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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.

Background: Lymphatic filariasis (LF) is a neglected tropical disease targeted for elimination as a public health problem by 2030. Although mass treatments have led to huge reductions in LF prevalence, some countries or regions may find it difficult to achieve elimination by 2030 owing to various factors, including local differences in transmission. Subnational projections of intervention impact are a useful tool in understanding these dynamics, but correctly characterizing their uncertainty is challenging. Methods: We developed a computationally feasible framework for providing subnational projections for LF across 44 sub-Saharan African countries using ensemble models, guided by historical control data, to allow assessment of the role of subnational heterogeneities in global goal achievement. Projected scenarios include ongoing annual treatment from 2018 to 2030, enhanced coverage, and biannual treatment. Results: Our projections suggest that progress is likely to continue well. However, highly endemic locations currently deploying strategies with the lower World Health Organization recommended coverage (65%) and frequency (annual) are expected to have slow decreases in prevalence. Increasing intervention frequency or coverage can accelerate progress by up to 5 or 6 years, respectively. Conclusions: While projections based on baseline data have limitations, our methodological advancements provide assessments of potential bottlenecks for the global goals for LF arising from subnational heterogeneities. In particular, areas with high baseline prevalence may face challenges in achieving the 2030 goals, extending the "tail"of interventions. Enhancing intervention frequency and/or coverage will accelerate progress. Our approach facilitates preimplementation assessments of the impact of local interventions and is applicable to other regions and neglected tropical diseases.

Paenibacillus thiaminolyticus may be an underdiagnosed cause of neonatal sepsis. We prospectively enrolled a cohort of 800 full-term neonates presenting with a clinical diagnosis of sepsis at two Ugandan hospitals. Quantitative polymerase chain reaction specific to P. thiaminolyticus and to the Paenibacillus genus were performed on the blood and cerebrospinal fluid (CSF) of 631 neonates who had both specimen types available. Neonates with Paenibacillus genus or species detected in either specimen type were considered to potentially have paenibacilliosis, (37/631, 6%). We described antenatal, perinatal, and neonatal characteristics, presenting signs, and 12-month developmental outcomes for neonates with paenibacillosis vs. clinical sepsis. Median age at presentation was 3 days (interquartile range 1, 7). Fever (92%), irritability (84%) and clinical signs of seizures (51%) were common. Eleven (30%) had an adverse outcome: 5 (14%) neonates died during the first year of life; 5 of 32 (16%) survivors developed postinfectious hydrocephalus (PIH) and one (3%) additional survivor had neurodevelopmental impairment without hydrocephalus. Paenibacillus species was identified in 6% of neonates with signs of sepsis who presented to two Ugandan referral hospitals; 70% were P. thiaminolyticus. Improved diagnostics for neonatal sepsis are urgently needed. Optimal antibiotic treatment for this infection is unknown but ampicillin and vancomycin will be ineffective in many cases. These results highlight the need to consider local pathogen prevalence and the possibility of unusual pathogens when determining antibiotic choice for neonatal sepsis. [Abstract copyright: © The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.]

Paenibacillus thiaminolyticus is a cause of postinfectious hydrocephalus among Ugandan infants. To determine whether Paenibacillus spp is a pathogen in neonatal sepsis, meningitis, and postinfectious hydrocephalus, we aimed to complete three separate studies of Ugandan infants. The first study was on peripartum prevalence of Paenibacillus in mother-newborn pairs. The second study assessed Paenibacillus in blood and cerebrospinal fluid (CSF) from neonates with sepsis. The third study assessed Paenibacillus in CSF from infants with hydrocephalus. In this observational study, we recruited mother-newborn pairs with and without maternal fever (mother-newborn cohort), neonates (aged ≤28 days) with sepsis (sepsis cohort), and infants (aged ≤90 days) with hydrocephalus with and without a history of neonatal sepsis and meningitis (hydrocephalus cohort) from three hospitals in Uganda between Jan 13, 2016 and Oct 2, 2019. We collected maternal blood, vaginal swabs, and placental samples and the cord from the mother-newborn pairs, and blood and CSF from neonates and infants. Bacterial content of infant CSF was characterised by 16S rDNA sequencing. We analysed all samples using quantitative PCR (qPCR) targeting either the Paenibacillus genus or Paenibacillus thiaminolyticus spp. We collected cranial ultrasound and computed tomography images in the subset of participants represented in more than one cohort. No Paenibacillus spp were detected in vaginal, maternal blood, placental, or cord blood specimens from the mother-newborn cohort by qPCR. Paenibacillus spp was detected in 6% (37 of 631 neonates) in the sepsis cohort and, of these, 14% (5 of 37 neonates) developed postinfectious hydrocephalus. Paenibacillus was the most enriched bacterial genera in postinfectious hydrocephalus CSF (91 [44%] of 209 patients) from the hydrocephalus cohort, with 16S showing 94% accuracy when validated by qPCR. Imaging showed progression from Paenibacillus spp-related meningitis to postinfectious

Current WHO guidelines set prevalence thresholds below which a neglected tropical disease can be considered to have been eliminated as a public health problem, and specify how surveys to assess whether elimination has been achieved should be designed and analysed, based on classical survey sampling methods. In this paper, we describe an alternative approach based on geospatial statistical modelling. We first show the gains in efficiency that can be obtained by exploiting any spatial correlation in the underlying prevalence. We then suggest that the current guidelines' implicit use of a significance testing argument is not appropriate; instead, we argue for a predictive inferential framework, leading to design criteria based on controlling the rates at which areas whose true prevalence lies above and below the elimination threshold are incorrectly classified. We describe how this approach naturally accommodates context-specific information in the form of georeferenced covariates that have been shown to be predictive of disease prevalence. Finally, we give a progress report of an ongoing collaboration with the Guyana Ministry of Health Neglected Tropical Disease programme on the design of an IDA (ivermectin, diethylcarbamazine and albendazole) Impact Survey of lymphatic filariasis to be conducted in Guyana in early 2023. 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’.

Background: Infections caused by both Schistosoma mansoni and Schistosoma haematobium are endemic in Kenya, with over six million children at risk. A national school-based deworming programme was launched in 2012 with the goal of eliminating parasitic worms as a public health problem. This study used a model-based geostatistical (MBG) approach to design and analyse the impact of the programme and inform treatment strategy changes for schistosomiasis (SCH). Methods: A cross-sectional survey of 200 schools across 27 counties of Kenya was utilised. The study design, selection of the schools, and analysis followed the MBG approach, which incorporated historical data on treatment, morbidity, and environmental covariates. Results: The overall SCH prevalence was 5.0% (95% CI 4.9%–5.2%) and was estimated, with a high predictive probability of 0.999, to be between 1% and< 10%. The predictive probabilities at county level revealed county heterogeneity, with that of four counties estimated to be between 0% and< 1%, that of 20 counties estimated to be between 1% and< 10%, that of two counties estimated to be between 10% and< 20%, and that of one county estimated to be between 20% and< 50%. Conclusion: SCH treatment requirements can now be confidently refined based on the World Health Organization’s guidelines. The four counties with prevalences of between 0% and< 1% may consider suspending treatment only in areas (i.e., sub-counties and wards) where the prevalence is< 1%.

Background Kenya is endemic for soil-transmitted helminths (STH) with over 6 million children in 27 counties currently at-risk. A national school-based deworming programme (NSBDP) was launched in 2012 with a goal to eliminate parasitic worms as a public health problem. This study used model-based geostatistical (MBG) approach to design and analyse the impact of the NSBDP and inform treatment strategy changes. Methods A cross-sectional study was used to survey 200 schools across 27 counties in Kenya. The study design, school selection and analysis followed the MBG approach which incorporated historical data on treatment, morbidity and environmental covariates to efficiently predict the helminths prevalence in Kenya. Results Overall, the NSBDP geographic area prevalence for any STH was estimated to sit between 2 % and 0.999. Species-specific thresholds were between 2 % and 0.999. Conclusions Based on the World Health Organization guidelines, STH treatment requirements can now be confidently refined. Ten counties may consider suspending treatment and implement appropriate surveillance system, while another 10 will require treatment once every two years, and the remaining seven will require treatment once every year.

In the originally published version of this manuscript, a funding statement and disclaimer were omitted in error. The following passages have been added to the Funding section: a note reading “AWS is a staff member of the World Health Organization.” a disclaimer reading, “The authors alone are responsible for the views expressed in this article and they do not necessarily represent the views, decisions or policies of the institutions with which they are affiliated. The boundaries and names shown and the designations used on the maps in this article do not imply the expression of any opinion whatsoever on the part of the authors, or the institutions with which they are affiliated, concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries.” These errors have been corrected online.

Objective To estimate the prevalence of cytomegalovirus (CMV) infections in newborn-mother pairs, neonates with sepsis, and infants with hydrocephalus in Uganda. Design and Methods Three populations: (1) newborn-mother pairs, (2) neonates with sepsis, and (3) infants (≤ 3 months) with non-postinfectious (NPIH) or postinfectious (PIH) hydrocephalus, were evaluated for CMV infection at three medical centers in Uganda. Quantitative PCR (qPCR) was used to characterize the prevalence of CMV. Results The overall CMV prevalence in 2498 samples in duplicate across all groups was 9%. In newborn-mother pairs, there was a 3% prevalence of cord blood CMV positivity and 33% prevalence of maternal vaginal shedding. In neonates with clinical sepsis there was a 2% CMV prevalence. Maternal HIV seropositivity (aOR, 25.20; 95% CI, 4.43-134.26; p= 0.0001), residence in Eastern Uganda (aOR, 11.06; 95% CI, 2.30-76.18; p=0.003), maternal age < 25 years (aOR, 4.54; 95% CI, 1.40-19.29; p=0.02), and increasing neonatal age (aOR, 1.08 for each day older; 95% CI, 1.00-1.16; p= 0.05), were associated risk factors for CMV in neonates with clinical sepsis. We found a two-fold higher maternal vaginal shedding in Eastern (45%) vs Western (22%) Uganda during parturition (n=22/49 vs. 11/50, Fisher's exact test, p=0.02). In infants with PIH, the prevalence in blood was 24% and in infants with NPIH it was 20%. CMV was present in the CSF of 13% of infants with PIH compared to 0.5% of infants with NPIH (n=26/205 vs. 1/194, p<0.0001). Conclusion Our findings highlight that congenital and postnatal CMV prevalence is substantial in this African setting and the long-term consequences are uncharacterized.

Background As the prevalences of neglected tropical diseases reduce to low levels in some countries, policymakers require precise disease estimates to decide whether the set public health targets have been met. At low prevalence levels, traditional statistical methods produce imprecise estimates. More modern geospatial statistical methods can deliver the required level of precision for accurate decision-making. Methods Using spatially referenced data from 3567 cluster locations in Ethiopia in the years 2017, 2018 and 2019, we developed a geostatistical model to estimate the prevalence of trachomatous trichiasis and to calculate the probability that the trachomatous trichiasis component of the elimination of trachoma as a public health problem has already been achieved for each of 482 evaluation units. We also compared the precision of traditional and geostatistical approaches by the ratios of the lengths of their 95% predictive intervals. Results The elimination threshold of trachomatous trichiasis (prevalence ≤ 0.2% in individuals aged ≥15 years) is met with a probability of 0.9 or more in 8 out of the 482 evaluation units assessed, and with a probability of ≤0.1 in 469 evaluation units. For the remaining five evaluation units, the probability of elimination is between 0.45 and 0.65. Prevalence estimates were, on average, 10 times more precise than estimates obtained using the traditional approach. Conclusions By accounting for and exploiting spatial correlation in the prevalence data, we achieved remarkably improved precision of prevalence estimates compared with the traditional approach. The geostatistical approach also delivers predictions for unsampled evaluation units that are geographically close to sampled evaluation units.

Background The etiology of neonatal sepsis is often not identified. Molecular methods can identify pathogens that culture-based methods miss. Most cases of neonatal sepsis globally are treated empirically per WHO guidelines with intravenous ampicillin and gentamicin, which may not be the best regimen for all pathogens. Methods We prospectively enrolled 800 neonates presenting with signs of sepsis to two Ugandan hospitals. Blood and cerebrospinal fluid were subjected to 16S rRNA sequencing, which identified Paenibacillus thiaminolyticus in 33/800 (4%) neonates. We confirmed the presence of P. thiaminolyticus by quantitative polymerase chain reaction (PCR). We describe neonatal and birth characteristics, presenting signs, and 12-month developmental outcomes for neonates with paenibacillosis. We performed antibiotic susceptibility testing and genomic analyses on three clinical isolates successfully grown in the laboratory. Results Neonates presented at a median age of 3 (1, 7) days. Fever (86%), irritability (78%) and seizures (52%) were common presenting signs (Figure). Most neonates were born vaginally (73%) at a medical facility (79%). Twelve (36%) had an adverse outcome: 5 (15%) neonates died; 4 (14%) survivors developed postinfectious hydrocephalus and three (9%) additional survivors had neurodevelopmental impairment. All three isolates were resistant to vancomycin, two were resistant to penicillin and ampicillin and one was unlikely to be sensitive to ceftriaxone; all were susceptible to gentamicin and meropenem. The genomes of all three strains contained multiple beta-lactamase genes and a cluster of genes that encodes a type IV pilus. Clinical signs at presentation for neonates with good and poor outcomes followng paenibacillosis. Conclusion Molecular methods such as 16S rRNA sequencing and PCR can be used to improve the identification of pathogens causing neonatal sepsis. Paenibacillosis is an important emerging cause of neonatal sepsis in Uganda and is likely

Mycetoma is widespread in tropical and subtropical regions favouring arid areas with low humidity and a short rainy season. Sudan is one of the highly endemic countries for mycetoma. Estimating the population at risk and the number of cases is critical for delivering targeted and equitable prevention and treatment services. In this study, we have combined a large dataset of mycetoma cases recorded by the Mycetoma Research Centre (MRC) in Sudan over 28 years (1991–2018) with a collection of environmental and water and hygiene-related datasets in a geostatistical framework to produce estimates of the disease burden across the country. We developed geostatistical models to predict the number of cases of actinomycetoma and eumycetoma in areas considered environmentally suitable for the two mycetoma forms. Then used the raster dataset (gridded map) with the population estimates for 2020 to compute the potentially affected population since 1991. The geostatistical models confirmed this heterogeneous and distinct distribution of the estimated cases of eumycetoma and actinomycetoma across Sudan. For eumycetoma, these higher-risk areas were smaller and scattered across Al Jazirah, Khartoum, White Nile and Sennar states, while for actinomycetoma a higher risk for infection is shown across the rural districts of North and West Kurdufan. Nationally, we estimated 63,825 people (95%CI: 13,693 to 197,369) to have been suffering from mycetoma since 1991 in Sudan,51,541 people (95%CI: 9,893–166,073) with eumycetoma and 12,284 people (95%CI: 3,800–31,296) with actinomycetoma. In conclusion, the risk of mycetoma in Sudan is particularly high in certain restricted areas, but cases are ubiquitous across all states. Both prevention and treatment services are required to address the burden. Such work provides a guide for future control and prevention programs for mycetoma, highly endemic areas are clearly targeted, and resources are directed to areas with high demand.