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Nisha S Joseph,1 Yu-Tzu Tai,2 Kenneth C Anderson,2 Sagar Lonial1 1Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA; 2Dana-Farber Cancer Institute, Harvard University, Boston, MA, USACorrespondence: Kenneth C AndersonDana-Farber Cancer Institute, Blood Compont, D289, 44 Binney St, Boston, MA, 02115, USATel +1 617 632-2569Email kenneth_anderson@dfci.harvard.eduAbstract: Though survival outcomes in multiple myeloma patients have improved drastically over the past few decades, there still remains an ongoing need for effective and tolerable treatment options in the relapsed and refractory space. Encouragingly, there have been three recent FDA approvals for triple-class refractory multiple myeloma, and there is promising ongoing development of additional agents with varying novel mechanisms of action. Here, we will review the most recent data on both belantamab mafodotin, an antibody drug conjugate (ADC) targeting BCMA, and selinexor, a first-in-class selective inhibitor of XPO1, as well as touch on some of the recently published data for other immunotherapies in development, namely bispecific T cell engagers, ADCs, and CAR-T cell therapies.Keywords: belantamab mafodotin, belamaf, selinexor, relapsed/refractory myeloma, myeloma

Infectious diseases exploit niches that are often spatially defined as urban and/or rural. Yet spatial research on infectious diseases often fails to define "urban" and "rural" and how these contexts might influence their epidemiology. We use dengue fever, thought to be mostly an urban disease with rural foci, as a device to explore local definitions of urban and rural spaces and the impact of these spaces on dengue risk in the provinfine urban and rural locales. Interviews conducted from 2019 to 2021 with 71 residents and 23 health personce of Esmeraldas, Ecuador. Ecuador, like many countries, only uses population size and administrative function to denel found that they identified the availability of basic services, extent of their control over their environment, and presence of underbrush and weeds (known in Ecuador as monte and maleza and conceptualized in this paper as natural disorder) as important links to their conceptions of space and dengue risk. This broader conceptualization of space articulated by local residents and professionals reflects a more sophisticated approach to characterizing dengue risk than using categories of urban and rural employed by the national census and government. Rather than this dichotomous category of space, dengue fever can be better framed for health interventions in terms of specific environmental features and assemblages of high-risk spaces. An understanding of how community members perceive risk enhances our ability to collaborate with them to develop optimal mitigation strategies.

The relative importance of environmental pathways that results in enteropathogen transmission may vary by context. However, measurement of contact events between individuals and the environment remains a challenge, especially for infants and young children who may use their mouth and hands to explore their environment. Using a mixed-method approach, we combined 1) semistructured observations to characterize key behaviors associated with enteric pathogen exposure and 2) structured observations using Livetrak, a customized software application, to quantify the frequency and duration of contacts events among infants in rural Ecuador. After developing and iteratively piloting the structured observation instrument, we loaded the final list of prompts onto a LiveTrak pallet to assess environmental exposures of 6-month infants (N = 19) enrolled in a prospective cohort study of diarrheal disease. Here we provide a detailed account of the lessons learned. For example, in our field site, 1) most mothers reported washing their hands after diaper changes (14/18, 77.8%); however only a third (4/11, 36.4%) were observed washing their hands; 2) the observers noted that animal ownership differed from observed animal exposure because animals owned by neighboring households were reported during the observation; and 3) using Livetrak, we found that infants frequently mouthed their hands (median = 1.9 episodes/hour, median duration: 1.6 min) and mouthed surroundings objects (1.8 episodes/hour, 1.9 min). Structured observations that track events in real time, can complement environmental sampling, quantitative survey data and qualitative interviews. Customizing these observations enabled us to quantify enteric exposures most relevant to our rural Ecuadorian context.

BackgroundThe urban-rural designation has been an important risk factor in infectious disease epidemiology. Many studies rely on a politically determined dichotomization of rural versus urban spaces, which fails to capture the complex mosaic of infrastructural, social and environmental factors driving risk. Such evaluation is especially important for Plasmodium transmission and malaria disease. To improve targeting of anti-malarial interventions, a continuous composite measure of urbanicity using spatially-referenced data was developed to evaluate household-level malaria risk from a house-to-house survey of children in Malawi.MethodsChildren from 7564 households from eight districts throughout Malawi were tested for presence of Plasmodium parasites through finger-prick blood sampling and slide microscopy. A survey questionnaire was administered and latitude and longitude coordinates were recorded for each household. Distances from households to features associated with high and low levels of development (health facilities, roads, rivers, lakes) and population density were used to produce a principal component analysis (PCA)-based composite measure for all centroid locations of a fine geo-spatial grid covering Malawi. Regression methods were used to test associations of the urbanicity measure against Plasmodium infection status and to predict parasitaemia risk for all locations in Malawi.ResultsInfection probability declined with increasing urbanicity. The new urbanicity metric was more predictive than either a governmentally defined rural/urban dichotomous variable or a population density variable. One reason for this was that 23% of cells within politically defined rural areas exhibited lower risk, more like those normally associated with "urban" locations.ConclusionsIn addition to increasing predictive power, the new continuous urbanicity metric provided a clearer mechanistic understanding than the dichotomous urban/rural designations. Such designations often ignore urban-like, low-risk pockets within traditionally rural areas, as were found in Malawi, along with rural-like, potentially high-risk environments within urban areas. This method of characterizing urbanicity can be applied to other infectious disease processes in rapidly urbanizing contexts.

Dengue is recognized as a major health issue in large urban tropical cities but is also observed in rural areas. In these environments, physical characteristics of the landscape and sociodemographic factors may influence vector populations at small geographic scales, while prior immunity to the four dengue virus serotypes affects incidence. In 2019, a rural northwestern Ecuadorian community, only accessible by river, experienced a dengue outbreak. The village is 2-3 hours by boat away from the nearest population center and comprises both Afro-Ecuadorian and Indigenous Chachi households. We used multiple data streams to examine spatial risk factors associated with this outbreak, combining maps collected with an unmanned aerial vehicle (UAV), an entomological survey, a community census, and active surveillance of febrile cases. We mapped visible water containers seen in UAV images and calculated both the green-red vegetation index (GRVI) and household proximity to public spaces like schools and meeting areas. To identify risk factors for symptomatic dengue infection, we used mixed-effect logistic regression models to account for the clustering of symptomatic cases within households. We identified 55 dengue cases (9.5% of the population) from 37 households. Cases peaked in June and continued through October. Rural spatial organization helped to explain disease risk. Afro-Ecuadorian (versus Indigenous) households experience more symptomatic dengue (OR = 3.0, 95%CI: 1.3, 6.9). This association was explained by differences in vegetation (measured by GRVI) near the household (OR: 11.3 95% 0.38, 38.0) and proximity to the football field (OR: 13.9, 95% 4.0, 48.4). The integration of UAV mapping with other data streams adds to our understanding of these dynamics.

BackgroundProjected increases in extreme weather may change relationships between rain-related climate exposures and diarrheal disease. Whether rainfall increases or decreases diarrhea rates is unclear based on prior literature. The concentration-dilution hypothesis suggests that these conflicting results are explained by the background level of rain: Rainfall following dry periods can flush pathogens into surface water, increasing diarrhea incidence, whereas rainfall following wet periods can dilute pathogen concentrations in surface water, thereby decreasing diarrhea incidence.ObjectivesIn this analysis, we explored the extent to which the concentration-dilution hypothesis is supported by published literature.MethodsTo this end, we conducted a systematic search for articles assessing the relationship between rain, extreme rain, flood, drought, and season (rainy vs. dry) and diarrheal illness.ResultsA total of 111 articles met our inclusion criteria. Overall, the literature largely supports the concentration-dilution hypothesis. In particular, extreme rain was associated with increased diarrhea when it followed a dry period [incidence rate ratio (IRR)=1.26; 95% confidence interval (CI): 1.05, 1.51], with a tendency toward an inverse association for extreme rain following wet periods, albeit nonsignificant, with one of four relevant studies showing a significant inverse association (IRR=0.911; 95% CI: 0.771, 1.08). Incidences of bacterial and parasitic diarrhea were more common during rainy seasons, providing pathogen-specific support for a concentration mechanism, but rotavirus diarrhea showed the opposite association. Information on timing of cases within the rainy season (e.g., early vs. late) was lacking, limiting further analysis. We did not find a linear association between nonextreme rain exposures and diarrheal disease, but several studies found a nonlinear association with low and high rain both being associated with diarrhea.DiscussionOur meta-analysis suggests that the effect of rainfall depends on the antecedent conditions. Future studies should use standard, clearly defined exposure variables to strengthen understanding of the relationship between rainfall and diarrheal illness. https://doi.org/10.1289/EHP6181.

The use of antimicrobial growth promoters in chicken farming has been commonly associated with high levels of antimicrobial resistance (AMR) in humans. Most of this work, however, has been focused on intensive large-scale operations. Intensive small-scale farming that regularly uses antibiotics is increasing worldwide and has different exposure pathways compared with large-scale farming, most notably the spatial connection between chickens and households. In these communities, free-ranging backyard chickens (not fed antibiotics) can roam freely, whereas broiler chickens (fed antibiotics) are reared in the same husbandry environment but confined to coops. We conducted an observational field study to better understand the spatial distribution of AMR in communities that conduct small-scale farming in northwestern Ecuador. We analyzed phenotypic resistance of Escherichia coli sampled from humans and backyard chickens to 12 antibiotics in relation to the distance to the nearest small-scale farming operation within their community. We did not find a statistically significant relationship between the distance of a household to small-scale farming and antibiotic-resistant E. coli isolated from chicken or human samples. To help explain this result, we monitored the movement of backyard chickens and found they were on average 17 m (min-max: 0-59 m) from their household at any given time. These backyard chickens on average ranged further than the average distance from any study household to its closest neighbor. This level of connectivity provides a viable mechanism for the spread of antimicrobial-resistant bacteria and genes throughout the community.

Infections with enteric pathogens impose a heavy disease burden, especially among young children in low-income countries. Recent findings from randomized controlled trials of water, sanitation, and hygiene interventions have raised questions about current methods for assessing environmental exposure to enteric pathogens. Approaches for estimating sources and doses of exposure suffer from a number of shortcomings, including reliance on imperfect indicators of fecal contamination instead of actual pathogens and estimating exposure indirectly from imprecise measurements of pathogens in the environment and human interaction therewith. These shortcomings limit the potential for effective surveillance of exposures, identification of important sources and modes of transmission, and evaluation of the effectiveness of interventions. In this review, we summarize current and emerging approaches used to characterize enteric pathogen hazards in different environmental media as well as human interaction with those media (external measures of exposure), and review methods that measure human infection with enteric pathogens as a proxy for past exposure (internal measures of exposure). We draw from lessons learned in other areas of environmental health to highlight how external and internal measures of exposure can be used to more comprehensively assess exposure. We conclude by recommending strategies for advancing enteric pathogen exposure assessments.

Domestic animals in the household environment have the potential to affect a child's carriage of zoonotic enteric pathogens and risk of diarrhea. This study examines the risk factors associated with pediatric diarrhea and carriage of zoonotic enteric pathogens among children living in communities where smallholder livestock production is prevalent. We conducted an observational study of children younger than 5 years that included the analysis of child (n = 306) and animal (n = 480) fecal samples for Campylobacter spp., atypical enteropathogenic Escherichia coli, Shiga toxin-producing E. coli, Salmonella spp., Yersinia spp., Cryptosporidium parvum, and Giardia lamblia. Among these seven pathogens, Giardia was the most commonly identified pathogen among children and animals in the same household, most of which was found in child-dog pairs. Campylobacter spp. was also relatively common within households, particularly among child-chicken and child-guinea pig pairs. We used multivariable Poisson regression models to assess risk factors associated with a child being positive for at least one zoonotic enteric pathogen or having diarrhea during the last week. Children who interacted with domestic animals-a behavior reported by nearly three-quarters of households owning animals-were at an increased risk of colonization with at least one zoonotic enteric pathogen (prevalence ratio [PR] = 1.56, 95% CI: 1.00-2.42). The risk of diarrhea in the last seven days was elevated but not statistically significant (PR = 2.27, CI: 0.91, 5.67). Interventions that aim to reduce pediatric exposures to enteric pathogens will likely need to be incorporated with approaches that remove animal fecal contamination from the domestic environment and encourage behavior change aimed at reducing children's contact with animal feces through diverse exposure pathways.

Climate change affects biophysical processes related to the transmission of many infectious diseases, with potentially adverse consequences for the health of communities. While our knowledge of biophysical associations between meteorological factors and disease is steadily improving, our understanding of the social processes that shape adaptation to environmental perturbations lags behind. Using computational modeling methods, we explore the ways in which social cohesion can affect adaptation of disease prevention strategies when communities are exposed to different environmental scenarios that influence transmission pathways for diseases such as diarrhea. We developed an agent-based model in which household agents can choose between two behavioral strategies that offer different levels of protection against environmentally mediated disease transmission. One behavioral strategy is initially set as more protective, leading households to adopt it widely, but its efficacy is sensitive to variable weather conditions and stressors such as floods or droughts that modify the disease transmission system. The efficacy of the second strategy is initially moderate relative to the first and is insensitive to environmental changes. We examined how social cohesion (defined as average number of household social network connections) influences health outcomes when households attempt to identify an optimal strategy by copying the behaviors of socially connected neighbors who seem to have adapted successfully in the past. Our simulation experiments suggest that high-cohesion communities are able to rapidly disseminate the initially optimal behavioral strategy compared to low-cohesion communities. This rapid and pervasive change, however, decreases behavioral diversity; i.e., once a high cohesion community settles on a strategy, most or all households adopt that behavior. Following environmental changes that reduce the efficacy of the initially optimal strategy, rendering it suboptimal relative to the alternative strategy, high-cohesion communities can fail to adapt. As a result, despite faring better early in the course of computational experiments, high-cohesion communities may ultimately experience worse outcomes. In the face of uncertainty in predicting future environmental stressors due to climate change, strategies to improve effective adaptation to optimal disease prevention strategies should balance between intervention efforts that promote protective behaviors based on current scientific understanding and the need to guard against the crystallization of inflexible norms. Developing generalizable models allows us to integrate a wide range of theories multiple datasets pertaining to the relationship between social mechanisms and adaptation, which can provide further understanding of future climate change impacts. Models such as the one we present can generate hypotheses about the mechanisms that underlie the dynamics of adaptation events and suggest specific points of measurement to assess the impact of these mechanisms. They can be incorporated as modules within predictive simulations for specific socio-ecological contexts.

Mass gatherings exacerbate infectious disease risks by creating crowded, high-contact conditions and straining the capacity of local infrastructure. While mass gatherings have been extensively studied in the context of epidemic disease transmission, the role of gatherings in incidence of high-burden, endemic infections has not been previously studied. Here, we examine diarrheal incidence among 17 communities in Esmeraldas, Ecuador, in relation to recurrent gatherings characterized using ethnographic data collected during and after the epidemiologic surveillance period (2004-2007). Using distributed-lag generalized estimating equations, adjusted for seasonality, trend, and heavy rainfall events, we found significant increases in diarrhea risk in host villages, peaking 2 weeks after an event's conclusion (incidence rate ratio, 1.21; confidence interval, adjusted for false coverage rate of ≤0.05: 1.02, 1.43). Stratified analysis revealed heightened risks associated with events where crowding and travel were most likely (2-week-lag incidence rate ratio, 1.51; confidence interval, adjusted for false coverage rate of ≤0.05: 1.09, 2.10). Our findings suggest that community-scale mass gatherings might play an important role in endemic diarrheal disease transmission and could be an important focus for interventions to improve community health in low-resource settings.

The relationship between rainfall, especially extreme rainfall, and increases in waterborne infectious diseases is widely reported in the literature. Most of this research, however, has not formally considered the impact of exposure measurement error contributed by the limited spatiotemporal fidelity of precipitation data. Here, we evaluate bias in effect estimates associated with exposure misclassification due to precipitation data fidelity, using extreme rainfall as an example. We accomplished this via a simulation study, followed by analysis of extreme rainfall and incident diarrheal disease in an epidemiologic study in Ecuador. We found that the limited fidelity typical of spatiotemporal rainfall data sets biases effect estimates towards the null. Use of spatial interpolations of rain-gauge data or satellite data biased estimated health effects due to extreme rainfall (occurrence) and wet conditions (accumulated totals) downwards by 35%-45%. Similar biases were evident in the Ecuadorian case study analysis, where spatial incompatibility between exposed populations and rain gauges resulted in the association between extreme rainfall and diarrheal disease incidence being approximately halved. These findings suggest that investigators should pay greater attention to limitations in using spatially heterogeneous environmental data sets to assign exposures in epidemiologic research.

There is increasing appreciation that latrine access does not imply use-many individuals who own latrines do not consistently use them. Little is known, however, about the determinants of latrine use, particularly among those with variable defecation behaviors. Using the integrated behavior model of water, sanitation, and hygiene framework, we sought to characterize determinants of latrine use in rural Ecuador. We interviewed 197 adults living in three communities with a survey consisting of 70 psychosocial defecation-related questions. Questions were excluded from analysis if responses lacked variability or at least 10% of respondents did not provide a definitive answer. All interviewed individuals had access to a privately owned or shared latrine. We then applied adaptive elastic nets (ENET) and supervised principal component analysis (SPCA) to a reduced dataset of 45 questions among 154 individuals with complete data to select determinants that predict self-reported latrine use. Latrine use was common, but not universal, in the sample (76%). The SPCA model identified six determinants and adaptive ENET selected five determinants. Three indicators were represented in both models-latrine users were more likely to report that their latrine is clean enough to use and also more likely to report daily latrine use; while those reporting that elderly men were not latrine users were less likely to use latrines themselves. Our findings suggest that social norms are important predictors of latrine use, whereas knowledge of the health benefits of sanitation may not be as important. These determinants are informative for promotion of latrine adoption.

Small-scale farming may have large impacts on the selection and spread of antimicrobial resistance to humans. We conducted an observational study to evaluate antibiotic-resistant Escherichia coli populations from poultry and humans in rural northwestern Esmeraldas, Ecuador. Our study site is a remote region with historically low resistance levels of third-generation antibiotics such cefotaxime (CTX), a clinically relevant antibiotic, in both poultry and humans. Our study revealed 1) high CTX resistance (66.1%) in farmed broiler chickens, 2) an increase in CTX resistance over time in backyard chicken not fed antibiotics (2.3-17.9%), and 3) identical bla CTX-M sequences from human and chicken bacteria, suggesting a spillover event. These findings provide evidence that small-scale meat production operations have direct impacts on the spread and selection of clinically important antibiotics among underdeveloped settings.

Rotavirus is considered a directly transmitted disease due to its high infectivity. Environmental pathways have, therefore, largely been ignored. Rotavirus, however, persists in water sources, and both its surface water concentrations and infection incidence vary with temperature. Here, we examine the potential for waterborne rotavirus transmission. We use a mechanistic model that incorporates both direct and waterborne transmission pathways, coupled with a hydrological model, and we simulate rotavirus transmission between two communities with interconnected water sources. To parameterize temperature dependency, we estimated temperature-dependent decay rates in water through a meta-analysis. Our meta-analysis suggests that rotavirus decay rates are positively associated with temperature (n = 39, P [Formula: see text] 0.001). This association is stronger at higher temperatures (over 20 °C), consistent with tropical climate conditions. Our model analysis demonstrates that water could disseminate rotavirus between the two communities for all modeled temperatures. While direct transmission was important for disease amplification within communities, waterborne transmission could also amplify transmission. In standing-water systems, the modeled increase in decay led to decreased disease, with every 1 °C increase in temperature leading to up to a 2.4% decrease in incidence. These effect sizes are consistent with prior meta-analyses, suggesting that environmental transmission through water sources may partially explain the observed associations between temperature and rotavirus incidence. Waterborne rotavirus transmission is likely most important in cooler seasons and in communities that use slow-moving or stagnant water sources. Even when indirect transmission through water cannot sustain outbreaks, it can seed outbreaks that are maintained by high direct transmission rates.

SummarySmall-scale food animal production is widely practiced around the globe, yet it is often overlooked in terms of the environmental health risks. Evidence suggests that small-scale food animal producers often employ the use of antimicrobials to improve the survival and growth of their animals, and that this practice leads to the development of antimicrobial resistance (AMR) that can potentially spread to humans. The nature of human-animal interactions in small-scale food animal production systems, generally practiced in and around the home, likely augments spillover events of AMR into the community on a scale that is currently unrecognized and deserves greater attention. https://doi.org/10.1289/EHP2116.

Children living in homes with livestock may have both an increased risk of enteric infections and improved access to food, and therefore improved nutritional status. Few studies, however, have characterized these relationships in tandem. This study investigated the association between child health and household ownership of livestock. A cross-sectional study was performed using data from Demographic and Health Surveys conducted in 30 sub-Saharan African countries with 215,971 rural children under 5 years of age from 2005 to 2015. Logistic regression was performed for each country to estimate the relationship between a log2 increase in the number of livestock owned by the household and three child-health outcomes: 2-week prevalence of diarrhea, stunting, and all-cause mortality. Results for each country were combined using meta-analyses. Most countries (22 of 30) displayed an odds ratio (OR) less than 1 for child stunting associated with livestock (pooled OR = 0.97; 95% confidence interval [CI] = 0.95, 0.99). The results for diarrhea were more even with 14 countries displaying ORs greater than 1 and 10 displaying ORs less than 1. Most countries (22 of 30) displayed an OR greater than 1 for child mortality (pooled OR = 1.04; 95% CI = 1.02, 1.06). All meta-analyses displayed significant heterogeneity by country. Our analysis is consistent with the theory that livestock may have a dual role as protective against stunting, an indicator of chronic malnutrition, and a risk factor for all-cause mortality in children, which may be linked to acute infections. The heterogeneity by country, however, indicates more data are needed on specific household livestock management practices.

As the appreciation for the importance of the environment in infectious disease transmission has grown, so too has interest in pathogen fate and transport. Fate has been traditionally described by simple exponential decay, but there is increasing recognition that some pathogens demonstrate a biphasic pattern of decay-fast followed by slow. While many have attributed this behavior to population heterogeneity, we demonstrate that biphasic dynamics can arise through a number of plausible mechanisms. We examine the identifiability of a general model encompassing three such mechanisms: population heterogeneity, hardening off, and the existence of viable-but-not-culturable states. Although the models are not fully identifiable from longitudinal sampling studies of pathogen concentrations, we use a differential algebra approach to determine identifiable parameter combinations. Through case studies using Cryptosporidium and Escherichia coli, we show that failure to consider biphasic pathogen dynamics can lead to substantial under- or overestimation of disease risks and pathogen concentrations, depending on the context. More reliable models for environmental hazards and human health risks are possible with an improved understanding of the conditions in which biphasic die-off is expected. Understanding the mechanisms of pathogen decay will ultimately enhance our control efforts to mitigate exposure to environmental contamination.

Mosquito management within households remains central to the control of dengue virus transmission. An important factor in these management decisions is the spatial clustering of Aedes aegypti. We measured spatial clustering of Ae. aegypti in the town of Borbón, Ecuador and assessed what characteristics of breeding containers influenced the clustering. We used logistic regression to assess the spatial extent of that clustering. We found strong evidence for juvenile mosquito clustering within 20 m and for adult mosquito clustering within 10 m, and stronger clustering associations for containers ≥ 40 L than those < 40 L. Aedes aegypti clusters persisted after adjusting for various container characteristics, suggesting that patterns are likely attributable to short dispersal distances rather than shared characteristics of containers in cluster areas. These findings have implications for targeting Ae. aegypti control efforts.

BackgroundAlthough the U.S. Environmental Protection Agency has a long history of using risk-based approaches for regulatory purposes, pollutant limits for pathogens in biosolids are not currently based on quantitative risk assessments.ObjectivesWe developed and demonstrated a risk-based methodology for assessing the risk to human health from exposure to pathogens via biosolids.MaterialsFour models were developed, incorporating direct ingestion, groundwater, and aerosol exposure pathways. Three sources of environmental data were used to estimate risk: pathogen monitoring of sludge, efficacy of sludge treatment, and pathogen monitoring of biosolids.ResultsRisk estimates were obtainable even for Class A biosolids, where posttreatment monitoring data are below detectable levels, demonstrating that risk assessments for biosolids exposure are practical. Model analyses suggest that: a) a two-digester design decreases the probability of risks >10(-4) compared with one-digester designs, b) risks associated with exposures to groundwater and aerosol pathways were, in general, lower than exposures to the direct ingestion pathway, and c) secondary transmission can be an important factor in risk estimation.ConclusionsThe risk-based approach presented here provides a tool to a) help biosolids producers interpret the results of biosolids monitoring data in terms of its health implications, b) help treatment plant engineers evaluate the risk-based benefits of operational changes to existing or projected treatment processes, and c) help environmental managers evaluate potential capital improvements and/or land application site placement issues. Regulation of pathogens can now be based on human health risk in a manner parallel to other water-related risks.

Risk assessments and intervention trials have been used by the U.S. Environmental Protection Agency to estimate drinking water health risks. Seldom are both methods used concurrently. Between 2001 and 2003, illness data from a trial were collected simultaneously with exposure data, providing a unique opportunity to compare direct risk estimates of waterborne disease from the intervention trial with indirect estimates from a risk assessment. Comparing the group with water treatment (active) with that without water treatment (sham), the estimated annual attributable disease rate (cases per 10,000 persons per year) from the trial provided no evidence of a significantly elevated drinking water risk [attributable risk=-365 cases/year, sham minus active; 95% confidence interval (CI) , -2,555 to 1,825]. The predicted mean rate of disease per 10,000 persons per person-year from the risk assessment was 13.9 (2.5, 97.5 percentiles: 1.6, 37.7) assuming 4 log removal due to viral disinfection and 5.5 (2.5, 97.5 percentiles: 1.4, 19.2) assuming 6 log removal. Risk assessments are important under conditions of low risk when estimates are difficult to attain from trials. In particular, this assessment pointed toward the importance of attaining site-specific treatment data and the clear need for a better understanding of viral removal by disinfection. Trials provide direct risk estimates, and the upper confidence limit estimates, even if not statistically significant, are informative about possible upper estimates of likely risk. These differences suggest that conclusions about waterborne disease risk may be strengthened by the joint use of these two approaches. Key words: drinking water, gastrointestinal, intervention trial, microbial risk assessment, waterborne pathogens.

Despite numerous studies, uncertainty remains about how water quality indicators can best be used in the regulation of recreational water. We conducted a systematic review of this topic with the goal of quantifying the association between microbial indicators of recreational water quality and gastrointestinal (GI) illness. A secondary goal was to evaluate the potential for GI illness below current guidelines. We screened 976 potentially relevant studies and from these identified 27 studies. From the latter, we determined summary relative risks for GI illness in relation to water quality indicator density. Our results support the use of enterococci in marine water at U.S. Environmental Protection Agency guideline levels. In fresh water, (Italic)Escherichia(/Italic) coli was a more consistent predictor of GI illness than are enterococci and other bacterial indicators. A log (base 10) unit increase in enterococci was associated with a 1.34 [95% confidence intervals (CI), 1.00-1.75] increase in relative risk in marine waters, and a log (base 10) unit increase in E. coli was associated with a 2.12 (95% CI, 0.925-4.85) increase in relative risk in fresh water. Indicators of viral contamination were strong predictors of GI illness in both fresh and marine environments. Significant heterogeneity was noted among the studies. In our analysis of heterogeneity, studies that used a nonswimming control group, studies that focused on children, and studies of athletic or other recreational events found elevated relative risks. Future studies should focus on the ability of new, more rapid and specific microbial methods to predict health effects, and estimating the risks of recreational water exposure among susceptible persons.

Developing effective policy for environmental health issues requires integrating large collections of information that are diverse, highly variable, and uncertain. Despite these uncertainties in the science, decisions must be made. These decisions often have been based on risk assessment. We argue that two important features of risk assessment are to identify research needs and to provide information for decision making. One type of information that a model can provide is the sensitivity of making one decision over another on factors that drive public health risk. To achieve this goal, a risk assessment framework must be based on a description of the exposure and disease processes. Regarding exposure to waterborne pathogens, the appropriate framework is one that explicitly models the disease transmission pathways of pathogens. This approach provides a crucial link between science and policy. Two studies--a Giardia risk assessment case study and an analysis of the 1993 Milwaukee, Wisconsin, Cryptosporidium outbreak--illustrate the role that models can play in policy making.

Abstract Purpose Survivin/BIRC5 is a proliferation marker that is associated with poor prognosis in breast cancer and an attractive therapeutic target. However, BIRC5 has not been well studied among racially diverse populations where aggressive breast cancers are prevalent. Experimental design We studied BIRC5 expression in association with clinical and demographic variables and as a predictor of recurrence in 2174 participants in the Carolina Breast Cancer Study (CBCS), a population-based study that oversampled Black (n = 1113) and younger ( 2 cm). Relative to BIRC5-low, BIRC5-high tumors were associated with poor 5-year recurrence-free survival (RFS) among ER-positive tumors, both in unadjusted models [HR (95% CI): 2.7 (1.6, 4.6)] and after adjustment for age and stage [Adjusted HR (95% CI): 1.87 (1.07, 3.25)]. However, this relationship was not observed among ER-negative tumors [Crude HR (95% CI): 0.7 (0.39, 1.2); Adjusted HR (95% CI): 0.67 (0.37, 1.2)]. Conclusion Black and younger women with breast cancer have a higher burden of BIRC5-high tumors than older and non-Black women. Emerging anti-survivin treatment strategies may be an important future direction for equitable breast cancer outcomes.

Three months after the first shipment of RTS,S1/AS01 vaccines, Cameroon started, on 22 January 2024, to roll out malaria vaccines in 42 districts among the most at risk for malaria. Cameroon adopted and implemented the World Health Organization (WHO) malaria vaccine readiness assessment tool to monitor the implementation of preintroduction activities at the district and national levels. One week before the start of the vaccine rollout, overall readiness was estimated at 89% at a national level with two out of the five components of readiness assessment surpassing 95% of performance (vaccine, cold chain and logistics and training) and three components between 80% and 95% (planning, monitoring and supervision, and advocacy, social mobilisation and communication). ‘Vaccine, cold chain and logistics’ was the component with the highest number of districts recording below 80% readiness. The South-West and North-West, two regions with a high level of insecurity, were the regions with the highest number of districts that recorded a readiness performance below 80% in the five components. To monitor progress in vaccine rollout daily, Cameroon piloted a system for capturing immunisation data by vaccination session coupled with an interactive dashboard using the R Shiny platform. In addition to displaying data on vaccine uptake, this dashboard allows the generation of the monthly immunisation report for all antigens, ensuring linkage to the regular immunisation data system based on the end-of-month reporting through District Health Information Software 2. Such a hybrid system complies with the malaria vaccine rollout principle of full integration into routine immunisation coupled with strengthened management of operations.

Objective: Social and economic changes associated with new roads can bring about rapid nutritional transitions. To study this process, we: (1) describe trends in adult overweight and obesity (OW/OB) among rural Afro-Ecuadorians over time and across a gradient of community remoteness from the nearest commercial centre; (2) examine the relationship between male and female adult OW/OB and factors associated with market integration such as changing livelihoods and (3) examine the co-occurrence of adult OW/OB and under-five stunting and anaemia.Design: Adult anthropometry was collected through serial case-control studies repeated over a decade across twenty-eight communities. At the same time, anthropometry and Hb were measured for all children under 5 years of age in every community.Setting: Northern coastal Ecuador.Participants: Adults (n 1665) and children under 5 years of age (n 2618).Results: From 2003 and 2013, OW/OB increased from 25·1 % to 44·8 % among men and 59·9 % to 70·2 % among women. The inverse relationship between remoteness and OW/OB in men was attenuated when adjusting for urban employment, suggesting that livelihoods mediated the remoteness-OW/OB relationship. No such relationship was observed among women. Communities with a higher prevalence of male OW/OB also had a greater prevalence of stunting, but not anaemia, in children under 5 years of age.Conclusions: The association between male OW/OB and child stunting at the community level, but not the household level, suggests that changing food environments, rather than household- or individual-level factors, drove these trends. A closer examination of changing socio-economic structures and food environments in communities undergoing rapid development could help mitigate future public health burdens. [ABSTRACT FROM AUTHOR]

This study was conducted to investigate the effects of different process parameters on the degree of fusion of two adjacent tracks produced by fused deposition modelling of acrylonitrile butadiene styrene. Incorrectly defined process parameters adversely influence the geometrical accuracy, surface roughness, and mechanical properties of the printed parts. Therefore, numerous studies have been conducted to this effect, but few investigations have focused on the defects of tracks, monolayers, double, or few layers despite significantly influencing the shape of the entire component and causing other printing defects. In this respect, the current study assesses the fusion of two adjacent tracks when printed using different key process parameters (layer thickness, infill density, printing speed, air gap, and extrusion temperature). The printed adjacent double track parts were examined using a scanning electron microscope and their degree of fusion calculated as a ratio of the height of the neck (h) and diameter of adjacent double tracks (d) after fusion and cooling. It was concluded that the highest degree of fusion of two adjacent tracks of acrylonitrile butadiene styrene material was obtained at 0.25 mm, 40 mm/s, −0.10 mm, and 255 °C layer thickness, printing speed, air gap, and extrusion temperature, respectively.

(1) Background: Laboratories supporting the invasive bacteria preventable disease (IB-VPD) network are expected to demonstrate the capacity to identify the main etiological agents of pediatric bacterial meningitis (PBM) (Neisseria meningitidis, Streptococcus pneumoniae and Haemophilus influenzae) on Gram stains and in phenotypic identification. Individual reports of sentinel site (SSL), national (NL) and regional reference (RRL) laboratories participating in the World Health Organization (WHO)-coordinated external quality assessment, distributed by the United Kingdom National External Quality Assessment (EQA) Services (UK NEQAS) for Microbiology between 2014 and 2019 were analyzed. (2) Methods: The panels consisted of (1) unstained bacterial smears for Gram staining, (2) viable isolates for identification and serotyping/serogrouping (ST/SG) and (3) simulated cerebral spinal fluid (CSF) samples for species detection and ST/SG using polymerase chain reaction (PCR). SSLs and NLs tested for Gram staining and species identification (partial panel). RRLs, plus any SSLs and NLs (optionally) also analyzed the simulated CSF samples (full panel). The passing score was ≥75% for NLs and SSLs, and ≥90% for RRLs and NLs/SSLs testing the full panel. (3) Results: Overall, 63% (5/8) of the SSLs and NLs were able to correctly identify the targeted pathogens, in 2019; but there were challenges to identify Haemophilus influenzae either on Gram stains (35% of the labs failed 2014), or in culture. Individual performance showed inconsistent capacity, with only 39% (13/33) of the SSLs/NLs passing the EQA exercise throughout all surveys in which they participated. RRLs performed well over the study period, but one of the two failed to reach the minimal passing score in 2016 and 2018; while the SSLs/NLs that optionally tested the full panel scored between 75% and 90% (intermediate pass category). (4) Conclusions: We identified a need for implementing a robust quality management system for timely identification of the gaps and then implementing corrective and preventive actions, in addition to continuous refresher training in the SSLs and NLs supporting the IB-VPD surveillance in the World Health Organization, Regional Office for Africa (WHO AFRO).

The country's strong reliance on oil and gas exports exposes it to the considerable risk of global oil market instability, as external debt continues to rise as exports fall, more attention is being paid to the consequences of this trend. The major goal of this paper is to determine Nigeria's rising external debt and declining exports, using an autoregressive distributed lag (ARDL) model, we investigated Nigeria's rising external debt and declining exports using annual time series data from 1986 to 2020. In the short run across the study period, the study reveals evidence of a negligible beneficial impact of both external debt and export on economic growth meaning that in the short run, both foreign debt and export have a negligible beneficial impact on economic growth, according to the estimates in Nigeria, in reality, in the long run, the impact is negative, with exports having a greater negative impact than foreign debt, as a result, the paper submits that Nigeria's economy is at a fork in the road, based on these findings, it is suggested that external borrowing be restricted until current debt stocks are repaid, that external loans be tied to specific projects to avoid inefficient fund allocation, that domestic capital markets be explored as an alternative to external borrowing, that more export diversification be undertaken to mitigate poor performance of primary commodity exports, and that commodity exchanges be established to attract more speculators, external borrowing should be limited until current debt stocks are serviced in order to achieve economic growth.

Background: Following the World Health Organization (WHO) recommendation, 38/47 countries have introduced rotavirus vaccines into the program of immunization in the WHO Regional Office for Africa (WHO/AFRO). Initially, two vaccines (Rotarix and Rotateq) were recommended and recently two additional vaccines (Rotavac and Rotasiil) have become available. However, the global supply challenges have increasingly forced some countries in Africa to switch vaccine products. Therefore, the recent WHO pre-qualified vaccines (Rotavac, Rotasiil) manufactured in India, offer alternatives and reduce global supply challenges related to rotavirus vaccines; Methods: Using a questionnaire, we administered to the Program Managers, Expanded Program for Immunization, we collected data on vaccine introduction and vaccine switch and the key drivers of the decisions for switching vaccines products, in the WHO/AFRO. Data was also collected fromliterature review and the global new vaccine introduction status data base maintained by WHO and other agencies. Results: Of the 38 countries that introduced the vaccine, 35 (92%) initially adopted Rotateq or Rotarix; and 23% (8/35) switched between products after rotavirus vaccine introduction to either Rotavac (n = 3), Rotasiil (n = 2) or Rotarix (n = 3). Three countries (Benin, Democratic Republic of Congo and Nigeria) introduced the rotavirus vaccines manufactured in India. The decision to either introduce or switch to the Indian vaccines was predominately driven by global supply challenges or supply shortage. The withdrawal of Rotateq from the African market, or cost-saving for countries that graduated or in transition from Gavi support was another reason to switch the vaccine; Conclusions: The recently WHO pre-qualified vaccines have offered the countries, opportunities to adopt these cost-effective products, particularly for countries that have graduated or transitioning from full Gavi support, to sustain the demand of vaccines products.

TB Programs should promote the use of digital health platforms, like Electronic Medical Records (EMR) to collect patients' information, thus reducing data incompleteness and low accuracy and eventually improving patients' care. Nevertheless, the potential of digital health systems remains largely unexploited in low-resource settings. Angola is one of the 14 countries with a triple burden of TB, TB/HIV and MDR-TB (multidrug-resistant TB) and it is among the three countries, together with Congo and Liberia that have never completed a drug-resistance survey so far. The Sanatorium Hospital of Luanda and the Tuberculosis Dispensary of Luanda are the two reference health facilities in Luanda dealing with most of the TB cases, and they both rely entirely on paper-based data collection. The aim of this paper is to describe a three-stage process for the development of a TB EMR system in these two health facilities of Luanda and to share the lessons learned. The description is focused on the activities that took place from March 2019 to January 2020. Main lessons learned were identified in the importance of engaging all the stakeholders in the development process, in the mainstream of the “think digital” transition, in the promotion of a monitoring and evaluation (M&E) culture and in the planning of the system's sustainability. This approach may be replicated in similar contexts where the development of a TB EMR system is sought, and the lessons learned could assist and facilitate the programming of the interventions.

Childhood tuberculosis (TB) is consistently under-detected in most high-burden countries, including Uganda, especially in young children at high risk for severe disease and mortality. TB preventive treatment (TPT) for high-risk child contacts is also poorly implemented. The centralised concentration of services for child TB at the referral level is a major challenge in the prevention, detection and treatment of TB in children. In 2015, the DETECT Child TB Project was implemented in two districts of Uganda and involved decentralisation of healthcare services for child TB from tertiary to primary healthcare facilities, along with establishing linkages to support community-based household contact screening and management. The intervention resulted in improved case finding of child and adult TB cases, improved treatment outcomes for child TB and high uptake and completion of TPT for eligible child contacts. A detailed description of the development and implementation of this project is provided, along with findings from an external evaluation. The ongoing mentorship and practical support for health workers to deliver optimal services in this context were critical to complement the use of training and training tools. A summary of the project’s outcomes is provided along with the key challenges identified and the lessons learnt.

INTRODUCTION : il y a plus de 2 millions de cas de fistule génitale en Afrique subsaharienne et en Asie. Elles surviennent dans les zones où l'accès aux soins à l'accouchement est limité ou de qualité médiocre et où peu d'hôpitaux offrent les interventions chirurgicales correctives nécessaires. L'objectif de cette étude est de développer un score prédictif permettant d'identifier les facteurs influant sur l'échec de la réparation chirurgicale de la fistule obstétricale vésico-vaginale (ERCF) dans la partie Sud-Est de la province du Haut-Katanga.Méthodes: il s'agit d'une étude transversale analytique menée sur 384 femmes porteuses d'une fistule obstétricale vésico-vaginale ayant bénéficié d'une prise en charge chirurgicale. Nous avons procédé par une analyse univariée puis multivariée. La discrimination du score était évaluée à l'aide de la courbe Receiving Operating Characteristics (ROC) et du C-index et la calibration du score selon le test d'Hosmer-Lemeshow.Résultats: la réparation chirurgicale de la fistule obstétricale vésico-vaginale s'était soldée par un échec dans 17,19% des cas (66/384). Après modélisation logistique, quatre critères ressortent comme facteurs prédictifs d'ERCF: la présence d'une fibrose cicatricielle (ORa=15,22; IC95%: 7,34-31,58), la présence de 2 fistules ou plus (ORa=7,41 ; IC95%: 3,05-17,97), l'abord trans-vésical comme voie d'abord (ORa=4,26; IC95%: 1,92-9,44) et l'atteinte urétrale (ORa=3,93; IC95%: 1,99-7,77). L'aire sous la courbe ROC du score est de 0,8759 avec une sensibilité de 57,58%, une spécificité de 91,82% et une valeur prédictive positive de 91,25%.Conclusion: cette étude a démontré que le nombre de fistules, la fibrose cicatricielle, l'atteinte urétrale et l'abord transvésical sont des facteurs permettant de prédire l'ERCF.

Background: Uganda is located in East Africa and is among the countries with the lowest income globally. The ten health centres in this project serve populations in the under-privileged communities of Kampala. The objective of the study was to implement diabetes mellitus (DM) screening among tuberculosis (TB) patients in a routine program setting with limited resources and high human immunodeficiency virus (HIV) prevalence. Methods: A descriptive cross-sectional observational study was conducted in ten health centres in Kampala, Uganda. As part of a project to implement DM screening in a routine setting, TB patients were screened for DM by trained health workers. A fasting blood glucose (FBG) value ≥7.0mmol/l was considered to indicate DM. For this study, aggregate data was collected and analysed using SPSS for Windows, version 13.0. Results: Among 4,590 TB patients registered, 4,016 (88.0%) were screened with random blood glucose (RBG). Of those with RBG ≥6.1mmol/l, 1,093 (83.3%) were screened with FBG. In total, 92 (2.3%) patients were diagnosed with DM and 66 (71.8%) of them were newly diagnosed. The proportion of TB patients screened with FBG in the health centres varied from 58.2% to 100%. The proportion of patients screened with FBG and the prevalence of DM were significantly higher in private health centres compared with public health centres. The health centres in peri-urban areas screened more patients with RBG than those in urban areas. These health centres without DM services screened a larger number of patients with RBG and FBG than those with DM services. Conclusions: It appears feasible to implement screening TB patients for DM in routine program settings with limited resources and high HIV prevalence. Its introduction requires close collaboration between TB and DM services. The challenges identified need government attention and certain institutional and service-related factors need to be better managed at times

INTRODUCTION: La parturition des primipares est associée à de nombreuses complications et par conséquent, elles sont considérées comme étant à haut risque en raison des préoccupations maternelles et fétales. La présente étude s'est fixé comme objectifs de déterminer la fréquence d'accouchement chez les primipares dans notre milieu, d'identifier les facteurs associés à laccouchement par césarienne et d'évaluer la morbi-mortalité maternelle et périnatale lors de l'accouchement chez la primipare dans la ville de Lubumbashi. METHODES: c'était une étude transversale analytique des accouchées d'une grossesse monofétale de Décembre 2013 à Mai 2014 dans 10 maternités de référence à Lubumbashi. Les accouchées primipares ont été comparées aux multipares. Les paramètres sociodémographiques maternels, la morbi-mortalité maternelle et périnatale ont été analysées. L'odds ratio et son intervalle de confiance ont été calculés. Le seuil de signification a été fixé à une valeur de p = 0,05. RESULTATS: la fréquence de la primiparité était de 19,9%. Comparativement aux multipares, les accouchées primipares étaient significativement adolescentes (OR = 11,27 (7,98-15,91)), élèves/étudiantes (OR=5,61 (3,33-9,45)) et vivaient seules (OR = 7,62 (4,36-13,30)). Les facteurs de risque associés à l'accouchement par césarienne chez les primipares étaient l'évacuation obstétricale (OR=9,69 (4,75-19,74)), le manque de suivi de consultations prénatales (OR=2,57 (1,32-5,01)), la taille =150 cm (OR = 2,42 (1,04-5,65)), la hauteur utérine 34 cm (OR=2,33 (1,32-4,10)) et la mal présentation fétale (OR=6,37 (2,92-13,87)). S'agissant du pronostic maternel, nous avons observé que la pression artérielle élevée (OR=1,91 (1,32-2,74)), la mal présentation fétale (OR=1,95 (1,16-3,17)), le recours à l'utilisation d'ocytociques (OR=2,03 (1,64-2,52)), la césarienne (OR=2,04 (1,47-2,83)), l'épisiotomie (OR=11,89 (8,61-16,43)) et l'éclampsie (OR = 4,21 (1,55-11,44)), étaient significativement associées à la primiparité. Les taux de score d'Apgar déprimé à la fin de la 5 ème minute (OR=1,55 (1,03-2,32)) et de décès en période néonatale précoce (OR=1,80 (1,08-2,98)) étaient significativement plus élevés chez les primipares que chez les multipares. CONCLUSION: cette étude montre que l'accouchement de la primipare reste un problème à Lubumbashi. D'où l'amélioration de la sante du couple mère-enfant lors de l'accouchement chez la primipare passe par l'élaboration des protocoles de prise en charge des accouchements adéquats.