Incretin-based drugs and risk of lung cancer among individuals with type 2 diabetes.

AIM: To assess whether dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists are associated with an increased lung cancer risk among individuals with type 2 diabetes. METHODS: We conducted a population-based cohort study using the UK Clinical Practice Research Datalink. We identified 130 340 individuals newly treated with antidiabetes drugs between January 2007 and March 2017, with follow-up until March 2018. We used a time-varying approach to model use of dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists compared with use of other second- or third-line antidiabetes drugs. We used Cox proportional hazards models to estimate the adjusted hazard ratios, with 95% CIs, of incident lung cancer associated with use of dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists, separately, by cumulative duration of use, and by time since initiation. RESULTS: A total of 790 individuals were newly diagnosed with lung cancer (median follow-up 4.6 years, incidence rate 1.5/1000 person-years, 95% CI 1.4-1.6). Compared with use of second-/third-line drugs, use of dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists was not associated with an increased lung cancer risk (hazard ratio 1.07, 95% CI 0.87-1.32, and hazard ratio 1.02, 95% CI 0.68-1.54, respectively). There was no evidence of duration-response relationships. CONCLUSIONS: In individuals with type 2 diabetes, use of incretin-based drugs was not associated with increased lung cancer risk.

Obstetric haemorrhage and risk of cardiovascular disease after three decades: a population-based cohort study.

OBJECTIVE: To investigate the association between obstetric haemorrhage and cardiovascular disease up to three decades after pregnancy. DESIGN: Population-based cohort study. SETTING AND POPULATION: All women who delivered between 1989 and 2016 in Quebec, Canada. METHODS: Using hospital admissions data, 1 224 975 women were followed from their first delivery until March 2018. The main exposure measures were antenatal (placenta praevia, placental abruption, peripartum haemorrhage) or postpartum haemorrhage, with or without transfusion. Adjusted Cox regression models were used to assess the association between obstetric haemorrhage and future cardiovascular disease. MAIN OUTCOME MEASURE: Cardiovascular hospitalisation. RESULTS: Among 104 291 (8.5%) women with haemorrhage, 4612 (4.4%) required transfusion. Women with haemorrhage had a higher incidence of cardiovascular hospitalisation than women without haemorrhage (15.5 versus 14.1 per 10 000 person-years; 2437 versus 28 432 events). Risk of cardiovascular hospitalisation was higher for obstetric haemorrhage, with or without transfusion, compared with no haemorrhage (adjusted hazard ratio [aHR] 1.06, 95% CI 1.02-1.10). Women with haemorrhage and transfusion had a substantially greater risk of cardiovascular hospitalisation (aHR 1.47, 95% CI 1.23-1.76). Among transfused women, placental abruption (aHR 1.79, 95% CI 1.06-3.00) and postpartum haemorrhage (aHR 1.38, 95% CI 1.13-1.68) were both associated with risk of cardiovascular hospitalisation. Antenatal haemorrhage with transfusion was associated with 2.46 times the risk of cardiovascular hospitalisation at 5 years (95% CI 1.59-3.80) and 2.14 times the risk at 10 years (95% CI 1.47-3.12). CONCLUSIONS: Obstetric haemorrhage requiring transfusion is associated with maternal cardiovascular disease. The benefit of cardiovascular risk prevention in pregnant women with obstetric haemorrhage requires further investigation. TWEETABLE ABSTRACT: Risk of future cardiovascular disease is increased for women with obstetric haemorrhage who require transfusion.

A systematic review of observational studies of the association between pioglitazone use and bladder cancer.

AIM: To conduct a systematic review of all observational studies on the effect of pioglitazone on the risk of bladder cancer. METHODS: The MEDLINE and EMBASE databases were queried for papers published between 1 January 2000 and 30 October 2017. We took into consideration observational studies (both retrospective and prospective) that included participants with Type 2 diabetes prescribed anti-hyperglycaemic drugs. RESULTS: While some studies reported an association, others did not, and meta-analyses of these studies showed a significantly increased risk; however, while meta-analysis is a powerful and practical statistical tool, its results should be considered with caution when applied to widely heterogeneous studies. We describe how many of these studies are affected by different types of bias, most notably time-related biases, which should preclude a pooled analysis that would result in biased estimation of the risk. CONCLUSIONS: Given existing data, it is not appropriate to pool the outcomes of highly heterogeneous studies and further rigorously conducted observational research is needed to clarify the role of pioglitazone use on the incidence of bladder cancer.

Probabilistic Multiple-Bias Modeling Applied to the Canadian Data From the Interphone Study of Mobile Phone Use and Risk of Glioma, Meningioma, Acoustic Neuroma, and Parotid Gland Tumors.

We undertook a re-analysis of the Canadian data from the 13-country case-control Interphone Study (2001-2004), in which researchers evaluated the associations of mobile phone use with the risks of brain, acoustic neuroma, and parotid gland tumors. In the main publication of the multinational Interphone Study, investigators concluded that biases and errors prevented a causal interpretation. We applied a probabilistic multiple-bias model to address possible biases simultaneously, using validation data from billing records and nonparticipant questionnaires as information on recall error and selective participation. In our modeling, we sought to adjust for these sources of uncertainty and to facilitate interpretation. For glioma, when comparing those in the highest quartile of use (>558 lifetime hours) to those who were not regular users, the odds ratio was 2.0 (95% confidence interval: 1.2, 3.4). After adjustment for selection and recall biases, the odds ratio was 2.2 (95% limits: 1.3, 4.1). There was little evidence of an increase in the risk of meningioma, acoustic neuroma, or parotid gland tumors in relation to mobile phone use. Adjustments for selection and recall biases did not materially affect interpretation in our results from Canadian data.

A cautionary note about estimating effects of secondary exposures in cohort studies.

Cohort studies are often enriched for a primary exposure of interest to improve cost-effectiveness, which presents analytical challenges not commonly discussed in epidemiology. In this paper, we use causal diagrams to represent exposure-enriched cohort studies, illustrate a scenario wherein the risk ratio for the effect of a secondary exposure on an outcome is biased, and propose an analytical method for correcting for such bias. In our motivating example, maternal smoking (Z) is a cause of fetal growth restriction (X), which subsequently affects preterm birth (Y) (i.e., Z → X → Y); strong positive associations exist between both Z, X and X, Y; and enrichment for X increases its prevalence from 10% to 50%. In the X-enriched cohort, unadjusted and X-adjusted analyses lead to bias in the risk ratio for the total effect of Z on Y. After application of inverse probability weights, the bias is corrected, with a small loss of efficiency in comparison with a same-sized study without X-enrichment. With increasing interest in conducting secondary analyses to reduce research costs, caution should be employed when analyzing studies that have already been enriched, intentionally or unintentionally, for a primary exposure of interest. Causal diagrams can help identify scenarios in which secondary analyses may be biased. Inverse probability weights can be used to remove the bias.

Fetal death and preterm birth associated with maternal influenza vaccination: systematic review.

BACKGROUND: Before 2012, few studies had addressed pregnancy outcomes following maternal influenza vaccination; however, the number of publications on this topic has increased recently. OBJECTIVES: To review comparative studies evaluating fetal death or preterm birth associated with influenza vaccination during pregnancy. SEARCH STRATEGY: We searched bibliographic databases from inception to April 2014. SELECTION CRITERIA: Experimental or observational studies assessing the relationship between influenza vaccination during pregnancy and fetal death or preterm birth. DATA COLLECTION AND ANALYSIS: Two reviewers independently abstracted data from studies meeting the inclusion criteria. MAIN RESULTS: We included one randomised clinical trial and 26 observational studies. Meta-analyses were not considered appropriate because of high clinical and statistical heterogeneity. Three studies of fetal death at any gestational age reported adjusted effect estimates in the range 0.56-0.79, and four of five studies of fetal death at <20 weeks reported adjusted estimates between 0.89 and 1.23, all with confidence intervals including 1.0. Adjusted effect estimates for four of five studies of fetal death at ≥20 weeks ranged from 0.44 to 0.77 (two with confidence intervals not crossing 1.0), whereas a fifth reported a non-significant effect in the opposite direction. Among 19 studies of preterm birth, there was no strong evidence suggesting any increased risk, and meta-regression did not explain the moderate between-study heterogeneity (I(2) = 57%). AUTHORS' CONCLUSIONS: Most studies reported no association between fetal death or preterm birth and influenza vaccination during pregnancy. Although several reported risk reductions, results may be biased by methodological shortcomings of observational studies of influenza vaccine effectiveness.

Small-for-gestational-age birth and maternal plasma antioxidant levels in mid-gestation: a nested case-control study.

OBJECTIVE: To assess whether maternal plasma antioxidant levels in mid-pregnancy are associated with small-for-gestational-age (SGA) birth. DESIGN: Case-control study nested within a population-based cohort study. SETTING: Four hospitals in Montreal, Canada. POPULATION: Pregnant women recruited before 24 weeks of gestation, whose pregnancies were not complicated by pre-eclampsia or preterm delivery. METHODS: Blood samples were obtained at 24-26 weeks and assayed for nutritionally derived antioxidant levels in SGA cases (n = 324) and randomly selected controls with birthweights between the 25th and 75th centiles (n = 672). We performed logistic regression analyses using the standardised z-score of each antioxidant as the main independent variable, after summing highly correlated antioxidants or combining via principle component analysis. We adjusted for risk factors for SGA that were associated with antioxidant levels. MAIN OUTCOME MEASURES: SGA, birthweight <10th centile for gestational age and sex. RESULTS: Retinol was positively associated with risk of SGA (adjusted odds ratio [OR] 1.41; 95% confidence interval [95% CI] 1.22-1.63, per SD increase). Carotenoids (log of the sum of ß-carotene, lutein/zeaxanthin, α- and ß-cryptoxanthin) were negatively associated with SGA (adjusted OR 0.64; 95% CI 0.54-0.78, per SD increase). We found no significant associations between SGA and lycopene or any of the forms of vitamin E assessed, including α-tocopherol, corrected α-tocopherol (per nmol/l of low-density lipoprotein articles), or γ-tocopherol. CONCLUSIONS: Elevated retinol may be associated with an increased risk of SGA, whereas elevated carotenoid levels may reduce the risk. A better understanding of the nature of these associations is required, however, before recommending specific nutritional interventions in an attempt to prevent SGA birth.

Impact of HLA mismatch at first kidney transplant on lifetime with graft function in young recipients.

As HLA matching has been progressively de-emphasized in the American deceased donor (DD) kidney allocation algorithm, concerns have been raised that poor matching at first transplant may lead to greater sensitization and more difficulty finding an acceptable donor for a second transplant should the first transplant fail. We compared proportion of total observed lifetime with graft function after first transplant, and waiting times for a second transplant between individuals with different levels of HLA mismatch (MM) at first transplant. We studied patients recorded in the United States Renal Data System (1988-2009) who received a first DD transplant at age ≤21 years (n = 8433), and the subgroup who were listed for a second DD transplant following first graft failure (n = 2498). Compared with recipients of 2-3 MM first grafts, 4-6 MM graft recipients spent 12% less of their time and 0-1 MM recipients 15% more time with a functioning graft after the first transplant (both p < 0.0001); 4-6 MM recipients were significantly less likely (hazard ratio [HR] 0.87 [95% confidence interval 0.76, 0.98]; p = 0.03), and 0-1 MM recipients more likely (HR 1.26 [0.99, 1.60]; p = 0.06) to receive a second transplant after listing. The benefits of better HLA matching at first transplant on lifetime with graft function are significant, but relatively small.

Measuring antimicrobial use in hospitalized patients: a systematic review of available measures applicable to paediatrics.

OBJECTIVES: The optimal measure to use for surveillance of antimicrobial usage in hospital settings, especially when including paediatric populations, is unknown. This systematic review of literature aims to list, define and compare existing measures of antimicrobial use that have been applied in settings that included paediatric inpatients, to complement surveillance of resistance. METHODS: We identified cohort studies and repeated point-prevalence studies presenting data on antimicrobial use in populations of inpatients or validations/comparisons of antimicrobial measures through a systematic search of literature using MEDLINE, EMBASE, CINAHL and LILACS (1975-2011) and citation tracking. Study populations needed to include hospitalized paediatric patients. Two reviewers independently extracted data on study characteristics and results. RESULTS: Overall, 3878 records were screened and 79 studies met selection criteria. Twenty-six distinct measures were found, the most frequently used being defined daily doses (DDD)/patient-days and exposed patients/patients. Only two studies compared different measures quantitatively, showing (i) a positive correlation between proportion of exposed patients and antimicrobial-days/patient-days and (ii) a strong correlation between doses/patient-days and agent-days/patient-days (r = 0.98), with doses/patient-days correlating more with resistance rates (r = 0.80 versus 0.55). CONCLUSIONS: The measure of antimicrobial use that best predicts antimicrobial resistance prevalence and rates, for surveillance purposes, has still not been identified; additional evidence on this topic is a necessity.

Neurodevelopmental disorders in children born to mothers with systemic lupus erythematosus.

Children born to women with systemic lupus erythematosus seem to have a potentially increased risk of neurodevelopmental disorders compared to children born to healthy women. Recent experimental data suggest in utero exposure to maternal antibodies and cytokines as important risk factors for neurodevelopmental disorders. Interestingly, women with systemic lupus erythematosus display high levels of autoantibodies and cytokines, which have been shown, in animal models, to alter fetal brain development and induce behavioral anomalies in offspring. Furthermore, subjects with systemic lupus erythematosus and neurodevelopmental disorders share a common genetic predisposition, which could impair the fetal immune response to in utero immunologic insults. Moreover, systemic lupus erythematosus pregnancies are at increased risk of adverse obstetrical outcomes and medication exposures, which have been implicated as potential risk factors for neurodevelopmental disorders. In this article, we review the current state of knowledge on neurodevelopmental disorders and their potential determinants in systemic lupus erythematosus offspring.

Change in mortality risk over time in young kidney transplant recipients.

Mortality risk for kidney transplant recipients may change with increasing accumulated exposure to the "transplantation milieu." We sought to characterize changes over time in mortality rate and in age-, sex- and race-standardized mortality ratios (SMR) relative to the general population, and to estimate the association between increasing time since first transplant and mortality risk. A total of 18 911 patients who received a first transplant at <21 years old (1983-2006), and whose data were recorded in the USRDS, were studied. There were 2713 deaths over a median follow-up of 8.9 (interquartile range 4.0-14.5; maximum 23) years. Among those with graft function, mortality was highest in the first post transplant year; beyond the first year of the first transplant, age-adjusted mortality rates and SMRs decreased slightly over follow-up. Cause of death was cardiovascular for 34.6%, infection for 19.5%, malignancy for 5.8%, other for 21.4% and unknown for 18.7%. For every 1-year time increment after the end of the first post transplant year, age-adjusted all-cause and cardiovascular mortality rates fell by 1% (p = 0.06) and 16% (p = 0.007), respectively; infection-related mortality rate did not change over time (p = 0.5). These results suggest that exposure to the transplantation milieu has no cumulative negative effects on cardiovascular health over the long term.

Direct inoculation of Mycobacterium avium subspecies Paratuberculosis into ileocecal Peyer's patches results in colonization of the intestine in a calf model.

The objective of this study was to develop an intestinal model of Mycobacterium avium subspecies paratuberculosis (Map) infection in the calf for evaluation of mucosal pathology and local and systemic immunologic responses. Map was inoculated into Peyer's patches of young calves using a right flank surgical approach in standing calves to exteriorize the ileocecal junction. Inoculum doses ranging from 10(3) to 10(9) colony-forming units of strain K10 Map were injected through the serosal surface into Peyer's patches of the distal ileum near the ileocecal valve. Fecal samples were collected for culture from each calf weekly until termination of the study. Calves were necropsied at 7, 30, 60, and 90 days after infection, when inoculation sites, lymph nodes, spleen, and peripheral blood were collected for evaluation. Ileocecal lymph nodes were consistently colonized by Map in the 10(5) to 10(9) groups. The ileocecal valve was also colonized in 10(7) and 10(9) groups. This correlated with fecal culture results as infected calves intermittently shed Map in their feces throughout the study. Granulomatous lesions with giant cells and acid-fast bacilli at the ileocecal junction, ileocecal lymph nodes, and lamina propria of high-dose animals (10(7) and 10(9)) were identified from each time point. Flow cytometry was used to detect antigen-specific production of interferon-γ and interleukin-4 locally (ileocecal lymph node) and systemically (peripheral blood mononuclear cells), which defined distinct immunologic profiles in low-dose and high-dose calves. This study demonstrates intestinal Map infection via Peyer's patch inoculation, a novel model with many shared features of natural Map infection.

Cytokine response modifier A (CrmA) inhibits ceramide formation in response to tumor necrosis factor (TNF)-alpha: CrmA and Bcl-2 target distinct components in the apoptotic pathway.

Proteases are now firmly established as major regulators of the "execution" phase of apoptosis. Here, we examine the role of proteases and their relationship to ceramide, a proposed mediator of apoptosis, in the tumor necrosis factor-alpha (TNF-alpha)-induced pathway of cell death. Ceramide induced activation of prICE, the protease that cleaves the death substrate poly(ADP-ribose) polymerase. Bcl-2 inhibited ceramide-induced death, but not ceramide generation. In contrast, Cytokine response modifier A (CrmA), a potent inhibitor of Interleukin-1 beta converting enzyme and related proteases, inhibited ceramide generation and prevented TNF-alpha-induced death. Exogenous ceramide could overcome the CrmA block to cell death, but not the Bcl-2 block. CrmA, however, did not inhibit the activation of nuclear factor (NF)-kappa B by TNF-alpha, demonstrating that other signaling functions of TNF-alpha remain intact and that ceramide does not play a role in the activation of NF-kappa B. These studies support a distinct role for proteases in the signaling/activation phase of apoptosis acting upstream of ceramide formation.

Automated use of WHONET and SaTScan to detect outbreaks of Shigella spp. using antimicrobial resistance phenotypes.

Antimicrobial resistance is a priority emerging public health threat, and the ability to detect promptly outbreaks caused by resistant pathogens is critical for resistance containment and disease control efforts. We describe and evaluate the use of an electronic laboratory data system (WHONET) and a space-time permutation scan statistic for semi-automated disease outbreak detection. In collaboration with WHONET-Argentina, the national network for surveillance of antimicrobial resistance, we applied the system to the detection of local and regional outbreaks of Shigella spp. We searched for clusters on the basis of genus, species, and resistance phenotype and identified 19 statistical 'events' in a 12-month period. Of the six known outbreaks reported to the Ministry of Health, four had good or suggestive agreement with SaTScan-detected events. The most discriminating analyses were those involving resistance phenotypes. Electronic laboratory-based disease surveillance incorporating statistical cluster detection methods can enhance infectious disease outbreak detection and response.

Influence of ultrasound-to-delivery interval and maternal-fetal characteristics on validity of estimated fetal weight.

OBJECTIVES: To explore the effects of ultrasound-to-delivery interval and maternal-fetal characteristics on the distribution of measurement error in estimated fetal weights (EFWs), and to determine the predictive ability of EFW for diagnosis of small-for-gestational age (SGA) and large-for-gestational age (LGA) among infants delivered within 1 day of an ultrasound examination. METHODS: Percentage differences between EFW and birth weights were calculated in 3697 pregnancies. Linear regression was used to compare the accuracy of EFW for births on each of the 6 days after an ultrasound scan with the accuracy observed among births on the same day. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value for diagnosis of SGA and LGA according to EFW was assessed. RESULTS: The mean +/- SD percentage difference among deliveries within 1 day of the last ultrasound scan was 0.2 +/- 9.0%. Mean percentage differences were not significantly different from day 0 on days 1, 2 and 3; however, combining the data from these 4 days obscured a slight bias towards an overestimation of weight evident on day 0 and day 1. Among deliveries within 1 day of an ultrasound scan, the PPV was 61% for SGA diagnosis and 54% for LGA diagnosis. CONCLUSION: Combining data from births > 1 day after the last ultrasound examination may lead to a false conclusion that there is systematic underestimation of weight. EFW tended to underestimate the weight of macrosomic fetuses and overestimate that of small fetuses which limited sensitivity and PPV. Maternal-fetal characteristics are weak predictors of individual errors in EFW.

The low prevalence of allergic disease in Eastern Europe: are risk factors consistent with the hygiene hypothesis?

BACKGROUND: The prevalence of allergic disease is known to be low in Eastern Europe. OBJECTIVE: To assess the association of suspected risk factors, including several closely linked to the hygiene hypothesis, with allergic symptoms and atopic sensitization in young school-aged children. METHODS: Observational study of 13 889 Belarusian children followed up at age 6.5 years in the Promotion of Breastfeeding Intervention Trial (PROBIT). Allergic symptoms and diseases were based on parental responses to the International Study of Asthma and Allergy in Childhood questionnaire, and prick tests to five common inhalant allergens were performed using standard methods. RESULTS: Significantly increased risks of wheezing and hayfever symptoms in the past 12 months, and of recurrent itchy rash were observed in boys, children with a positive first-degree family atopic history, and those who had received probiotics (especially as prophylaxis with antibiotic use). Pet ownership, contact with farm animals, the presence and number of younger and (especially) older siblings, and residency in rural areas of Western Belarus were associated with reduced risks. Maternal postnatal smoking was associated with wheezing and hayfever symptoms, while the duration of exclusive breastfeeding was not protective against any of the studied outcomes. The risk factors for allergic symptoms were similar in children with positive skin-prick tests to those in the overall cohort. CONCLUSION: Many of the risk and protective factors we identified are consistent with those reported in Western countries and with the hygiene hypothesis. Further research on dietary and other environmental and genetic factors is necessary to understand the low prevalence of allergic disease in Belarus and other Eastern European countries.

Using encounters versus episodes in syndromic surveillance.

BACKGROUND: Automated electronic medical records may be useful for syndromic surveillance to quickly detect infectious disease outbreaks. Some syndromic surveillance systems include every encounter in the analysis, whereas others exclude individuals' repeat encounters within the same syndrome occurring within a short period of time, with the rationale that these represent follow-up visits rather than new episodes of illness. METHODS: We evaluate the effect of keeping all encounters as compared with removing repeat encounters. Using the prospective space-time permutation scan statistic, we performed daily analyses on all encounters versus on episodes defined as encounters new within 2, 6 or 12 weeks. Data were taken from a Massachusetts Health Maintenance Organization (HMO) for the calendar year 1999 for four different syndromes. RESULTS: We found extensive disagreement in the number of signals detected: 70, 68, 21 and 15 signals when using all encounters versus 15-20, 3, 4-5 and 0 signals when using only new episodes for lower respiratory, lower gastrointestinal, upper gastrointestinal and neurologic syndromes, respectively. CONCLUSION: Using all encounters in syndromic surveillance may not only create too many signals but may also miss some signals by masking the anomalies generated by actual episodes. However, it is also possible to miss signals when using episodes.

Customised birthweight percentiles: does adjusting for maternal characteristics matter?

OBJECTIVE: The objective of this study was to determine whether the improved prediction of risk for perinatal mortality obtained with the use of a customised birthweight standard can also be obtained with the use of a non-customised but intrauterine-based standard. DESIGN: Population-based cohort study. SETTING: Sweden. POPULATION: Births in the Swedish Medical Birth Register between 1992 and 2001 (n = 782 303) with complete data on birthweight, gestational age, sex, maternal age, pre-pregnancy body mass index, height, parity, and ethnicity. METHODS: We calculated the relative risks (RRs) of stillbirth and early neonatal mortality among small-for-gestational-age (SGA) births as established by (1) a customised standard, (2) a population standard based on birthweights, and (3) a population standard based on a best estimate of intrauterine weights. MAIN OUTCOME MEASURES: Stillbirth and early neonatal mortality (<7 days). RESULTS: The RRs of stillbirth and early neonatal mortality among SGA births as classified by the intrauterine standard were similar to those among SGA births as classified by the customised standard and much higher than those among SGA births as classified by the birthweight standard. CONCLUSIONS: A non-customised but intrauterine-based standard has a similar ability to predict risk for stillbirth and early neonatal mortality as a customised birthweight standard. The process of customising population weight-for-gestational-age standards to account for maternal characteristics does little to improve prediction of perinatal mortality.