Metformin and the risk of endometrial cancer: a case-control analysis

OBJECTIVE To explore the risk of endometrial cancer in relation to metformin and other antidiabetic drugs. METHODS We conducted a case-control analysis to explore the association between use of metformin and other antidiabetic drugs and the risk of endometrial cancer using the UK-based General Practice Research Database (GPRD). Cases were women with an incident diagnosis of endometrial cancer, and up to 6 controls per case were matched in age, sex, calendar time, general practice, and number of years of active history in the GPRD prior to the index date. Odds ratios (ORs) with 95% confidence intervals (95% CI) were calculated and results were adjusted by multivariate logistic regression analyses for BMI, smoking, a recorded diagnosis of diabetes mellitus, and diabetes duration. RESULTS A total of 2554 cases with incident endometrial cancer and 15,324 matched controls were identified. Ever use of metformin compared to never use of metformin was not associated with an altered risk of endometrial cancer (adj. OR 0.86, 95% CI 0.63-1.18). Stratified by exposure duration, neither long-term (≥25 prescriptions) use of metformin (adj. OR 0.79, 95% CI 0.54-1.17), nor long-term use of sulfonylureas (adj. OR 0.96, 95% CI 0.65-1.44), thiazolidinediones (≥15 prescriptions; adj. OR 1.22, 95% CI 0.67-2.21), or insulin (adj. OR 1.05 (0.79-1.82) was associated with the risk of endometrial cancer. CONCLUSION Use of metformin and other antidiabetic drugs were not associated with an altered risk of endometrial cancer.

Exposure to Radio-Frequency Electromagnetic Fields From Broadcast Transmitters and Risk of Childhood Cancer: A Census-based Cohort Study

We investigated the association between exposure to radio-frequency electromagnetic fields (RF-EMFs) from broadcast transmitters and childhood cancer. First, we conducted a time-to-event analysis including children under age 16 years living in Switzerland on December 5, 2000. Follow-up lasted until December 31, 2008. Second, all children living in Switzerland for some time between 1985 and 2008 were included in an incidence density cohort. RF-EMF exposure from broadcast transmitters was modeled. Based on 997 cancer cases, adjusted hazard ratios in the time-to-event analysis for the highest exposure category (>0.2 V/m) as compared with the reference category (<0.05 V/m) were 1.03 (95% confidence interval (CI): 0.74, 1.43) for all cancers, 0.55 (95% CI: 0.26, 1.19) for childhood leukemia, and 1.68 (95% CI: 0.98, 2.91) for childhood central nervous system (CNS) tumors. Results of the incidence density analysis, based on 4,246 cancer cases, were similar for all types of cancer and leukemia but did not indicate a CNS tumor risk (incidence rate ratio = 1.03, 95% CI: 0.73, 1.46). This large census-based cohort study did not suggest an association between predicted RF-EMF exposure from broadcasting and childhood leukemia. Results for CNS tumors were less consistent, but the most comprehensive analysis did not suggest an association.

Site- and species-specific responses of forest growth to climate across the European continent

Aim To evaluate the climate sensitivity of model-based forest productivity estimates using a continental-scale tree-ring network. Location Europe and North Africa (30–70° N, 10° W–40° E). Methods We compiled close to 1000 annually resolved records of radial tree growth for all major European tree species and quantified changes in growth as a function of historical climatic variation. Sites were grouped using a neural network clustering technique to isolate spatiotemporal and species-specific climate response patterns. The resulting empirical climate sensitivities were compared with the sensitivities of net primary production (NPP) estimates derived from the ORCHIDEE-FM and LPJ-wsl dynamic global vegetation models (DGVMs). Results We found coherent biogeographic patterns in climate response that depend upon (1) phylogenetic controls and (2) ambient environmental conditions delineated by latitudinal/elevational location. Temperature controls dominate forest productivity in high-elevation and high-latitude areas whereas moisture sensitive sites are widespread at low elevation in central and southern Europe. DGVM simulations broadly reproduce the empirical patterns, but show less temperature sensitivity in the boreal zone and stronger precipitation sensitivity towards the mid-latitudes. Main conclusions Large-scale forest productivity is driven by monthly to seasonal climate controls, but our results emphasize species-specific growth patterns under comparable environmental conditions. Furthermore, we demonstrate that carry-over effects from the previous growing season can significantly influence tree growth, particularly in areas with harsh climatic conditions – an element not considered in most current-state DGVMs. Model–data discrepancies suggest that the simulated climate sensitivity of NPP will need refinement before carbon-cycle climate feedbacks can be accurately quantified.

Personality dimensions in persons symptomatically at risk of psychosis: pronounced but lacking a characteristic profile

AIM Personality dimensions are frequently abnormal in psychosis. We examined if these abnormalities form a personality profile that is characteristic for patients symptomatically at risk of psychosis. METHODS Four higher order personality dimensions were assessed in 104 at-risk patients, 67 clinical and 97 healthy controls with the 'Dimensional Assessment of Personality Pathology', and analysed by two-step cluster procedure to detect personality profiles. Logistic regression was used to test for predictors of profile assignment. RESULTS Low and high scorers were distinguished by two profiles. Patients were more likely high scorers. The presence of clinically relevant depression, though equally frequent in clinical groups, best predicted high scorers among patients. CONCLUSIONS Though at-risk patients were significantly more often high scorers, this seemed to be a general reflection of the level of psychopathology rather than a group characteristic. Thus, personality dimensions might be of little value for facilitating early detection but might be important to consider in early intervention approaches.

Multicentre validation of the Geneva Risk Score for hospitalised medical patients at risk of venous thromboembolism. Explicit ASsessment of Thromboembolic RIsk and Prophylaxis for Medical PATients in SwitzErland (ESTIMATE).

There is a need to validate risk assessment tools for hospitalised medical patients at risk of venous thromboembolism (VTE). We investigated whether a predefined cut-off of the Geneva Risk Score, as compared to the Padua Prediction Score, accurately distinguishes low-risk from high-risk patients regardless of the use of thromboprophylaxis. In the multicentre, prospective Explicit ASsessment of Thromboembolic RIsk and Prophylaxis for Medical PATients in SwitzErland (ESTIMATE) cohort study, 1,478 hospitalised medical patients were enrolled of whom 637 (43%) did not receive thromboprophylaxis. The primary endpoint was symptomatic VTE or VTE-related death at 90 days. The study is registered at ClinicalTrials.gov, number NCT01277536. According to the Geneva Risk Score, the cumulative rate of the primary endpoint was 3.2% (95% confidence interval [CI] 2.2-4.6%) in 962 high-risk vs 0.6% (95% CI 0.2-1.9%) in 516 low-risk patients (p=0.002); among patients without prophylaxis, this rate was 3.5% vs 0.8% (p=0.029), respectively. In comparison, the Padua Prediction Score yielded a cumulative rate of the primary endpoint of 3.5% (95% CI 2.3-5.3%) in 714 high-risk vs 1.1% (95% CI 0.6-2.3%) in 764 low-risk patients (p=0.002); among patients without prophylaxis, this rate was 3.2% vs 1.5% (p=0.130), respectively. Negative likelihood ratio was 0.28 (95% CI 0.10-0.83) for the Geneva Risk Score and 0.51 (95% CI 0.28-0.93) for the Padua Prediction Score. In conclusion, among hospitalised medical patients, the Geneva Risk Score predicted VTE and VTE-related mortality and compared favourably with the Padua Prediction Score, particularly for its accuracy to identify low-risk patients who do not require thromboprophylaxis.

Subgingival Aggregatibacter actinomycetemcomitans associates with the risk of coronary artery disease

AIM We investigated the association between angiographically verified coronary artery disease (CAD) and subgingival Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Tannerella forsythia and Treponema denticola. MATERIALS AND METHODS The cross-sectional study population (n = 445) comprised 171 (38.4%) patients with Stable CAD, 158 (35.5%) with acute coronary syndrome (ACS) and 116 (26.1%) with no significant CAD (No CAD). All patients participated in clinical and radiological oral health examinations. Pooled subgingival bacterial samples were analysed by checkerboard DNA-DNA hybridization assays. RESULTS In all study groups, the presence of P. gingivalis, T. forsythia and T. denticola indicated a significant (p ≤ 0.001) linear association with the extent of alveolar bone loss (ABL), but A. actinomycetemcomitans did not (p = 0.074). With a threshold level of bacterial cells 1 × 10(5) A. actinomycetemcomitans was significantly more prevalent in the Stable CAD group (42.1%) compared to the No CAD group (30.2%) (p = 0.040). In a multi-adjusted logistic regression analysis using this threshold, A. actinomycetemcomitans positivity associated with Stable CAD (OR 1.83, 95% CI 1.00-3.35, p = 0.049), but its level or levels of other bacteria did not. CONCLUSIONS The presence of subgingival A. actinomycetemcomitans associates with an almost twofold risk of Stable CAD independently of alveolar bone loss.

Poor Reliability between Cochrane Reviewers and Blinded External Reviewers When Applying the Cochrane Risk of Bias Tool in Physical Therapy Trials

OBJECTIVES To test the inter-rater reliability of the RoB tool applied to Physical Therapy (PT) trials by comparing ratings from Cochrane review authors with those of blinded external reviewers. METHODS Randomized controlled trials (RCTs) in PT were identified by searching the Cochrane Database of Systematic Reviews for meta-analysis of PT interventions. RoB assessments were conducted independently by 2 reviewers blinded to the RoB ratings reported in the Cochrane reviews. Data on RoB assessments from Cochrane reviews and other characteristics of reviews and trials were extracted. Consensus assessments between the two reviewers were then compared with the RoB ratings from the Cochrane reviews. Agreement between Cochrane and blinded external reviewers was assessed using weighted kappa (κ). RESULTS In total, 109 trials included in 17 Cochrane reviews were assessed. Inter-rater reliability on the overall RoB assessment between Cochrane review authors and blinded external reviewers was poor (κ  =  0.02, 95%CI: -0.06, 0.06]). Inter-rater reliability on individual domains of the RoB tool was poor (median κ  = 0.19), ranging from κ  =  -0.04 ("Other bias") to κ  =  0.62 ("Sequence generation"). There was also no agreement (κ  =  -0.29, 95%CI: -0.81, 0.35]) in the overall RoB assessment at the meta-analysis level. CONCLUSIONS Risk of bias assessments of RCTs using the RoB tool are not consistent across different research groups. Poor agreement was not only demonstrated at the trial level but also at the meta-analysis level. Results have implications for decision making since different recommendations can be reached depending on the group analyzing the evidence. Improved guidelines to consistently apply the RoB tool and revisions to the tool for different health areas are needed.

Higher Risk of Incident HCV-Coinfections in MSM with a Wide HIV Transmission Bottleneck

BACKGROUND  High-risk sexual behaviors have been suggested as drivers of the recent dramatic increase of sexually-transmitted HCV among HIV-infected men who have sex with men(MSM). METHODS  We assessed the association between the HIV-transmission-bottleneck and the prevalence and incidence of HCV-coinfections in HIV-infected MSM from the Swiss-HIV-Cohort-Study(SHCS). As a proxy for the width of the transmission bottleneck we used the fraction of ambiguous nucleotides in Genotypic-Resistance-Tests(GRTs) from recent HIV-infections. We defined a broad bottleneck as a fraction of ambiguous nucleotides exceeding a previously-established threshold(0.5%). RESULTS  From the SHCS, we identified 671 MSMs with available HCV-serologies and with a HIV-GRT sampled during recent infection. Of those, 161(24.0%) exhibited a broad HIV-transmission-bottleneck, 38(5.7%) had at least one positive HCV test, and 26(3.9%) had an incident HCV infection. Individuals with broad HIV-transmission bottlenecks exhibited a twofold-higher odds of having ever experienced an HCV coinfection(OR[95%CI]=2.2[1.1, 4.3]) and a threefold-higher hazard of an incident HCV infection(HR[95%CI]= 3.0[1.4, 6.6]) than individuals with narrow HIV-transmission-bottlenecks. CONCLUSIONS  Our results indicate that the currently occurring sexual spread of HCV is focused on those MSMs that are prone to exhibit broad HIV-transmission-bottlenecks. This is consistent with an important role of high-risk behavior and mucosal-barrier-impairment in the transmission of HCV among MSM.

Risk of late effects of treatment in children newly diagnosed with standard-risk acute lymphoblastic leukaemia: a report from the Childhood Cancer Survivor Study cohort

BACKGROUND Treatment of patients with paediatric acute lymphoblastic leukaemia has evolved such that the risk of late effects in survivors treated in accordance with contemporary protocols could be different from that noted in those treated decades ago. We aimed to estimate the risk of late effects in children with standard-risk acute lymphoblastic leukaemia treated with contemporary protocols. METHODS We used data from similarly treated members of the Childhood Cancer Survivor Study cohort. The Childhood Cancer Survivor Study is a multicentre, North American study of 5-year survivors of childhood cancer diagnosed between 1970 and 1986. We included cohort members if they were aged 1·0-9·9 years at the time of diagnosis of acute lymphoblastic leukaemia and had received treatment consistent with contemporary standard-risk protocols for acute lymphoblastic leukaemia. We calculated mortality rates and standardised mortality ratios, stratified by sex and survival time, after diagnosis of acute lymphoblastic leukaemia. We calculated standardised incidence ratios and absolute excess risk for subsequent neoplasms with age-specific, sex-specific, and calendar-year-specific rates from the Surveillance, Epidemiology and End Results Program. Outcomes were compared with a sibling cohort and the general US population. FINDINGS We included 556 (13%) of 4329 cohort members treated for acute lymphoblastic leukaemia. Median follow-up of the survivors from 5 years after diagnosis was 18·4 years (range 0·0-33·0). 28 (5%) of 556 participants had died (standardised mortality ratio 3·5, 95% CI 2·3-5·0). 16 (57%) deaths were due to causes other than recurrence of acute lymphoblastic leukaemia. Six (1%) survivors developed a subsequent malignant neoplasm (standardised incidence ratio 2·6, 95% CI 1·0-5·7). 107 participants (95% CI 81-193) in each group would need to be followed-up for 1 year to observe one extra chronic health disorder in the survivor group compared with the sibling group. 415 participants (376-939) in each group would need to be followed-up for 1 year to observe one extra severe, life-threatening, or fatal disorder in the group of survivors. Survivors did not differ from siblings in their educational attainment, rate of marriage, or independent living. INTERPRETATION The prevalence of adverse long-term outcomes in children treated for standard risk acute lymphoblastic leukaemia according to contemporary protocols is low, but regular care from a knowledgeable primary-care practitioner is warranted. FUNDING National Cancer Institute, American Lebanese-Syrian Associated Charities, Swiss Cancer Research.

Childhood Trauma and PTSD symptoms increase the risk of cognitive impairment in a sample of former indetured child laborers in old Age.

A growing body of evidence suggests a link between early childhood trauma, post-traumatic stress disorder (PTSD) and higher risk for dementia in old age. The aim of the present study was to investigate the association between childhood trauma exposure, PTSD and neurocognitive function in a unique cohort of former indentured Swiss child laborers in their late adulthood. To the best of our knowledge this is the first study ever conducted on former indentured child laborers and the first to investigate the relationship between childhood versus adulthood trauma and cognitive function. According to PTSD symptoms and whether they experienced childhood trauma (CT) or adulthood trauma (AT), participants (n = 96) were categorized as belonging to one of four groups: CT/PTSD+, CT/PTSD-, AT/PTSD+, AT/PTSD-. Information on cognitive function was assessed using the Structured Interview for Diagnosis of Dementia of Alzheimer Type, Multi-infarct Dementia and Dementia of other Etiology according to ICD-10 and DSM-III-R, the Mini-Mental State Examination, and a vocabulary test. Depressive symptoms were investigated as a potential mediator for neurocognitive functioning. Individuals screening positively for PTSD symptoms performed worse on all cognitive tasks compared to healthy individuals, independent of whether they reported childhood or adulthood adversity. When controlling for depressive symptoms, the relationship between PTSD symptoms and poor cognitive function became stronger. Overall, results tentatively indicate that PTSD is accompanied by cognitive deficits which appear to be independent of earlier childhood adversity. Our findings suggest that cognitive deficits in old age may be partly a consequence of PTSD or at least be aggravated by it. However, several study limitations need to considered. Consideration of cognitive deficits when treating PTSD patients and victims of lifespan trauma (even without a diagnosis of a psychiatric condition) is crucial. Furthermore, early intervention may prevent long-term deficits in memory function and development of dementia in adulthood.

The influence of sampling design on tree-ring-based quantification of forest growth

Tree-rings offer one of the few possibilities to empirically quantify and reconstruct forest growth dynamics over years to millennia. Contemporaneously with the growing scientific community employing tree-ring parameters, recent research has suggested that commonly applied sampling designs (i.e. how and which trees are selected for dendrochronological sampling) may introduce considerable biases in quantifications of forest responses to environmental change. To date, a systematic assessment of the consequences of sampling design on dendroecological and-climatological conclusions has not yet been performed. Here, we investigate potential biases by sampling a large population of trees and replicating diverse sampling designs. This is achieved by retroactively subsetting the population and specifically testing for biases emerging for climate reconstruction, growth response to climate variability, long-term growth trends, and quantification of forest productivity. We find that commonly applied sampling designs can impart systematic biases of varying magnitude to any type of tree-ring-based investigations, independent of the total number of samples considered. Quantifications of forest growth and productivity are particularly susceptible to biases, whereas growth responses to short-term climate variability are less affected by the choice of sampling design. The world's most frequently applied sampling design, focusing on dominant trees only, can bias absolute growth rates by up to 459% and trends in excess of 200%. Our findings challenge paradigms, where a subset of samples is typically considered to be representative for the entire population. The only two sampling strategies meeting the requirements for all types of investigations are the (i) sampling of all individuals within a fixed area; and (ii) fully randomized selection of trees. This result advertises the consistent implementation of a widely applicable sampling design to simultaneously reduce uncertainties in tree-ring-based quantifications of forest growth and increase the comparability of datasets beyond individual studies, investigators, laboratories, and geographical boundaries.