Moderate Increase In Risk Research Articles

Caesarean delivery and the risk of offspring overweight and obesity over the life course: a systematic review and bias-adjusted meta-analysis.

A causal role of Caesarean delivery (CD) on developing overweight and obesity in the life course of offspring has been postulated. However, the true strength of this association is not clear and the potential for confounding has not been adequately addressed. A systematic review and meta-analysis were conducted to evaluate the strength of this association, this time using a bias-adjusted model in addition to conventional methods. Our search yielded 32 estimates from 14 publications (n = 261,000) for meta-analysis. The pooled analysis of seven estimates (n = 194,463) demonstrated a trend only towards a risk increase (RR = 1.15; 95% CI:0.94, 1.40) in overweight and obesity combined (ow+ob) due to CD in early childhood (0-5 years) and a similar trend was observed for mid-childhood and adolescence (5-18 years). In adulthood, a moderate increase in risk for ow+ob due to CD was observed (n = 30,200) (RR = 1.28; 95% CI 1.02, 1.34). Results for obesity and overweight separately were stronger for obesity and demonstrated a decreasing effect across the three life stages. Conventional methods of analysis suggested less uncertainty than we report and publication bias assessment was strongly suggestive of a bias in favour of positive studies. The current analysis therefore suggests that the small effects seen with CD in this and previous meta-analyses are probably a cumulative consequence of several biases we have outlined, including confounding effect and publication bias.

A Swedish National Prospective and Co-relative Study of School Achievement at Age 16, and Risk for Schizophrenia, Other Nonaffective Psychosis, and Bipolar Illness

While cognitive ability is inversely associated with risk for schizophrenia (SZ), the association is less clear with other nonaffective psychoses (ONAP) and bipolar illness (BPI). Using national Swedish hospital registry data, we examined the prospective relationship between school achievement (SA) and development of SZ, ONAP, and BPI in 1800643 adolescents born 1972-1990. We used Cox proportional hazard and co-relative control models to predict onset of SZ, ONAP, and BPI from standardized SA scores at age 16. The hazard ratio (HRs; and 95% CIs) for first onset of SZ as a function of SA was 0.66 (0.64-0.68) for both sexes. For ONAP, the HRs equaled 0.66 (0.64-0.68) for males and 0.72 (0.70-0.75) for females. For BPI, parallel HRs were 0.81 (0.78-0.84) and 0.71 (0.70-0.73). The association between SA and risk was stronger in the lower vs the higher ranges of SA. In most analyses, moderate increases in risk were observed at the highest levels of SA, with the strongest evidence for females and risk of ONAP. Co-relative control analyses indicated that common genetic or familial-environmental effects only marginally confounded these associations. Consistent with prior studies, these results have 3 major implications for neurodevelopmental models: (1) adolescent cognitive deficits that increase risk are not the result of prodromal changes,( 2) individual specific environmental exposures are largely responsible for the association between low SA and psychosis risk, and (3) neurodevelopmental disturbances (as indicated by low SA) are not unique to SZ but also occur in ONAP and to a lesser degree BPI.

Abstract P4-12-04: Clinical evaluation of multigene testing for hereditary breast and ovarian cancer

Abstract Background: Advances in DNA sequencing technology have fueled the development of multigene panels for hereditary cancer testing. While such assays are potentially both practical and affordable for routine clinical genetic testing, there remains uncertainty regarding their proper application and interpretation. Among the unanswered questions are which patients are appropriate candidates for such expanded testing; what is the likelihood that finding deleterious variants will alter risk assessment and management, and what is the prevalence of variants of unknown significance (VUS) that may create uncertainty for providers and anxiety for patients. Methods: 821 patients who met NCCN guidelines for BRCA1/2 testing for hereditary breast/ovarian cancer (HBOC) were prospectively recruited at two major academic medical centers. These patients received traditional BRCA1/2 tests as part of their clinical care and also were later tested for a panel of 29 known cancer risk genes. This panel also re-tested BRCA1/2. Both sequence changes and deletions/duplications were reported, and the panel-testing laboratory was blind to the earlier results. Panel testing results were validated by comparison with the earlier data or by independent testing using established technologies. Family history information was collected directly by genetic counselors. Results: 13.8% of the patients carried BRCA1 or BRCA2 mutations, with >99% concordance between the traditional and panel results for these two genes. 53 (7.6%) of the BRCA1/2-negative patients carried mutations in other cancer risk genes. Some of these findings confer a high risk for breast/ovarian cancer (e.g. TP53), while others (i.e. CHEK2, BRIP1, PALB2, RAD51C, CDKN2A, ATM, and NBN) confer a moderate increase in risk. 10 of these 55 patients were positive for genes involved in Lynch syndrome (MLH1, MSH2, MSH6, and PMS2), although breast and ovarian cancer are not uniformly accepted as part of this syndrome. 40% of these patients were heterozygous carriers of pathogenic variants in MUTYH, which have a less clear impact on breast/ovarian cancer, although this rate (3%) is higher than the expected carrier frequency in this population. About 60% of patients had one or more VUS in the 29 genes. The rate of VUS was highly gene dependent, with ATM, APC, and PTCH1 providing the largest number. A small but significant subset of patients did not have personal or family histories consistent with the classical presentation of their identified mutation. Nevertheless, a majority of the non-BRCA1/2 findings would have prompted consideration of a management change for the tested patient even considering the personal and family cancer history. Conclusions: Multigene panel testing for hereditary cancer risk assessment increased the yield of findings with potential clinical impact for almost 8% of patients. This is consistent with prior data from our laboratory and others. This study, carried out in a uniform clinical practice setting and with data collected directly by health care providers, provides a representative view of the benefit from such testing in an unselected patient population. Citation Format: Leif Ellisen, Allison Kurian, Stephen Lincoln, Andrea Desmond, Meredith Mills, Kristen Shannon, Michelle Gabree, Michael Anderson, Yuya Kobayashi, Federico Monzon, James Ford. Clinical evaluation of multigene testing for hereditary breast and ovarian cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-12-04.

Genetic association between PER3 genetic polymorphisms and cancer susceptibility: a meta-analysis.

The genes along the circadian pathways control and modulate circadian rhythms essential for the maintenance of physiological homeostasis through self-sustained transcription-translation feedback loops. PER3 (period 3) is a circadian pathway gene and its variants (rs1012477, 4/5-repeat) have frequently been associated with human cancer. The mixed findings, however, make the role of the 2 variants in cancer susceptibility elusive. We aimed in this article to clarify the association of PER3 variants with cancer.We collected genetic data from 8 studies, providing 6149 individuals for rs1012477 and 5241 individuals for 4/5-repeat. Based on the genotype and allele frequency, we chose the fixed-effects model to estimate risk of cancer.Overall analysis did not suggest a global role of rs1012477 in cancer susceptibility. For PER3 4/5-repeat variant, we found a moderate increase in risk of cancer among individuals with the 5-allele compared to individuals with the 4-allele, although this association was not statistically significant (homozygous model: odds ratio [OR] 1.17, 95% confidence interval [CI] 0.81–1.67; recessive model: OR 1.17, 95% CI 0.82–1.67). No substantial heterogeneity was revealed in this analysis.Our meta-analysis provides no evidence supporting a global association of PER3 genetic variants with the incidence of cancer.

The Link between IVF Children and Cancer: What Do We Know So Far?

Most studies on the risk for childhood cancer after in vitro fertilization (IVF) found no increased risk. These studies were, however, underpowered to identify a mild or moderate increase in risk. A large study from Sweden found an about 40% increased cancer risk among IVF children which reached statistical significance. This review summarizes characteristics of women undergoing IVF and their children which could possibly influence childhood cancer risk. No major confounding factor was found but some neonatal characteristics may be intermediaries for the increased risk. Further studies are needed to verify or reject the moderate risk increase. Large materials are needed in order to investigate the contribution of the neonatal morbidity which follows IVF. Some rare tumour forms which have been suggested to occur at an increased rate after IVF also need to be studied further.

Fracture risk in long term care: a systematic review and meta-analysis of prospective observational studies.

BackgroundThe risk factors associated with fractures have been well-characterized in community dwelling populations, but have not been clearly defined in long-term care (LTC) settings. The objective of this review was to identify risk factors for fractures in LTC settings.MethodsWe searched MEDLINE, the Cochrane Library, EMBASE and CINAHL up to June 2014, scanned reference lists of articles and consulted with experts in the field to identify relevant prospective cohort studies that evaluated risk factors associated with fracture incidence in LTC. We included studies that assessed the association between risk factors included in the WHO-Fracture Risk Assessment Tool (FRAX®) or other predictors relevant to LTC (psychotropic medications, cognitive impairment, mobility, and falls). All articles were screened and extracted by two authors. Available data on the association between a given risk factor and fracture incidence were pooled when possible. We used the GRADE criteria to provide a summary of evidence. The GRADE approach defines the quality of a body of evidence as the extent to which one can be confident that an estimate of effect or association is close to the quantity of specific interest.ResultsWe identified 13 prospective cohort studies which examined fracture incidence among LTC residents. Most predictors showed moderate increases in fracture risk, but the quality of the evidence was often low. Moderate quality evidence showed that prior fractures and falls may moderately increase the risk of fractures. Being a woman and cognitive impairment are probably associated with a small increase. The effect of mobility and psychotropic medication use is still uncertain primarily due to the various definitions used in the studies and difficulty summarising the results.ConclusionsIn addition to criteria used in the FRAX assessment tool, such as a previous fracture and female gender, we found that falls and cognitive impairment are also associated with a small to moderate increases in the risk of fractures in LTC. Developing an assessment tool that includes risk factors that are specific to LTC may improve the identification of individuals who can benefit from fracture prevention programs in these settings.

Opinions of Maternity Care Professionals About Integration of Care During Labor for “Moderate Risk” Indications: A Delphi Study in The Netherlands

The percentage of referrals during labor from primary midwife-led care to obstetrician-led care has increased over the past years in The Netherlands. Most women are referred for indications with a moderate increase in risk and are looked after by clinical midwives. This study aims to provide insight into the opinions of maternity care professionals about integration of care and involvement of primary care midwives in the intrapartum care of women with "moderate risk" factors. A Delphi study consisting of three rounds was conducted. A purposively selected heterogenic panel of 50 professionals, including obstetricians, primary care midwives, clinical midwives, and obstetric nurses, answered questions anonymously. Although primary care midwives would like to expand their responsibilities and tasks with respect to "moderate risk" indications, consensus among panel members was only reached concerning prolonged rupture of membranes for which the primary care midwife could remain the caregiver. This study shows that most participants support more integration of care during labor. The lack of consensus among Dutch maternity care professionals with regard to the distribution of responsibilities and tasks for "moderate risk" indications is a challenge. Further studies should explore how to deal with differences in opinions among professionals when integrating maternity care systems.

External Validation of the SEDAN Score for Prediction of Intracerebral Hemorrhage in Stroke Thrombolysis

The SEDAN score is a prediction rule for assessment of the risk of symptomatic intracerebral hemorrhage (SICH) per the European Cooperative Acute Stroke Study (ECASS) II definition in patients with acute ischemic stroke treated with intravenous thrombolysis. We assessed the performance of the score in predicting SICH per the ECASS II and Safe Implementation of Treatments in Stroke Monitoring Study (SITS-MOST) definitions in the SITS-International Stroke Thrombolysis Register (SITS-ISTR). We calculated the SEDAN score in 34 251 patients with complete data, enrolled into the SITS-ISTR. The risk for SICH by both definitions was calculated per score category. Odds ratios for SICH per point increase of the score were obtained using logistic regression. The predictive performance was assessed using area under the curve of the receiver operating characteristic (AUC-ROC). The predictive capability for SICH per ECASS II was moderate at AUC-ROC=0.66. With rising scores, there was a moderate increase in risk for SICH per ECASS II (odds ratio, 1.65 per point; 95% confidence interval, 1.59-1.72; P<0.001), with SICH rates between 1.6% for 0 points and 16.9% for ≥ 5 points, average 5.1%. The predictive capability for SICH per SITS-MOST was weaker, AUC-ROC=0.60, with lower increase per score point (odds ratio, 1.36 per point; 95% confidence interval, 1.28-1.46; P<0.001), and SICH rates between 0.8% for 0 points and 5.4% for ≥ 5 points, average 1.8%. In this very large data set, the predictive and discriminatory performances of the SEDAN score were only moderate for SICH per ECASS II and low for SICH per SITS-Monitoring Study.

Parenting behavior and the risk of becoming a victim and a bully/victim: A meta-analysis study

ObjectiveBeing bullied has adverse effects on children's health. Children's family experiences and parenting behavior before entering school help shape their capacity to adapt and cope at school and have an impact on children's peer relationship, hence it is important to identify how parenting styles and parent–child relationship are related to victimization in order to develop intervention programs to prevent or mitigate victimization in childhood and adolescence. MethodsWe conducted a systematic review of the published literature on parenting behavior and peer victimization using MEDLINE, PsychINFO, Eric and EMBASE from 1970 through the end of December 2012. We included prospective cohort studies and cross-sectional studies that investigated the association between parenting behavior and peer victimization. ResultsBoth victims and those who both bully and are victims (bully/victims) were more likely to be exposed to negative parenting behavior including abuse and neglect and maladaptive parenting. The effects were generally small to moderate for victims (Hedge's g range: 0.10–0.31) but moderate for bully/victims (0.13–0.68). Positive parenting behavior including good communication of parents with the child, warm and affectionate relationship, parental involvement and support, and parental supervision were protective against peer victimization. The protective effects were generally small to moderate for both victims (Hedge's g: range: −0.12 to −0.22) and bully/victims (−0.17 to −0.42). ConclusionsNegative parenting behavior is related to a moderate increase of risk for becoming a bully/victim and small to moderate effects on victim status at school. Intervention programs against bullying should extend their focus beyond schools to include families and start before children enter school.

Migraine, headache and development of metabolic syndrome: An 11-year follow-up in the Nord-Trøndelag Health Study (HUNT)

Migraine with aura is associated with an increased incidence of stroke and cardiovascular disease, but the biological mechanisms are poorly understood. This study examined the incidence of metabolic syndrome and its relationship to migraine with and without aura and to nonmigraine headache. In the population-based the Nord-Trøndelag Health Study (HUNT), 19,895 individuals were followed for the development of metabolic syndrome, with a median follow-up time of 11.3years. Headache diagnoses were based on a validated headache questionnaire, and metabolic syndrome was based on a modified version of the National Cholesterol Education Program’s Adult Treatment Panel (ATP) III criteria, using objective anthropometric measurements and blood biochemistry. Using the Poisson regression model, migraine with aura was associated with an increased risk for developing metabolic syndrome. The effect was modified by smoking, with an adjusted incident risk ratio (IRR) among smokers of 2.10 (95% CI 1.53-2.89) and among nonsmokers of 1.39 (95% CI 1.03-1.86), when compared to headache-free controls. A moderate risk increase was seen for migraine without aura (IRR 1.26, 95% CI 1.12-1.42) and nonmigraine headache (IRR 1.22, 95% CI 1.13-1.32), not modified by smoking. The results suggest that traditional risk factors may be one of the mechanisms through which migraine with aura is linked to an increased risk for cardiovascular disease. A heightened vigilance concerning cardiovascular risk factors in this patient group may be warranted.

Gene polymorphisms, tobacco exposure and oral cancer susceptibility: a study from Gujarat, West India

Polymorphic variability in the enzymes involved in biotransformation of tobacco-related pro-carcinogens plays an important role in modulating oral cancer susceptibility. CYP1A1*2A, CYP1A1*2C, GSTM1 and GSTT1 polymorphisms were determined in 122 oral carcinoma cases and 127 controls from Gujarat, West India using PCR-based methods. The results revealed that the polymorphic variants of CYP1A1 gene did not show association towards oral cancer risk. The GSTM1 and GSTT1 null genotypes were found to be over-represented in patients than controls, suggesting a moderate increase in risk of oral cancer. The oral cancer risk was significantly increased in the patients having either alone or concurrent deletion of GSTM1 and GSTT1. The results also suggested significant association between tobacco habits, especially chewing, variant genotypes of CYP1A1, GSTM1 and GSTT1 and oral cancer risk. Our data have provided evidence that GST polymorphism modified the susceptibility to oral cancer and individuals with variant genotypes of the three genes with tobacco habits are at significant risk of developing oral cancer.

Detecting cancer clusters in a regional population with local cluster tests and Bayesian smoothing methods: a simulation study

BackgroundThere is a rising public and political demand for prospective cancer cluster monitoring. But there is little empirical evidence on the performance of established cluster detection tests under conditions of small and heterogeneous sample sizes and varying spatial scales, such as are the case for most existing population-based cancer registries. Therefore this simulation study aims to evaluate different cluster detection methods, implemented in the open soure environment R, in their ability to identify clusters of lung cancer using real-life data from an epidemiological cancer registry in Germany.MethodsRisk surfaces were constructed with two different spatial cluster types, representing a relative risk of RR = 2.0 or of RR = 4.0, in relation to the overall background incidence of lung cancer, separately for men and women. Lung cancer cases were sampled from this risk surface as geocodes using an inhomogeneous Poisson process. The realisations of the cancer cases were analysed within small spatial (census tracts, N = 1983) and within aggregated large spatial scales (communities, N = 78). Subsequently, they were submitted to the cluster detection methods. The test accuracy for cluster location was determined in terms of detection rates (DR), false-positive (FP) rates and positive predictive values. The Bayesian smoothing models were evaluated using ROC curves.ResultsWith moderate risk increase (RR = 2.0), local cluster tests showed better DR (for both spatial aggregation scales > 0.90) and lower FP rates (both < 0.05) than the Bayesian smoothing methods. When the cluster RR was raised four-fold, the local cluster tests showed better DR with lower FPs only for the small spatial scale. At a large spatial scale, the Bayesian smoothing methods, especially those implementing a spatial neighbourhood, showed a substantially lower FP rate than the cluster tests. However, the risk increases at this scale were mostly diluted by data aggregation.ConclusionHigh resolution spatial scales seem more appropriate as data base for cancer cluster testing and monitoring than the commonly used aggregated scales. We suggest the development of a two-stage approach that combines methods with high detection rates as a first-line screening with methods of higher predictive ability at the second stage.

Risk of Death in Dual-eligible Nursing Home Residents Using Typical or Atypical Antipsychotic Agents

Antipsychotic use among dual-eligible nursing home residents is a concern for cost and safety considerations. To examine the comparative risk of death in dual-eligible elderly nursing home residents using typical and atypical agents. A retrospective cohort design matched on propensity score was used to examine the risk of death due to antipsychotic use among dual-eligible nursing home residents 65 years or older from four states. New typical and atypical users in nursing homes were followed for 6 months after the exposure without any censoring. The risk of death was modeled using the Cox proportional model and the extended Cox hazard model stratified on matched pairs based on propensity score. The unadjusted mortality rate was 18.42% for atypical antipsychotic users and 24.06% for typical antipsychotic users. The Cox proportional-hazards regression model revealed significant increased risk of death [hazard ratio (HR), 1.41; 95% confidence interval (CI), 1.27-1.57] among typical users when compared with atypical users. The extended Cox model, used due to the violation of proportional hazards assumption, revealed that risk of death was nearly twice as great among typical antipsychotic users within 40 days of antipsychotic treatment (HR, 1.81; 95% CI, 1.49-2.18) when compared with atypical users. However, moderate increase in risk (HR, 1.24; 95% CI, 1.09-1.42] was observed for 40-180 days of typical antipsychotic exposure. The use of typical antipsychotic agents was associated with highest risk of all-cause mortality within 40 days of typical antipsychotic use when compared with atypical use, and the risk decreased after 40 days among dual-eligible elderly nursing home residents.

Leukemia in children and youths of the Azuay province, Ecuador: 2000–2010

We mapped leukemia risk among children and youths in the Azuay province, Rio Paute river basin, Ecuador, in 2000–2010, using a Bayesian disease mapping model. We assessed the comprehensiveness of the list of leukemia cases from the Sociedad de Lucha contra el Càncer en el Ecuador (SOLCA) Hospital in Cuenca, the only referral center for oncology in the whole Rio Paute area, by comparison to the Quito cancer registry. Risk of leukemia did not vary significantly by canton within the Azuay province. However, a moderate increase in risk of borderline statistical significance was observed in the city of Cuenca and particularly among males in a heavily industrialized parish, who had an almost eight-fold excess (95% CI 3.03, 20.39, p = 0.01) of AML. Analytical studies are warranted to properly address specific etiological factor of leukemia among children and youths of the Azuay province of Ecuador.

Is Diabetes a Risk Factor for Colorectal Cancer?

Throughout the world, adoption of a Western life style has paralleled an increase in the incidence of both type 2 diabetes mellitus and colorectal cancer. This is perhaps not surprising, as the major environmental determinants for type 2 diabetes, including body mass index (BMI), central obesity, physical inactivity, and Western dietary patterns are remarkably consistent with the constellation of risk factors that have been identified for colorectal cancer. Perhaps what has been less clear is whether diabetes, independent of these other risk factors, influences the risk of colorectal cancer. If so, such a finding would have potential implications for more vigorous lifestyle modification or cancer screening of individuals with type 2 diabetes. Moreover, understanding the mechanistic basis for such an association may provide fresh insights into the pathogenesis of both conditions. A number of early studies reported a higher risk of colon cancer among individuals with diabetes. These studies were limited by small sample size, reliance on death certificates and autopsies for endpoint ascertainment, and inability to control for important confounders including BMI and physical inactivity [1‐4]. As such, it was difficult to determine if the association between diabetes and colorectal cancer was merely a reflection of the greater prevalence of known lifestyle risk factors for cancer among those with diabetes. However, more recent high quality prospective studies have shown a significant, albeit more modest association between diabetes and risk of colorectal cancer even after accounting for shared risk factors for both diseases. One of these large, prospective studies, the Cancer Prevention Study, included 866,793 individuals, 15,847 of whom had diabetes [5]. Over 13 years of follow-up, an increased risk of colorectal cancer, even after accounting for BMI and physical inactivity, was noted in men with diabetes (RR = 1.30; 95 % CI 1.03‐1.65) and a modest non-significant elevation was seen in women with diabetes (RR = 1.16; 95 % CI 0.87‐1.53). In the Nurses’ Health Study, diabetes was similarly associated with an increase in the risk of colon cancer after adjustment for BMI and physical activity (multivariate-adjusted RR = 1.49; 95 % CI 1.09‐2.06) [6]. By 2005, several case‐control and cohort studies had examined this relationship, which was systematically reviewed by Larsson et al. [7]. In their metaanalysis of 6 case‐control and 9 cohort studies encompassing more than 2 million participants, a history of diabetes was associated with an increased risk of colorectal cancer (summary RR = 1.30, 95 % CI 1.20‐1.40). The results did not vary according to study design, geographic origin (United States vs. Europe), sex, or cancer site. However, not all subsequent studies have been consistent. In the Cancer Prevention Study II Nutrition Cohort, Campbell et al. [8] found a moderate increase in risk of colorectal cancer among men with diabetes (pooled RR = 1.24; 95 % CI 1.08‐1.44), but no such association among women. Inoue et al. [9] using the Japan Public Health Center-Based Prospective Study, observed no increase in risk of colon cancer with diabetes after excluding cancer cases diagnosed within 5 years of diagnosis of diabetes (HR = 1.19, 95 % CI 0.91‐1.55 for men and 1.14, 95 % CI 0.70‐1.87 for women). Similarly, data from the Japan

A Bayesian approach for generalized linear models with explanatory biomarker measurement variables subject to detection limit: an application to acute lung injury

Biomarkers have the potential to improve our understanding of disease diagnosis and prognosis. Biomarker levels that fall below the assay detection limits (DLs), however, compromise the application of biomarkers in research and practice. Most existing methods to handle non-detects focus on a scenario in which the response variable is subject to the DL; only a few methods consider explanatory variables when dealing with DLs. We propose a Bayesian approach for generalized linear models with explanatory variables subject to lower, upper, or interval DLs. In simulation studies, we compared the proposed Bayesian approach to four commonly used methods in a logistic regression model with explanatory variable measurements subject to the DL. We also applied the Bayesian approach and other four methods in a real study, in which a panel of cytokine biomarkers was studied for their association with acute lung injury (ALI). We found that IL8 was associated with a moderate increase in risk for ALI in the model based on the proposed Bayesian approach.

Genetisches Profil der Multiplen Sklerose: Risikogene und die „dunkle Materie“

Multiple sclerosis (MS) is a genetically complex disease caused by the interplay of genetic and environmental factors. While it shows substantial familial accumulation, there is no evidence for typical Mendelian transmission within families. Instead, MS risk is likely governed by dozens to hundreds of genetic variants, which can also be present in the general population. The strongest genetic risk factor for MS was identified 40 years ago and lies within the HLA locus. It increases the risk of developing MS by two- to threefold. Within the last few years, genome-wide association studies (GWAS) have led to the identification of nearly 60 additional genetic risk loci. Each of these loci yields a modest to moderate risk increase (odds ratios of 1.1-1.3). Even in combination, however, the currently known risk variants merely account for a small fraction of the disease's heritability. It is likely that a major fraction of genetic MS risk that cannot be explained by GWAS, sometimes termed the "dark matter" of GWAS, is caused by other factors, such as structural variations of the genome, rare sequence variants, or inherited epigenetic modifications.

Health Effects of Flooding in Rural Bangladesh

There is little information available on nontraumatic health risks as the result of floods, and on the factors that determine vulnerability to them (especially in low-income settings). We estimated the pattern of mortality, diarrhea, and acute respiratory infection following the 2004 floods in rural Bangladesh. We conducted controlled interrupted time-series analysis of adverse health outcomes, from 2001 to 2007, in a cohort of 211,000 residents of the Matlab region classified as flooded or nonflooded in 2004. Ratios of mortality, diarrhea, and acute respiratory infection rates in flooded compared with nonflooded areas were calculated by week for mortality and diarrhea, and by month for acute respiratory infection. We controlled for baseline differences as well as normal seasonal patterns in the flooded and nonflooded areas. Variations in flood-related health risks were examined by age, income level, drinking-water source, latrine type, and service area. After fully controlling for pre-flood rate differences and for seasonality, there was no clear evidence of excesses in mortality or diarrhea risk during or after flooding. For acute respiratory infection, we found no evidence of excess risk during the flood itself but a moderate increase in risk during the 6 months after the flood (relative risk = 1.25 [95% confidence interval = 1.06-1.47]) and the subsequent 18 months. We found little evidence of increased risk of diarrhea or mortality following the floods, but evidence of a moderate elevation in risk of acute respiratory infection during the 2 years after flooding. The discrepancies between our results and the apparent excesses for mortality and diarrhea reported in other situations, using less- controlled estimates, emphasize the importance of stringent confounder control.

Protein Expressions and Genetic Variations of SLC5A8 in Prostate Cancer Risk and Aggressiveness

To understand the role in prostate cancer risk and aggressiveness, we investigated the expression in prostate tumor and single nucleotide polymorphisms of SLC5A8. Previous studies have suggested that SLC5A8 might function as a tumor suppressor gene, whose silencing by epigenetic changes might contribute to carcinogenesis. We constructed tissue microarrays from 183 prostate tumor tissues, 43 adjacent non-neoplastic tissues from the same patients, and 13 tissue samples from patients with benign prostatic hyperplasia or prostatic intraepithelial neoplasia. A semiquantitative assessment of SLC5A8 protein expression was determined as the product of immunostaining intensity and the percentage of cells stained. In addition, we compared the frequencies of 4 single nucleotide polymorphisms (rs164365, rs1709189, rs1399236, and rs1681096) in SLC5A8 between 668 prostate cancer cases and 385 controls. SLC5A8 expression was significantly greater in the tumor tissues than in the paired non-neoplastic tissues (P < .0001). In the Moffitt samples, we observed a borderline moderate risk increase in patients with a genotype containing ≥1 "A" allele of rs164365 (odds ratio 1.35, 95% confidence interval 1.00-1.80), especially among tall men (≥70 in.; odds ratio 1.80, 95% confidence interval 1.20-2.68). However, these results were not confirmed in the Cancer Genetic Markers of Susceptibility population. These data suggest that the expression pattern of SLC5A8 might be used as a diagnostic biomarker, and a larger study is required to assess the importance of SLC5A8 single nucleotide polymorphisms in prostate cancer.

Risk of Serious Cardiac Events in Older Adults Using Antipsychotic Agents

Background Antipsychotic agents can lead to severe cardiovascular adverse events due to multiple mechanisms involving electrophysiologic and metabolic effects. Few epidemiologic studies have evaluated the risk of serious cardiovascular-related events in typical and atypical antipsychotic users. Objective The purpose of this study was to compare the risk of serious cardiac events in older adults taking typical antipsychotics with those taking atypical antipsychotics. Methods Prescription and medical information were derived from the IMS LifeLink Health Plan Claims database. The study involved a retrospective cohort of older adults (≥50 years) taking atypical or typical antipsychotics from July 1, 2000, to December 31, 2007. The primary outcome measure was hospitalization or emergency room visit due to serious cardiac events, including thromboembolism, myocardial infarction, cardiac arrest, and ventricular arrhythmias within 1 year after the index date. The 2 groups were matched on a propensity score to minimize the baseline differences between the groups. Survival analysis was conducted on the matched cohort to assess the risk of serious cardiovascular events in typical versus atypical users. Results A total of 5580 patients were selected in each antipsychotic users group after propensity score matching. Serious cardiac events were found in 666 (11.9 %) atypical antipsychotic users and 698 (12.4%) typical antipsychotic users. Survival analysis revealed that typical antipsychotic users were at increased risk of serious cardiovascular events compared with atypical antipsychotic users (hazard ratio = 1.21; 95% CI, 1.04–1.40) after controlling for other factors. Conclusions Moderate increases in risk of serious cardiac events are associated with older adults using typical antipsychotic agents compared with atypical users. Health care professionals should carefully evaluate the benefit/risk ratio of antipsychotic agents before prescribing these agents to a vulnerable population.