A systematic review of the epidemiology evidence on talc and cancer.

Over the past several decades, there have been many epidemiology studies on talc and cancer published in the scientific literature, and several reviews and meta-analyses of talc and respiratory, female reproductive, and stomach cancers, specifically. To help provide a resource for the evaluation of talc as a potential human carcinogen, we applied a consistent set of examination methods and criteria for all epidemiology studies that examined the association between talc exposure (by various routes) and cancers (of various types). We identified 30 cohort, 35 case-control, and 12 pooled studies that evaluated occupational, medicinal, and personal-care product talc exposure and cancers of the respiratory system, the female reproductive tract, the gastrointestinal tract, the urinary system, the lymphohematopoietic system, the prostate, male genital organs, and the central nervous system, as well as skin, eye, bone, connective tissue, peritoneal, and breast cancers. We tabulated study characteristics, quality, and results in a systematic manner, and evaluated all cancer types for which studies of at least three unique populations were available in a narrative review. We focused on study quality aspects most likely to impact the interpretation of results. We found that only one study, of medicinal talc use, evaluated direct exposure measurements for any individuals, though some used semi-quantitative exposure metrics, and few studies adequately assessed potential confounders. The only consistent associations were with ovarian cancer in case-control studies and these associations were likely impacted by recall and potentially other biases. This systematic review indicates that epidemiology studies do not support a causal association between occupational, medicinal, or personal talc exposure and any cancer in humans.

A comparative analysis of regional infection risk due to wastewater recontamination in the Mezquital Valley, Mexico.

Urban wastewater reuse for agriculture provides reliable nutrient-rich water, reduces water stress, and strengthens food systems. However, wastewater reuse also presents health risks and characterizing the spatial dynamics of wastewater can help optimize risk mitigation. We conducted comparative risk analysis of exposure to wastewater in irrigation canals, where we compared those exposed to a) treated vs. untreated wastewater, and b) wastewater upstream vs. downstream from communities in the Mezquital Valley. The canal system with treated wastewater was sampled prior to being treated, directly after treatment, as well as before and after it flowed through a community. Along the canal system that carried untreated wastewater, we sampled before and after a community. We quantified the concentrations of bacterial, protozoal, and viral pathogens in the wastewater. Pathogen concentration data were used to calculate measures of relative risk between sampling points. Wastewater treatment reduced predicted bacterial pathogen infection risk in post-treatment locations (RR = 0.73, 95 % CI 0.61, 0.87), with no evidence of similar reductions in Giardia or viral pathogens (RR = 1.02, 95 % CI 0.56, 1.86 and RR = 1.18, 95 % CI 0.70, 2.02 respectively). Although infection risk decreased further down the canals, infection risk increased for bacterial pathogens after our sentinel community (RR = 1.94, 95 % 1.34, 2.86). For Giardia and viral pathogens infection risk was elevated but not significantly. We found similar evidence for increases in risk when comparing the treated section of the canal system with a canal section whose wastewater was not treated, i.e., the risk benefits of wastewater treatment were lost after our sentinel community for bacteria (RR = 5.27 vs. 2.08 for sampling points before and after our sentinel community respectively) and for Giardia (RR = 6.98 vs. 3.35 respectively). The increase in risk after transit through communities could have resulted from local community recontamination of the treated wastewater stream.

Multiscalar Evaluation of the Water Distribution System and Diarrheal Disease Risk in Addis Ababa, Ethiopia.

Despite growing urbanization, our understanding of the impacts of water and sanitation on human health has largely come from studies in rural sectors. To this end, we collected data at both regional (water quality measures from water treatment systems) and community (cross-sectional surveys) scales to examine determinants of enteric pathogen infection and diarrheal disease among infants in Addis Ababa, Ethiopia. Regionally, the Legedadi water treatment plant had significantly lower heterotrophic plate counts, total coliform counts, and fecal coliform counts compared with the Gefersa water treatment plant. The number of pathogen types in infant stool also differed by plant. Decreases in chlorine levels and increases in the relative abundance of Gammaproteobacteria with distance from treatment plants suggest a compromised water distribution system. In communities, infants in households that obtained water from yard pipes or public taps had significantly lower odds of diarrhea compared to households that had water piped into their dwellings (OR = 0.35, 95% CI 0.16, 0.76, and OR = 0.39, 95% CI 0.15, 1.00, respectively). Similarly, infants in households that boiled or filtered water had significantly lower odds of diarrhea compared to households that did not treat water (OR = 0.40, 95% CI 0.19, 0.86 and OR = 0.23, 95% CI 0.06, 0.84, respectively). Integrating multiscalar data better informs the health impacts of water in urban settings.

Stool biomarkers as measures of enteric pathogen infection in infants from Addis Ababa informal settlements.

Frequent enteric infections in children may be an important cause of growth faltering; however, we do not fully understand the mechanisms by which pathogen infections and the physiological responses to these infections result in poorer growth. Commonly used protein fecal biomarkers (anti-alpha trypsin, neopterin, and myeloperoxidase) provide broad immunological information on an inflammatory response; however, they do not provide information on non-immune processes (e.g., gut integrity) that may be important indicators of chronic end states such as environmental enteric dysfunction (EED). To explore how additional biomarkers will better inform which physiological pathways (both immune and non-immune) are impacted by pathogen exposure we added to the traditional panel of 3 protein fecal biomarkers 4 novel fecal mRNA transcript biomarkers (sucrase isomaltase, caudal homeobox 1, S100A8, and mucin 12) and analyzed stool samples from infants living in informal settlements in Addis Ababa, Ethiopia. To test how this expanded biomarker panel captures distinct pathogen exposure processes we used two different scoring systems. First, we used a theory-based approach to assign each biomarker to specific physiological attributes based on prior understanding of each biomarker. Second, we used data reduction methods to categorize biomarkers and then assign physiological attributes to those categories. We used linear models to examine the association between the derived biomarker scores (based on mRNA and protein levels) and stool pathogen gene counts to determine pathogen specific effects on gut physiology and immune responses. Inflammation scores were positively associated with Shigella and enteropathogenic E.Coli (EPEC) infection, while gut integrity scores were negatively associated with Shigella, EPEC and, shigatoxigenic E.coli (STEC) infection. Our expanded panel of biomarkers hold promise as tools to measure systemic outcomes of enteric pathogen infection. mRNA biomarkers complement established protein biomarkers by providing important cell-specific physiological and immunological consequences of pathogen carriage that can lead to chronic end states such as EED.

COVID-19 vaccination refusal trends in Kenya over 2021.

BACKGROUND: Vaccination refusal exacerbates global COVID-19 vaccination inequities. No studies in East Africa have examined temporal trends in vaccination refusal, precluding addressing refusal. We assessed vaccine refusal over time in Kenya, and characterized factors associated with changes in vaccination refusal. METHODS: We analyzed data from the Kenya Rapid Response Phone Survey (RRPS), a household cohort survey representative of the Kenyan population including refugees. Vaccination refusal (defined as the respondent stating they would not receive the vaccine if offered to them at no cost) was measured in February and October 2021. Proportions of vaccination refusal were plotted over time. We analyzed factors in vaccination refusal using a weighted multivariable logistic regression including interactions for time. FINDINGS: Among 11,569 households, vaccination refusal in Kenya decreased from 24 % in February 2021 to 9 % in October 2021. Vaccination refusal was associated with having education beyond the primary level (-4.1[-0.7,-8.9] percentage point difference (ppd)); living with somebody who had symptoms of COVID-19 in the past 14 days (-13.72[-8.9,-18.6]ppd); having symptoms of COVID-19 in the past 14 days (11.0[5.1,16.9]ppd); and distrusting the government in responding to COVID-19 (14.7[7.1,22.4]ppd). There were significant interactions with time and: refugee status and geography, living with somebody with symptoms of COVID-19, having symptoms of COVID-19, and believing in misinformation. INTERPRETATION: The temporal reduction in vaccination refusal in Kenya likely represents substantial strides by the Kenyan vaccination program and possible learnt lessons which require examination. Going forward, there are still several groups which need specific targeting to decrease vaccination refusal and improve vaccination equity, including those with lower levels of education, those with recent COVID-19 symptoms, those who do not practice personal COVID-19 mitigation measures, refugees in urban settings, and those who do not trust the government. Policy and program should focus on decreasing vaccination refusal in these populations, and research focus on understanding barriers and motivators for vaccination.

Ambient air pollution and non-communicable respiratory illness in sub-Saharan Africa: a systematic review of the literature.

INTRODUCTION: Aerosol pollutants are known to raise the risk of development of non-communicable respiratory diseases (NCRDs) such as asthma, chronic bronchitis, chronic obstructive pulmonary disease, and allergic rhinitis. Sub-Saharan Africa's rapid pace of urbanization, economic expansion, and population growth raise concerns of increasing incidence of NCRDs. This research characterizes the state of research on pollution and NCRDs in the 46 countries of Sub-Saharan Africa (SSA). This research systematically reviewed the literature on studies of asthma; chronic bronchitis; allergic rhinitis; and air pollutants such as particulate matter, ozone, NOx, and sulfuric oxide. METHODS: We searched three major databases (PubMed, Web of Science, and Scopus) using the key words "asthma", "chronic bronchitis", "allergic rhinitis", and "COPD" with "carbon monoxide (CO)", "sulfuric oxide (SO)", "ozone (O3)", "nitrogen dioxide (NO2)", and "particulate matter (PM)", restricting the search to the 46 countries that comprise SSA. Only papers published in scholarly journals with a defined health outcome in individuals and which tested associations with explicitly measured or modelled air exposures were considered for inclusion. All candidate papers were entered into a database for review. RESULTS: We found a total of 362 unique research papers in the initial search of the three databases. Among these, 14 met the inclusion criteria. These papers comprised studies from just five countries. Nine papers were from South Africa; two from Malawi; and one each from Ghana, Namibia, and Nigeria. Most studies were cross-sectional. Exposures to ambient air pollutants were measured using spectrometry and chromatography. Some studies created composite measures of air pollution using a range of data layers. NCRD outcomes were measured by self-reported health status and measures of lung function (spirometry). Populations of interest were primarily schoolchildren, though a few studies focused on secondary school students and adults. CONCLUSIONS: The paucity of research on NCRDs and ambient air pollutant exposures is pronounced within the African continent. While capacity to measure air quality in SSA is high, studies targeting NCRDs should work to draw attention to questions of outdoor air pollution and health. As the climate changes and SSA economies expand and countries urbanize, these questions will become increasingly important.

Long-Term PM2.5 Exposure Is Associated with Symptoms of Acute Respiratory Infections among Children under Five Years of Age in Kenya, 2014.

Introduction: Short-term exposures to air pollutants such as particulate matter (PM) have been associated with increased risk for symptoms of acute respiratory infections (ARIs). Less well understood is how long-term exposures to fine PM (PM2.5) might increase risk of ARIs and their symptoms. This research uses georeferenced Demographic Health Survey (DHS) data from Kenya (2014) along with a remote sensing based raster of PM2.5 concentrations to test associations between PM2.5 exposure and ARI symptoms in children for up to 12 monthly lags. Methods: Predicted PM2.5 concentrations were extracted from raster of monthly averages for latitude/longitude locations of survey clusters. These data and other environmental and demographic data were used in a logistic regression model of ARI symptoms within a distributed lag nonlinear modeling framework (DLNM) to test lag associations of PM2.5 exposure with binary presence/absence of ARI symptoms in the previous two weeks. Results: Out of 7036 children under five for whom data were available, 46.8% reported ARI symptoms in the previous two weeks. Exposure to PM2.5 within the same month and as an average for the previous 12 months was 18.31 and 22.1 µg/m3, respectively, far in excess of guidelines set by the World Health Organization. One-year average PM2.5 exposure was higher for children who experienced ARI symptoms compared with children who did not (22.4 vs. 21.8 µg/m3, p < 0.0001.) Logistic regression models using the DLNM framework indicated that while PM exposure was not significantly associated with ARI symptoms for early lags, exposure to high concentrations of PM2.5 (90th percentile) was associated with elevated odds for ARI symptoms along a gradient of lag exposure time even when controlling for age, sex, types of cooking fuels, and precipitation. Conclusions: Long-term exposure to high concentrations of PM2.5 may increase risk for acute respiratory problems in small children. However, more work should be carried out to increase capacity to accurately measure air pollutants in emerging economies such as Kenya.

Dilution of Epidemic Potential of Environmentally Transmitted Infectious Diseases for Species with Partially Overlapping Habitats.

AbstractSpecies diversity may play an important role in the modulation of pathogen transmission through the dilution effect. Infectious disease models can help elucidate mechanisms that may underlie this effect. While many modeling studies have assumed direct host-to-host transmission, many pathogens are transmitted through the environment. We present a mathematical modeling analysis exploring conditions under which we observe the dilution effect in systems with environmental transmission where host species interact through fully or partially overlapping habitats. We measure the strength of the dilution effect by the relative decrease in the basic reproduction number of two-species assemblages compared with that of a focal host species. We find that a dilution effect is most likely when the pathogen is environmentally persistent (frequency-dependent-like transmission). The magnitude of this effect is strongest when the species with the greater epidemic potential is relatively slow to pick up pathogens in the environment (density-dependent transmission) and the species with the lesser epidemic potential is efficient at picking up pathogens (frequency-dependent transmission). These findings suggest that measurable factors, including pathogen persistence and the host's relative efficiency of pathogen pickup, can guide predictions of when biodiversity might lead to a dilution effect and may thus give concrete direction to future ecological work.

Determinants of Pathogen Contamination of the Environment in the Greater Yangon Area, Myanmar.

Recent results from water, sanitation, and hygiene interventions highlight the need to better understand environmental influences on enteropathogen transmission. We quantified a range of viral, bacterial, and protozoal pathogens and one indicator, Enterococcus faecalis in soil and water from urban and rural sites in and around Yangon, Myanmar. We found that environmental characteristics associated with contamination differed by pathogens and substrates. In soil, bacterial pathogen gene counts were associated with elevation and drainage ditches (compared to stagnant water) (RR = 0.96, 95% CI 0.93, 0.99 and RR = 1.70, 95% CI 1.18, 2.45, respectively), while viral gene counts were associated with the presence of sanitation facilities within 50 m of the collection point (RR = 3.99, 95% CI 1.12, 14.24). In water, E. faecalis, total pathogen, and bacterial pathogen gene counts were associated with drainage ditches (RR = 1.86, 95% CI 1.27, 2.72, RR = 1.38 95% CI 1.09, 1.74, and RR = 1.38 95% CI 1.07, 1.77, respectively). E. faecalis, total pathogen, bacterial pathogen, and viral gene counts were associated with the presence of uncollected garbage within 50 m of the collection point (RR = 1.57, 95% CI 1.00, 2.47, RR = 1.52, 95% CI 1.16, 2.00, RR = 1.52, 95% CI 1.13, 2.06, and RR = 1.75, 95% CI 1.17, 2.61 respectively). Measuring the environment provides added specificity toward identifying important environmental pathways that require mitigation.

The sero-epidemiology of Coxiella burnetii (Q fever) across livestock species and herding contexts in Laikipia County, Kenya.

Coxiella burnetii, the causative agent of Query fever (Q fever), is among the most highly infectious zoonotic pathogens transmitted among livestock, with chronic effects challenging to veterinary and medical detection and care systems. Transmission among domestic livestock species can vary regionally due to herd management practices that determine which livestock species are raised, whether or not livestock are in contact with wildlife, and the susceptibility of these livestock to infection. To explore how different livestock management practices are associated with the risk of infection in multispecies environments, we carried out a comparative study of three types of herd management systems in the central Kenyan county of Laikipia: agro-commercial, mixed conservancy/commercial, and smallholder ranches. We tested C. burnetii antibody seroprevalence in four common livestock species. Across all management types, the highest seroprevalence was in camels (20%), followed by goats (18%), sheep (13%), and cattle (6%). We observed a lower odds of testing seropositive for young compared to adult animals (adjusted OR = 0.44 [95% CI 0.24, 0.76]), and for males compared to females (adjusted OR = 0.52 [95% CI 0.33, 0.80]). Animals from mixed conservancy/commercial and smallholder operations had a higher odds of testing seropositive compared to animals from agro-commercial ranches (adjusted OR = 5.17 [95% CI 2.71, 10.44] and adjusted OR = 2.21 [95% CI 1.17, 4.43] respectively). These data suggest that herd management practices might affect the transmission dynamics of C. burnetiiin arid African ecosystems like those seen in Kenya where several transmission modes are possible, risk of drought has promoted new livestock species such as camels, and multiple wildlife species may co-occur with livestock on the landscape. Further longitudinal studies are needed to disentangle the mechanisms underlying these patterns, and further explore transmission patterns between wildlife, domestic animal, and human populations.

The transcription factor scleraxis is a critical regulator of cardiac fibroblast phenotype.

BACKGROUND: Resident fibroblasts synthesize the cardiac extracellular matrix, and can undergo phenotype conversion to myofibroblasts to augment matrix production, impairing function and contributing to organ failure. A significant gap in our understanding of the transcriptional regulation of these processes exists. Given the key role of this phenotype conversion in fibrotic disease, the identification of such novel transcriptional regulators may yield new targets for therapies for fibrosis. RESULTS: Using explanted primary cardiac fibroblasts in gain- and loss-of-function studies, we found that scleraxis critically controls cardiac fibroblast/myofibroblast phenotype by direct transcriptional regulation of myriad genes that effectively define these cells, including extracellular matrix components and α-smooth muscle actin. Scleraxis furthermore potentiated the TGFß/Smad3 signaling pathway, a key regulator of myofibroblast conversion, by facilitating transcription complex formation. While scleraxis promoted fibroblast to myofibroblast conversion, loss of scleraxis attenuated myofibroblast function and gene expression. These results were confirmed in scleraxis knockout mice, which were cardiac matrix-deficient and lost ~50% of their complement of cardiac fibroblasts, with evidence of impaired epithelial-to-mesenchymal transition (EMT). Scleraxis directly transactivated several EMT marker genes, and was sufficient to induce mesenchymal/fibroblast phenotype conversion of A549 epithelial cells. Conversely, loss of scleraxis attenuated TGFß-induced EMT marker expression. CONCLUSIONS: Our results demonstrate that scleraxis is a novel and potent regulator of cellular progression along the continuum culminating in the cardiac myofibroblast phenotype. Scleraxis was both sufficient to drive conversion, and required for full conversion to occur. Scleraxis fulfills this role by direct transcriptional regulation of key target genes, and by facilitating TGFß/Smad signaling. Given the key role of fibroblast to myofibroblast conversion in fibrotic diseases in the heart and other tissue types, scleraxis may be an important target for therapeutic development.

Emerging concepts in cardiac matrix biology.

The cardiac extracellular matrix, far from being merely a static support structure for the heart, is now recognized to play central roles in cardiac development, morphology, and cell signaling. Recent studies have better shaped our understanding of the tremendous complexity of this active and dynamic network. By activating intracellular signal cascades, the matrix transduces myocardial physical forces into responses by myocytes and fibroblasts, affecting their function and behavior. In turn, cardiac fibroblasts and myocytes play active roles in remodeling the matrix. Coupled with the ability of the matrix to act as a dynamic reservoir for growth factors and cytokines, this interplay between the support structure and embedded cells has the potential to exert dramatic effects on cardiac structure and function. One of the clearest examples of this occurs when cell-matrix interactions are altered inappropriately, contributing to pathological fibrosis and heart failure. This review will examine some of the recent concepts that have emerged regarding exactly how the cardiac matrix mediates these effects, how our collective vision of the matrix has changed as a result, and the current state of attempts to pharmacologically treat fibrosis.

The basic helix-loop-helix transcription factor scleraxis regulates fibroblast collagen synthesis.

The transcription factor scleraxis has been implicated in regulating the development of collagen-rich tissues such as tendons and cardiac valves, but its role in general collagen synthesis in the heart is unknown. Scleraxis expression in cardiac fibroblasts was examined, and its ability to regulate gene expression of collagen I alpha 2, the predominant cardiac collagen isoform, was assayed. Using real-time PCR, we demonstrate here that scleraxis mRNA is up-regulated by the profibrotic agonist TGF-beta(1) in rat cardiac myofibroblasts, and that phenoconversion of fibroblasts to myofibroblasts similarly increases scleraxis expression. Over-expression of scleraxis in NIH-3T3 or primary rat cardiac fibroblasts by adenoviral gene delivery is sufficient to significantly increase collagen I alpha 2 gene expression. Using luciferase reporter assays, we demonstrate that scleraxis transactivates the human collagen I alpha 2 promoter in a DNA- and protein-binding dependent manner. Intriguingly, examination of infarcted rat hearts reveals a nearly four-fold increase in scleraxis expression in the infarct scar, but not in non-infarcted tissue. These data support a novel and previously unknown role for scleraxis in the regulation of collagen gene expression in the heart, including in post-infarct scar formation.

The role of sex in cardiac function and disease.

In the past decade, increasing attention has been paid to the importance of sex in the etiology of cardiac dysfunction. While focus has been primarily on how sex modulates atherogenesis, it is becoming clear that sex is both a predictor of outcome and an independent risk factor for a number of other cardiac diseases. Animal models and human studies have begun to shed light on the mechanisms by which sex influences the function of cardiomyocytes in health and disease. This review will survey the current literature on cardiac diseases that are influenced by sex and discuss the intracellular mechanisms by which steroid sex hormones affect heart function. A theory on how sex may regulate myocardial energy metabolism to affect disease susceptibility and progression will be presented, as well as a discussion of how sex may influence outcomes of experiments on isolated cardiomyocytes by epigenetic marking.