Evidence Of Statistical Heterogeneity Research Articles

Mosquito control exposures and breast cancer risk: analysis of 1071 cases and 2096 controls from the Ghana Breast Health Study

Epidemiologic data on insecticide exposures and breast cancer risk are inconclusive and mostly from high-income countries. Using data from 1071 invasive pathologically confirmed breast cancer cases and 2096 controls from the Ghana Breast Health Study conducted from 2013 to 2015, we investigated associations with mosquito control products to reduce the spread of mosquito-borne diseases, such as malaria. These mosquito control products were insecticide-treated nets, mosquito coils, repellent room sprays, and skin creams for personal protection against mosquitos. Multivariable and polytomous logistic regression models were used to estimate odds ratios (ORadj) and 95% confidence intervals (CI) with breast cancer risk-adjusted for potential confounders and known risk factors. Among controls, the reported use of mosquito control products were mosquito coils (65%), followed by insecticide-treated nets (56%), repellent room sprays (53%), and repellent skin creams (15%). Compared to a referent group of participants unexposed to mosquito control products, there was no significant association between breast cancer risk and mosquito coils. There was an association in breast cancer risk with reported use of insecticide-treated nets; however, that association was weak and not statistically significant. Participants who reported using repellent sprays were at elevated risks compared to women who did not use any mosquito control products, even after adjustment for all other mosquito control products (OR = 1.42, 95% CI=1.15–1.75). We had limited power to detect an association with repellent skin creams. Although only a few participants reported using repellent room sprays weekly/daily or < month-monthly, no trends were evident with increased frequency of use of repellent sprays, and there was no statistical evidence of heterogeneity by estrogen receptor (ER) status (p-het > 0.25). Our analysis was limited when determining if an association existed with repellent skin creams; therefore, we cannot conclude an association. We found limited evidence of risk associations with widely used mosquito coils and insecticide-treated nets, which are reassuring given their importance for malaria prevention. Our findings regarding specific breast cancer risk associations, specifically those observed between repellent sprays, require further study.

Clinical Outcomes of Enzalutamide in Metastatic Hormone-sensitive Prostate Cancer in Patients Aged

BackgroundIn ARCHES, treatment intensification of androgen deprivation therapy (ADT) with enzalutamide versus placebo improved clinical outcomes in metastatic hormone-sensitive prostate cancer (mHSPC). Understanding the benefits and tolerability of enzalutamide for men aged ≥75 yr may inform disease management. ObjectiveTo determine whether age is associated with clinical outcomes in mHSPC.Design, setting, and participants: A post hoc analysis of the multinational, double-blind, randomized, placebo-controlled, phase 3 ARCHES trial in 1150 men with mHSPC (median follow-up [mo]: <75 yr, 44.6; ≥75 yr, 44.3) was performed.Intervention: Randomization 1:1 to enzalutamide (160 mg/d) plus ADT or placebo plus ADT; stratification by disease volume and prior docetaxel use.Outcome measurements and statistical analysis: Overall survival (OS), radiographic progression-free survival (rPFS), safety, and other secondary endpoints were compared between age groups (<75 and ≥75 yr) and treatment arms (Cox proportional hazard models). Resultsand limitations: Men aged <75 versus ≥75 yr had longer OS (enzalutamide plus ADT: hazard ratio [HR] 0.66; 95% confidence interval [CI] 0.47–0.91; p = 0.02; placebo plus ADT: HR 0.81; 95% CI 0.60–1.09; p = 0.13) and rPFS (enzalutamide plus ADT: HR 0.78; 95% CI 0.58–1.04; p = 0.12; placebo plus ADT: HR 0.98; 95% CI 0.74–1.30; p = 0.007). Enzalutamide improved OS (<75 yr: HR 0.61; 95% CI 0.47–0.79; ≥75 yr: HR 0.76; 95% CI 0.54–1.09) and secondary efficacy endpoints without evidence of statistical heterogeneity, and was generally well tolerated in both age groups, with minimal quality-of-life impact. Older versus younger patients experienced more frequent dose interruptions (20.2% vs 10.9%) and treatment-emergent adverse events (95.2% vs 89.1%). Post hoc examination and small sample size preclude definitive conclusions. ConclusionsEnzalutamide plus ADT improved efficacy outcomes and was generally well tolerated despite shorter treatment exposure in older patients, indicating enzalutamide’s utility in patients with mHSPC aged <75 and ≥75 yr. Patient summaryEnzalutamide is a drug approved to treat men with prostate cancer. In this report, we compared patients aged <75 and ≥75 yr treated with enzalutamide plus androgen deprivation therapy, to determine whether age affected how long they lived without the cancer spreading to other parts of their body. We found that, although younger patients had more favorable survival outcomes, enzalutamide was associated with longer survival and reduced disease spread in both age groups.

The Impact of Hypoalbuminemia on Postoperative Complications in Patients Undergoing Shoulder Arthroplasty: A Meta-Analysis.

The objective of this meta-analysis was to investigate the association between hypoalbuminemia and postoperative complications in patients undergoing shoulder arthroplasty. This meta-analysis study was registered in PROSPERO (CRD42023442466) and adhered to the PRISMA guidelines. Studies focused on shoulder arthroplasty that compared hypoalbuminemia and normal albumin levels were included. A systematic literature search was conducted in PubMed, EMBASE, Scopus, and the Cochrane Collaboration database. Seven comparative studies were included, and odds ratios with a 95% confidence interval were calculated for the dichotomous variables. A fixed-effect model was used when there was no statistical evidence of heterogeneity, and a random-effect model was used when significant heterogeneity was observed. Review Manager 5.4 software was used for data analysis. The meta-analysis included a total of 20,290 patients from seven studies. Hypoalbuminemia was significantly associated with a higher risk of readmissions (OR 2.92, 95%CI 1.74 to 4.91), reoperations (OR 3.23, 95%CI 1.98 to 5.27), an increase in hospital stay duration (MD 1.59, 95%CI 0.86 to 2.32), and complications such as death (OR 5.75, 95% CI 2.98 to 11.08; studies = 4), thromboembolic events (OR 2.43, 95% CI 1.46 to 4.06; studies = 4), cardiac events (OR 2.78, 95% CI 1.07 to 7.24; studies = 3), pulmonary infections (OR 3.09, 95% CI 1.54 to 6.20; studies = 3), systemic infections (OR 2.19, 95% CI 1.51 to 3.16; studies = 3), and transfusions (OR 3.16, 95% CI 2.23 to 4.48; studies = 2). However, there was no significant association between hypoalbuminemia and renal complications, surgical site infections, urinary tract infections, wound problems, or cardiovascular events. This meta-analysis provides strong evidence that hypoalbuminemia is associated with a higher risk of postoperative complications in patients undergoing shoulder arthroplasty.

Therapy with direct oral anticoagulants for secondary prevention of thromboembolic events in the antiphospholipid syndrome: a systematic review and meta-analysis of randomised trials

ObjectiveAntiphospholipid syndrome (APS) is a systemic autoimmune disorder characterised by venous thrombosis (VT) or arterial thrombosis (AT) and/or pregnancy morbidity and the presence of antiphospholipid antibodies. Direct oral anticoagulants (DOACs)...

A Systematic Review and Meta-analysis of Rituximab-Associated Infections Among Children and Adolescents With Glomerular Disease: Focus on the Risk of Infections.

This systematic review and meta-analysis aimed to explore rituximab (RTX) associated infectious complications in children with glomerular disease. We performed an electronic search of PubMed, International Scientific Information (ISI), Scopus, and EMBASE between January 2010 and July 2021. Infection rates and total drug-related adverse events were the outcomes. Statistical heterogeneity was evaluated by using the I2 statistic. When there was statistical evidence of heterogeneity (I2 > 50%, p > 0.1), a random-effect model was adopted. Data analysis was performed with Stata17.0 software. A total of 7 studies with 668 patients (136 with lupus nephritis [LN] and 532 with nephrotic syndrome were included in the meta-analysis. The pooled risk ratio showed that the administration of RTX was significantly associated with lower risk of infectious complications in patients with LN and nephrotic syndrome (0.72 [95% CI 0.58, 0.85]) when compared with population data of patients without glomerular disease (p = 0.2). There was no significant difference between the LN and nephrotic syndrome groups in terms of total serious adverse events or the occurrence of infections. There was significant heterogeneity among the reported studies (Q = 42.39, p < 0.001, I2 = 81%). Administration of RTX in children with glomerular disease is associated with a lower rate of infections when compared with population data of patients without LN or nephrotic syndrome. Additional high-quality randomized controlled trials with long-term follow-up are needed to identify the long-term potential complications. Trial registration PROPERO ID: CRD42021274869 (https://www.crd.york.ac/prospero/display_record.php?).

The effect of systemic iron status on osteoarthritis: A mendelian randomization study.

Objective: To assess the causal effect of systemic iron status by using four biomarkers (serum iron; transferrin saturation; ferritin; total iron-binding capacity) on knee osteoarthritis (OA), hip OA, total knee replacement, and total hip replacement using 2-sample Mendelian randomization (MR) design. Methods: Three instrument sets were used to construct the genetic instruments for the iron status: Liberal instruments (variants associated with one of the iron biomarkers), sensitivity instruments (liberal instruments exclude variants associated with potential confounders), and conservative instruments (variants associated with all four iron biomarkers). Summary-level data for four OA phenotypes, including knee OA, hip OA, total knee replacement, and total hip replacement were obtained from the largest genome-wide meta-analysis with 826,690 individuals. Inverse-variance weighted based on the random-effect model as the main approach was conducted. Weighted median, MR-Egger, and Mendelian randomization pleiotropy residual sum and outlier methods were used as sensitivity MR approaches. Results: Based on liberal instruments, genetically predicted serum iron and transferrin saturation were significantly associated with hip OA and total hip replacement, but not with knee OA and total knee replacement. Statistical evidence of heterogeneity across the MR estimates indicated that mutation rs1800562 was the SNP significantly associated with hip OA in serum iron (odds ratio, OR = 1.48), transferrin saturation (OR = 1.57), ferritin (OR = 2.24), and total-iron binding capacity (OR = 0.79), and hip replacement in serum iron (OR = 1.45), transferrin saturation (OR = 1.25), ferritin (OR = 1.37), and total-iron binding capacity (OR = 0.80). Conclusion: Our study suggests that high iron status might be a causal factor of hip OA and total hip replacement where rs1800562 is the main contributor.

MRI for collateral assessment pre-thrombectomy and association with outcome: a systematic review and meta-analysis

PurposeVarious neuroimaging methods exist to assess the collateral circulation in stroke patients but much of the evidence is based on computed tomography. Our aim was to review the evidence for using magnetic resonance imaging for collateral status evaluation pre-thrombectomy and assess the impact of these methods on functional independence.MethodsWe systematically reviewed EMBASE and MEDLINE for studies that evaluated baseline collaterals using MRI pre-thrombectomy and conducted a meta-analysis to express the relationship between good collaterals (defined variably as the presence [good] vs absence [poor] or quality [ordinal scores binarized as good-moderate vs poor] of collaterals) and functional independence (modified Rankin score mRS≤2) at 90 days. Outcome data were presented as relative risk (RR, 95% confidence interval, 95%CI). We assessed for study heterogeneity, publication bias, and conducted subgroup analyses of different MRI methods and affected arterial territories.ResultsFrom 497 studies identified, we included 24 (1957 patients) for the qualitative synthesis, and 6 (479 patients) for the metanalysis. Good pre-thrombectomy collaterals were significantly associated with favorable outcome at 90 days (RR=1.91, 95%CI=1.36–2.68], p= 0.0002) with no difference between MRI methods and affected arterial territory subgroups. There was no evidence of statistical heterogeneity (I2=25%) among studies but there was evidence of publication bias.ConclusionIn stroke patients treated with thrombectomy, good pre-treatment collaterals assessed using MRI are associated with double the rate of functional independence. However, we found evidence that relevant MR methods are heterogenous and under-reported. Greater standardization and clinical validation of MRI for collateral evaluation pre-thrombectomy are required.

Outcomes in Ankle Fracture Surgery: A Systematic Review and Meta-Analysis of Fibular Intramedullary Nail Fixation vs Open Reduction and Internal Fixation in Randomized Controlled Trials

Category: Trauma; Ankle; Ankle Arthritis; Diabetes Introduction/Purpose: What level I evidence exists to support the use of FNF for surgical management of ankle fractures in high risk patients? The purpose of this study was to compare clinical outcomes following fibular intramedullary nail fixation (FNF) and open reduction and internal fixation (ORIF) of ankle fractures. Methods: A systematic review of the current literature was performed according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Certainty of evidence reported according to GRADE (Grading of Recommendations Assessment, Development, and Evaluation). Our primary hypothesis was that patients undergoing FNF procedures to manage an ankle fracture would have significantly higher patient reported outcome scores (PROs) than patients undergoing ORIF. Primary study outcome measures were validated PROs. Secondary outcome measures included complication rate, secondary surgery rate, and bony union. Results: The primary outcome analysis revealed no evidence of a significant effect difference on Olerud and Molander Ankle Score (OMAS) PRO and no evidence of statistical heterogeneity. Secondary outcome analysis revealed a significant 0.30 (0.12-0.74 95CI) relative risk reduction for complications in FNF (P=0.008). No evidence of an effect difference for bony union. No evidence of reporting bias was appreciated. Sensitivity analyses did not significantly alter effect estimates. Conclusion: The quality of evidence is reasonably strong and likely sufficient to conclude: (1) there is likely no clinically important difference between FNF and ORIF up to 12 months post-operatively, as defined by OMS (moderate certainty); (2) surgeons may reasonably expect reduced complications in 14 out of every 100 patients treated with FNF (moderate certainty); (3) there is likely no difference in bony union (low certainty). Future studies should investigate more patient-centered outcomes and if short-term findings are durable over time if these findings apply to lower risk populations.

Effectiveness of root canal instrumentation for the treatment of apical periodontitis: A systematic review and meta-analysis.

The development of endodontic instruments has rapidly advanced, but their impact on endodontic outcome parameters remains unclear. This systematic review aimed to answer the following PICOT questions: In patients with apical periodontitis (P) what is the effectiveness of root canal instrumentation ([Q1] performed with contemporary techniques [I] in comparison with 'traditional' techniques [C]] and ([Q2] performed with contemporary engine-driven NiTi instruments [I] compared with other types of contemporary engine-driven NiTi instruments [with different design and/or technology] [C]) in terms of clinical and patient-related outcomes (O)? After PROSPERO protocol registration, a literature search was conducted using Clarivate Analytics' Web of Science, Scopus, PubMed and Cochrane Central Register of Controlled Trials. Grey literature and major journal contents were examined. Two independent reviewers performed the study selection, data extraction and appraisal of included studies. A quantitative meta-analysis was considered, and statistical heterogeneity and overall quality of evidence were assessed. Nine studies were identified showing substantial methodological differences. Five studies addressed PICOT 1 and three PICOT 2, whereas one study aimed both. A random-effects meta-analysis model was considered for the outcome 'radiographic evidence of normal periodontal ligament space or reduction of apical lesion size' (PICOT 1) based on three studies with 332 evaluable participants and showed that contemporary instrumentation was associated with a more favourable outcome (p=.005) compared with root canal preparation with stainless steel instruments (odds ratio=2.07 [95%-confidence interval=1.25-3.44]) with no evidence of statistical heterogeneity (I2 = 0%) but low quality of evidence. Albeit a few studies fulfilled eligible criteria, no study had a low risk of bias. Compelling evidence indicating significantly different outcome rates using different endodontic instruments when treating teeth with apical periodontitis is lacking. In terms of healing, the results of the meta-analysis determined the higher effectiveness of root canal instrumentation performed with contemporary techniques in comparison with conventional stainless steel instruments in patients with apical periodontitis followed for a minimum of 1year with low quality of evidence. No differences could be demonstrated between preparations with traditional stainless steel and contemporary NiTi instruments for other clinical and patient-related outcomes. PROSPERO (CRD42021274642).

870-P: Newer Glucose-Lowering Drugs and Risk of Dementia: A Meta-analysis of Cardiovascular Outcome Trials

Background: Existing observational studies yielded mixed results between cognitive and dementia outcomes and newer glucose-lowering drugs (GLDs) , i.e., dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1RAs) , and sodium-glucose co-transporter-2 (SGLT2) inhibitors, while individual randomized trials have inadequate power to examine such an effect. Thus, we aimed to evaluate the effect of these newer GLDs on the risk of dementia by performing a meta-analysis of randomized outcome trials. Methods: We included published randomized placebo-controlled cardiovascular and renal outcome trials that evaluated DPP-4 inhibitors, GLP-1RAs, and SGLT2 inhibitors and reported dementia events. The study outcomes were all-cause dementia and vascular dementia, extracted from clinicaltrials.gov. We calculated pooled odds ratios (OR) and 95% CIs using the Peto method. Results: We included 21 trials involving 1all-cause dementia cases (including 22 vascular dementia cases) among 167,5patients with or without type 2 diabetes over a median follow-up of 2.2 years. Neither DPP-4 inhibitors (OR, 0.65 [0.33-1.29]) , GLP-1RAs (OR, 0.88 [0.51-1.52]) , or SGLT2 inhibitors (OR, 1.22 [0.54-2.74]) were significantly associated with all-cause dementia incidence. For vascular dementia, compared with placebo, SGLT2 inhibitors were significantly associated with a decreased risk (OR, 0.[0.02-0.66]) , while DPP-4 inhibitors (OR, 0.67 [0.12-3.85]) and GLP-1RAs (OR, 0.37 [0.12-1.14]) did not significantly decrease the risk. No evidence of statistical heterogeneity or publication bias was detected in the meta-analysis (p &amp;gt;0.05) . Conclusion: SGLT2 inhibitors may have a beneficial effect on lowering the vascular dementia risk, thus may be a drug repurposing signal. Nevertheless, future randomized controlled trials and/or comparative effectiveness studies using real-world data are warranted to further confirm our conclusion. Disclosure H.Tang: None. S.Niu: None. J.D.Brown: None. J.Wei: None. A.G.Winterstein: Consultant; Genentech, Inc., Research Support; Merck &amp; Co., Inc. J.Bian: None. J.Guo: None.

Clinical outcomes and safety of enzalutamide (ENZA) plus androgen-deprivation therapy (ADT) in metastatic hormone-sensitive prostate cancer (mHSPC) in patients aged &lt; 75 and ≥ 75 years: ARCHES post hoc analysis.

5069 Background: Patients with metastatic prostate cancer aged ≥75 years have a poorer prognosis compared with younger patients. In ARCHES (NCT02677896), ENZA + ADT improved radiographic progression-free survival (rPFS), overall survival (OS), and other key secondary endpoints vs. placebo (PBO) + ADT in patients with mHSPC. Final OS results confirmed a long-term survival benefit with ENZA + ADT. This post hoc analysis of ARCHES data investigated OS and other clinical outcomes in patients aged &lt;75 and ≥75 years. Methods: Patients with mHSPC (n=1150) were randomized 1:1 to ENZA (160 mg/day) + ADT or PBO + ADT, stratified by disease volume and prior docetaxel use. Subgroup analysis was performed in patients aged &lt;75 and ≥75 years. Efficacy and safety outcomes were compared across treatment arms. Results: Of the ARCHES population, 339 patients (29.5%) were aged ≥75 years (ENZA + ADT, n=170; PBO + ADT, n=169); PBO patients crossing over to ENZA were aged: &lt;75 years, n=133; ≥75 years, n=47. Some differences in baseline characteristics were observed between age groups, such as higher prior docetaxel use in patients aged &lt;75 years (ENZA + ADT, 21.0%; PBO + ADT, 20.4%) vs. those aged ≥75 years (ENZA + ADT, 10.6%; PBO + ADT, 11.2%). When compared to PBO + ADT, ENZA + ADT improved OS and other secondary efficacy endpoints in both age groups without evidence of statistical heterogeneity (Table); however, 95% confidence intervals for OS and rPFS hazard ratios spanned 1 in the older age group. The safety profile of treatment arms was generally similar in both age groups, with a higher incidence of falls, cognitive impairment, and cardiovascular events among elderly patients receiving ENZA + ADT vs. PBO + ADT. Conclusions: This post hoc analysis of ARCHES data demonstrated that ENZA + ADT provides clinical benefit and is generally well-tolerated in patients with mHSPC aged ≥75 years, supporting the therapeutic role of ENZA in these patients. Clinical trial information: NCT02677896. [Table: see text]

Body Mass Index and Mammographic Density in a Multiracial and Multiethnic Population-Based Study.

Mammographic density (MD) is strongly associated with breast cancer risk. We examined whether body mass index (BMI) partially explains racial and ethnic variation in MD. We used multivariable Poisson regression to estimate associations between BMI and binary MD [Breast Imaging Reporting and Database System (BI-RADS) A&B versus BI-RADS C&D] among 160,804 women in the Utah mammography cohort. We estimated associations overall and within racial and ethnic subgroups and calculated population attributable risk percents (PAR%). We observed the lowest BMI and highest MD among Asian women, the highest BMI among Native Hawaiian and Pacific Islander women, and the lowest MD among American Indian and Alaska Native (AIAN) and Black women. BMI was inversely associated with MD [RRBMI≥30 vs. BMI<25 = 0.43; 95% confidence interval (CI), 0.42-0.44] in the full cohort, and estimates in all racial and ethnic subgroups were consistent with this strong inverse association. For women less than 45 years of age, although there was statistical evidence of heterogeneity in associations between BMI and MD by race and ethnicity (P = 0.009), magnitudes of association were similar across groups. PAR%s for BMI and MD among women less than 45 years were considerably higher in White women (PAR% = 29.2, 95% CI = 28.4-29.9) compared with all other groups with estimates ranging from PAR%Asain = 17.2%; 95% CI, 8.5 to 25.8 to PAR%Hispanic = 21.5%; 95% CI, 19.4 to 23.6. For women ≥55 years, PAR%s for BMI and MD were highest among AIAN women (PAR% = 37.5; 95% CI, 28.1-46.9). While we observed substantial differences in the distributions of BMI and MD by race and ethnicity, associations between BMI and MD were generally similar across groups. Distributions of BMI and MD may be important contributors to breast cancer disparities.

Comparative efficacy of non-statin lipid-lowering therapies in patients with hypercholesterolemia at increased cardiovascular risk: a network meta-analysis

Objective Network meta-analysis was used to derive estimates of the relative efficacy of inclisiran, evolocumab, alirocumab, bempedoic acid, and ezetimibe in patients with hypercholesterolemia and/or at increased cardiovascular risk due to elevated low-density lipoprotein cholesterol taking maximum tolerated dose statins. Methods Clinical trials published through February 2021 comparing percent change from baseline in low-density lipoprotein cholesterol were identified via a systematic review. Bayesian network meta-analyses were performed for patients with atherosclerotic cardiovascular disease and/or high cardiovascular risk on maximally tolerated statins in the base case, which included 23 trials. Results Results from the base-case analyses demonstrated that inclisiran, evolocumab, and alirocumab provide superior efficacy over placebo, bempedoic acid, and ezetimibe in terms of reduction in low-density lipoprotein cholesterol. Inclisiran was also comparable to alirocumab (mean difference: 0.78% [95% CrI: −8.35, 9.88]) and evolocumab (8.16%, [95% CrI: −1.82, 18.49]). Findings of a scenario which also included trials conducted in patients with heterozygous familial hypercholesterolemia were consistent with the base case. There was evidence of statistical heterogeneity across the included trials, roughly equivalent to variation of 5–10% change in low-density lipoprotein cholesterol, suggesting that any differences between treatments that were greater than 5–10% are generalizable. Conclusions This study provides insight regarding the comparative efficacy of drugs for which no head-to-head trials exist and suggests that inclisiran, alirocumab, and evolocumab are expected to provide similar clinically meaningful improvements in low-density lipoprotein cholesterol in patients with hypercholesterolemia on maximally tolerated statins who are at increased cardiovascular risk.

Association of overweight and obesity with vertebral fractures: a systematic review and meta-analysis.

Over the past decade, there has been increasing interest in exploring the relationship between overweight, obesity and vertebral fractures. Nonetheless, available data from studies on the relationship between overweight, obesity and vertebral fractures remains controversial. A systematic search was performed in the PubMed and Cochrane Library databases. We selected relevant literature by using these keywords: fracture, vertebral fracture, vertebral compression fracture, overweight, obese, obesity. The retrieval mainly collected publicly published observational studies on the correlation between overweight, obesity and vertebral fractures, excluding the literature that did not meet the inclusion criteria. Meta-analysis for the data extracted from all the included literatures was performed by STATA 12.0 to summarize test performance with forest plots and assess the heterogeneity. Ten studies, including 1,024,181 subjects satisfied the predefined eligibility criteria. The results showed that the overweight (25.0≤ body mass index (BMI) ≤29.9 kg/m2) and obesity (BMI ≥30.0kg/m2) were associated with a decreased risk of vertebral fractures, respectively. The pooled RR is 0.86 [95% CI: 0.79, 0.95] and 0.81[95% CI:0.74-0.90] with no evidence of statistical heterogeneity. However, the relationship between overweight/obesity (BMI ≥25 kg/m2) and vertebral fractures is not statistically significant. This study showed that overweight and obesity might decrease the risk of vertebral fractures, respectively. However, we did not observe a significant association between overweight/obesity (BMI≥25 kg/m2) and vertebral fractures.

Greater cardiorespiratory fitness reduces incidence of atrial fibrillation: a meta-analysis

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Atrial Fibrillation (AF) is the most common sustained cardiac arrhythmia affecting 1-2% of the global population, with the prevalence of AF increasing dramatically over the past two decades. Although low levels of cardiorespiratory fitness (CRF) and physical activity are predictive of cardiovascular disease onset and mortality, only recently has this emerged as a potential risk factor for AF. Purpose The aim of this meta-analysis was therefore to quantify the relationship between CRF, measured by a symptom limited exercise stress test, and incident AF. We hypothesised that there would be an inverse relationship between CRF and the incidence of AF. Methods The systematic literature review was conducted using PUBMED, MEDLINE and EMBASE databases, with seven studies meeting the inclusion criteria. A random-effects meta-analysis was then used to compare the multivariate risk estimates of the lowest CRF group from each cohort with the group of the highest CRF. Results Data from 206,925 individuals (55.8% males) was used for analysis with a mean age of 55 ± 2.5 years and a mean follow-up period of 10.3 ± 5 years. The total number of AF events across the studies was 19,913. The overall pooled risk of AF in the high-CRF group versus the low-CRF group showed a significant lower risk of incident AF in those with high-CRF (OR: 0.52, 95% CI, 0.44-0.605, p &amp;lt; 0.001). There was evidence of statistical heterogeneity between the studies (I2 = 81%, p &amp;lt; 0.001). AF incidence rates demonstrated an overall decline in rates across the CRF quartiles from low to high. The mean incidence rate for low-CRF was 21 ± 13.4 compared to 6.9 ± 0.7 per 1000 person-years for the high CRF group (p = 0.03). Conclusion There is an inverse association between a lower CRF and an increased risk of AF, with a higher level of CRF protective against AF. This study highlights that low-CRF may be an additional risk factor for AF along with already other established lifestyle-based risk factors such as obesity and hypertension. Exercise interventions should be promoted as a primary prevention strategy in those at risk of developing AF with known risk factors. Future studies are warranted to identify the mechanism(s) through which improved CRF confers a reduction in AF incidence. Abstract Figure. AF risk between high and low-CRF

Rivaroxaban monotherapy versus combination therapy according to patient risk of stroke and bleeding in atrial fibrillation and stable coronary disease: AFIRE trial subanalysis

In the AFIRE trial, rivaroxaban monotherapy was noninferior to combination therapy with rivaroxaban and an antiplatelet agent for thromboembolic events or death, and superior for major bleeding in patients with atrial fibrillation (AF) and stable coronary artery disease. Little is known about impacts of stroke and bleeding risks on the efficacy and safety of rivaroxaban monotherapy. In this subanalysis of the AFIRE trial, we assessed the risk of stroke and bleeding by the CHADS2, CHA2DS2-VASc, and HAS-BLED scores. The primary efficacy end point was the composite of stroke, systemic embolism, myocardial infarction (MI), unstable angina requiring revascularization, or death from any cause. The primary safety end point was major bleeding defined by the International Society on Thrombosis and Haemostasis. Rivaroxaban monotherapy significantly reduced the primary efficacy and safety end points with no evidence of differential effects by stroke risk (CHADS2, p for interaction = 0.727 for efficacy, 0.395 for safety; CHA2DS2-VASc, p for interaction = 0.740 for efficacy, 0.265 for safety) or bleeding risk (HAS-BLED, p for interaction = 0.581 for efficacy, 0.225 for safety). There was also no evidence of statistical heterogeneity across patient risk categories for other end points; stroke or systemic embolism, ischemic stroke, hemorrhagic stroke, MI, MI or unstable angina, death from any cause, any bleeding, or net adverse clinical events. The advantages of rivaroxaban monotherapy compared with those of combination therapy with respect to all prespecified end points, including thromboembolism, bleeding, and mortality were similar across patients with AF and stable coronary artery disease, irrespective of their risk for stroke and bleeding. UMIN Clinical Trials Registry number, UMIN000016612, and ClinicalTrials.gov number, NCT02642419.

Radiation and Risk of Liver, Biliary Tract, and Pancreatic Cancers among Atomic Bomb Survivors in Hiroshima and Nagasaki: 1958-2009.

The Life Span Study (LSS) of atomic bomb survivors has consistently demonstrated significant excess radiation-related risks of liver cancer since the first cancer incidence report. Here, we present updated information on radiation risks of liver, biliary tract and pancreatic cancers based on 11 additional years of follow-up since the last report, from 1958 to 2009. The current analyses used improved individual radiation doses and accounted for the effects of alcohol consumption, smoking and body mass index. The study participants included 105,444 LSS participants with known individual radiation dose and no known history of cancer at the start of follow-up. Cases were the first primary incident cancers of the liver (including intrahepatic bile duct), biliary tract (gallbladder and other and unspecified parts of biliary tract) or pancreas identified through linkage with population-based cancer registries in Hiroshima and Nagasaki. Poisson regression methods were used to estimate excess relative risks (ERRs) and excess absolute risks (EARs) associated with DS02R1 doses for liver (liver and biliary tract cancers) or pancreas (pancreatic cancer). We identified 2,016 incident liver cancer cases during the follow-up period. Radiation dose was significantly associated with liver cancer risk (ERR per Gy: 0.53, 95% CI: 0.23 to 0.89; EAR per 10,000 person-year Gy: 5.32, 95% CI: 2.49 to 8.51). There was no evidence for curvature in the radiation dose response (P=0.344). ERRs by age-at-exposure categories were significantly increased among those who were exposed at 0-9, 10-19 and 20-29 years, but not significantly increased after age 30 years, although there was no statistical evidence of heterogeneity in these ERRs (P = 0.378). The radiation ERRs were not affected by adjustment for smoking, alcohol consumption or body mass index. As in previously reported studies, radiation dose was not associated with risk of biliary tract cancer (ERR per Gy: -0.02, 95% CI: -0.25 to 0.30). Radiation dose was associated with a nonsignificant increase in pancreatic cancer risk (ERR per Gy: 0.38, 95% CI: <0 to 0.83). The increased risk was statistically significant among women (ERR per Gy: 0.70, 95% CI: 0.12 to 1.45), but not among men.

Smoking, Alcohol, and Biliary Tract Cancer Risk: A Pooling Project of 26 Prospective Studies.

Tobacco and alcohol are well-established risk factors for numerous cancers, yet their relationship to biliary tract cancers remains unclear. We pooled data from 26 prospective studies to evaluate associations of cigarette smoking and alcohol consumption with biliary tract cancer risk. Study-specific hazard ratios (HRs) and 95% confidence intervals (CIs) for associations with smoking and alcohol consumption were calculated. Random-effects meta-analysis produced summary estimates. All statistical tests were two-sided. Over a period of 38369156 person-years of follow-up, 1391 gallbladder, 758 intrahepatic bile duct, 1208 extrahepatic bile duct, and 623 ampulla of Vater cancer cases were identified. Ever, former, and current smoking were associated with increased extrahepatic bile duct and ampulla of Vater cancers risk (eg, current vs never smokers HR = 1.69, 95% CI = 1.34 to 2.13 and 2.22, 95% CI = 1.69 to 2.92, respectively), with dose-response effects for smoking pack-years, duration, and intensity (all Ptrend < .01). Current smoking and smoking intensity were also associated with intrahepatic bile duct cancer (eg, >40 cigarettes per day vs never smokers HR = 2.15, 95 % CI = 1.15 to 4.00; Ptrend = .001). No convincing association was observed between smoking and gallbladder cancer. Alcohol consumption was only associated with intrahepatic bile duct cancer, with increased risk for individuals consuming five or more vs zero drinks per day (HR = 2.35, 95%CI = 1.46 to 3.78; Ptrend = .04). There was evidence of statistical heterogeneity among several cancer sites, particularly between gallbladder cancer and the other biliary tract cancers. Smoking appears to increase the risk of developing all biliary tract cancers except gallbladder cancer. Alcohol may increase the risk of intrahepatic bile duct cancer. Findings highlight etiologic heterogeneity across the biliary tract.

Smoking Cessation Pharmacotherapy Based on Genetically-Informed Biomarkers: What is the Evidence?

Pharmacogenomic studies have used genetic variants to identify smokers likely to respond to pharmacological treatments for smoking cessation. We performed a systematic review and meta-analysis of primary and secondary analyses of trials of smoking cessation pharmacotherapies. Eligible were trials with data on a priori selected single nucleotide polymorphisms, replicated non-single nucleotide polymorphisms, and/or the nicotine metabolite ratio. We estimated the genotype × treatment interaction as the ratio of risk ratios (RRR) for treatment effects across genotype groups. We identified 18 trials (N = 9017 participants), including 40 active (bupropion, nicotine replacement therapy [NRT], varenicline, or combination therapies) versus placebo comparisons and 16 active versus active comparisons. There was statistical evidence of heterogeneity across rs16969968 genotypes in CHRNA5 with regard to both 6-month abstinence and end-of-treatment abstinence in non-Hispanic black smokers and end-of-treatment abstinence in non-Hispanic white smokers. There was also heterogeneity across rs1051730 genotypes in CHRNA3 with regard to end-of-treatment abstinence in non-Hispanic white smokers. There was no clear statistical evidence for other genotype-by-treatment combinations. Compared with placebo, NRT was more effective among non-Hispanic black smokers with rs16969968-GG with regard to both 6-month abstinence (RRR for GG vs. GA or AA, 3.51; 95% confidence interval [CI] = 1.19 to 10.30) and end-of-treatment abstinence (RRR for GG vs. GA or AA, 5.84; 95% CI = 1.89 to 18.10). Among non-Hispanic white smokers, NRT effectiveness relative to placebo was comparable across rs1051730 and rs169969960 genotypes. We did not identify widespread differential effects of smoking cessation pharmacotherapies based on genotype. The quality of the evidence is generally moderate. Although we identified some evidence of genotype × treatment interactions, the vast majority of analyses did not provide evidence of differential treatment response by genotype. Where we find some evidence, these results should be considered preliminary and interpreted with caution because of the small number of contributing trials per genotype comparison, the wide confidence intervals, and the moderate quality of evidence. Prospective trials and individual-patient data meta-analyses accounting for heterogeneity of treatment effects through modeling are needed to assess the clinical utility of genetically informed biomarkers to guide pharmacotherapy choice for smoking cessation.

Genetic data and cognitively defined late-onset Alzheimer\u2019s disease subgroups

Categorizing people with late-onset Alzheimer’s disease into biologically coherent subgroups is important for personalized medicine. We evaluated data from five studies (total n = 4050, of whom 2431 had genome-wide single-nucleotide polymorphism (SNP) data). We assigned people to cognitively defined subgroups on the basis of relative performance in memory, executive functioning, visuospatial functioning, and language at the time of Alzheimer’s disease diagnosis. We compared genotype frequencies for each subgroup to those from cognitively normal elderly controls. We focused on APOE and on SNPs with p < 10−5 and odds ratios more extreme than those previously reported for Alzheimer’s disease (<0.77 or >1.30). There was substantial variation across studies in the proportions of people in each subgroup. In each study, higher proportions of people with isolated substantial relative memory impairment had ≥1 APOE ε4 allele than any other subgroup (overall p = 1.5 × 10−27). Across subgroups, there were 33 novel suggestive loci across the genome with p < 10−5 and an extreme OR compared to controls, of which none had statistical evidence of heterogeneity and 30 had ORs in the same direction across all datasets. These data support the biological coherence of cognitively defined subgroups and nominate novel genetic loci.