to current recommendations, incretin drugs such as Exenatide, a synthetic analog of Exendin-4, and Liraglutide are used as therapy for the type 2 diabetes (T2D). We studied the effects of GLP-1 and Exendin-4 on migration, apoptosis and metalloproteinase production in two human ovarian cancer cells (SKOV-3 and CAOV-3). Exendin-4 inhibited migration and promoted apoptosis through caspase 3/7 activation. Exendin-4 also modulated the expression of key metalloproteinases (MMP-2 and MMP-9) and their inhibitors (TIMP-1 and TIMP-2). Vascular endothelial cells, which contribute to the formation and progression of metastasis, were also analyzed. TNF-α-stimulated endothelial cells from iliac artery after Exendin-4 treatment showed reduced production of adhesion molecules (ICAM-1 and VCAM-1). Additionally, incretin treatment inhibited activation of apoptosis in TNF-α-stimulated endothelial cells. In the same experiment, MMPs (MMP-1 and MMP-9), which are relevant for tumor development, were also reduced. Our study demonstrated that incretin drugs may reduce cancer cell proliferation and dissemination potential, hence limiting the risk of metastasis in epithelial ovarian cancer.

Childhood body mass index in relation to subsequent risk of type 1 diabetes-A Danish cohort study.

The incidence of type 1 diabetes (T1D) is increasing, and obesity may be a contributing factor by increasing the risk and accelerating the onset. We investigated the relation between childhood body mass index z-scores (BMIz) and the later risk of T1D, including association with age at onset of T1D. The study included 238 cases and 10 147 controls selected from the Copenhagen School Health Record Register (CSHRR). Cases of T1D were identified in the Danish Registry of Childhood and Adolescent Diabetes and 2 regional studies and linked to CSHRR. Using conditional logistic regression models, the association of childhood prediagnostic BMIz at 7 and 13 years of age and changes between these ages with subsequent risk (odds ratio, OR) of T1D was estimated. A greater BMIz at 7 and 13 years of age was associated with increased risk of T1D with OR of 1.23 (confidence interval, CI 1.09-1.37; P = .0001) and 1.20 (CI 1.04-1.40; P = .016), respectively. The risk was increased by upward changes in z-scores from birth to 7 years (OR=1.21, P = .003) and from 7 to 13 years of age (OR=1.95, P = .023), but in the latter age interval also by a decline in BMIz (OR = 1.91, P = .034). There were no associations between BMIz at 7 and 13 years of age and the age of onset (P = .34 and P = .42, respectively). Increased BMIz is associated with a moderate increase in risk of T1D, but with no relation to age at onset within the analyzed age range. Increased BMIz over time is unlikely to explain the rising incidence of T1D.

Thinking About Theta: An Analysis of Time Decay, Early Unwind and Closeout Feedback Effects

Near-the-money options experience a rapid decline in time value over the weeks leading up to the expiry date. A possible strategy to alleviate the impact of the time decay effect is to unwind the hedge prior to expiry. However, appreciable time value is present for a reason: it is an indication that the final expiry value the option is uncertain and that there is a chance that the option could increase further in value. In this work, historical data is examined in order to determine whether or not a South African equity index exhibits any abnormal behaviour prior to expiry that would affect one’s view on the likelihood of a hedge expiring in-the-money. We present the results of analyses for two types of expiry-related effect in the local market, namely abnormal returns for periods immediately prior to expiry and price clustering where the underlying exhibits a higher probability of closing near a strike price on an expiry date. We also discuss the historical performance of a strategy aimed at reducing exposure to time decay in a systematic manner in which a derivative strategy is rolled well before the expiry date. It is shown that for the period analysed, an investor who wished to roll a hedge every 3 months achieved an appreciable increase in realised return for a moderate increase in risk by rolling a longer term option every 3 months compared to holding a 3 month option for the full term.

Germline whole exome sequencing and large-scale replication identifies FANCM as a likely high grade serous ovarian cancer susceptibility gene.

We analyzed whole exome sequencing data in germline DNA from 412 high grade serous ovarian cancer (HGSOC) cases from The Cancer Genome Atlas Project and identified 5,517 genes harboring a predicted deleterious germline coding mutation in at least one HGSOC case. Gene-set enrichment analysis showed enrichment for genes involved in DNA repair (p = 1.8×10-3). Twelve DNA repair genes - APEX1, APLF, ATX, EME1, FANCL, FANCM, MAD2L2, PARP2, PARP3, POLN, RAD54L and SMUG1 – were prioritized for targeted sequencing in up to 3,107 HGSOC cases, 1,491 cases of other epithelial ovarian cancer (EOC) subtypes and 3,368 unaffected controls of European origin. We estimated mutation prevalence for each gene and tested for associations with disease risk. Mutations were identified in both cases and controls in all genes except MAD2L2, where we found no evidence of mutations in controls. In FANCM we observed a higher mutation frequency in HGSOC cases compared to controls (29/3,107 cases, 0.96 percent; 13/3,368 controls, 0.38 percent; P=0.008) with little evidence for association with other subtypes (6/1,491, 0.40 percent; P=0.82). The relative risk of HGSOC associated with deleterious FANCM mutations was estimated to be 2.5 (95% CI 1.3 – 5.0; P=0.006). In summary, whole exome sequencing of EOC cases with large-scale replication in case-control studies has identified FANCM as a likely novel susceptibility gene for HGSOC, with mutations associated with a moderate increase in risk. These data may have clinical implications for risk prediction and prevention approaches for high-grade serous ovarian cancer in the future and a significant impact on reducing disease mortality.

Issue Highlights

Issue Highlights

Use of Statins and the Risk of Incident Diabetes: A Retrospective Cohort Study.

Even though several landmark statin trials have demonstrated the beneficial effects of statin therapy in both primary and secondary prevention of cardiovascular disease, several studies have suggested that statins are associated with a moderate increase in risk of new-onset diabetes. These observations prompted the US FDA to revise statin labels to include a warning of an increased risk of incident diabetes mellitus as a result of increases in glycosylated hemoglobin (HbA1c) and fasting plasma glucose. However, few studies have used US-based data to investigate this statin-associated increased risk of diabetes. The primary objective of our study was to examine whether the use of statins increases the risk of incident diabetes mellitus using data from the Thomson Reuters MarketScan (®) Commercial Claims and Encounters Database. This study was a retrospective cohort analysis utilizing data for the period 2003-2004. The study population included new statin users aged 20-63years at index who did not have a history of diabetes. The proportion (3.4%) of statin users (N=53,212) who had incident diabetes was higher than the proportion (1.2%) of non-statin users (N=53,212) who had incident diabetes. Compared with no statin use and controlling for demographic and clinical covariates, statin use was significantly associated with increased risk of incident diabetes (hazard ratio 2.01; 99% confidence interval 1.74-2.33; p<0.0001). In addition, risk of diabetes was highest among users of lovastatin, atorvastatin, simvastatin, and fluvastatin. Diabetes risk was lowest among pravastatin and rosuvastatin users. Because the potential for diabetogenicity differs among different statin types, healthcare professionals should individualize statin therapy by identifying patients who would benefit more from less diabetogenic statin types.

Biologic Therapies and Risk of Infection and Malignancy in Patients With Inflammatory Bowel Disease: A Systematic Review and Network Meta-analysis.

Safety issues are a major concern for patients considering treatments for inflammatory bowel disease (IBD). We performed a systematic review and meta-analysis to determine whether biologic agents affect the risk of infection or malignancy in adults with IBD. We searched PubMed, Embase, Scopus, Cochrane IBD Group Specialized Trials Register, World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov through March 2016 for randomized placebo-controlled or head-to-head trials of biologic agents approved for treatment of adults with IBD (ie, adalimumab, certolizumab, golimumab, infliximab, natalizumab, or vedolizumab). Two reviewers independently extracted study data and outcomes (serious infections, opportunistic infections, tuberculosis, any infection, and malignancies) and rated each trial's risk of bias. We used conventional meta-analysis to synthesize direct evidence and a network meta-analysis for adjusted indirect treatment comparisons. We identified 49 randomized placebo-controlled studies comprising 14,590 participants. Synthesis of the evidence indicated that patients treated with biologics had a moderate increase in risk of any infection (odds ratio [OR], 1.19; 95% confidence interval [CI], 1.10-1.29) and a significant increase in risk of opportunistic infections (OR, 1.90; 95% CI, 1.21-3.01). Risk ofserious infections was not increased in patients treated with biologics (OR, 0.89; 95% CI, 0.71-1.12). On the contrary, biologics appeared to significantly reducerisk of serious infections in studies with low risk of bias (OR, 0.56; 95% CI, 0.35-0.90). We did not find an increased risk of malignancy with use of biologic agents (OR, 0.90; 95% CI, 0.54-1.50), but data were insufficient in terms of exposure and follow-up times. None of the indirect comparisons, either among the individual agents or between the anti-tumor necrosis factor and anti-integrin classes, reached significance for any of the outcomes analyzed. On the basis of a systematic review and meta-analysis, biologic agents increase the risk of opportunistic infections in patients with IBD, but not the risk of serious infections. It is necessary to continue to monitor the comparative and long-term safety profiles of these drugs.

PDB15 - USE OF STATINS AND THE RISK OF INCIDENT DIABETES: A RETROSPECTIVE COHORT STUDY

Even though several landmark statin trials have demonstrated the beneficial effects of statin therapy in both primary and secondary prevention of cardiovascular disease, several studies have suggested that statins are associated with a moderate increase in risk of new-onset diabetes. These observations prompted the US FDA to revise statin labels to include a warning of an increased risk of incident diabetes mellitus as a result of increases in glycosylated hemoglobin (HbA1c) and fasting plasma glucose. However, few studies have used US-based data to investigate this statin-associated increased risk of diabetes. The primary objective of our study was to examine whether the use of statins increases the risk of incident diabetes mellitus using data from the Thomson Reuters MarketScan ® Commercial Claims and Encounters Database. This study was a retrospective cohort analysis utilizing data for the period 2003–2004. The study population included new statin users aged 20–63 years at index who did not have a history of diabetes. The proportion (3.4 %) of statin users (N = 53,212) who had incident diabetes was higher than the proportion (1.2 %) of non-statin users (N = 53,212) who had incident diabetes. Compared with no statin use and controlling for demographic and clinical covariates, statin use was significantly associated with increased risk of incident diabetes (hazard ratio 2.01; 99 % confidence interval 1.74–2.33; p < 0.0001). In addition, risk of diabetes was highest among users of lovastatin, atorvastatin, simvastatin, and fluvastatin. Diabetes risk was lowest among pravastatin and rosuvastatin users. Because the potential for diabetogenicity differs among different statin types, healthcare professionals should individualize statin therapy by identifying patients who would benefit more from less diabetogenic statin types.

Atrial fibrillation and risk of stroke: a nationwide cohort study.

Although the relation between stroke risk factors and stroke in patients with atrial fibrillation (AF) has been extensively examined, only few studies have explored the association of AF and the risk of ischaemic stroke/systemic thromboembolism/transient ischaemic attack (stroke/TE/TIA) in the presence of concomitant stroke risk factors. From nationwide registries, all persons who turned 50, 60, 70, or 80 from 1997 to 2011 were identified. Persons receiving warfarin were excluded. The absolute risk of stroke/TE/TIA was reported for a 5-year period, as was the absolute risk ratios for AF vs. no AF according to prior stroke and the number of additional risk factors. The study cohort comprised of 3 076 355 persons without AF and 48 189 with AF. For men aged 50 years, with no risk factors, the 5-year risk of stroke was 1.1% (95% confidence interval 1.1-1.1); with AF alone 2.5% (1.8-3.2); with one risk factor and no prior stroke or AF 2.5% (2.3-2.7); and with one factor, no prior stroke and AF 2.9% (1.4-4.3). In men aged 50 years with prior stroke as the only risk factor, 5-year risk was 10.2% (9.1-11.3). In men aged 70 years, the corresponding risks were 4.8% (4.7-4.9), 6.8% (5.7-7.9), 6.6% (6.3-6.8), 8.7 (7.4-9.9), and 19.1% (18.1-20.1), respectively. In women aged 50 years, the risk was of 0.7% (0.7-0.7), 2.1% (0.9-3.2), 1.6% (1.4-1.8), 4.1% (0.6-7.6), and 7.2% (6.3-8.2), respectively, and in women aged 70 years 3.4% (3.3-3.5), 8.2% (7.0-9.5), 4.6% (4.4-4.8), 9.1% (7.5-10.6), and 15.4% (14.5-16.4), respectively. Stroke/TE/TIA risk was particularly increased when prior stroke/TE/TIA was present. Atrial fibrillation is associated with an increase in risk of stroke/TE/TIA in the absence of other risk factors but only a moderate increase in risk when other risk factors are present.

Abortion, substance abuse and mental health in early adulthood: Thirteen-year longitudinal evidence from the United States.

Objective:To examine the links between pregnancy outcomes (birth, abortion, or involuntary pregnancy loss) and mental health outcomes for US women during the transition into adulthood to determine the extent of increased risk, if any, associated with exposure to induced abortion.Method:Panel data on pregnancy history and mental health history for a nationally representative cohort of 8005 women at (average) ages 15, 22, and 28 years from the National Longitudinal Study of Adolescent to Adult Health were examined for risk of depression, anxiety, suicidal ideation, alcohol abuse, drug abuse, cannabis abuse, and nicotine dependence by pregnancy outcome (birth, abortion, and involuntary pregnancy loss). Risk ratios were estimated for time-dynamic outcomes from population-averaged longitudinal logistic and Poisson regression models.Results:After extensive adjustment for confounding, other pregnancy outcomes, and sociodemographic differences, abortion was consistently associated with increased risk of mental health disorder. Overall risk was elevated 45% (risk ratio, 1.45; 95% confidence interval, 1.30–1.62; p < 0.0001). Risk of mental health disorder with pregnancy loss was mixed, but also elevated 24% (risk ratio, 1.24; 95% confidence interval, 1.13–1.37; p < 0.0001) overall. Birth was weakly associated with reduced mental disorders. One-eleventh (8.7%; 95% confidence interval, 6.0–11.3) of the prevalence of mental disorders examined over the period were attributable to abortion.Conclusion:Evidence from the United States confirms previous findings from Norway and New Zealand that, unlike other pregnancy outcomes, abortion is consistently associated with a moderate increase in risk of mental health disorders during late adolescence and early adulthood.

Active and passive smoking and risk of breast cancer: a meta-analysis.

Studies on active and passive tobacco smoking and breast cancer have found inconsistent results. A meta-analysis of observational studies on tobacco smoking and breast cancer occurrence was conducted based on systematic searches for studies with retrospective (case-control) and prospective (cohort) designs. Eligible studies were identified, and relative risk measurements were extracted for active and passive tobacco exposures. Random-effects meta-analyses were used to compute summary relative risks (SRR). Heterogeneity of results between studies was evaluated using the (I (2)) statistics. For ever active smoking, in 27 prospective studies, the SRR for breast cancer was 1.10 (95% CI [1.09-1.12]) with no heterogeneity (I (2)=0%). In 44 retrospective studies, the SRR was 1.08 (95% CI [1.02-1.14]) with high heterogeneity (I (2)=59%). SRRs for current active smoking were 1.13 (95% CI [1.09-1.17]) in 27 prospective studies and 1.08 (95% CI [0.97-1.20]) in 22 retrospective studies. The results were stable across different subgroup analyses, notably pre/post-menopause, alcohol consumption adjustments, including/excluding passive smokers from the referent group. For ever passive smoking, in 11 prospective studies, the SRR for breast cancer was 1.07 (95% CI [1.02-1.13]) with no heterogeneity (I (2)=1%). In 20 retrospective studies, the SRR was 1.30 (95% CI [1.10-1.54]) with high heterogeneity (I (2)=74%). Too few prospective studies were available for meaningful subgroup analyses. There is consistent evidence for a moderate increase in the risk of breast cancer in women who smoke tobacco. The evidence for a moderate increase in risk with passive smoking is more substantial than a few years ago.

Smoking, smoking cessation, and 7-year mortality in a cohort of Thai adults.

BackgroundSmoking is a strong risk factor for mortality in both the developed and the developing world. However, there is still limited research to examine the impact of smoking cessation and mortality in middle-income Southeast Asian populations.MethodsWe use longitudinal data from a large Thai cohort of adult Open University students residing nationwide, linked with official death records to assess the association of smoking status and mortality risks during a 7-year follow-up. The log-rank test was used to evaluate the statistical probability of differential survival according to baseline smoking status. Multivariate hazard ratios (HR) were reported for smoking status and all-cause and cause-specific mortality.ResultsFrom 2005 baseline to 2012, current smokers were more likely to die than cohort members who ceased smoking and never smokers (1.9 vs 1.3 vs 0.6 %, p < 0.05). The hazard of all-cause mortality increased with the daily amount of cigarette consumption among both current and former smokers. Cause of death analyses showed that current male smokers had a significantly increased risk of cardiovascular disease related mortality (HR 3.9 [95 % CI 1.8–8.1]). Former male smokers had a moderate increase in risk of dying from cardiovascular diseases compared to never smokers (HR 1.6 [95 % CI 0.7–3.4]). Current male smokers between 2005 and 2009 experienced highest subsequent mortality hazards during the period 2009–2012 compared to never smokers (HR 2.1 [95 % CI 1.4–3.4]). The higher risk of dying reduced if people quit smoking during the 2005–2009 follow-up period (HR 1.5 [95 % CI 0.7–3.3]). Risk for mortality fell even further among long-term quitters (HR 1.4 [95 % CI 0.9–2.2]).ConclusionAmong a large nationwide cohort of Thai adults, current smokers were at a significantly and substantially higher risk of all-cause mortality, especially cardiovascular-related mortality. The higher risk of dying fell if people quit smoking and the risk for mortality was even lower among long-term quitters. Promotion of smoking cessation will contribute substantially to the reduction in avoidable mortality in Thailand.