Individual and spousal education, mortality and life expectancy in Switzerland: a national cohort study.

BACKGROUND Household measures of socioeconomic position may better account for the shared nature of material resources, lifestyle, and social position of cohabiting persons, but household measures of education are rarely used. We aimed to evaluate the association of combined educational attainment of married couples on mortality and life expectancy in Switzerland. METHODS The study included 3 496 163 ever-married persons aged ≥30 years. The 2000 census was linked to mortality records through 2008. Mortality by combined educational attainment was assessed by gender-age-specific HRs, with 95% CIs from adjusted models, life expectancy was derived using abridged life tables. RESULTS Having a less educated partner was associated with increased mortality. For example, the HR comparing men aged 50-64 years with tertiary education married to women with tertiary education to men with compulsory education married to women with compulsory education was 2.05 (1.92-2.18). The estimated remaining life expectancy in tertiary educated men aged 30 years married to women with tertiary education was 4.6 years longer than in men with compulsory education married to women with compulsory education. The gradient based on individual education was less steep: the HR comparing men aged 50-64 years with tertiary education with men with compulsory education was 1.74 (1.67-1.81). CONCLUSIONS Using individual educational attainment of married persons is common in epidemiological research, but may underestimate the combined effect of education on mortality and life expectancy. These findings are relevant to epidemiologic studies examining socio-demographic characteristics or aiming to adjust results for these characteristics.

Environmental Effects and Aquatic Organisms: Investigations of Molecular Mechanisms of Carcinogenesis

Cancers of the reproductive system are among the leading causes of mortality in women in the United States. While both genetic and environmental factors have been implicated in their etiology, the extent of the contribution of environmental factors to human diseases remains controversial. To better address the role of environmental exposures in cancer etiology, there has been an increasing focus on the development of nontraditional, environmentally relevant models. Our research involves the development of one such model, Gonadal tumors have been described in the softshell clam (Mya arenaria) in Maine and the hardshell clam (Mercenaria spp.) from Florida. Prevalence of these tumors is as high as 40% in some populations in eastern Maine and 60% in Some areas along the Indian River in Florida. The average tumor prevalence in Maine and Florida is approximately 20 and 11%, respectively. An association has been suggested between the use of herbicides and the incidence of gonadal tumors in the softshell clam in Maine. The role of environmental exposures in the development of the tumors in Mercenaria in Florida is unknown, however, there is evidence that genetic factors may contribute to its etiology. Epidemiologic studies of human populations in these same areas show a higher than average mortality rate due to cancers of the reproductive system in women, including both ovarian and breast career. The relationship, if any, among these observations is unknown, Our studies on the molecular basis of this disease in clams may provide additional information on environmental exposures and their possible link to cancer in clams and other organisms, including humans.

The potential of microfluidic lung epithelial wounding: towards in vivo-like alveolar microinjuries

Idiopathic pulmonary fibrosis (IPF) remains a major clinical challenge to date. Repeated alveolar epithelial microinjuries are considered as the starting point and the key event in both the development and the progression of IPF. Various pro-fibrotic agents have been identified and shown to cause alveolar damage. In IPF, however, no leading cause of alveolar epithelial microinjuries can be identified and the exact etiology remains elusive. New results from epidemiologic studies suggest a causal relation between IPF and frequent episodes of gastric refluxes resulting in gastric microaspirations into the lung. The effect of gastric contents on the alveolar epithelium has not been investigated in detail. Here, we present a microfluidic lung epithelial wounding system that allows for the selective exposure of alveolar epithelial cells to gastric contents. The system is revealed to be robust and highly reproducible. The thereby created epithelial microwounds are of tiny dimensions and best possibly reproduce alveolar damage in the lung. We further demonstrate that exposure to gastric contents, namely hydrochloric acid (HCl) and pepsin, directly damages the alveolar epithelium. Together, this novel in vitro wounding system allows for the creation of in vivo-like alveolar microinjuries with the potential to study lung injury and alveolar wound repair in vitro.

White matter matters: a multimodal approach to investigate white matter microstructure and metabolism

White matter connects different brain areas and applies electrical insulation to the neuron’s axons with myelin sheaths in order to enable quick signal transmission. Due to its modulatory properties in signal conduction, white matter plays an essential role in learning, cognition and psychiatric disorders (Fields, 2008a). In respect thereof, the non-invasive investigation of white matter anatomy and function in vivo provides the unique opportunity to explore the most complex organ of our body. Thus, the present thesis aimed to apply a multimodal neuroimaging approach to investigate different white matter properties in psychiatric and healthy populations. On the one hand, white matter microstructural properties were investigated in a psychiatric population; on the other hand, white matter metabolic properties were assessed in healthy adults providing basic information about the brain’s wiring entity. As a result, three research papers are presented here. The first paper assessed the microstructural properties of white matter in relation to a frequent epidemiologic finding in schizophrenia. As a result, reduced white matter integrity was observed in patients born in summer and autumn compared to patients born in winter and spring. Despite the large genetic basis of schizophrenia, accumulating evidence indicates that environmental exposures may be implicated in the development of schizophrenia (A. S. Brown, 2011). Notably, epidemiologic studies have shown a 5–8% excess of births during winter and spring for patients with schizophrenia on the Northern Hemisphere at higher latitudes (Torrey, Miller, Rawlings, & Yolken, 1997). Although the underlying mechanisms are unclear, the seasonal birth effect may indicate fluctuating environmental risk factors for schizophrenia. Thus, exposure to harmful factors during foetal development may result in the activation of pathologic neural circuits during adolescence or young adulthood, increasing the risk of schizophrenia (Fatemi & Folsom, 2009). While white matter development starts during the foetal period and continues until adulthood, its major development is accomplished by the age of two years (Brody, Kinney, Kloman, & Gilles, 1987; Huang et al., 2009). This indicates a vulnerability period of white matter that may coincide with the fluctuating environmental risk factors for schizophrenia. Since microstructural alterations of white matter in schizophrenia are frequently observed, the current study provided evidence for the neurodevelopmental hypothesis of schizophrenia. In the second research paper, the perfusion of white matter showed a positive correlation between white matter microstructure and its perfusion with blood across healthy adults. This finding was in line with clinical studies indicating a tight coupling between cerebral perfusion and WM health across subjects (Amann et al., 2012; Chen, Rosas, & Salat, 2013; Kitagawa et al., 2009). Although relatively little is known about the metabolic properties of white matter, different microstructural properties, such as axon diameter and myelination, might be coupled with the metabolic demand of white matter. Furthermore, the ability to detect perfusion signal in white matter was in accordance with a recent study showing that technical improvements, such as pseudo-continuous arterial spin labeling, enabled the reliable detection of white matter perfusion signal (van Osch et al., 2009). The third paper involved a collaboration within the same department to assess the interrelation between functional connectivity networks and their underlying structural connectivity.

Effects of short- and long-term variations in RLS severity on perceived health status - the COR-study.

In a cohort study among 2751 members (71.5% females) of the German and Swiss RLS patient organizations changes in restless legs syndrome (RLS) severity over time was assessed and the impact on quality of life, sleep quality and depressive symptoms was analysed. A standard set of scales (RLS severity scale IRLS, SF-36, Pittsburgh Sleep Quality Index and the Centre for Epidemiologic Studies Depression Scale) in mailed questionnaires was repeatedly used to assess RLS severity and health status over time and a 7-day diary once to assess short-term variations. A clinically relevant change of the RLS severity was defined by a change of at least 5 points on the IRLS scale. During 36 months follow-up minimal improvement of RLS severity between assessments was observed. Men consistently reported higher severity scores. RLS severity increased with age reaching a plateau in the age group 45-54 years. During 3 years 60.2% of the participants had no relevant (±5 points) change in RLS severity. RLS worsening was significantly related to an increase in depressive symptoms and a decrease in sleep quality and quality of life. The short-term variation showed distinctive circadian patterns with rhythm magnitudes strongly related to RLS severity. The majority of participants had a stable course of severe RLS over three years. An increase in RLS severity was accompanied by a small to moderate negative, a decrease by a small positive influence on quality of life, depressive symptoms and sleep quality.

Why does placement of persons with Alzheimer's disease into long-term care improve caregivers' well-being? Examination of psychological mediators.

Caregiving for individuals with Alzheimer's disease is associated with chronic stress and elevated symptoms of depression. Placement of the care receiver (CR) into a long-term care setting may be associated with improved caregiver well-being; however, the psychological mechanisms underlying this relationship are unclear. This study evaluated whether decreases in activity restriction and increases in personal mastery mediated placement-related reductions in caregiver depressive symptoms. In a 5-year longitudinal study of 126 spousal Alzheimer's disease caregivers, we used multilevel models to evaluate placement-related changes in depressive symptoms (short form of the Center for Epidemiologic Studies Depression scale), activity restriction (Activity Restriction Scale), and personal mastery (Pearlin Mastery Scale) in 44 caregivers who placed their spouses into long-term care relative to caregivers who never placed their CRs. The Monte Carlo method for assessing mediation was used to evaluate the significance of the indirect effect of activity restriction and personal mastery on postplacement changes in depressive symptoms. Placement of the CR was associated with significant reductions in depressive symptoms and activity restriction and was also associated with increased personal mastery. Lower activity restriction and higher personal mastery were associated with reduced depressive symptoms. Furthermore, both variables significantly mediated the effect of placement on depressive symptoms. Placement-related reductions in activity restriction and increases in personal mastery are important psychological factors that help explain postplacement reductions in depressive symptoms. The implications for clinical care provided to caregivers are discussed.

Diabetes, use of antidiabetic drugs, and the risk of glioma

BACKGROUND Prior epidemiologic studies suggest inverse relations between diabetes and glioma risk, but the underlying mechanisms, including use of antidiabetic drugs, are unknown. METHODS We therefore performed a matched case-control analysis using the Clinical Practice Research Datalink (CPRD). We identified incident glioma cases diagnosed between 1995 and 2012 and matched each case with 10 controls on age, gender, calendar time, general practice, and years of active history in the CPRD. We performed conditional logistic regression to estimate odds ratios (ORs) with 95% CIs, adjusted for body mass index and smoking. RESULTS We identified 2005 cases and 20 050 controls. Diabetes was associated with decreased risk of glioma (OR = 0.74; 95% CI = 0.60-0.93), particularly glioblastoma (OR = 0.69; 95% CI = 0.51-0.94). Glioblastoma risk reduction was markedly pronounced among diabetic men (OR = 0.60; 95% CI = 0.40-0.90), most apparently for those with diabetes of long-term duration (OR for >5 vs 0 y = 0.46; 95% CI = 0.26-0.82) or poor glycemic control (OR for HbA1c ≥8 vs <6.5% = 0.20; 95% CI = 0.06-0.70). In contrast, the effect of diabetes on glioblastoma risk was absent among women (OR = 0.85; 95% CI = 0.53-1.36). No significant associations with glioma were found for use of metformin (OR for ≥30 vs 0 prescriptions = 0.72; 95% CI = 0.38-1.39), sulfonylureas (OR = 0.71; 95% CI = 0.39-1.30), or insulin (OR = 0.79; 95% CI = 0.37-1.69). CONCLUSIONS Antidiabetic treatment appears to be unrelated to glioma, but long-term diabetes duration and increased HbA1c both show decreased glioma risk. Stronger findings in men than women suggest low androgen levels concurrent with diabetes as a biologic mechanism.

Incidence and outcomes of symptomatic neonatal arterial ischemic stroke.

BACKGROUND AND OBJECTIVES Neonatal arterial ischemic stroke (NAIS) is associated with considerable lifetime burdens such as cerebral palsy, epilepsy, and cognitive impairment. Prospective epidemiologic studies that include outcome assessments are scarce. This study aimed to provide information on the epidemiology, clinical manifestations, infarct characteristics, associated clinical variables, treatment strategies, and outcomes of NAIS in a prospective, population-based cohort of Swiss children. METHODS This prospective study evaluated the epidemiology, clinical manifestations, vascular territories, associated clinical variables, and treatment of all full-term neonates diagnosed with NAIS and born in Switzerland between 2000 and 2010. Follow-up was performed 2 years (mean 23.3 months, SD 4.3 months) after birth. RESULTS One hundred neonates (67 boys) had a diagnosis of NAIS. The NAIS incidence in Switzerland during this time was 13 (95% confidence interval [CI], 11-17) per 100,000 live births. Seizures were the most common symptom (95%). Eighty-one percent had unilateral (80% left-sided) and 19% had bilateral lesions. Risk factors included maternal risk conditions (32%), birth complications (68%), and neonatal comorbidities (54%). Antithrombotic and antiplatelet therapy use was low (17%). No serious side effects were reported. Two years after birth, 39% were diagnosed with cerebral palsy and 31% had delayed mental performance. CONCLUSIONS NAIS in Switzerland shows a similar incidence as other population-based studies. About one-third of patients developed cerebral palsy or showed delayed mental performance 2 years after birth, and children with normal mental performance may still develop deficits later in life.

Are functional and genetic components of platelets linked to coronary artery disease: A case-control study

Coronary artery disease (CAD) is a multifactorial disease process involving behavioral, inflammatory, clinical, thrombotic, and genetic components. Previous epidemiologic studies focused on identifying behavioral and demographic risk factors of CAD, but none focused on platelets. Current platelet literature lacks the known effects of platelet function and platelet receptor polymorphisms on CAD. This case-control analysis addressed these issues by analyzing data collected for a previous study. Cases were individuals who had undergone CABG and thus had been diagnosed with CAD, while the controls were volunteers presumed to be CAD free. The platelet function variables analyzed included fibrinogen Von Willebrand Factor activity (VWF), shear-induced platelet aggregation (SIPA), sCD40L, and mean platelet volume; and the platelet polymorphisms studied included PIA, α2 807, Ko, Kozak, and VNTR. Univariate analysis found fibrinogen, VWF, SIPA, and PIA to be independent risk factors of CAD. Logistic regression was used to build a predictive model for CAD using the platelet function and platelet polymorphism data adjusted for age, sex, race, and current smoking status. A model containing only platelet polymorphisms and their respective receptor densities, found polymorphisms within GPIbα to be associated with CAD, yielding an 86% (95% C.I. 0.97–3.55) increased risk with the presence of at least 1 polymorphism in Ko, Kozak, or VNTR. Another model included both platelet function and platelet polymorphism data. Fibrinogen, the receptor density of GPIbα, and the polymorphism in GPIa-IIa (α2 807) were all associated with CAD with odds ratios of 1.10, 1.04, and 2.30 for fibrinogen (10mg/dl increase), GPIbα receptors (1 MFI increase), and GPIa-IIa, respectively. In addition, risk estimates and 99% confidence intervals adjusted for race were calculated to determine if the presence of a platelet receptor polymorphism was associated with CAD. The results were as follows: PIA (1.64, 0.74–3.65); α2 807 (1.35, 0.77–2.37); Ko (1.71, 0.70–4.16); Kozak (1.17, 0.54–2.52); and VNTR (1.24, 0.52–2.91). Although not statistically significant, all platelet polymorphisms were associated with an increased risk for CAD. These exploratory findings indicate that platelets do appear to have a role in atherosclerosis and that anti-platelet drugs targeting GPI-IIa and GPIbα may be better treatment candidates for individuals with CAD. ^

Prevalence of depressive symptoms among Hispanic women attending a public health clinic

Background. Estimates of perinatal depression have ranged from 5% to more than 25% of women (Gavin et al. 2005). Although Hispanics have one of the highest birthrates, few studies have looked at the prevalence of depression among this population. This study aims to describe the prevalence of depressive symptoms among a sample of Hispanic women. Methods. A convenience sample of 439 Hispanic women were screened for depression using the Center for Epidemiologic Studies Depression Scale. Sociodemographic data relating to pregnancy were also collected. Results. Although bivariate analysis found several variables to be significant, multivariate analysis found only marital and pregnancy status to be significant in predicting depression. Conclusions. While marital and pregnancy status proved to the strongest predictors for depression, future research would benefit from collecting information on timing of pregnancy and postpartum to further explore the role of pregnancy status and depressive symptoms. ^

Variation of genotype and prevalence of Noro virus in U.S. students in Mexico with Traveler's Diarrhea, summer of 2004 and 2005

Noro virus, a positive single stranded RNA virus has been identified as a major etiologic agent in food borne gastroenteritis and diarrheal diseases. The emergence of this organism as a major non-bacterial cause in such outbreaks is partly due to the improved diagnostic tools like Reverse Transcription Polymerase chain reaction (RTPCR) that enable its detection. Noro virus accounts for nearly 96% of non-bacterial gastroenteritis outbreaks in US (1). Travelers' Diarrhea (TD) has remained a constant public health risk in the developed nations for decades and bacteria like Entero toxigenic Escherichia coli, Entero aggregative Escherichia coli have been described as the main etiologic agents for TD (2-4). A possible viral contribution to TD has been discovered in two studies (5, 6). The current study was designed to determine the prevalence of Noro virus in a population of 107 US students with TD acquired in Mexico in 2005 and to compare the prevalence to the prevalence of Noro virus in a similar study done in 2004. This study involved the testing of clinical stool specimens from 107 subjects in 2005 for the presence of Noro virus using RTPCR. The prevalence of Noro virus in 2004 used for comparison to 2005 data was obtained from published data (5). All subjects were recruited as TD subjects in a randomized, double-blinded clinical trial comparing a standard three day dosing of Rifaximin with and without an anti motility drug Loperamide. The prevalence of Noro virus geno group I was similar in both years, but geno group II prevalence differed across the two years (p = 0.003). This study finding suggests that the prevalence of Noro virus geno groups varies with time even within a specific geographic location. This study emphasizes the need for further systematic epidemiologic studies to determine the molecular epidemiology and the prevalence patterns of different geno groups of this virus. These are essential to planning and implementation of public health measures to lessen the burden of TD due to Noro virus infection among US travelers. ^

Factors associated with diabetes in tuberculosis patients in Harris County, Texas 1995--2004

Objective. To determine the prevalence and factors associated with diabetes in tuberculosis patients in Harris County, Texas. ^ Background. Tuberculosis and diabetes mellitus are two diseases of immense public health significance. Various epidemiologic studies have established an association between the two conditions. While many studies have identified factors associated with the conditions individually, few have looked at factors associated with their co-occurrence particularly in the United States. Furthermore, most of those studies are hospital-based and may not be representative of the population. The aim of this study was to determine the prevalence and distribution of diabetes among tuberculosis patients in Harris County, Texas and to identify the factors associated with diabetes in tuberculosis. ^ Methods. A population-based case control study was performed using secondary data from the Houston Tuberculosis Initiative (HTI) collected from October 1995 to September 2004. Socio-demographic characteristics and clinical variables were compared between tuberculosis patients with diabetes and non-diabetic tuberculosis patients. Logistic regression analysis was performed to identify associations. Survival at 180 days post tuberculosis diagnosis was assessed by Cox regression. ^ Results. The prevalence of diabetes among the tuberculosis (TB) population was 14.4%. The diabetics (cases) with a mean age 53 ± 13.3 years were older than the non-diabetics (controls) with a mean age of 39 ± 18.5 years (p<0.001). Socio-demographic variables that were independently associated with the risk of diabetes were age (OR 1.04, p<0.001) and Hispanic ethnicity (OR 2.04, p<0.001). Diabetes was associated with an increased risk of pulmonary tuberculosis disease (OR 1.33, p<0.028). Among individuals with pulmonary TB, diabetes was associated with positive sputum acid-fast bacilli (AFB) smear (OR 1.47, p<0.005) and culture (OR 1.83, p<0.018). Diabetics were more likely to have cavitary lung disease than non-diabetics (OR 1.50, p<0.002). After adjustment for age and HIV status, the risk of dying within 180 days of TB diagnosis was significantly increased in the diabetics (HR 1.51, p<0.002). ^ Conclusion. Diabetes mellitus was more prevalent in our tuberculosis patients than in the general population. The tuberculous diabetic may be more infectious and has a higher risk of death. It is therefore imperative to screen diabetics for TB and TB patients for diabetes. ^

Selection of body fat distribution indices in adults and associations with plasma lipid metabolism variables

Body fat distribution is a cardiovascular health risk factor in adults. Body fat distribution can be measured through various methods including anthropometry. It is not clear which anthropometric index is suitable for epidemiologic studies of fat distribution and cardiovascular disease. The purpose of the present study was to select a measure of body fat distribution from among a series of indices (those traditionally used in the literature and others constructed from the analysis) that is most highly correlated with lipid-related variables and is independent of overall fatness. Subjects were Mexican-American men and women (N = 1004) from a study of gallbladder disease in Starr County, Texas. Multivariate associations were sought between lipid profile measures (lipids, lipoproteins, and apolipoproteins) and two sets of anthropometric variables (4 circumferences and 6 skinfolds). This was done to assess the association between lipid-related measures and the two sets of anthropometric variables and guide the construction of indices.^ Two indices emerged from the analysis that seemed to be highly correlated with lipid profile measures independent of obesity. These indices are: 2*arm circumference-thigh skinfold in pre- and post-menopausal women and arm/thigh circumference ratio in men. Next, using the sum of all skinfolds to represent obesity and the selected body fat distribution indices, the following hypotheses were tested: (1) state of obesity and centrally/upper distributed body fat are equally predictive of lipids, lipoproteins and apolipoproteins, and (2) the correlation among the lipid-related measures is not altered by obesity and body fat distribution.^ With respect to the first hypothesis, the present study found that most lipids, lipoproteins and apolipoproteins were significantly associated with both overall fatness and anatomical location of body fat in both sex and menopausal groups. However, within men and post-menopausal women, certain lipid profile measures (triglyceride and HDLT among post-menopausal women and apos C-II, CIII, and E among men) had substantially higher correlation with body fat distribution as compared with overall fatness.^ With respect to the second hypothesis, both obesity and body fat distribution were found to alter the association among plasma lipid variables in men and women. There was a suggestion from the data that the pattern of correlations among men and post-menopausal women are more comparable. Among men correlations involving apo A-I, HDLT, and HDL$\sb2$ seemed greatly influenced by obesity, and A-II by fat distribution; among post-menopausal women correlations involving apos A-I and A-II were highly affected by the location of body fat.^ Thus, these data point out that not only can obesity and fat distribution affect levels of single measures, they also can markedly influence the pattern of relationship among measures. The fact that such changes are seen for both obesity and fat distribution is significant, since the indices employed were chosen because they were independent of one another. ^

Leukemia and occupational exposure to electromagnetic fields: An incident case-control study

The existence of an association between leukemia and electromagnetic fields (EMF) is still controversial. The results of epidemiologic studies of leukemia in occupational groups with exposure to EMF are inconsistent. Weak associations have been seen in a few studies. EMF assessment is lacking in precision. Reported dose-response relationships have been based on qualitative levels of exposure to EMF without regard to duration of employment or EMF intensity on the jobs. Furthermore, potential confounding factors in the associations were not often well controlled. The current study is an analysis of the data collected from an incident case-control study. The primary objective was to test the hypothesis that occupational exposure to EMF is associated with leukemia, including total leukemia (TL), myelogenous leukemia (MYELOG) and acute non-lymphoid leukemia (ANLL). Potential confounding factors: occupational exposure to benzene, age, smoking, alcohol consumption, and previous medical radiation exposures were controlled in multivariate logistic regression models. Dose-response relationships were estimated by cumulative occupational exposure to EMF, taking into account duration of employment and EMF intensity on the jobs. In order to overcome weaknesses of most previous studies, special efforts were made to improve the precision of EMF assessment. Two definitions of EMF were used and result discrepancies using the two definitions were observed. These difference raised a question as to whether the workers at jobs with low EMF exposure should be considered as non-exposed in future studies. In addition, the current study suggested use of lifetime cumulative EMF exposure estimates to determine dose-response relationship. The analyses of the current study suggest an association between ANLL and employment at selected jobs with high EMF exposure. The existence of an association between three types of leukemia and broader categories of occupational EMF exposure, is still undetermined. If an association does exist between occupational EMF exposure and leukemia, the results of the current study suggest that EMF might only be a potential factor in the promotion of leukemia, but not its initiation. ^

The evidence for groundwater as a source of enteric illness in developing countries: A systematic review of the literature

Groundwater constitutes approximately 30% of freshwater globally and serves as a source of drinking water in many regions. Groundwater sources are subject to contamination with human pathogens (viruses, bacteria and protozoa) from a variety of sources that can cause diarrhea and contribute to the devastating global burden of this disease. To attempt to describe the extent of this public health concern in developing countries, a systematic review of the evidence for groundwater microbially-contaminated at its source as risk factor for enteric illness under endemic (non-outbreak) conditions in these countries was conducted. Epidemiologic studies published in English language journals between January 2000 and January 2011, and meeting certain other criteria, were selected, resulting in eleven studies reviewed. Data were extracted on microbes detected (and their concentrations if reported) and on associations measured between microbial quality of, or consumption of, groundwater and enteric illness; other relevant findings are also reported. In groundwater samples, several studies found bacterial indicators of fecal contamination (total coliforms, fecal coliforms, fecal streptococci, enterococci and E. coli), all in a wide range of concentrations. Rotavirus and a number of enteropathogenic bacteria and parasites were found in stool samples from study subjects who had consumed groundwater, but no concentrations were reported. Consumption of groundwater was associated with increased risk of diarrhea, with odds ratios ranging from 1.9 to 6.1. However, limitations of the selected studies, especially potential confounding factors, limited the conclusions that could be drawn from them. These results support the contention that microbial contamination of groundwater reservoirs—including with human enteropathogens and from a variety of sources—is a reality in developing countries. While microbially-contaminated groundwaters pose risk for diarrhea, other factors are also important, including water treatment, water storage practices, consumption of other water sources, water quantity and access to it, sanitation and hygiene, housing conditions, and socio-economic status. Further understanding of the interrelationships between, and the relative contributions to disease risk of, the various sources of microbial contamination of groundwater can guide the allocation of resources to interventions with the greatest public health benefit. Several recommendations for future research, and for practitioners and policymakers, are presented.^