An analytically tractable, age-structured model of the impact of vector control on mosquito-transmitted infections.

Vector control is a vital tool utilised by malaria control and elimination programmes worldwide, and as such it is important that we can accurately quantify the expected public health impact of these methods. There are very few previous models that consider vector-control-induced changes in the age-structure of the vector population and the resulting impact on transmission. We analytically derive the steady-state solution of a novel age-structured deterministic compartmental model describing the mosquito feeding cycle, with mosquito age represented discretely by parity-the number of cycles (or successful bloodmeals) completed. Our key model output comprises an explicit, analytically tractable solution that can be used to directly quantify key transmission statistics, such as the effective reproductive ratio under control, Rc, and investigate the age-structured impact of vector control. Application of this model reinforces current knowledge that adult-acting interventions, such as indoor residual spraying of insecticides (IRS) or long-lasting insecticidal nets (LLINs), can be highly effective at reducing transmission, due to the dual effects of repelling and killing mosquitoes. We also demonstrate how larval measures can be implemented in addition to adult-acting measures to reduce Rc and mitigate the impact of waning insecticidal efficacy, as well as how mid-ranges of LLIN coverage are likely to experience the largest effect of reduced net integrity on transmission. We conclude that whilst well-maintained adult-acting vector control measures are substantially more effective than larval-based interventions, incorporating larval control in existing LLIN or IRS programmes could substantially reduce transmission and help mitigate any waning effects of adult-acting measures.

Reducing the Antigen Prevalence Target Threshold for Stopping and Restarting Mass Drug Administration for Lymphatic Filariasis Elimination: A Model-Based Cost-effectiveness Simulation in Tanzania, India and Haiti.

BACKGROUND: The Global Programme to Eliminate Lymphatic Filariasis (GPELF) aims to reduce and maintain infection levels through mass drug administration (MDA), but there is evidence of ongoing transmission after MDA in areas where Culex mosquitoes are the main transmission vector, suggesting that a more stringent criterion is required for MDA decision making in these settings. METHODS: We use a transmission model to investigate how a lower prevalence threshold (<1% antigenemia [Ag] prevalence compared with <2% Ag prevalence) for MDA decision making would affect the probability of local elimination, health outcomes, the number of MDA rounds, including restarts, and program costs associated with MDA and surveys across different scenarios. To determine the cost-effectiveness of switching to a lower threshold, we simulated 65% and 80% MDA coverage of the total population for different willingness to pay per disability-adjusted life-year averted for India ($446.07), Tanzania ($389.83), and Haiti ($219.84). RESULTS: Our results suggest that with a lower Ag threshold, there is a small proportion of simulations where extra rounds are required to reach the target, but this also reduces the need to restart MDA later in the program. For 80% coverage, the lower threshold is cost-effective across all baseline prevalences for India, Tanzania, and Haiti. For 65% MDA coverage, the lower threshold is not cost-effective due to additional MDA rounds, although it increases the probability of local elimination. Valuing the benefits of elimination to align with the GPELF goals, we find that a willingness to pay per capita government expenditure of approximately $1000-$4000 for 1% increase in the probability of local elimination would be required to make a lower threshold cost-effective. CONCLUSIONS: Lower Ag thresholds for stopping MDAs generally mean a higher probability of local elimination, reducing long-term costs and health impacts. However, they may also lead to an increased number of MDA rounds required to reach the lower threshold and, therefore, increased short-term costs. Collectively, our analyses highlight that lower target Ag thresholds have the potential to assist programs in achieving lymphatic filariasis goals.

Accelerating Progress Towards the 2030 Neglected Tropical Diseases Targets: How Can Quantitative Modeling Support Programmatic Decisions?

Over the past decade, considerable progress has been made in the control, elimination, and eradication of neglected tropical diseases (NTDs). Despite these advances, most NTD programs have recently experienced important setbacks; for example, NTD interventions were some of the most frequently and severely impacted by service disruptions due to the coronavirus disease 2019 (COVID-19) pandemic. Mathematical modeling can help inform selection of interventions to meet the targets set out in the NTD road map 2021-2030, and such studies should prioritize questions that are relevant for decision-makers, especially those designing, implementing, and evaluating national and subnational programs. In September 2022, the World Health Organization hosted a stakeholder meeting to identify such priority modeling questions across a range of NTDs and to consider how modeling could inform local decision making. Here, we summarize the outputs of the meeting, highlight common themes in the questions being asked, and discuss how quantitative modeling can support programmatic decisions that may accelerate progress towards the 2030 targets.

Conservation of Earth's biodiversity is embedded in Indigenous fire stewardship.

Increasingly, severe wildfires have led to declines in biodiversity across all of Earth's vegetated biomes [D. B. McWethy et al., Nat. Sustain. 2, 797-804 (2019)]. Unfortunately, the displacement of Indigenous peoples and place-based societies that rely on and routinely practice fire stewardship has resulted in significant declines in biodiversity and the functional roles of people in shaping pyrodiverse systems [R. Bliege Bird et al., Proc. Natl. Acad. Sci. U.S.A. 117, 12904-12914 (2020)]. With the aim of assessing the impacts of Indigenous fire stewardship on biodiversity and species function across Earth's major terrestrial biomes, we conducted a review of relevant primary data papers published from 1900 to present. We examined how the frequency, seasonality, and severity of human-ignited fires can improve or reduce reported metrics of biodiversity and habitat heterogeneity as well as changes to species composition across a range of taxa and spatial and temporal scales. A total of 79% of applicable studies reported increases in biodiversity as a result of fire stewardship, and 63% concluded that habitat heterogeneity was increased by the use of fire. All studies reported that fire stewardship occurred outside of the window of uncontrollable fire activity, and plants (woody and nonwoody vegetation) were the most intensively studied life forms. Three studies reported declines in biodiversity associated with increases in the use of high-severity fire as a result of the disruption of Indigenous-controlled fire regimes with the onset of colonization. Supporting Indigenous-led fire stewardship can assist with reviving important cultural practices while protecting human communities from increasingly severe wildfires, enhancing biodiversity, and increasing ecosystem heterogeneity.

Bacterial Metabolism and Transport Genes Are Associated with the Preference of Drosophila melanogaster for Dietary Yeast.

Many animal traits are influenced by their associated microorganisms ("microbiota"). To expand our understanding of the relationship between microbial genotype and host phenotype, we report an analysis of the influence of the microbiota on the dietary preference of the fruit fly Drosophila melanogaster. First, we confirmed through experiments on flies reared bacteria-free ("axenic") or in monoassociation with two different strains of bacteria that the microbiota significantly influences fruit fly dietary preference across a range of ratios of dietary yeast:dietary glucose. Then, focusing on microbiota-dependent changes in fly dietary preference for yeast (DPY), we performed a metagenome-wide association (MGWA) study to define microbial species specificity for this trait and to predict bacterial genes that influence it. In a subsequent mutant analysis, we confirmed that disrupting a subset of the MGWA-predicted genes influences fly DPY, including for genes involved in thiamine biosynthesis and glucose transport. Follow-up tests revealed that the bacterial influence on fly DPY did not depend on bacterial modification of the glucose or protein content of the fly diet, suggesting that the bacteria mediate their effects independent of the fly diet or through more specific dietary changes than broad ratios of protein and glucose. Together, these findings provide additional insight into bacterial determinants of host nutrition and behavior by revealing specific genetic disruptions that influence D. melanogaster DPY. IMPORTANCE Associated microorganisms ("microbiota") impact the physiology and behavior of their hosts, and defining the mechanisms underlying these interactions is a major gap in the field of host-microbe interactions. This study expands our understanding of how the microbiota can influence dietary preference for yeast (DPY) of a model host, Drosophila melanogaster. First, we show that fly preferences for a range of different dietary yeast:dietary glucose ratios vary significantly with the identity of the microbes that colonize the fruit flies. We then performed a metagenome-wide association study to identify candidate bacterial genes that contributed to some of these bacterial influences. We confirmed that disrupting some of the predicted genes, including genes involved in glucose transport and thiamine biosynthesis, resulted in changes to fly DPY and show that the influence of two of these genes is not through changes in dietary ratios of protein to glucose. Together, these efforts expand our understanding of the bacterial genetic influences on a feeding behavior of a model animal host.

Predicted Impact of COVID-19 on Neglected Tropical Disease Programs and the Opportunity for Innovation.

Due to the COVID-19 pandemic, many key neglected tropical disease (NTD) activities have been postponed. This hindrance comes at a time when the NTDs are progressing towards their ambitious goals for 2030. Mathematical modelling on several NTDs, namely gambiense sleeping sickness, lymphatic filariasis, onchocerciasis, schistosomiasis, soil-transmitted helminthiases (STH), trachoma, and visceral leishmaniasis, shows that the impact of this disruption will vary across the diseases. Programs face a risk of resurgence, which will be fastest in high-transmission areas. Furthermore, of the mass drug administration diseases, schistosomiasis, STH, and trachoma are likely to encounter faster resurgence. The case-finding diseases (gambiense sleeping sickness and visceral leishmaniasis) are likely to have fewer cases being detected but may face an increasing underlying rate of new infections. However, once programs are able to resume, there are ways to mitigate the impact and accelerate progress towards the 2030 goals.

Elimination or Resurgence: Modelling Lymphatic Filariasis After Reaching the 1% Microfilaremia Prevalence Threshold.

The low prevalence levels associated with lymphatic filariasis elimination pose a challenge for effective disease surveillance. As more countries achieve the World Health Organization criteria for halting mass treatment and move on to surveillance, there is increasing reliance on the utility of transmission assessment surveys (TAS) to measure success. However, the long-term disease outcomes after passing TAS are largely untested. Using 3 well-established mathematical models, we show that low-level prevalence can be maintained for a long period after halting mass treatment and that true elimination (0% prevalence) is usually slow to achieve. The risk of resurgence after achieving current targets is low and is hard to predict using just current prevalence. Although resurgence is often quick (<5 years), it can still occur outside of the currently recommended postintervention surveillance period of 4-6 years. Our results highlight the need for ongoing and enhanced postintervention monitoring, beyond the scope of TAS, to ensure sustained success.

When, Who, and How to Sample: Designing Practical Surveillance for 7 Neglected Tropical Diseases as We Approach Elimination.

As neglected tropical disease programs look to consolidate the successes of moving towards elimination, we need to understand the dynamics of transmission at low prevalence to inform surveillance strategies for detecting elimination and resurgence. In this special collection, modelling insights are used to highlight drivers of local elimination, evaluate strategies for detecting resurgence, and show the importance of rational spatial sampling schemes for several neglected tropical diseases (specifically schistosomiasis, soil-transmitted helminths, lymphatic filariasis, trachoma, onchocerciasis, visceral leishmaniasis, and gambiense sleeping sickness).

Flower-visitor communities of an arcto-alpine plant-Global patterns in species richness, phylogenetic diversity and ecological functioning.

Pollination is an ecosystem function of global importance. Yet, who visits the flower of specific plants, how the composition of these visitors varies in space and time and how such variation translates into pollination services are hard to establish. The use of DNA barcodes allows us to address ecological patterns involving thousands of taxa that are difficult to identify. To clarify the regional variation in the visitor community of a widespread flower resource, we compared the composition of the arthropod community visiting species in the genus Dryas (mountain avens, family Rosaceae), throughout Arctic and high-alpine areas. At each of 15 sites, we sampled Dryas visitors with 100 sticky flower mimics and identified specimens to Barcode Index Numbers (BINs) using a partial sequence of the mitochondrial COI gene. As a measure of ecosystem functioning, we quantified variation in the seed set of Dryas. To test for an association between phylogenetic and functional diversity, we characterized the structure of local visitor communities with both taxonomic and phylogenetic descriptors. In total, we detected 1,360 different BINs, dominated by Diptera and Hymenoptera. The richness of visitors at each site appeared to be driven by local temperature and precipitation. Phylogeographic structure seemed reflective of geological history and mirrored trans-Arctic patterns detected in plants. Seed set success varied widely among sites, with little variation attributable to pollinator species richness. This pattern suggests idiosyncratic associations, with function dominated by few and potentially different taxa at each site. Taken together, our findings illustrate the role of post-glacial history in the assembly of flower-visitor communities in the Arctic and offer insights for understanding how diversity translates into ecosystem functioning.

Preclinical In-Vivo Evaluation and Screening of Zinc Based Degradable Metals for Endovascular Stents.

Zinc alloy development and characterization for vascular stent application has been facilitated by many standardized and inexpensive methods. In contrast, overly simplistic in vitro approaches dominate the preliminary biological testing of materials. In 2012, our group introduced a metal wire implantation model in rats as a cost effective and realistic approach for the biocompatibility evaluation of degradable materials in the vascular environment. Here, we have adapted metrics routinely used for evaluating stents to quantitatively characterize the long-term progression of the neointima that forms around zinc based wire implants. Histological cross-sections were used to measure the length of neointimal protrusion from the wire into the lumen (denoted wire to lumen thickness), the base neointimal length (describing the breadth of neointimal activation), and the neointimal area. These metrics were used to provide in depth characterization details for neointimal responses to Zn-Mg and Zn-Li alloys and may be used to compare different materials.

Limited prospects for future alpine treeline advance in the Canadian Rocky Mountains.

Treeline advance has occurred throughout the twentieth century in mountainous regions around the world; however, local variation and temporal lags in responses to climate warming indicate that the upper limits of some treelines are not necessarily in climatic equilibrium. These observations suggest that factors other than climate are constraining tree establishment beyond existing treelines. Using a seed addition experiment, we tested the effects of seed availability, predation and microsite limitation on the establishment of two subalpine tree species (Picea engelmannii and Abies lasiocarpa) across four treelines in the Canadian Rocky Mountains. The effect of vegetation removal on seedling growth was also determined, and microclimate conditions were monitored. Establishment limitations observed in the field were placed in context with the effects of soil properties observed in a parallel experiment. The seed addition experiment revealed reduced establishment with increasing elevation, suggesting that although establishment within the treeline ecotone is at least partially seed limited, other constraints are more important beyond the current treeline. The effects of herbivory and microsite availability significantly reduced seedling establishment but were less influential beyond the treeline. Microclimate monitoring revealed that establishment was negatively related to growing season temperatures and positively related to the duration of winter snow cover, counter to the conventional expectation that establishment is limited by low temperatures. Overall, it appears that seedling establishment beyond treeline is predominantly constrained by a combination of high soil surface temperatures during the growing season, reduced winter snowpack and unfavourable soil properties. Our study supports the assertion that seedling establishment in alpine treeline ecotones is simultaneously limited by various climatic and nonclimatic drivers. Together, these factors may limit future treeline advance in the Canadian Rocky Mountains and should be considered when assessing the potential for treeline advance in alpine systems elsewhere.

Association of anthropometric measures with kidney disease progression and mortality: a retrospective cohort study of pre-dialysis chronic kidney disease patients referred to a specialist renal service.

BACKGROUND: Although elevated body mass index (BMI) is a predictor of better clinical outcomes in dialysis patients, the evidence in pre-dialysis chronic kidney disease (CKD) is conflicting. Clinical measures of central obesity may be better prognostic indicators, although investigation has been limited. The aim of this study was to assess the predictive value of anthropometric measures for kidney failure progression and mortality in stage 3-4 CKD. METHODS: The study included newly referred stage 3-4 CKD patients at a single centre between 1/1/2008 and 31/12/2010. The associations between clinical measures of obesity (BMI, waist circumference [WC] and conicity index [ConI]) and time to a composite primary outcome of doubling of serum creatinine, commencement of renal replacement therapy or mortality were evaluated using the Kaplan-Meier method and multivariable Cox regression models. RESULTS: Over a median follow-up period of 3.3 years, 229 (25.4 %) patients of a total population of 903 experienced the composite primary renal outcome. When compared to normal BMI (18.5-24.9 kg/m(2), n = 174), the risk of the composite primary outcome was significantly lower in both the overweight (BMI 25-29.9 kg/m(2), n = 293; adjusted hazard ratio [HR] 0.50, 95 % CI 0.33-0.75) and obese class I/II groups (BMI 30-39.9 kg/m(2), n = 288; HR 0.62, 95 % CI 0.41-0.93), but not in the obese class III group (BMI ≥40 kg/m(2), n = 72; HR 0.94, 95 % CI 0.52-1.69). All-cause mortality was also lower in the overweight group (HR 0.50, 95 % CI 0.30-0.83). WC and ConI were not associated with either the composite primary outcome or mortality. CONCLUSION: BMI in the overweight range is associated with reduced risks of kidney disease progression and all-cause mortality in stage 3-4 CKD. WC and ConI were not independent predictors of these outcomes in this population.

Beta oscillations reflect changes in motor cortex inhibition in healthy ageing.

Beta oscillations are involved in movement and have previously been linked to levels of the inhibitory neurotransmitter GABA. We examined changes in beta oscillations during rest and movement in primary motor cortex (M1). Amplitude and frequency of beta power at rest and movement-related beta desynchronization (MRBD) were measured during a simple unimanual grip task and their relationship with age was explored in a group of healthy participants. We were able to show that at rest, increasing age was associated with greater baseline beta power in M1 contralateral to the active hand, with a similar (non-significant) trend in ipsilateral M1. During movement, increasing age was associated with increased MRBD amplitude in ipsilateral M1 and reduced frequency (in contralateral and ipsilateral M1). These findings would be consistent with greater GABAergic inhibitory activity within motor cortices of older subjects. These oscillatory parameters have the potential to reveal changes in the excitatory-inhibitory balance in M1 which in turn may be a useful marker of plasticity in the brain, both in healthy ageing and disease.

The proteomic landscape of microglia in health and disease.

Microglia are the resident immune cells of the central nervous system (CNS) and as such play crucial roles in regulating brain homeostasis. Their presence in neurodegenerative diseases is known, with neurodegeneration-associated risk genes heavily expressed in microglia, highlighting their importance in contributing to disease pathogenesis. Transcriptomics studies have uncovered the heterogeneous landscape of microglia in health and disease, identifying important disease-associated signatures such as DAM, and insight into both the regional and temporal diversity of microglia phenotypes. Quantitative mass spectrometry methods are ever increasing in the field of neurodegeneration, utilised as ways to identify disease biomarkers and to gain deeper understanding of disease pathology. Proteins are the main mechanistic indicators of cellular function, yet discordance between transcript and proteomic findings has highlighted the need for in-depth proteomic phenotypic and functional analysis to fully understand disease kinetics at the cellular and molecular level. This review details the current progress of using proteomics to define microglia biology, the relationship between gene and protein expression in microglia, and the future of proteomics and emerging methods aiming to resolve heterogeneous cell landscapes.

Contribution of the veterinary profession to the Australian animal health surveillance system and opportunities for future contributions.

Animal health surveillance is crucial for early detection of emergency animal diseases and effective responses. However, surveillance systems are complex and rely on the contributions of many animal health stakeholders. Veterinarians are key stakeholders in this system, given their role and skills in investigating, diagnosing, and reporting notifiable diseases. This study investigated the contribution of the veterinary workforce to the Australian animal health surveillance system and opportunities for future involvement. To achieve the aims of the study, an online cross-sectional survey among the veterinary profession was conducted. Descriptive statistics and regression analyses were used to provide an overview and investigate drivers of attitudes and practices of veterinarians in relation to animal health surveillance. A total of 311 usable responses were obtained, with 191 being from veterinarians who worked in private practice in the previous 12 months. Among private practitioners, 58.6% worked with companion animals, 34.0% were mixed practice veterinarians and 7.3% were equine veterinarians. Over half (56.6%) of all participants considered themselves active participants in the local animal disease management system. The level of confidence in understanding the reporting system and knowing and identifying signs of endemic and exotic diseases was moderate among those working in private practice, with companion animal veterinarians reporting the lowest levels of confidence (p < 0.05). Approximately 40% of veterinarians had taken samples for diagnosis for notifiable diseases in the last year, with just over 20% reporting a notifiable disease. Awareness of and participation in training and surveillance programs for animal diseases by veterinarians was low, with those working in private practice having lower levels of both awareness and participation for most programs. In relation to potential future contribution to the surveillance system, over half of participants reported being interested and available to undertake surveillance work on behalf of the government, with those in mixed practice reporting higher levels of interest (69.6%) compared to those in companion (49.5%) and equine practice (30.8%). However, key challenges identified were related to perceived conflict of interest, and tensions between client needs and government agenda, followed by profitability and suitability of the business. This study provides evidence of a significant existing contribution by the veterinary profession to the surveillance system, and the capacity and willingness to increase this contribution. However, there are gaps in awareness, confidence and participation, as well as financial and veterinary-client relationship challenges that should be considered in any future planning to strengthen the Australian surveillance system.

Xenografted human microglia display diverse transcriptomic states in response to Alzheimer's disease-related amyloid-ß pathology.

Microglia are central players in Alzheimer's disease pathology but analyzing microglial states in human brain samples is challenging due to genetic diversity, postmortem delay and admixture of pathologies. To circumvent these issues, here we generated 138,577 single-cell expression profiles of human stem cell-derived microglia xenotransplanted in the brain of the AppNL-G-F model of amyloid pathology and wild-type controls. Xenografted human microglia adopt a disease-associated profile similar to that seen in mouse microglia, but display a more pronounced human leukocyte antigen or HLA state, likely related to antigen presentation in response to amyloid plaques. The human microglial response also involves a pro-inflammatory cytokine/chemokine cytokine response microglia or CRM response to oligomeric Aß oligomers. Genetic deletion of TREM2 or APOE as well as APOE polymorphisms and TREM2R47H expression in the transplanted microglia modulate these responses differentially. The expression of other Alzheimer's disease risk genes is differentially regulated across the distinct cell states elicited in response to amyloid pathology. Thus, we have identified multiple transcriptomic cell states adopted by human microglia in a multipronged response to Alzheimer's disease-related pathology, which should be taken into account in translational studies.

Environment and diet shape the geography-specific Drosophila melanogaster microbiota composition.

Geographic and environmental variation in the animal microbiota can be directly linked to the evolution and wild fitness of their hosts but often appears to be disordered. Here, we sought to better understand patterns that underlie wild variation in the microbiota composition of Drosophila melanogaster . First, environmental temperature predicted geographic variation in fly microbial communities better than latitude did. The microbiota also differed between wild flies and their diets, supporting previous conclusions that the fly microbiota is not merely a reflection of diet. Flies feeding on different diets varied significantly in their microbiota composition, and flies sampled from individual apples were exceptionally depauperate for the Lactic Acid Bacteria (LAB), a major bacterial group in wild and laboratory flies. However, flies bore significantly more LAB when sampled from other fruits or compost piles. Follow-up analyses revealed that LAB abundance in the flies uniquely responds to fruit decomposition, whereas other microbiota members better indicate temporal seasonal progression. Finally, we show that diet-dependent variation in the fly microbiota is associated with phenotypic differentiation of fly lines collected in a single orchard. These last findings link covariation between the flies' dietary history, microbiota composition, and genetic variation across relatively small (single-orchard) landscapes, reinforcing the critical role that environment-dependent variation in microbiota composition can play in local adaptation and genomic differentiation of a model animal host. SIGNIFICANCE STATEMENT: The microbial communities of animals influence their hosts' evolution and wild fitness, but it is hard to predict and explain how the microbiota varies in wild animals. Here, we describe that the microbiota composition of wild Drosophila melanogaster can be ordered by temperature, humidity, geographic distance, diet decomposition, and diet type. We show how these determinants of microbiota variation can help explain lactic acid bacteria (LAB) abundance in the flies, including the rarity of LAB in some previous studies. Finally, we show that wild fly phenotypes segregate with the flies' diet and microbiota composition, illuminating links between the microbiota and host evolution. Together, these findings help explain how variation in microbiota compositions can shape an animal's life history.

How correlations between treatment access and surveillance inclusion impact neglected tropical disease monitoring and evaluation-A simulated study.

Neglected tropical diseases (NTDs) largely impact marginalised communities living in tropical and subtropical regions. Mass drug administration is the leading intervention method for five NTDs; however, it is known that there is lack of access to treatment for some populations and demographic groups. It is also likely that those individuals without access to treatment are excluded from surveillance. It is important to consider the impacts of this on the overall success, and monitoring and evaluation (M&E) of intervention programmes. We use a detailed individual-based model of the infection dynamics of lymphatic filariasis to investigate the impact of excluded, untreated, and therefore unobserved groups on the true versus observed infection dynamics and subsequent intervention success. We simulate surveillance in four groups-the whole population eligible to receive treatment, the whole eligible population with access to treatment, the TAS focus of six- and seven-year-olds, and finally in >20-year-olds. We show that the surveillance group under observation has a significant impact on perceived dynamics. Exclusion to treatment and surveillance negatively impacts the probability of reaching public health goals, though in populations that do reach these goals there are no signals to indicate excluded groups. Increasingly restricted surveillance groups over-estimate the efficacy of MDA. The presence of non-treated groups cannot be inferred when surveillance is only occurring in the group receiving treatment.

A modelling analysis of a new multi-stage pathway for classifying achievement of public health milestones for leprosy.

Several countries have come close to eliminating leprosy, but leprosy cases continue to be detected at low levels. Due to the long, highly variable delay from infection to detection, the relationship between observed cases and transmission is uncertain. The World Health Organization's new technical guidance provides a path for countries to reach elimination. We use a simple probabilistic model to simulate the stochastic dynamics of detected cases as transmission declines, and evaluate progress through the new public health milestones. In simulations where transmission is halted, 5 years of zero incidence in autochthonous children, combined with 3 years of zero incidence in all ages is a flawed indicator that transmission has halted (54% correctly classified). A further 10 years of only occasional sporadic cases is associated with a high probability of having interrupted transmission (99%). If, however, transmission continues at extremely low levels, it is possible that cases could be misidentified as historic cases from the tail of the incubation period distribution, although misleadingly achieving all three milestones is unlikely (less than 1% probability across a 15-year period of ongoing low-level transmission). These results demonstrate the feasibility and challenges of a phased progression of milestones towards interruption of transmission, allowing assessment of programme status. This article is part of the theme issue 'Challenges and opportunities in the fight against neglected tropical diseases: a decade from the London Declaration on NTDs'.

Associations of Socioeconomic Status With Disease Progression in African Americans With Early Rheumatoid Arthritis.

OBJECTIVE: In prior cross-sectional analyses of African American patients with rheumatoid arthritis (RA), measures of socioeconomic status (SES) were associated with clinical joint damage and poorer patient-reported outcome scores. The purpose of this study was to determine whether SES measures are associated with disease progression in a cohort of African American patients with early RA (<2 years duration). METHODS: We analyzed baseline SES and change in 60-month clinical radiographs and patient-reported outcomes data (n = 101 and 177, respectively) in individuals with early RA. SES measures were educational attainment, occupation, homeownership, household income, and block group poverty. Outcomes were based on radiographs (total erosion and joint space narrowing [JSN] scores on hands and feet) and patient-reported outcomes (pain, fatigue, disability, and learned helplessness). We used logistic regression with mixed effects accounting for study site to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs). RESULTS: Both low education and occupation status were associated with worsening pain (adjusted OR 5.86 [95% CI 3.05-11.3] and adjusted OR 2.55 [95% CI 1.54-4.21], respectively). Patients without a high-school diploma were more likely to have worsened reports of learned helplessness (OR 1.92 [95% CI 1.37-2.67]). Community measures of SES were also significantly associated with patient-reported outcomes score changes. Patients living in areas of block group poverty ≥20% were twice as likely to experience increased disability scores over 60 months of disease duration (OR 1.95 [95% CI 1.17-3.25]). We found no association between SES measures and erosion or JSN score progression. CONCLUSION: Low educational attainment and nonprofessional occupation status were associated with increased worsening of patient-reported outcomes. However, there were no corresponding increases in radiographically assessed erosion or JSN score progression.