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Private sector engagement in health reform has been suggested to help reduce healthcare inequities in sub-Saharan Africa, where populations with the most need seek the least care. We study the effects of African Health Markets for Equity (AHME), a cluster randomized controlled trial carried out in Kenya from 2012 to 2020 at 199 private health clinics. AHME included four clinic-level interventions: social health insurance, social franchising, SafeCare quality-of-care certification programme and business support. This paper evaluates whether AHME increased the capacity of private health clinics to serve poor clients while maintaining or enhancing the quality of care provided. At endline, clinics that received AHME were 14.5 percentage points (pp) more likely to be empanelled with the National Health Insurance Fund (NHIF), served 51% more NHIF clients and served more clients from the middle three quintiles of the wealth distribution compared to control clinics. Comparing individuals living in households near AHME treatment and control clinics (N = 8241), AHME led to a 6.7-pp increase in the probability of holding any health insurance on average. We did not find any additional effect of AHME on insurance holding among poor households. We measured quality of care using a standardized patient (SP) experiment (N = 596 SP-provider interactions) where recruited and trained SPs were randomized to present as either not poor, and able to afford all services provided, or poor by telling the provider they could only afford ∼300 Kenyan Shillings (US$3) in fees. We found that poor SPs received lower levels of both correct and unnecessary services, and AHME did not affect this. More work must be done to ensure that clients of all wealth levels receive high-quality care.

In breast cancer, the increased stiffness of the extracellular matrix is a key driver of malignancy. Yet little is known about the epigenomic changes that underlie the tumorigenic impact of extracellular matrix mechanics. Here, we show in a three-dimensional culture model of breast cancer that stiff extracellular matrix induces a tumorigenic phenotype through changes in chromatin state. We found that increased stiffness yielded cells with more wrinkled nuclei and with increased lamina-associated chromatin, that cells cultured in stiff matrices displayed more accessible chromatin sites, which exhibited footprints of Sp1 binding, and that this transcription factor acts along with the histone deacetylases 3 and 8 to regulate the induction of stiffness-mediated tumorigenicity. Just as cell culture on soft environments or in them rather than on tissue-culture plastic better recapitulates the acinar morphology observed in mammary epithelium in vivo, mammary epithelial cells cultured on soft microenvironments or in them also more closely replicate the in vivo chromatin state. Our results emphasize the importance of culture conditions for epigenomic studies, and reveal that chromatin state is a critical mediator of mechanotransduction.

In breast cancer, the increased stiffness of the extracellular matrix is a key driver of malignancy. Yet little is known about the epigenomic changes that underlie the tumorigenic impact of extracellular matrix mechanics. Here, we show in a three-dimensional culture model of breast cancer that stiff extracellular matrix induces a tumorigenic phenotype through changes in chromatin state. We found that increased stiffness yielded cells with more wrinkled nuclei and with increased lamina-associated chromatin, that cells cultured in stiff matrices displayed more accessible chromatin sites, which exhibited footprints of Sp1 binding, and that this transcription factor acts along with the histone deacetylases 3 and 8 to regulate the induction of stiffness-mediated tumorigenicity. Just as cell culture on soft environments or in them rather than on tissue-culture plastic better recapitulates the acinar morphology observed in mammary epithelium in vivo, mammary epithelial cells cultured on soft microenvironments or in them also more closely replicate the in vivo chromatin state. Our results emphasize the importance of culture conditions for epigenomic studies, and reveal that chromatin state is a critical mediator of mechanotransduction.

Low adoption and compliance levels for household water treatment and safe storage (HWTS) technologies have made it challenging for these systems to achieve measurable health benefits in the developing world. User compliance remains an inconsistently defined and poorly understood feature of HWTS programs. In this article, we develop a comprehensive approach to understanding HWTS compliance. First, our Safe Drinking Water Compliance Framework disaggregates and measures the components of compliance from initial adoption of the HWTS to exclusive consumption of treated water. We apply this framework to an ultraviolet (UV)-based safe water system in a cluster-randomized controlled trial in rural Mexico. Second, we evaluate a no-frills (or "Basic") variant of the program as well as an improved (or "Enhanced") variant, to test if subtle changes in the user interface of HWTS programs could improve compliance. Finally, we perform a full-cost analysis of both variants to assess their cost effectiveness (CE) in achieving compliance. We define "compliance" strictly as the habit of consuming safe water. We find that compliance was significantly higher in the groups where the UV program variants were rolled out than in the control groups. The Enhanced variant performed better immediately postintervention than the Basic, but compliance (and thus CE) degraded with time such that no effective difference remained between the two versions of the program.

13-cis-retinoic acid (isotretinoin, INN) is an oral pharmaceutical drug used for the treatment of skin acne, and is also a known teratogen. In this study, the molecular mechanisms underlying INN-induced developmental toxicity during early cardiac differentiation were investigated using both human induced pluripotent stem cells (hiPSCs) and human embryonic stem cells (hESCs). Pre-exposure of hiPSCs and hESCs to a sublethal concentration of INN did not influence cell proliferation and pluripotency. However, mesodermal differentiation was disrupted when INN was included in the medium during differentiation. Transcriptomic profiling by RNA-seq revealed that INN exposure leads to aberrant expression of genes involved in several signaling pathways that control early mesoderm differentiation, such as TGF-beta signaling. In addition, genome-wide chromatin accessibility profiling by ATAC-seq suggested that INN-exposure leads to enhanced DNA-binding of specific transcription factors (TFs), including HNF1B, SOX10 and NFIC, often in close spatial proximity to genes that are dysregulated in response to INN treatment. Altogether, these results identify potential molecular mechanisms underlying INN-induced perturbation during mesodermal differentiation in the context of cardiac development. This study further highlights the utility of human stem cells as an alternative system for investigating congenital diseases of newborns that arise as a result of maternal drug exposure during pregnancy.

13-cis-retinoic acid (isotretinoin, INN) is an oral pharmaceutical drug used for the treatment of skin acne, and is also a known teratogen. In this study, the molecular mechanisms underlying INN-induced developmental toxicity during early cardiac differentiation were investigated using both human induced pluripotent stem cells (hiPSCs) and human embryonic stem cells (hESCs). Pre-exposure of hiPSCs and hESCs to a sublethal concentration of INN did not influence cell proliferation and pluripotency. However, mesodermal differentiation was disrupted when INN was included in the medium during differentiation. Transcriptomic profiling by RNA-seq revealed that INN exposure leads to aberrant expression of genes involved in several signaling pathways that control early mesoderm differentiation, such as TGF-beta signaling. In addition, genome-wide chromatin accessibility profiling by ATAC-seq suggested that INN-exposure leads to enhanced DNA-binding of specific transcription factors (TFs), including HNF1B, SOX10 and NFIC, often in close spatial proximity to genes that are dysregulated in response to INN treatment. Altogether, these results identify potential molecular mechanisms underlying INN-induced perturbation during mesodermal differentiation in the context of cardiac development. This study further highlights the utility of human stem cells as an alternative system for investigating congenital diseases of newborns that arise as a result of maternal drug exposure during pregnancy.

Low adoption and compliance levels for household water treatment and safe storage (HWTS) technologies have made it challenging for these systems to achieve measurable health benefits in the developing world. User compliance remains an inconsistently defined and poorly understood feature of HWTS programs. In this article, we develop a comprehensive approach to understanding HWTS compliance. First, our Safe Drinking Water Compliance Framework disaggregates and measures the components of compliance from initial adoption of the HWTS to exclusive consumption of treated water. We apply this framework to an ultraviolet (UV)-based safe water system in a cluster-randomized controlled trial in rural Mexico. Second, we evaluate a no-frills (or "Basic") variant of the program as well as an improved (or "Enhanced") variant, to test if subtle changes in the user interface of HWTS programs could improve compliance. Finally, we perform a full-cost analysis of both variants to assess their cost effectiveness (CE) in achieving compliance. We define "compliance" strictly as the habit of consuming safe water. We find that compliance was significantly higher in the groups where the UV program variants were rolled out than in the control groups. The Enhanced variant performed better immediately postintervention than the Basic, but compliance (and thus CE) degraded with time such that no effective difference remained between the two versions of the program.

Complier average causal effects (CACE) estimate the impact of an intervention among treatment compliers in randomized trials. Methods used to estimate CACE have been outlined for parallel-arm trials (e.g., using an instrumental variables (IV) estimator) but not for other randomized study designs. Here, we propose a method for estimating CACE in randomized stepped wedge trials, where experimental units cross over from control conditions to intervention conditions in a randomized sequence. We illustrate the approach with a cluster-randomized drinking water trial conducted in rural Mexico from 2009 to 2011. Additionally, we evaluated the plausibility of assumptions required to estimate CACE using the IV approach, which are testable in stepped wedge trials but not in parallel-arm trials. We observed small increases in the magnitude of CACE risk differences compared with intention-to-treat estimates for drinking water contamination (risk difference (RD) = -22% (95% confidence interval (CI): -33, -11) vs. RD = -19% (95% CI: -26, -12)) and diarrhea (RD = -0.8% (95% CI: -2.1, 0.4) vs. RD = -0.1% (95% CI: -1.1, 0.9)). Assumptions required for IV analysis were probably violated. Stepped wedge trials allow investigators to estimate CACE with an approach that avoids the stronger assumptions required for CACE estimation in parallel-arm trials. Inclusion of CACE estimates in stepped wedge trials with imperfect compliance could enhance reporting and interpretation of the results of such trials.

Background: Current guidelines recommend the use of Escherichia coli (EC) or thermotolerant (“fecal”) coliforms (FC) as indicators of fecal contamination in drinking water. Despite their broad use as measures of water quality, there remains limited evidence for an association between EC or FC and diarrheal illness: a previous review found no evidence for a link between diarrhea and these indicators in household drinking water.Objectives: We conducted a systematic review and meta-analysis to update the results of the previous review with newly available evidence, to explore differences between EC and FC indicators, and to assess the quality of available evidence.Methods: We searched major databases using broad terms for household water quality and diarrhea. We extracted study characteristics and relative risks (RR) from relevant studies. We pooled RRs using random effects models with inverse variance weighting, and used standard methods to evaluate heterogeneity and publication bias.Results: We identified 20 relevant studies; 14 studies provided extractable results for meta-analysis. When combining all studies, we found no association between EC or FC and diarrhea (RR 1.26 [95% CI: 0.98, 1.63]). When analyzing EC and FC separately, we found evidence for an association between diarrhea and EC (RR: 1.54 [95% CI: 1.37, 1.74]) but not FC (RR: 1.07 [95% CI: 0.79, 1.45]). Across all studies, we identified several elements of study design and reporting (e.g., timing of outcome and exposure measurement, accounting for correlated outcomes) that could be improved upon in future studies that evaluate the association between drinking water contamination and health.Conclusions: Our findings, based on a review of the published literature, suggest that these two coliform groups have different associations with diarrhea in household drinking water. Our results support the use of EC as a fecal indicator in household drinking water.

Background: Current guidelines recommend the use of Escherichia coli (EC) or thermotolerant (“fecal”) coliforms (FC) as indicators of fecal contamination in drinking water. Despite their broad use as measures of water quality, there remains limited evidence for an association between EC or FC and diarrheal illness: a previous review found no evidence for a link between diarrhea and these indicators in household drinking water.Objectives: We conducted a systematic review and meta-analysis to update the results of the previous review with newly available evidence, to explore differences between EC and FC indicators, and to assess the quality of available evidence.Methods: We searched major databases using broad terms for household water quality and diarrhea. We extracted study characteristics and relative risks (RR) from relevant studies. We pooled RRs using random effects models with inverse variance weighting, and used standard methods to evaluate heterogeneity and publication bias.Results: We identified 20 relevant studies; 14 studies provided extractable results for meta-analysis. When combining all studies, we found no association between EC or FC and diarrhea (RR 1.26 [95% CI: 0.98, 1.63]). When analyzing EC and FC separately, we found evidence for an association between diarrhea and EC (RR: 1.54 [95% CI: 1.37, 1.74]) but not FC (RR: 1.07 [95% CI: 0.79, 1.45]). Across all studies, we identified several elements of study design and reporting (e.g., timing of outcome and exposure measurement, accounting for correlated outcomes) that could be improved upon in future studies that evaluate the association between drinking water contamination and health.Conclusions: Our findings, based on a review of the published literature, suggest that these two coliform groups have different associations with diarrhea in household drinking water. Our results support the use of EC as a fecal indicator in household drinking water.

Complier average causal effects (CACE) estimate the impact of an intervention among treatment compliers in randomized trials. Methods used to estimate CACE have been outlined for parallel-arm trials (e.g., using an instrumental variables (IV) estimator) but not for other randomized study designs. Here, we propose a method for estimating CACE in randomized stepped wedge trials, where experimental units cross over from control conditions to intervention conditions in a randomized sequence. We illustrate the approach with a cluster-randomized drinking water trial conducted in rural Mexico from 2009 to 2011. Additionally, we evaluated the plausibility of assumptions required to estimate CACE using the IV approach, which are testable in stepped wedge trials but not in parallel-arm trials. We observed small increases in the magnitude of CACE risk differences compared with intention-to-treat estimates for drinking water contamination (risk difference (RD) = -22% (95% confidence interval (CI): -33, -11) vs. RD = -19% (95% CI: -26, -12)) and diarrhea (RD = -0.8% (95% CI: -2.1, 0.4) vs. RD = -0.1% (95% CI: -1.1, 0.9)). Assumptions required for IV analysis were probably violated. Stepped wedge trials allow investigators to estimate CACE with an approach that avoids the stronger assumptions required for CACE estimation in parallel-arm trials. Inclusion of CACE estimates in stepped wedge trials with imperfect compliance could enhance reporting and interpretation of the results of such trials.

Globally, diarrhea is one of the leading causes of morbidity and mortality. Populations living in developing countries disproportionally experience the burden of diarrhea; in these areas contaminated drinking water remains one of the primary environmental pathways for the transmission of diarrheagenic pathogens. Centrally treated "piped" water is largely recognized as the best method to provide human populations with consistent access to safe drinking water. Piped water requires little additional input from end users, and therefore has few additional barriers to the adoption and sustained consumption of water that is free of microbial contamination. In areas where the construction of piped water systems is not feasible due to capital or maintenance costs, or dispersed rural populations, the promotion of household water treatment and safe storage (HWTS) strategies have been recommended as the best method to deliver to safe water to households that lack affordable alternatives.Several HWTS strategies have been tested in field efficacy trials, including treatment by chlorine, filtration, boiling and solar disinfection. While various meta-analyses of these trials have suggested that HWTS strategies improve drinking water quality, and reduce diarrhea, there is some concern that: 1) the design and implementation of these trials may have biased results, and relatedly; 2) that these strategies themselves are not being used by target populations outside the context of these intensive trials. Specifically, each of the HWTS strategies listed above comes with small barriers to use: chlorine changes the taste and odor of the water and is not effective against spore forming pathogens (e.g., cryptosporidium), filters are slow and are have limited effectiveness against viruses, boiling changes the temperature of water and requires significant time and fuel inputs, and solar disinfection requires significant time inputs from end users to effectively produce safe water. In efficacy t

Globally, diarrhea is one of the leading causes of morbidity and mortality. Populations living in developing countries disproportionally experience the burden of diarrhea; in these areas contaminated drinking water remains one of the primary environmental pathways for the transmission of diarrheagenic pathogens. Centrally treated "piped" water is largely recognized as the best method to provide human populations with consistent access to safe drinking water. Piped water requires little additional input from end users, and therefore has few additional barriers to the adoption and sustained consumption of water that is free of microbial contamination. In areas where the construction of piped water systems is not feasible due to capital or maintenance costs, or dispersed rural populations, the promotion of household water treatment and safe storage (HWTS) strategies have been recommended as the best method to deliver to safe water to households that lack affordable alternatives.Several HWTS strategies have been tested in field efficacy trials, including treatment by chlorine, filtration, boiling and solar disinfection. While various meta-analyses of these trials have suggested that HWTS strategies improve drinking water quality, and reduce diarrhea, there is some concern that: 1) the design and implementation of these trials may have biased results, and relatedly; 2) that these strategies themselves are not being used by target populations outside the context of these intensive trials. Specifically, each of the HWTS strategies listed above comes with small barriers to use: chlorine changes the taste and odor of the water and is not effective against spore forming pathogens (e.g., cryptosporidium), filters are slow and are have limited effectiveness against viruses, boiling changes the temperature of water and requires significant time and fuel inputs, and solar disinfection requires significant time inputs from end users to effectively produce safe water. In efficacy t

Inconsistent use of household water treatment and safe storage (HWTS) systems reduces their potential health benefits. Ultraviolet (UV) disinfection is more convenient than some existing HWTS systems, but it does not provide post-treatment residual disinfectant, which could leave drinking water vulnerable to recontamination. In this paper, using as-treated analyses, we report on the field efficacy of a UV disinfection system at improving household drinking water quality in rural Mexico. We further assess the risk of post-treatment contamination from the UV system, and develop a process-based model to better understand household risk factors for recontamination. This study was part of a larger cluster-randomized stepped wedge trial, and the results complement previously published population-level results of the intervention on diarrheal prevalence and water quality. Based on the presence of Escherichia coli (proportion of households with ≥ 1 E. coli/100 mL), we estimated a risk difference of -28.0% (95% confidence interval (CI): -33.9%, -22.1%) when comparing intervention to control households; -38.6% (CI: -48.9%, -28.2%) when comparing post- and pre-intervention results; and -37.1% (CI: -45.2%, -28.9%) when comparing UV disinfected water to alternatives within the household. We found substantial increases in post-treatment E. coli contamination when comparing samples from the UV system effluent (5.0%) to samples taken from the storage container (21.1%) and drinking glasses (26.0%). We found that improved household infrastructure, additional extractions from the storage container, additional time from when the storage container was filled, and increased experience of the UV system operator were associated with reductions in post-treatment contamination. Our results suggest that the UV system is efficacious at improving household water quality when used as intended. Promoting safe storage habits is essential for an effective UV system dissemination. The drinking glass

Inconsistent use of household water treatment and safe storage (HWTS) systems reduces their potential health benefits. Ultraviolet (UV) disinfection is more convenient than some existing HWTS systems, but it does not provide post-treatment residual disinfectant, which could leave drinking water vulnerable to recontamination. In this paper, using as-treated analyses, we report on the field efficacy of a UV disinfection system at improving household drinking water quality in rural Mexico. We further assess the risk of post-treatment contamination from the UV system, and develop a process-based model to better understand household risk factors for recontamination. This study was part of a larger cluster-randomized stepped wedge trial, and the results complement previously published population-level results of the intervention on diarrheal prevalence and water quality. Based on the presence of Escherichia coli (proportion of households with ≥ 1 E. coli/100 mL), we estimated a risk difference of -28.0% (95% confidence interval (CI): -33.9%, -22.1%) when comparing intervention to control households; -38.6% (CI: -48.9%, -28.2%) when comparing post- and pre-intervention results; and -37.1% (CI: -45.2%, -28.9%) when comparing UV disinfected water to alternatives within the household. We found substantial increases in post-treatment E. coli contamination when comparing samples from the UV system effluent (5.0%) to samples taken from the storage container (21.1%) and drinking glasses (26.0%). We found that improved household infrastructure, additional extractions from the storage container, additional time from when the storage container was filled, and increased experience of the UV system operator were associated with reductions in post-treatment contamination. Our results suggest that the UV system is efficacious at improving household water quality when used as intended. Promoting safe storage habits is essential for an effective UV system dissemination. The drinking glass

Use of fecal indicator bacteria (FIB) for monitoring beach water quality is based on their co-occurrence with human pathogens, a relationship that can be dramatically altered by fate and transport processes after leaving the human intestine. We conducted a prospective cohort study at Avalon Beach, California (USA), where the indicator relationship is potentially affected by the discharge of sewage-contaminated groundwater and by solar radiation levels at this shallow, relatively quiescent beach. The goals of this study were to determine: 1) if swimmers exposed to marine water were at higher risk of illness than non-swimmers; 2) if FIB measured in marine water were associated with swimmer illness, and; 3) if the associations between FIB and swimmer health were modified by either submarine groundwater discharge or solar radiation levels. There were 7317 individuals recruited during the summers of 2007-08, 6165 (84%) of whom completed follow-up within two weeks of the beach visit. A total of 703 water quality samples were collected across multiple sites and time periods during recruitment days and analyzed for FIB using both culture-based and molecular methods. Adjusted odds ratios (AOR) indicated that swimmers who swallowed water were more likely to experience Gastrointestinal Illness (GI Illness) within three days of their beach visit than non-swimmers, and that this risk was significantly elevated when either submarine groundwater discharge was high (AOR [95% CI]:2.18 [1.22-3.89]) or solar radiation was low (2.45 [1.25-4.79]). The risk of GI Illness was not significantly elevated for swimmers who swallowed water when groundwater discharge was low or solar radiation was high. Associations between GI Illness incidence and FIB levels (Enterococcus EPA Method 1600) among swimmers who swallowed water were not significant when we did not account for groundwater discharge, but were strongly associated when groundwater discharge was high (1.85 [1.06, 3.23]) compared to when

BackgroundWater distribution systems are vulnerable to performance deficiencies that can cause (re)contamination of treated water and plausibly lead to increased risk of gastrointestinal illness (GII) in consumers.ObjectivesIt is well established that large system disruptions in piped water networks can cause GII outbreaks. We hypothesized that routine network problems can also contribute to background levels of waterborne illness and conducted a systematic review and meta-analysis to assess the impact of distribution system deficiencies on endemic GII.MethodsWe reviewed published studies that compared direct tap water consumption to consumption of tap water re-treated at the point of use (POU) and studies of specific system deficiencies such as breach of physical or hydraulic pipe integrity and lack of disinfectant residual.ResultsIn settings with network malfunction, consumers of tap water versus POU-treated water had increased GII [incidence density ratio (IDR) = 1.34; 95% CI: 1.00, 1.79]. The subset of nonblinded studies showed a significant association between GII and tap water versus POU-treated water consumption (IDR = 1.52; 95% CI: 1.05, 2.20), but there was no association based on studies that blinded participants to their POU water treatment status (IDR = 0.98; 95% CI: 0.90, 1.08). Among studies focusing on specific network deficiencies, GII was associated with temporary water outages (relative risk = 3.26; 95% CI: 1.48, 7.19) as well as chronic outages in intermittently operated distribution systems (odds ratio = 1.61; 95% CI: 1.26, 2.07).ConclusionsTap water consumption is associated with GII in malfunctioning distribution networks. System deficiencies such as water outages also are associated with increased GII, suggesting a potential health risk for consumers served by piped water networks.

BackgroundWater distribution systems are vulnerable to performance deficiencies that can cause (re)contamination of treated water and plausibly lead to increased risk of gastrointestinal illness (GII) in consumers.ObjectivesIt is well established that large system disruptions in piped water networks can cause GII outbreaks. We hypothesized that routine network problems can also contribute to background levels of waterborne illness and conducted a systematic review and meta-analysis to assess the impact of distribution system deficiencies on endemic GII.MethodsWe reviewed published studies that compared direct tap water consumption to consumption of tap water re-treated at the point of use (POU) and studies of specific system deficiencies such as breach of physical or hydraulic pipe integrity and lack of disinfectant residual.ResultsIn settings with network malfunction, consumers of tap water versus POU-treated water had increased GII [incidence density ratio (IDR) = 1.34; 95% CI: 1.00, 1.79]. The subset of nonblinded studies showed a significant association between GII and tap water versus POU-treated water consumption (IDR = 1.52; 95% CI: 1.05, 2.20), but there was no association based on studies that blinded participants to their POU water treatment status (IDR = 0.98; 95% CI: 0.90, 1.08). Among studies focusing on specific network deficiencies, GII was associated with temporary water outages (relative risk = 3.26; 95% CI: 1.48, 7.19) as well as chronic outages in intermittently operated distribution systems (odds ratio = 1.61; 95% CI: 1.26, 2.07).ConclusionsTap water consumption is associated with GII in malfunctioning distribution networks. System deficiencies such as water outages also are associated with increased GII, suggesting a potential health risk for consumers served by piped water networks.

Use of fecal indicator bacteria (FIB) for monitoring beach water quality is based on their co-occurrence with human pathogens, a relationship that can be dramatically altered by fate and transport processes after leaving the human intestine. We conducted a prospective cohort study at Avalon Beach, California (USA), where the indicator relationship is potentially affected by the discharge of sewage-contaminated groundwater and by solar radiation levels at this shallow, relatively quiescent beach. The goals of this study were to determine: 1) if swimmers exposed to marine water were at higher risk of illness than non-swimmers; 2) if FIB measured in marine water were associated with swimmer illness, and; 3) if the associations between FIB and swimmer health were modified by either submarine groundwater discharge or solar radiation levels. There were 7317 individuals recruited during the summers of 2007-08, 6165 (84%) of whom completed follow-up within two weeks of the beach visit. A total of 703 water quality samples were collected across multiple sites and time periods during recruitment days and analyzed for FIB using both culture-based and molecular methods. Adjusted odds ratios (AOR) indicated that swimmers who swallowed water were more likely to experience Gastrointestinal Illness (GI Illness) within three days of their beach visit than non-swimmers, and that this risk was significantly elevated when either submarine groundwater discharge was high (AOR [95% CI]:2.18 [1.22-3.89]) or solar radiation was low (2.45 [1.25-4.79]). The risk of GI Illness was not significantly elevated for swimmers who swallowed water when groundwater discharge was low or solar radiation was high. Associations between GI Illness incidence and FIB levels (Enterococcus EPA Method 1600) among swimmers who swallowed water were not significant when we did not account for groundwater discharge, but were strongly associated when groundwater discharge was high (1.85 [1.06, 3.23]) compared to when

BackgroundStudies of health risks associated with recreational water exposure require investigators to make choices about water quality indicator averaging techniques, exposure definitions, follow-up periods, and model specifications; however, investigators seldom describe the impact of these choices on reported results. Our objectives are to report illness risk from swimming at a marine beach affected by nonpoint sources of urban runoff, measure associations between fecal indicator bacteria levels and subsequent illness among swimmers, and investigate the sensitivity of results to a range of exposure and outcome definitions.MethodsIn 2009, we enrolled 5674 people in a prospective cohort at Malibu Beach, a coastal marine beach in California, and measured daily health symptoms 10-19 days later. Concurrent water quality samples were analyzed for indicator bacteria using culture and molecular methods. We compared illness risk between nonswimmers and swimmers, and among swimmers exposed to various levels of fecal indicator bacteria.ResultsDiarrhea was more common among swimmers than nonswimmers (adjusted odds ratio = 1.88 [95% confidence interval = 1.09-3.24]) within 3 days of the beach visit. Water quality was generally good (fecal indicator bacteria levels exceeded water quality guidelines for only 7% of study samples). Fecal indicator bacteria levels were not consistently associated with swimmer illness. Sensitivity analyses demonstrated that overall inference was not substantially affected by the choice of exposure and outcome definitions.ConclusionsThis study suggests that the 3 days following a beach visit may be the most relevant period for health outcome measurement in recreational water studies. Under the water quality conditions observed in this study, fecal indicator bacteria levels were not associated with swimmer illness.

BackgroundStudies of health risks associated with recreational water exposure require investigators to make choices about water quality indicator averaging techniques, exposure definitions, follow-up periods, and model specifications; however, investigators seldom describe the impact of these choices on reported results. Our objectives are to report illness risk from swimming at a marine beach affected by nonpoint sources of urban runoff, measure associations between fecal indicator bacteria levels and subsequent illness among swimmers, and investigate the sensitivity of results to a range of exposure and outcome definitions.MethodsIn 2009, we enrolled 5674 people in a prospective cohort at Malibu Beach, a coastal marine beach in California, and measured daily health symptoms 10-19 days later. Concurrent water quality samples were analyzed for indicator bacteria using culture and molecular methods. We compared illness risk between nonswimmers and swimmers, and among swimmers exposed to various levels of fecal indicator bacteria.ResultsDiarrhea was more common among swimmers than nonswimmers (adjusted odds ratio = 1.88 [95% confidence interval = 1.09-3.24]) within 3 days of the beach visit. Water quality was generally good (fecal indicator bacteria levels exceeded water quality guidelines for only 7% of study samples). Fecal indicator bacteria levels were not consistently associated with swimmer illness. Sensitivity analyses demonstrated that overall inference was not substantially affected by the choice of exposure and outcome definitions.ConclusionsThis study suggests that the 3 days following a beach visit may be the most relevant period for health outcome measurement in recreational water studies. Under the water quality conditions observed in this study, fecal indicator bacteria levels were not associated with swimmer illness.

Cell proliferation depends on the accurate and efficient processing of RNA transcripts to couple transcriptional and translational machineries to provide for rapid biomass accumulation. The 5' cap structure of RNA polymerase II transcripts and the nuclear cap binding complex (CBC) are important contributors to an array of post-transcriptional RNA processing events. This thesis identifies the protein Ars2 as a component of the nuclear CBC that is selectively expressed in proliferating cells. Ars2 is required for cell proliferation in vitro and in vivo in mammalian organisms. Ars2 serves as a biochemical bridge between the nuclear CBC and the microRNA processing machinery that contributes to gene silencing in proliferating cells. Furthermore, this thesis identifies Ars2 as an snRNA-binding protein that is required for the maintenance of snRNA levels. This work highlights the role of Ars2 as an RNA binding protein that has the potential to globally regulate various post-transcriptional maturation events to promote efficient gene expression in proliferating cells.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Economics, 1998., Includes bibliographical references (leaves 91-92)., by Jonah Benjamin Gelbach., Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Economics, 1998., Includes bibliographical references (leaves 91-92)., by Jonah Benjamin Gelbach., Ph.D.