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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.

Assessing the feasibility of 2030 as a target date for global elimination of trachoma, and identification of districts that may require enhanced treatment to meet World Health Organization (WHO) elimination criteria by this date are key challenges in operational planning for trachoma programmes. Here we address these challenges by prospectively evaluating forecasting models of trachomatous inflammation-follicular (TF) prevalence, leveraging ensemble-based approaches. Seven candidate probabilistic models were developed to forecast district-wise TF prevalence in 11 760 districts, trained using district-level data on the population prevalence of TF in children aged 1-9 years from 2004 to 2022. Geographical location, history of mass drug administration treatment, and previously measured prevalence data were included in these models as key predictors. The best-performing models were included in an ensemble, using weights derived from their relative likelihood scores. To incorporate the inherent stochasticity of disease transmission and challenges of population-level surveillance, we forecasted probability distributions for the TF prevalence in each geographic district, rather than predicting a single value. Based on our probabilistic forecasts, 1.46% (95% confidence interval [CI]: 1.43-1.48%) of all districts in trachoma-endemic countries, equivalent to 172 districts, will exceed the 5% TF control threshold in 2030 with the current interventions. Global elimination of trachoma as a public health problem by 2030 may require enhanced intervention and/or surveillance of high-risk districts.

BackgroundIn line with movement restrictions and physical distancing essential for the control of the COVID-19 pandemic, WHO recommended postponement of all neglected tropical disease (NTD) control activities that involve community-based surveys, active case finding, and mass drug administration in April, 2020. Following revised guidance later in 2020, and after interruptions to NTD programmes of varying lengths, NTD programmes gradually restarted in the context of an ongoing pandemic. However, ongoing challenges and service gaps have been reported. This study aimed to evaluate the potential effect of the programmatic interruptions and strategies to mitigate this effect.MethodsFor seven NTDs, namely soil-transmitted helminths, schistosomiasis, lymphatic filariasis, onchocerciasis, trachoma, visceral leishmaniasis, and human African trypanosomiasis, we used mathematical transmission models to simulate the effect of programme interruptions on the dynamics of each of these diseases in different endemic settings. We also explored the potential benefit of implementing mitigation strategies, primarily in terms of minimising the delays to control targets.FindingsWe show that the effect of the COVID-19-induced interruption in terms of delay to achieving elimination goals might in some cases be much longer than the duration of the interruption. For schistosomiasis, onchocerciasis, trachoma, and visceral leishmaniasis, a mean delay of 2-3 years for a 1-year interruption is predicted in areas of highest prevalence. We also show that these delays can largely be mitigated by measures such as additional mass drug administration or enhanced case-finding.InterpretationThe COVID-19 pandemic has brought infectious disease control to the forefront of global consciousness. It is essential that the NTDs, so long neglected in terms of research and financial support, are not overlooked, and remain a priority in health service planning and funding.FundingBill & Melinda Gates Foundation, Medical Research Council, and the UK Foreign, Commonwealth & Development Office.

Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to early development of the hindbrain1-4. Mutations that activate Sonic hedgehog signalling lead to Sonic hedgehog MB in the upper rhombic lip (RL) granule cell lineage5-8. By contrast, mutations that activate WNT signalling lead to WNT MB in the lower RL9,10. However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage3,4. Here we demonstrate that somatic mutations that cause G4 MB converge on the core binding factor alpha (CBFA) complex and mutually exclusive alterations that affect CBFA2T2, CBFA2T3, PRDM6, UTX and OTX2. CBFA2T2 is expressed early in the progenitor cells of the cerebellar RL subventricular zone in Homo sapiens, and G4 MB transcriptionally resembles these progenitors but are stalled in developmental time. Knockdown of OTX2 in model systems relieves this differentiation blockade, which allows MB cells to spontaneously proceed along normal developmental differentiation trajectories. The specific nature of the split human RL, which is destined to generate most of the neurons in the human brain, and its high level of susceptible EOMES+KI67+ unipolar brush cell progenitor cells probably predisposes our species to the development of G4 MB.

Abstract Sonic Hedgehog (SHH) medulloblastomas (MBs) exhibit an intermediate prognosis and extensive intertumoral heterogeneity. While SHH pathway antagonists are effective in post-pubertal patients, younger patients exhibit significant side effects, and tumors that harbor mutations in downstream SHH pathway genes will be drug resistant. Thus, novel targeted therapies are needed. Here, we performed preclinical testing of the potent MEK inhibitor (MEKi) trametinib on tumor properties across 2 human and 3 mouse SHH MB models in vitro and in 3 orthotopic MB xenograft models in vivo. Trametinib significantly reduces tumorsphere size, stem/progenitor cell proliferation, viability, and migration. RNA-sequencing on human and mouse trametinib treated cells corroborated these findings with decreased expression of cell cycle, stem cell pathways and SHH-pathway related genes concomitant with increases in genes associated with cell death and ciliopathies. Importantly, trametinib also decreases tumor growth and increases survival in vivo. Cell cycle related E2F target gene sets are significantly enriched for genes that are commonly downregulated in both trametinib treated tumorspheres and primary xenografts. However, IL6/JAK STAT3 and TNFα/NFκB signaling gene sets are specifically upregulated following trametinib treatment in vivo indicative of compensatory molecular changes following long-term MEK inhibition. Our study reveals a novel role for trametinib in effectively attenuating SHH MB tumor progression and warrants further investigation of this potent MEK1/2 inhibitor either alone or in combination with other targeted therapies for the treatment of SHH MB exhibiting elevated MAPK pathway activity.

BackgroundTremendous progress towards elimination of trachoma as a public health problem has been made. However, there are areas where the clinical indicator of disease, trachomatous inflammation-follicular (TF), remains prevalent. We quantify the progress that has been made, and forecast how TF prevalence will evolve with current interventions. We also determine the probability that a district is a transmission-hotspot based on its TF prevalence (ie, reproduction number greater than one).MethodsData on trachoma prevalence come from the GET2020 global repository organized by the World Health Organization and the International Trachoma Initiative. Forecasts of TF prevalence and the percent of districts with local control is achieved by regressing the coefficients of a fitted exponential distribution for the year-by-year distribution of TF prevalence. The probability of a district being a transmission-hotspot is extrapolated from the residuals of the regression.ResultsForecasts suggest that with current interventions, 96.5% of surveyed districts will have TF prevalence among children aged 1-9 years

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.

BackgroundProgress towards elimination of trachoma as a public health problem has been substantial, but the coronavirus disease 2019 (COVID-19) pandemic has disrupted community-based control efforts.MethodsWe use a susceptible-infected model to estimate the impact of delayed distribution of azithromycin treatment on the prevalence of active trachoma.ResultsWe identify three distinct scenarios for geographic districts depending on whether the basic reproduction number and the treatment-associated reproduction number are above or below a value of 1. We find that when the basic reproduction number is 1, significant delays can occur. In most districts, 1 y of COVID-related delay can be mitigated by a single extra round of mass drug administration. However, supercritical districts require a new paradigm of infection control because the current strategies will not eliminate disease.ConclusionsIf the pandemic can motivate judicious, community-specific implementation of control strategies, global elimination of trachoma as a public health problem could be accelerated.

BackgroundThe COVID-19 pandemic has disrupted planned annual antibiotic mass drug administration (MDA) activities that have formed the cornerstone of the largely successful global efforts to eliminate trachoma as a public health problem.MethodsUsing a mathematical model we investigate the impact of interruption to MDA in trachoma-endemic settings. We evaluate potential measures to mitigate this impact and consider alternative strategies for accelerating progress in those areas where the trachoma elimination targets may not be achievable otherwise.ResultsWe demonstrate that for districts that were hyperendemic at baseline, or where the trachoma elimination thresholds have not already been achieved after three rounds of MDA, the interruption to planned MDA could lead to a delay to reaching elimination targets greater than the duration of interruption. We also show that an additional round of MDA in the year following MDA resumption could effectively mitigate this delay. For districts where the probability of elimination under annual MDA was already very low, we demonstrate that more intensive MDA schedules are needed to achieve agreed targets.ConclusionThrough appropriate use of additional MDA, the impact of COVID-19 in terms of delay to reaching trachoma elimination targets can be effectively mitigated. Additionally, more frequent MDA may accelerate progress towards 2030 goals.

RNA sequencing of MEK inhibitor (selumetinib)-treated tumors reveals an upregulation of the JAK/STAT3 pathway, with combinatorial therapeutic strategies of JAK/STAT3 inhibitors and selumetinib investigated for the SHH subgroup of medulloblastoma.

Schistosomiasis is a major neglected tropical disease (NTD) affecting both humans and animals. The morbidity and mortality inflicted upon livestock in the Afrotropical region has been largely overlooked, in part due to a lack of validated sensitive and specific tests, which do not require specialist training or equipment to deliver and interpret. As stressed within the recent WHO NTD 2021-2030 Roadmap and Revised Guideline for schistosomiasis, inexpensive, non-invasive, and sensitive diagnostic tests for livestock-use would also facilitate both prevalence mapping and appropriate intervention programmes. The aim of this study was to assess the sensitivity and specificity of the currently available point-of-care circulating cathodic antigen test (POC-CCA), designed for Schistosoma mansoni detection in humans, for the detection of intestinal livestock schistosomiasis caused by Schistosoma bovis and Schistosoma curassoni. POC-CCA, together with the circulating anodic antigen (CAA) test, miracidial hatching technique (MHT), Kato-Katz (KK) and organ and mesentery inspection (for animals from abattoirs only), were applied to samples collected from 195 animals (56 cattle and 139 small ruminants (goats and sheep) from abattoirs and living populations) from Senegal. POC-CCA sensitivity was greater in the S. curassoni-dominated Barkedji livestock, both for cattle (median 81%; 95% credible interval (CrI): 55%-98%) and small ruminants (49%; CrI: 29%-87%), than in the S. bovis-dominated Richard Toll ruminants (cattle: 62%; CrI: 41%-84%; small ruminants: 12%, CrI: 1%-37%). Overall, sensitivity was greater in cattle than in small ruminants. Small ruminants POC-CCA specificity was similar in both locations (91%; CrI: 77%-99%), whilst cattle POC-CCA specificity could not be assessed owing to the low number of uninfected cattle surveyed. Our results indicate that, whilst the current POC-CCA does represent a potential diagnostic tool for cattle and possibly for predominantly S. curassoni-infected livestock, future work is needed to develop parasite- and/or livestock-specific affordable and field-applicable diagnostic tests to enable determination of the true extent of livestock schistosomiasis.

In 2013 the UK government introduced the primary physical education and sport premium (PPESP) to improve Physical Education (PE) provision in eligible schools. In 2017 this was doubled, and further funding was committed until 2020. There is currently a lack of information regarding the comprehension and implementation of the PPESP amongst staff within schools. This study provides an insight into the current understanding of the PPESP and explores concepts of knowledge, value, and the decisions being made to make sustainable improvements. A qualitative approach using semi-structured interviews was adopted.

Evaluations of the UK’s contact tracing programme have shown that it has had limited impact on COVID-19 control. Here, the authors show that with high levels of reporting and adherence, contact tracing could reduce transmission, but it should not be used as the sole control measure.

In West Africa, Schistosoma spp. are capable of infecting multiple definitive hosts, a lifecycle feature that may complicate schistosomiasis control. We characterized the evolutionary relationships among multiple Schistosoma mansoni isolates collected from snails (intermediate hosts), humans (definitive hosts), and rodents (definitive hosts) in Senegal. On a local scale, diagnosis of S. mansoni infection ranged 3.8%–44.8% in school-aged children, 1.7%–52.6% in Mastomys huberti mice, and 1.8%–7.1% in Biomphalaria pfeifferi snails. Our phylogenetic framework confirmed the presence of multiple S. mansoni lineages that could infect both humans and rodents; divergence times of these lineages varied (0.13–0.02 million years ago). We propose that extensive movement of persons across West Africa might have contributed to the establishment of these various multihost S. mansoni clades. High S. mansoni prevalence in rodents at transmission sites frequented by humans further highlights the implications that alternative hosts could have on future public health interventions.

The collective image of schistosomiasis in Africa remains that of a mainly human-driven disease; schistosomiasis inflicted a burden of >2.5 million disability-adjusted life-years in 2016 and required that [approximately equal [...]

Abstract Background Schistosomiasis and food-borne trematodiases are not only of major public health concern, but can also have profound implications for livestock production and wildlife conservation. The zoonotic, multi-host nature of many digenean trematodes is a significant challenge for disease control programmes in endemic areas. However, our understanding of the epidemiological role that animal reservoirs, particularly wild hosts, may play in the transmission of zoonotic trematodiases suffers a dearth of information, with few, if any, standardised, reliable diagnostic tests available. We combined qualitative and quantitative data derived from post-mortem examinations, coprological analyses using the Mini-FLOTAC technique, and molecular tools to assess parasite community composition and the validity of non-invasive methods to detect trematode infections in 89 wild Hubert’s multimammate mice (Mastomys huberti) from northern Senegal. Results Parasites isolated at post-mortem examination were identified as Plagiorchis sp., Anchitrema sp., Echinostoma caproni, Schistosoma mansoni, and a hybrid between Schistosoma haematobium and Schistosoma bovis. The reports of E. caproni and Anchitrema sp. represent the first molecularly confirmed identifications for these trematodes in definitive hosts of sub-Saharan Africa. Comparison of prevalence estimates derived from parasitological analysis at post-mortem examination and Mini-FLOTAC analysis showed non-significant differences indicating comparable results between the two techniques (P = 1.00 for S. mansoni; P = 0.85 for E. caproni; P = 0.83 for Plagiorchis sp.). A Bayesian model, applied to estimate the sensitivities of the two tests for the diagnosis of Schistosoma infections, indicated similar median posterior probabilities of 83.1% for Mini-FLOTAC technique and 82.9% for post-mortem examination (95% Bayesian credible intervals of 64.0–94.6% and 63.7–94.7%, respectively). Conclusions Our results showed that the Mini-FLOTAC could be applied as an alternative diagnostic technique for the detection of the zoonotic S. mansoni and other trematodes in rodent reservoirs. The implementation of non-invasive diagnostics in wildlife would offer numerous advantages over lethal sampling methodologies, with potential impact on control strategies of zoonotic helminthiases in endemic areas of sub-Saharan Africa and on fostering a framework of animal use reduction in scientific practice.

Abstract Multihost multiparasite systems are evolutionarily and ecologically dynamic, which presents substantial trans‐disciplinary challenges for elucidating their epidemiology and designing appropriate control. Evidence for hybridizations and introgressions between parasite species is gathering, in part in line with improvements in molecular diagnostics and genome sequencing. One major system where this is becoming apparent is within the Genus Schistosoma, where schistosomiasis represents a disease of considerable medical and veterinary importance, the greatest burden of which occurs in sub‐Saharan Africa. Interspecific hybridizations and introgressions bring an increased level of complexity over and above that already inherent within multihost, multiparasite systems, also representing an additional source of genetic variation that can drive evolution. This has the potential for profound implications for the control of parasitic diseases, including, but not exclusive to, widening host range, increased transmission potential and altered responses to drug therapy. Here, we present the challenging case example of haematobium group Schistosoma spp. hybrids in West Africa, a system involving multiple interacting parasites and multiple definitive hosts, in a region where zoonotic reservoirs of schistosomiasis were not previously considered to be of importance. We consider how existing mathematical model frameworks for schistosome transmission could be expanded and adapted to zoonotic hybrid systems, exploring how such model frameworks can utilize molecular and epidemiological data, as well as the complexities and challenges this presents. We also highlight the opportunities and value such mathematical models could bring to this and a range of similar multihost, multi and cross‐hybridizing parasites systems in our changing world.

Hybridization of infectious agents is a major emerging public and veterinary health concern at the interface of evolution, epidemiology, and control. Whilst evidence of the extent of hybridization amongst parasites is increasing, their impact on morbidity remains largely unknown. This may be predicted to be particularly pertinent where parasites of animals with contrasting pathogenicity viably hybridize with human parasites. Recent research has revealed that viable zoonotic hybrids between human urogenital Schistosoma haematobium with intestinal Schistosoma species of livestock, notably Schistosoma bovis, can be highly prevalent across Africa and beyond. Examining human populations in Senegal, we found increased hepatic but decreased urogenital morbidity, and reduced improvement following treatment with praziquantel, in those infected with zoonotic hybrids compared to non-hybrids. Our results have implications for effective monitoring and evaluation of control programmes, and demonstrate for the first time the potential impact of parasite hybridizations on host morbidity.