Browsing by Author "Pan, William"

American cutaneous leishmaniasis (CL) is a severely understudied and neglected“disease of poverty” widespread throughout Peru. Transmission dynamics of CL are complex, requiring sandfly vectors and mammalian reservoir hosts to maintain the pathogen in a local environment whereby incidental hosts (people) can become infected. We employed a One-Health approach to understand CL transmission in rapidly changing region of northern Peru. We describe the characteristics of 529 CL positive patients from four participating clinics. Using conditional logistic regression, we assessed risk factors of CL for residents of small urban areas through a matched case-control study with 63 patients who had visited one of the same clinics for CL (cases) or other medical reasons (controls). We later enrolled 343 households as part of a community based study occurring in 15 urban and rural areas of Soritor. We found 256 positive humans (n= 914) as tested via the Montenegro Skin Test; we found 11 positive dogs (n = 236) via an immunofluorescence antibody test. Our results suggest that most- if not all- of CL transmission is occurring in rural areas and that urban women and urban children engage in many high risk activities typically attributed to men. We find evidence that prevalence of past infection is highest among rural residents and men. We believe dogs are unlikely Leishmania reservoirs in either rural or urban settings. It remains unknown if the high number of MST positive children in rural areas is a result of peridomestic or intradomestic transmission.

Air pollution is a common problem. Particulate matter generated from air pollution has been tied to adverse health outcomes associated with cardiovascular disease. Biomass fuels are a specific contributor to increased particulate matter and arise as a result of indoor heating, cook stoves and indoor food preparation. This is a two part cross sectional study looking at communities in the Madre de Dios region. Survey data was collected from 9 communities along the Madre de Dios River. Individual level household PM2.5 was also collected as a means to generate average PM data stratified by fuel use. Data collection was affected by a number of outside factors, which resulted in a loss of data. Results from the cross-sectional study indicate that hypertension is not a significant source of morbidity. Obesity is prevalent and significantly associated with kitchen venting method indicating a potential relationship.

Background: Understanding the multifactorial causes of anemia on a population level is important for creating effective interventions that mitigate poor health outcomes associated with anemia, particularly in regions where these rates are highly elevated. This study aims to quantify the relative prevalence of iron deficiency anemia, anemia of inflammation, and micronutrient deficiency anemia within 2 – 11 year olds in Madre de Dios (MDD), Peru, where anemia rates are estimated to be between 40 and 50%. It further aims to assess varying risk factors for given etiologies by community type, particularly as many communities in this region experience varied exposure to gold-mining related methylmercury. Methods: Eight communities along the Madre de Dios River, within the Peruvian Amazon, were selected in order to screen 2 – 11 year olds for anemia. Those qualifying as anemic were invited to provide venous blood samples for iron level, inflammation, and nutrition biomarker analyses in order to differentiate between these anemia etiologies. Health history and household characteristics were gathered in survey format, and analyzed in relation to gathered biomarkers. Results: Overall anemia prevalence (18.5%) was significantly decreased from previous studies. 14.9% were iron deficient, 12.8% showed signs of inflammation, and 12.8% were Vitamin B12 deficient. Anemia prevalence varied significantly by sex. Risk factors for anemia did not vary significantly by community type, other than increased annual income in urban and mining communities, and a reduced likelihood for having been born prematurely within mining communities. Conclusions: Peru’s multi-sectoral approach to reducing anemia has shown promising results in MDD. Health determinant variations have proven largely insignificant for anemia outcomes within the screened communities.

Aims: Measurement of glycated hemoglobin (HbA1c) is an important indicator of glucose control over time. Point-of-care (POC) devices allow for rapid and convenient measurement of HbA1c, greatly facilitating diabetes care. We assessed two POC analyzers in the Peruvian Amazon where laboratory-based HbA1c testing is not available.

Methods: Venous blood samples were collected from 203 individuals from six different Amazonian communities with a wide range of HbA1c, 4.4-9.0% (25-75 mmol/mol). The results of the Afinion AS100 and the DCA Vantage POC analyzers were compared to a central laboratory using the Premier Hb9210 high-performance liquid chromatography (HPLC) method. Imprecision was assessed by performing 14 successive tests of a single blood sample.

Results: The correlation coefficient r for POC and HPLC results was 0.92 for the Afinion and 0.93 for the DCA Vantage. The Afinion generated higher HbA1c results than the HPLC (mean difference = +0.56% [+6 mmol/mol]; p < 0.001), as did the DCA Vantage (mean difference = +0.32% [4 mmol/mol]). The bias observed between POC and HPLC did not vary by HbA1c level for the DCA Vantage (p = 0.190), but it did for the Afinion (p < 0.001). Imprecision results were: CV = 1.75% for the Afinion, CV = 4.01% for the DCA Vantage. Sensitivity was 100% for both devices, specificity was 48.3% for the Afinion and 85.1% for the DCA Vantage, positive predictive value (PPV) was 14.4% for the Afinion and 34.9% for the DCA Vantage, and negative predictive value (NPV) for both devices was 100%. The area under the receiver operating characteristic (ROC) curve was 0.966 for the Afinion and 0.982 for the DCA Vantage. Agreement between HPLC and POC in classifying diabetes and prediabetes status was slight for the Afinion (Kappa = 0.12) and significantly different (McNemar’s statistic = 89; p < 0.001), and moderate for the DCA Vantage (Kappa = 0.45) and significantly different (McNemar’s statistic = 28; p < 0.001).

Conclusions: Despite significant variation of HbA1c results between the Afinion and DCA Vantage analyzers compared to HPLC, we conclude that both analyzers should be considered in health clinics in the Peruvian Amazon for therapeutic adjustments if healthcare workers are aware of the differences relative to testing in a clinical laboratory. However, imprecision and bias were not low enough to recommend either device for screening purposes, and the local prevalence of anemia and malaria may interfere with diagnostic determinations for a substantial portion of the population.

Non-essential trace metals (lead, mercury, arsenic, and cadmium) are ubiquitous in our environment and have overlapping routes of exposure, yet mixed trace metal exposures are rarely considered in epidemiological studies. Instead, research often follows a single research question that focuses on a single trace metal of concern and does not incorporate potential co-exposures. The published literature of artisanal small-scale mining in the Amazon is a prime example as it has predominantly focused on mercury exposure, due to its use in the mining process. Once exposures of concern are identified, further studies evaluate health outcomes; however, the health effects cannot be accurately determined without accounting for co-exposures. This verification is becoming more important as there is a growing recognition that mixed trace metal exposures are more common than previously believed.To address the prevalence of mixed trace metal exposures and their health effects in the Peruvian Amazon region of Madre de Dios, I use epidemiological data from the COhorte de NAcimiento de MAdre de Dios (CONAMAD) birth cohort study (2018-Present), and two cross-sectional epidemiological studies (Amarakaeri Communal Reserve study (ACR, 2015), and Etiology and Toxic Metals study (EATM, 2018)). CONAMAD collected survey data along with maternal and cord blood samples at birth, which were processed for minerals and trace metals. The cross-sectional studies collected venous blood for trace metal analysis and hair samples for total hair mercury. Blood samples from the ACR were also processed for amino acids. In-depth demographic and health survey data were collected in all three studies. Structural equation models and random mixed effect models were used to evaluate research questions. The cross-sectional studies demonstrate a high correlation of lead and mercury exposure in communities that rely on wild fish and wild game as protein sources, which is prevalent throughout the Amazon. Consuming a meal of wild game resulted in an estimated lead dose of 500 µg, with those who eat wild game (Yes/No) associated with 1.41 µg/dL (95% CI: 1.20 – 1.70) higher blood lead levels compared to those who do not. This furthers the notion that mixed exposures are likely more common than previously believed. Mixed exposures target the same toxicological pathway, which may lead to synergistic or antagonistic effects. My research found that lead disrupts the arginine pathway and is associated with increased blood pressure. Mercury exposure was a modifier of the arginine pathway, with high blood mercury levels changing the effect of global arginine bioavailability from 17.16 (95% CI: 9.09 – 25.84) to -14.17 (95% CI: -31.88 - -0.33) on systolic blood pressure. Interestingly, mercury was not directly associated with the arginine pathway. Results from the birth cohort demonstrate the importance of nutrition and prenatal care for fetal development, which had a large positive effect on birthweight and gestational age. However, even low maternal lead exposure had detrimental effects on fetal health. A 1% increase in maternal blood lead was associated with a shorter gestational age of 0.05 days (β: -0.75, 95% CI: -1.51 - -0.13), even with the CONAMAD birth cohort having lower blood lead levels than other birth cohorts. There is a need for an integrated approach of nutritional and exposure assessments to better understand neonatal health outcomes.

The Loreto Region of Peru has the highest malaria rates in the country. Insecticide treated nets are one of the best prevention malaria prevention methods. Deltamethrin and permethrin are two of the most commonly used insecticides for treating bed nets, however insects are known to develop resistance to these insecticides. This study aims to compare deltamethrin and permethrin in the Northern Peruvian Amazon. This study examines the effectiveness of deltamethrin and permethrin in decreases the number of the malaria vector, the Anopheles mosquito, all mosquitos, and all insects in homes that use insecticide treated nets that have been treated with either deltamethrin or permethrin. Insects were collected using CDC light traps that were hung next to bed nets. Regressions were run after collecting insects that examine the decrease in number of insects in the homes, and odds ratios were calculated looking at the odds of seeing a decrease in number of insects in homes that received either a deltamethrin or permethrin treated net. This study provides insight as to whether deltamethrin or permethrin is a more effective insecticide in treated bed nets in the Northern Peruvian Amazon.

Despite global improvements in maternal mortality rates, preventable maternal deaths are still an issue for many populations. Indigenous populations, especially those in Latin America, often do not utilize delivery services for a number of reasons, not the least of which are cultural beliefs, geographic challenges, and ability to pay for services. The primary objective of this study is to examine the birth location and birth attendance trends across time of Amazonian Indigenous women compared to women of Andean Highland decent. Additionally, the study aims to compare the education levels, urban status, and income levels of these populations. This analysis uses survey data from families in Amarakaeri Communal Reserve in Amazonian Peru. Bivariate analysis and multivariate logistic regression were used to examine birth location and birth attendance across time. Since 1990, Amazonian Indigenous women in the study sample are increasingly giving birth at health posts in the attendance of nurses, but most still elect to give birth at home with a relative as an attendant. From this, it is concluded that women of Amazonian Indigenous decent are increasingly seeking out skilled birth attendants, but barriers to utilization may remain. Further descriptive research is necessary to ascertain the reasons why Amazonian Indigenous women still prefer giving birth at home, and additional modeling is necessary to determine the effects of potential influencing variables, such as urban status, education levels, and income levels.

While the Madre de Dios department of Peru has the nation's highest leishmaniasis incidence, limited research on the disease and its sand fly vector exists in the region. Considering the diverse and adaptive nature of sand flies, understanding vector ecology is essential to directing leishmaniasis control efforts. This study addresses this need by investigating the following aims: 1) describe sand fly abundance and biodiversity in communities along the Madre de Dios River; 2) identify environmental and socio-demographic factors associated with sand fly abundance and biodiversity in these communities; and 3) examine ecological risk factors associated with leishmaniasis in the communities. In order to accomplish these aims, the research team collected sand flies, obtained leishmaniasis case data, conducted community and household surveys, measured soil samples and studied land cover data in communities along the Madre de Dios River. We compared sand fly abundance, sand fly biodiversity and leishmaniasis incidence with soil chemistry, socio-demographic and land cover measures. We ran negative binomial regressions and Poisson regressions to investigate bivariate relationships between dependent and independent variables. We developed a multivariate model that predicts greater potential vector and non-vector abundance in areas with greater forest coverage, lower infrastructure indices and lower soil pH. This study provides an important overview of endemic sand fly fauna in Madre de Dios and presents an initial description of factors associated with sand fly populations in the region.

Malaria is a life-threatening vector-borne disease (VBD) that remains a major health concern for the northernmost region of Loreto, Peru. Increased malaria incidence has been connected to extractive industries such as mining and logging through factors such as increased deforestation, human mobility, and limited healthcare access. Due to limited knowledge on the impact of concessionary activity on malaria incidence, this study aims to: (1) investigate district-level malaria outbreak patterns across concessionary mining sites in Loreto, Peru and (2) determine the districts and population at most risk of malaria exposure in concessionary areas. Data was obtained from the Peruvian Ministry of Mines, Agriculture, and Health, as well as the Global Forest Watch (GFW). A Bayesian spatiotemporal Poisson regression model was fit for P. vivax and P. falciparum for the epidemiological weeks of 2015 to 2020 to see test the relationship between active mining concessions (in hectares and site number) and malaria incidence for the 53 districts of Loreto, Peru. We found that as mining hectares increased, malaria increased. Conversely, as mining sites increased, malaria incidence fell, possibly due to distribution of health services in condensed concessionary areas. Overall, this research will contribute to a better understanding of malaria reemergence and incidence in the Peruvian Amazon, and the relationship between concessionary land activity and VBDs. Results from this project could improve malaria forecasting models and land-use management practices.

Mercury is a pollutant of global concern and is considered a priority compound to many organizations, including the Agency for Toxic Substances and Disease Registry (ATSDR), the US Environmental Protection Agency (USEPA), the World Health Organization (WHO), and the United Nations Environment Programme (UNEP), due to mercury’s toxicity profile and the potential for human exposure (ATSDR, EPA, WHO, UNEP) (USEPA 2014, ATSDR 2015). Toxic outcomes depend greatly on the chemical compound, as adverse nervous system impacts are associated with organic mercury exposures and renal system impacts with elemental and inorganic mercury exposures (Lebel et al. 1996, Drake et al. 2001, Jarosinska et al. 2008). In particular, developmental delays and nervous system impacts occur at low dose exposures (Grandjean et al. 1997, NRC 2000). Chronic exposure has broad impacts from disrupting many cellular processes, including genotoxic and immunomodulatory impacts (Asmuß et al. 2000, Gallagher et al. 2011), however, the extent of impacts from chronic low-dose exposures is not well understood. Understanding the impacts of chronic low-dose exposures is important because globally many populations, including US coastal populations, have this type of exposure from regularly consuming seafood contaminated with methylmercury and because in some regions the risk for this type of exposure is increasing. Populations near artisanal and small-scale gold mining (ASGM), which uses mercury in the process to retrieve gold, have increased risk for chronic exposure. In some regions ASGM is rapidly expanding (Swenson et al. 2011, Emel et al. 2014, Snapir et al. 2017), increasing the concern for human health risks.

The goals of this dissertation were to investigate mercury’s influence on mitochondrial toxicity, focusing on genotoxic and immunotoxic endpoints, and determine the extent that co-exposures, including selenium and other dietary factors, modify exposure and adverse outcomes. Mercury has the potential to induce DNA damage indirectly through inducing reactive oxygen species (ROS) that damage DNA (Yee and Choi 1996, Ni et al. 2010) and impair DNA repair enzymes (Crespo-Lopez et al. 2009). Studies to date have primarily assessed nuclear DNA damage, and though mitochondrial damage is plausible, it has not been directly measured. Concerning immune impacts, in both laboratory and field animal studies, mercury exposure induces T-cell mediated immunosuppression and reduced antibody titers (Koller 1973, Snoeijs et al. 2004, Hawley et al. 2009, Fallacara et al. 2011b, a). There is also evidence for immunomodulation in humans including altered innate and adaptive immune responses, but this data has not been consistent between studies (Gardner et al. 2010b, Heilmann et al. 2010a, Gallagher et al. 2011). Diet and nutritional status appear to be important modifying factors to neurotoxic and immune outcomes. Omega-3 fatty acids have beneficial impacts on neurological development and mitigate mercury induced neruotoxicity to an extent (Oken et al. 2005). When nutritional status was considered in a US population, mercury significantly reduced measles and rubella antibody concentrations in the majority of children and was associated with an increase in antibodies in a nutritionally deficient subpopulation (vitamin B12, folate) (Gallagher et al. 2011, Gallagher et al. 2013).

In order to address these goals, laboratory and human studies were conducted. Laboratory studies using Caenorhabditis elegans were utilized to test the hypothesis that the mitochondrial DNA (mtDNA), and thus mitochondria in general, may be more susceptible to damage from being spatially closer to ROS production and from having different DNA repair pathways from nuclear DNA repair. To test this hypothesis DNA damage and repair, mitochondrial parameters such as DNA copy number and steady-state ATP levels were measured. Results suggested that co-exposures to stressors including H2O2 and UVC were important to DNA damage and mitochondrial impacts. Though exposure to MeHg and HgCl2 increased nuclear and mitochondrial DNA damage, mtDNA damage was particularly increased with MeHg and H2O2 co-exposure. MeHg co-exposures with both DNA damage agents also decreased mtDNA copy number by approximately 60%. Species dependent impacts were also observed with ATP levels. For the hypothesis that innate immune signaling may be altered, experiments focused on PMK-1, a p38 mitogen-activated protein kinase that has a protective role in infection and is required for immune induction, and measured the survival of immunocompetent nematodes (pmk-1) and expression of genes involved in the PMK-1 pathway. I observed that both MeHg and HgCl2 impact this pathway as both mercury species reduced pmk-1 expression.

Cross-sectional human studies were used to identify factors important to mercury exposure and determine the influence of nutritional status and mercury exposure on child immune response to immunization. Human studies were conducted communities located near ASGM in Madre de Dios, Peru. Important findings included that reduced mercury exposure, using hair mercury content as a proxy, was associated with frequent consumption of antioxidant-rich dietary items including quinoa, kiwicha, and some fruits. Similar to co-exposures, co-morbidity was also important to child immune response to routine vaccinations, though the direction of impact was not identical for all antibodies analyzed. Children that had high mercury exposure and were anemic had increased antibodies in some cases (total IgG and measles) and reduced antibodies for others (hepatitis B, Hib, and pertussis). These observations indicate that while mercury has impacts on adaptive immunity and disease susceptibility, the impacts may not be the same for all diseases.

In conclusion, I observed that mitochondrial toxicities are dependent on mercury species, that frequent consumption of antioxidant rich dietary items is associated with lower mercury exposure, and that nutritional status can influence mercury related immune outcomes. This work demonstrated the importance of considering co-exposures and co-morbidities when assessing mercury exposure impacts and highlights potential health hazards that include mitochondrial and immune system impacts.