Variations in visceral leishmaniasis burden, mortality and the pathway to care within Bihar, India

BACKGROUND: Visceral leishmaniasis (VL) has been targeted by the WHO for elimination as a public health problem (< 1 case/10,000 people/year) in the Indian sub-continent (ISC) by 2020. Bihar State in India, which accounts for the majority of cases in the ISC, remains a major target for this elimination effort. However, there is considerable spatial, temporal and sub-population variation in occurrence of the disease and the pathway to care, which is largely unexplored and a threat to achieving the target. METHODS: Data from 6081 suspected VL patients who reported being clinically diagnosed during 2012-2013 across eight districts in Bihar were analysed. Graphical comparisons and Chi-square tests were used to determine differences in the burden of identified cases by season, district, age and sex. Log-linear regression models were fitted to onset (of symptoms)-to-diagnosis and onset-to-treatment waiting times to estimate their associations with age, sex, district and various socio-economic factors (SEFs). Logistic regression models were used to identify factors associated with mortality. RESULTS: Comparisons of VL caseloads suggested an annual cycle peaking in January-March. A 17-fold variation in the burden of identified cases across districts and under-representation of young children (0-5 years) relative to age-specific populations in Bihar were observed. Women accounted for a significantly lower proportion of the reported cases than men (41 vs 59%, P < 0.0001). Age, district of residence, house wall materials, caste, treatment cost, travelling for diagnosis and the number of treatments for symptoms before diagnosis were identified as correlates of waiting times. Mortality was associated with age, district of residence, onset-to-treatment waiting time, treatment duration, cattle ownership and cost of diagnosis. CONCLUSIONS: The distribution of VL in Bihar is highly heterogeneous, and reported caseloads and associated mortality vary significantly across different districts, posing different challenges to the elimination campaign. Socio-economic factors are important correlates of these differences, suggesting that elimination will require tailoring to population and sub-population circumstances

Impact of Changes in Detection Effort on Control of Visceral Leishmaniasis in the Indian Subcontinent.

BACKGROUND: Control of visceral leishmaniasis (VL) on the Indian subcontinent relies on prompt detection and treatment of symptomatic cases. Detection efforts influence the observed VL incidence and how well it reflects the underlying true incidence. As control targets are defined in terms of observed cases, there is an urgent need to understand how changes in detection delay and population coverage of improved detection affect VL control. METHODS: Using a mathematical model for transmission and control of VL, we predict the impact of reduced detection delays and/or increased population coverage of the detection programs on observed and true VL incidence and mortality. RESULTS: Improved case detection, either by higher coverage or reduced detection delay, causes an initial rise in observed VL incidence before a reduction. Relaxation of improved detection may lead to an apparent temporary (1 year) reduction in VL incidence, but comes with a high risk of resurging infection levels. Duration of symptoms in detected cases shows an unequivocal association with detection effort. CONCLUSIONS: VL incidence on its own is not a reliable indicator of the performance of case detection programs. Duration of symptoms in detected cases can be used as an additional marker of the performance of case detection programs

Feasibility of eliminating visceral leishmaniasis from the Indian subcontinent: explorations with a set of deterministic age-structured transmission models

textabstractBackground: Visceral leishmaniasis (VL) is a neglected tropical disease transmitted by sandflies. On the Indian subcontinent (ISC), VL is targeted for elimination as a public health problem by 2017. In the context of VL, the elimination target is defined as an annual VL incidence of <1 per 10,000 capita at (sub-)district level. Interventions focus on vector control, surveillance and on diagnosing and treating VL cases. Many endemic areas have not yet achieved optimal control due to logistical, biological as well as technical challenges. We used mathematical modelling to quantify VL transmission dynamics and predict the feasibility of achieving the VL elimination target with current control strategies under varying assumptions about the reservoir of infection in humans. Methods: We developed three deterministic age-structured transmission models with different main reservoirs of infection in humans: asymptomatic infections (model 1), reactivation of infection after initial infection (model 2), and post kala-azar dermal leishmaniasis (PKDL; model 3). For each model, we defined four sub-variants based on different assumptions about the duration of immunity and age-patterns in exposure to sandflies. All 12 model sub-variants were fitted to data from the KalaNet study in Bihar (India) and Nepal, and the best sub-variant was selected per model. Predictions were made for optimal and sub-optimal indoor residual spraying (IRS) effectiveness for three different levels of VL endemicity. Results: Structurally different models explained the KalaNet data equally well. However, the predicted impact of IRS varied substantially between models, such that a conclusion about reaching the VL elimination targets for the ISC heavily depends on assumptions about the main reservoir of infection in humans: asymptomatic cases, recovered (immune) individuals that reactivate, or PKDL cases. Conclusions: Available data on the impact of IRS so far suggest one model is probably closest to reality (model 1). According to this model, elimination of VL (incidence of <1 per 10,000) by 2017 is only feasible in low and medium endemic settings with optimal IRS. In highly endemic settings and settings with sub-optimal IRS, additional interventions will be required

Cluster randomised trial and development of a sandfly sex pheromone lure to reduce Leishmania infantum infection

Introduction: Vector control tools are needed to combat leishmaniasis. A semi-synthetic version of a Lutzomyia longipalpis aggregation/sex pheromone (9-methlygermacrene-B) has been developed, and shown efficacy to attract sandflies in the lab and to chicken sheds in the field. Here, we present results from a cluster-randomised trial performed in Brazil where we test the efficacy of the pheromone deployed with insecticide, a novel lure-and-kill intervention, to reduce leishmaniasis transmission to the canine reservoir. Aim: Investigate the efficacy of sandfly sex pheromone baited + insecticide treated chicken roosts to reduce transmission of Leishmania infantum among the reservoir population (dogs). Methods: We conducted a cluster-randomised trial across 42 communities in Brazil. Pheromone lures plus insecticide were applied in 14 communities, and outcomes compared to that of 28 other communities that received either a placebo (sham lure + insecticide) or deltamethrin-impregnated collars fitted to dogs. We quantify the primary intervention effects by comparison of the number of uninfected dogs that seroconverted in each arm over the course of the 2-year trial. Results: A reduction in canine incidence is attributed to the pheromone + insecticide intervention, which is consistent across the levels of hierarchical analysis, though the errors are broad. The performance of the pheromone followed similar patterns as the collar arm which significantly reduced seroconversion incidence. Conclusion: These data represent the first trial of a synthetic vector pheromone applied in public health control, and the first cluster-randomised trial of dog collars in Brazil. Both methods show potential for the control of zoonotic visceral leishmaniasis in the Americas; developments of the pheromone lure-and-kill strategy are underway

Altruism can proliferate through group/kin selection despite high random gene flow

The ways in which natural selection can allow the proliferation of cooperative behavior have long been seen as a central problem in evolutionary biology. Most of the literature has focused on interactions between pairs of individuals and on linear public goods games. This emphasis led to the conclusion that even modest levels of migration would pose a serious problem to the spread of altruism in group structured populations. Here we challenge this conclusion, by analyzing evolution in a framework which allows for complex group interactions and random migration among groups. We conclude that contingent forms of strong altruism can spread when rare under realistic group sizes and levels of migration. Our analysis combines group-centric and gene-centric perspectives, allows for arbitrary strength of selection, and leads to extensions of Hamilton's rule for the spread of altruistic alleles, applicable under broad conditions.Comment: 5 pages, 2 figures. Supplementary material with 50 pages and 26 figure

The potential impact of human visceral leishmaniasis vaccines on population incidence

Human visceral leishmaniasis (VL) vaccines are currently under development and there is a need to understand their potential impact on population wide VL incidence. We implement four characteristics from different human VL vaccine candidates into two published VL transmission model variants to estimate the potential impact of these vaccine characteristics on population-wide anthroponotic VL incidence on the Indian subcontinent (ISC). The vaccines that are simulated in this study 1) reduce the infectiousness of infected individuals towards sand flies, 2) reduce risk of developing symptoms after infection, 3) reduce the risk of developing post-kala-azar dermal leishmaniasis (PKDL), or 4) lead to the development of transient immunity. We also compare and combine a vaccine strategy with current interventions to identify their potential role in elimination of VL as a public health problem. We show that the first two simulated vaccine characteristics can greatly reduce VL incidence. For these vaccines, an approximate 60% vaccine efficacy would lead to achieving the ISC elimination target (<1 VL case per 10,000 population per year) within 10 years' time in a moderately endemic setting when vaccinating 100% of the population. Vaccinating VL cases to prevent the development of PKDL is a promising tool to sustain the low incidence elimination target after regular interventions are halted. Vaccines triggering the development of transient immunity protecting against infection lead to the biggest reduction in VL incidence, but booster doses are required to achieve perduring impact. Even though vaccines are not yet available for implementation, their development should be pursued as their potential impact on transmission can be substantial, both in decreasing incidence at the population level as well as in sustaining the ISC elimination target when other interventions are halted.Human visceral leishmaniasis (VL) vaccines are currently under development and there is a need to understand their potential impact on population wide VL incidence. We implement four characteristics from different human VL vaccine candidates into two published VL transmission model variants to estimate the potential impact of these vaccine characteristics on population-wide anthroponotic VL incidence on the Indian subcontinent (ISC). The vaccines that are simulated in this study 1) reduce the infectiousness of infected individuals towards sand flies, 2) reduce risk of developing symptoms after infection, 3) reduce the risk of developing post-kala-azar dermal leishmaniasis (PKDL), or 4) lead to the development of transient immunity. We also compare and combine a vaccine strategy with current interventions to identify their potential role in elimination of VL as a publi

Alichur Dome, South Pamir, Western India-Asia Collisional Zone: Detailing the Neogene Shakhdara-Alichur Syn-collisional Gneiss-Dome Complex and Connection to Lithospheric Processes

Neogene, syn‐collisional extensional exhumation of Asian lower–middle crust produced the Shakhdara–Alichur gneiss‐dome complex in the South Pamir. The <1 km‐thick, mylonitic–brittle, top‐NNE, normal‐sense Alichur shear zone (ASZ) bounds the 125 × 25 km Alichur dome to the north. The Shakhdara dome is bounded by the <4 km‐thick, mylonitic–brittle, top‐SSE South Pamir normal‐sense shear zone (SPSZ) to the south, and the dextral Gunt wrench zone to its north. The Alichur dome comprises Cretaceous granitoids/gneisses cut by early Miocene leucogranites; its hanging wall contains non/weakly metamorphosed rocks. The 22–17 Ma Alichur‐dome‐injection‐complex leucogranites transition from foliation‐parallel, centimeter‐ to meter‐thick sheets within the ASZ into discordant intrusions that may comprise half the volume of the dome core. Secondary fluid inclusions in mylonites and mylonitization‐temperature constraints suggest Alichur‐dome exhumation from 10–15 km depth. Thermochronologic dates bracket footwall cooling between ~410–130 °C from ~16–4 Ma; tectonic cooling/exhumation rates (~42 °C/Myr, ~1.1 km/Myr) contrast with erosion‐dominated rates in the hanging wall (~2 °C/Myr, <0.1 km/Myr). Dome‐scale boudinage, oblique divergence of the ASZ and SPSZ hanging walls, and dextral wrenching reflect minor approximately E–W material flow out of the orogen. We attribute broadly southward younging extensional exhumation across the central South Pamir between ~20–4 Ma to: (i) Mostly northward, foreland‐directed flow of hot crust into a cold foreland during the growth of the Pamir orocline; and (ii) Contrasting effects of basal shear related to underthrusting Indian lithosphere, enhancing extension in the underthrust South Pamir and inhibiting extension in the non‐underthrust Central Pamir

How many pennies for your pain? Willingness to compensate as a function of expected future interaction and intentionality feedback

Despite increased research efforts in the area of reconciliation and trust repair in economic relations, most studies depart from a victim’s perspective. Specifically, these studies evaluate the process of trust repair by looking at the impact of restoration tactics on victims’ reactions. We focused on the transgressor’s perspective and present findings from two studies that investigated how the amount of compensation that a transgressor is willing to pay depends on victims’ reactions to the transgression (i.e. whether they claim the transgression happened intentionally or unintentionally) and the time horizon of the relationship between the transgressor and the victim (future vs. no future interaction). We hypothesized and found that transgressors are willing to pay less compensation to a victim who believes the transgression happened intentionally (as opposed to unintentionally), but only so when they share no future interaction perspective together. When transgressors have a future interaction perspective with the victim, intentionality feedback does not affect compensation size

Socioeconomic benefit to individuals of achieving 2020 targets for four neglected tropical diseases controlled/eliminated by innovative and intensified disease management

__Background__ The control or elimination of neglected tropical diseases (NTDs) has targets defined by the WHO for 2020, reinforced by the 2012 London Declaration. We estimated the economic impact to individuals of meeting these targets for human African trypanosomiasis, leprosy, visceral leishmaniasis and Chagas disease, NTDs controlled or eliminated by innovative and intensified disease management (IDM). __Methods__ A systematic literature review identified information on productivity loss and out-of-pocket payments (OPPs) related to these NTDs, which were combined with projections of the number of people suffering from each NTD, country and year for 2011±2020 and 2021±2030. The ideal scenario in which the WHO's 2020 targets are met was compared with a counterfactual scenario that assumed the situation of 1990 stayed unaltered. Economic benefit equaled the difference between the two scenarios. Values are reported in 2005 US, purchasing power parity-adjusted, discounted at 3% per annum from 2010. Probabilistic sensitivity analyses were used to quantify the degree of uncertainty around the base-case impact estimate. __Results__ The total global productivity gained for the four IDM-NTDs was I 23.1 (I$15.9 ±I$ 34.0) billion in 2011±2020 and I$35.9 (I$ 25.0 ±I$51.9) billion in 2021±2030 (2.5th and 97.5th percentiles in brackets), corresponding to US$ 10.7 billion (US$7.4 ±US$ 15.7) and US$16.6 billion (US$ 11.6 ±US$24.0). Reduction in OPPs was I$ 14 billion (US$6.7 billion) and I$ 18 billion (US$ 10.4 billion) for the same periods. __Conclusions__ We faced important limitations to our work, such as finding no OPPs for leprosy. We had to combine limited data from various sources, heterogeneous background, and of variable quality. Nevertheless, based on conservative assumptions and subsequent uncertainty analyses, we estimate that the benefits of achieving the targets are considerable. Under plausible scenarios, the economic benefits far exceed the necessary investments by endemic country governments and their development partners. Given the higher frequency of NTDs among the poorest households, these investments represent good value for money in the effort to improve well-being, distribute the world's prosperity more equitably and reduce inequity

Overcoming roadblocks in the development of vaccines for leishmaniasis

INTRODUCTION: The leishmaniases represent a group of parasitic diseases caused by infection with one of several species of Leishmania parasites. Disease presentation varies because of differences in parasite and host genetics and may be influenced by additional factors such as host nutritional status or co-infection. Studies in experimental models of Leishmania infection, vaccination of companion animals and human epidemiological data suggest that many forms of leishmaniasis could be prevented by vaccination, but no vaccines are currently available for human use. AREAS COVERED: We describe some of the existing roadblocks to the development and implementation of an effective leishmaniasis vaccine, based on a review of recent literature found on PubMed, BioRxiv and MedRxiv. In addition to discussing scientific unknowns that hinder vaccine candidate identification and selection, we explore gaps in knowledge regarding the commercial and public health value propositions underpinning vaccine development and provide a route map for future research and advocacy. EXPERT OPINION: Despite significant progress, leishmaniasis vaccine development remains hindered by significant gaps in understanding that span the vaccine development pipeline. Increased coordination and adoption of a more holistic view to vaccine development will be required to ensure more rapid progress in the years ahead