Structure-activity relationships of antitubercular salicylanilides consistent with disruption of the proton gradient via proton shuttling.

A series of salicylanilides was synthesized based on a high-throughput screening hit against Mycobacterium tuberculosis. A free phenolic hydroxyl on the salicylic acid moeity is required for activity, and the structure-activity relationship of the aniline ring is largely driven by the presence of electron withdrawing groups. We synthesized 94 analogs exploring substitutions of both rings and the linker region in this series and we have identified multiple compounds with low micromolar potency. Unfortunately, cytotoxicity in a murine macrophage cell line trends with antimicrobial activity, suggesting a similar mechanism of action. We propose that salicylanilides function as proton shuttles that kill cells by destroying the cellular proton gradient, limiting their utility as potential therapeutics.

Baseline Prevalence of Trachoma in Refugee Settlements in Uganda: Results of 11 Population-based Surveys.

PURPOSE: There are several settlements in the Northern and Western Regions of Uganda serving refugees from South Sudan and Democratic Republic of Congo (DRC), respectively. Trachoma prevalence surveys were conducted in a number of those settlements with the aim of determining whether interventions for trachoma are required. METHODS: An evaluation unit (EU) was defined as all refugee settlements in one district. Cross-sectional population-based trachoma prevalence survey methodologies designed to adhere to World Health Organization recommendations were deployed in 11 EUs to assess prevalence of trachomatous inflammation-follicular (TF) in 1-9-year-olds and trachomatous trichiasis (TT) unknown to the health system in ≥15-year-olds. Household-level water, sanitation and hygiene coverage was also assessed in study populations. RESULTS: A total of 40,892 people were examined across 11 EUs between 2018 and 2020. The prevalence of TF in 1-9-year-olds was <5% in all EUs surveyed. The prevalence of trachomatous trichiasis (TT) unknown to the health system in ≥15-year-olds was <0.2% in 5 out of 11 EUs surveyed and ≥0.2% in the remaining 6 EUs. A high proportion of households had improved water sources, but a low proportion had improved latrines or quickly (within a 30-minute return journey) accessible water sources. CONCLUSIONS: Implementation of the antibiotic, facial cleanliness and environmental improvement components of the SAFE strategy is not needed for the purposes of trachoma's elimination as a public health problem in these refugee settlements; however, intervention with TT surgery is needed in six EUs. Since instability continues to drive displacement of people from South Sudan and DRC into Uganda, there is likely to be a high rate of new arrivals to the settlements over the coming years. These populations may therefore have trachoma surveillance needs that are distinct from the surrounding non-refugee communities.

Comparison of platforms for testing antibodies to Chlamydia trachomatis antigens in the Democratic Republic of the Congo and Togo.

Trachoma, caused by repeated ocular infection with Chlamydia trachomatis (Ct), is targeted for elimination as a public health problem. Serological testing for antibodies is promising for surveillance; determining useful thresholds will require collection of serological data from settings with different prevalence of the indicator trachomatous inflammation-follicular (TF). Dried blood spots were collected during trachoma mapping in two districts each of Togo and Democratic Republic of the Congo. Anti-Ct antibodies were detected by multiplex bead assay (MBA) and three different lateral flow assays (LFA) and seroprevalence and seroconversion rate (SCR) were determined. By most tests, the district with > 5% TF (the elimination threshold) had five-sixfold higher seroprevalence and tenfold higher SCR than districts with < 5% TF. The agreement between LFA and MBA was improved using a black latex developing reagent. These data show optimization of antibody tests against Ct to better differentiate districts above or below trachoma elimination thresholds.

Completing Baseline Mapping of Trachoma in Nepal: Results of 27 Population-Based Prevalence Surveys Conducted in 2013 and 2014.

PURPOSE: Trachoma is endemic in parts of Nepal; implementation of the surgery, antibiotics, facial cleanliness, environmental improvement (SAFE) strategy started in 2002. Some suspected-endemic districts had not previously been mapped. We aimed to estimate the prevalences of trachomatous inflammation-follicular (TF) and trichiasis in those districts. METHODS: Population-based prevalence surveys were undertaken in 27 districts. In each of those districts, two-stage cluster sampling was used to select a sample of 2000 children aged 1-9 years and 4000 adults aged ≥15 years from a total of 40 wards (clusters), drawn evenly from two subdistricts. Consenting eligible participants were examined for trachoma by Global Trachoma Mapping Project (GTMP)-certified graders, using the World Health Organization simplified grading system. Data were analyzed at district level using GTMP methods. RESULTS: A total of 43,200 households were surveyed, and 162,094 people were examined for trachoma. District-level TF prevalence in 1-9-year-olds ranged from 0% to 4.3% (95% confidence interval [CI] 2.4-6.2). Among adults aged ≥15 years, trichiasis prevalence ranged from 0% to 0.33% (95% CI 0.08-0.65). CONCLUSION: TF was not a public health problem in any of the 27 districts surveyed; thus, antibiotic mass drug administration is not needed. In two districts (Dhanusa and Gorkha), trichiasis prevalence in adults aged ≥15 years was ≥0.2%; thus, further trichiasis surgery interventions at public health level are warranted to achieve elimination. These findings will facilitate planning for elimination of trachoma as a public health problem in Nepal.

Early provision of oropharyngeal colostrum leads to sustained breast milk feedings in preterm infants.

BACKGROUND: Oropharyngeal colostrum (OC) application strategies have been shown to be feasible and safe for very low birth weight (VLBW) infants. Evidence to support the nutritional and clinical advantages of OC care remains somewhat theoretical. The objectives of this study were to a) confirm the feasibility and safety of OC application in preterm infants and b) determine if OC application is associated with improved nutritional and clinical outcomes from birth to discharge. We hypothesized that OC application in the first few days would promote sustained breast milk feedings through discharge. METHODS: An observational longitudinal study was conducted in 133 VLBW infants during 2013-14, after an OC protocol was adopted. Maternal and infant characteristics, infant vital signs during administration, nutritional outcomes, and common neonatal morbidities were assessed and compared to 85 age- and weight-matched VLBW infants from a retrospective control cohort from 2012, prior to the implementation of the OC protocol. RESULTS: There were no adverse events or changes in vital signs during the application of OC. VLBW infants who received OC continued to receive the majority of their enteral feeds from human breast milk at six 6 of age and through discharge (p < 0.01). There was no difference in maternal characteristics known to affect breast milk production, and rates of common neonatal morbidities were statistically similar between groups. CONCLUSION: OC application for VLBW infants is safe and practical in a neonatal intensive care unit setting and is associated with increased rates of breast milk feeding.

Impact of mass drug administration for elimination of lymphatic filariasis in Nepal.

BACKGROUND: Lymphatic filariasis (LF) is a neglected tropical disease transmitted by mosquitoes. Nepal has implemented a national effort to eliminate LF by 2020 through mass drug administration (MDA) using diethylcarbamazine (DEC) and albendazole (ALB). We assessed the impact of MDAs on LF in selected districts of Nepal after the recommended six MDA rounds had been completed. METHODOLOGY AND PRINCIPAL FINDINGS: Baseline surveys were conducted in seven districts and mapping data were used as baseline in the other three districts before starting MDA in 2009. LF antigen (Ag) prevalence ranged from 1.06% to 20% among districts included in the baseline and mapping study. The number of people who received DEC and ALB were recorded during each MDA round and population-based cluster surveys were conducted at least once in each district during the life of the program. The reported MDA coverage in five districts was consistently at least 65%. Two districts achieved the targeted coverage in four out of five rounds and the rest three districts achieved the target only in the first round. A pre-transmission assessment survey (pre-TAS) was conducted in one sentinel site and at least one spot check site in each of the districts after five MDA rounds. In pre-TAS, all the sites of five districts (Pyuthan, Arghakhanchi, Kaski, Bhaktapur, and Kathmandu) and all but one spot check site of Lalitpur district had LF Ag < 2% (ranging from 0.0% to 1.99%). Transmission assessment survey (TAS) was conducted in six evaluation units (EUs) consisting of six districts qualified on pre-TAS. Though MDA coverage of 65% was not achieved in three districts (Kathmandu, Lalitpur and Bhaktapur), Nepal government in consultation with World Health Organization (WHO) decided to conduct TAS. All six EUs achieved the LF Ag threshold required to stop MDA in TAS, despite the low reported MDA coverage in those three districts. CONCLUSIONS: Although Nepal has achieved significant progress towards LF elimination, five rounds of MDA were not sufficient to disrupt the transmission cycle in all districts, probably because of high baseline prevalence.

Applying a mobile survey tool for assessing lymphatic filariasis morbidity in Mtwara Municipal Council of Tanzania.

BACKGROUND: A number of methods have been used to estimate lymphatic filariasis (LF) morbidity, including: routine programmatic data, cluster random surveys and the "town crier" method. Currently, few accurate data exist on the global LF morbidity burden in Tanzania. We aimed to estimate prevalence of lymphedema and hydrocele in Mtwara Municipal Council using mobile phone based survey. METHODS: A cross-sectional survey was conducted among adults of Mtwara Municipal council with access to mobile phones. A sample size of at least 384 completed surveys was required to estimate prevalence of lymphedema (both males and females) and hydrocele (males only) morbidity of 50% within a 5% error margin given a 5% level of significance and 95% confidence level. Eligible mobile phone users received a short message text (SMS) requesting consent to participate in the survey. A total of 10 questions were administered via interactive SMS through the GeoPoll, a survey platform developed by Mobile Accord (www.geopoll.com). RESULTS: The survey was completed over a period of 4 days. A total of 8,759 surveys were sent to mobile phone subscribers of whom 1,330 (15.2%) opted-in to complete the survey. A total of 492 (37.0% of those opted-in, 384 male and 108 female) people completed the survey. Lymphedema and hydrocele signs were reported by 20.9% (95% CI, 17.4-24.8) and 20.6% (95% CI, 16.6-25.0) of respondents, respectively. Majority of hydrocele patients (59.5%) and 46.6% of lymphedema patients reported having sought treatment. The proportion of patients reporting similar symptoms among friends and relatives was 66.0% and 70.9% for lymphedema and hydrocele, respectively. CONCLUSIONS: The findings suggest that mobile phone based surveys are a practical approach of undertaking morbidity surveys. While further surveys are needed to verify the findings, this approach can be expected to encourage identification of lymphedema and hydrocele morbidity at community level and provide evidence where further morbidity surveys are warranted.

Surveillance Surveys for Reemergent Trachoma in Formerly Endemic Districts in Nepal From 2 to 10 Years After Mass Drug Administration Cessation.

Importance: To verify districts for elimination of blinding trachoma, the World Health Organization requires a population-based surveillance survey for follicular trachoma (TF) and trachomatous trichiasis (TT) 2 years after mass drug administration (MDA) activities have ceased. However, it is unknown if 2 years provides enough time to discover reemergence. Objective: To determine the prevalence of trachoma from surveys among 4 districts in Nepal (Dailekh, Dang, Surkhet, and Kanchanpur) that had surveillance intervals of 2, 4, 8, and 10 years, respectively, after cessation of MDA. Design, Setting, and Participants: Cross-sectional surveys were carried out in 2015 and 2016. Data analyses were done from March to September 2016. Among 20 clusters randomly selected from each district, 15 were randomly selected for infection and antibody testing: TF and TT were assessed, conjunctival swabs were tested for chlamydial infection, and blood spots were collected on filter paper to test for antibodies to Chlamydia trachomatis pgp3 using a multiplex bead assay. The study setting was 4 districts previously endemic for trachoma in Nepal. Participants were randomly selected and included 50 children aged 1 to 9 years and 100 adolescents and adults 15 years and older from each of the 20 clusters; this investigation reports on the children. Main Outcomes and Measures: Length of time since the last round of MDA and the prevalence of TF among children aged 1 to 9 years and the prevalence of TT among adolescents and adults 15 years and older. Results: Of 3024 children surveyed in the clusters, 48.0% (n = 1452) were female. The mean (SD) age of the children was 5.4 (2.6) years. Eleven cases of TF were found, with a TF prevalence less than 1% in all 4 districts. Three cases of infection were found. Seropositivity for pgp3 antibody varied from 1.4% (95% CI, 0.7-2.6) in the district with a 10-year surveillance interval to 2.5% (95% CI, 1.3-4.5) in the district with a 4-year surveillance interval. Seropositivity increased slightly with age in only one district. The TT prevalence was less than 1 case per 1000 among the total population in all 4 districts after accounting for cases known to the health system and cases with no scarred conjunctiva. Conclusions and Relevance: This study found no evidence of reemergence of trachoma up to 10 years after cessation of MDA in 4 districts in children in Nepal. The recommendation for a surveillance survey at 2 years, as proposed by the World Health Organization, is supported by these data. Determining if individuals with TT had scarring or are known to the health system was critical for meeting elimination criteria of blinding trachoma.

The World Health Organization Recommendations for Trachoma Surveillance, Experience in Nepal and Added Benefit of Testing for Antibodies to Chlamydia trachomatis pgp3 Protein: NESTS Study.

BACKGROUND: The World Health Organization (WHO) now requires a second surveillance survey for trachoma after an impact assessment has found follicular trachoma (TF) <5% to determine if re-emergence has occurred. Using new WHO guidelines, we undertook surveillance surveys, and determined the prevalence of infection and antibody positivity, in two districts in Nepal. METHODS: 20 clusters were randomly selected within each district, 15 were randomly selected for antibody testing. In each cluster, we randomly selected 50 children ages 1-9 years and 100 adults ≥15 years. TF and trachomatous trichiasis (TT) were evaluated. Conjunctival swabs to test for chlamydial infection using GenXpert platform were obtained, and dried blood spots were collected to test for antibodies to Chlamydia Trachomatis pgp3 using the Luminex platform. FINDINGS: 3 cases of TF were found in the two districts, and one case of infection. Pgp3 antibody positivity was 2·4% (95% confidence interval: 1·4%, 3·7%), and did not increase with age (P = 0.24). No clustering of antibody positivity within communities was found. TT prevalence was <1/1,000 population. INTERPRETATION: The surveillance surveys, as proposed by WHO, showed no evidence for re-emergence of trachoma in two districts of Nepal. The low level and no significant increase by age in seroprevalence of antibodies to C trachomatis pgp3 antigen deserve further investigation as a marker of interruption of transmission.

Integrating Neglected Tropical Disease and Immunization Programs: The Experiences of the Tanzanian Ministry of Health.

Global health practitioners are increasingly advocating for the integration of community-based health-care platforms as a strategy for increasing the coverage of programs, encouraging program efficiency, and promoting universal health-care goals. To leverage the strengths of compatible programs and avoid geographic and temporal duplications in efforts, the Tanzanian Ministry of Health and Social Welfare coordinated immunization and neglected tropical disease programs for the first time in 2014. Specifically, a measles and rubella supplementary vaccine campaign, mass drug administration (MDA) of ivermectin and albendazole, and Vitamin A were provisionally integrated into a shared community-based delivery platform. Over 21 million people were targeted by the integrated campaign, with the immunization program and MDA program reaching 97% and 93% of targeted individuals, respectively. The purpose of this short report is to share the Tanzanian experience of launching and managing this integrated campaign with key stakeholders.

Ethiopia and its steps to mobilize resources to achieve 2020 elimination and control goals for neglected tropical diseases webs joined can tie a lion.

In June 2013, at the launch of its National Neglected Tropical Disease (NTD) Master Plan, the Ethiopian government pledged to achieve WHO NTD elimination and control targets by 2020. With an estimated 80 million people living in areas where one or more NTDs are endemic, this goal presented an enormous challenge for the Federal Ministry of Health. However, as of September 2015, the Federal Ministry of Health has managed to mobilize support to implement mass drug administration in 84% of the trachoma endemic districts and 100% of the endemic districts for onchocerciasis, lymphatic filariasis, soil-transmitted helminthes and schistosomiasis. The national program still is facing large gaps in its podoconiosis and leishmaniasis programs, and it faces significant other challenges to stay on track for 2020 targets. However, this unprecedented scale-up in support was achieved through significant government investment in NTD interventions and creative coordination between donors and implementing partners, which may provide valuable lessons for other national NTD programs trying to achieve nationwide coverage.

Progress of Trachoma Mapping in Mainland Tanzania: Results of Baseline Surveys from 2012 to 2014.

PURPOSE: Following surveys in 2004-2006 in 50 high-risk districts of mainland Tanzania, trachoma was still suspected to be widespread elsewhere. We report on baseline surveys undertaken from 2012 to 2014. METHODS: A total of 31 districts were surveyed. In 2012 and 2013, 12 at-risk districts were selected based on proximity to known trachoma endemic districts, while in 2014, trachoma rapid assessments were undertaken, and 19 of 55 districts prioritized for baseline surveys. A multi-stage cluster random sampling methodology was applied whereby 20 villages (clusters) and 36 households per cluster were surveyed. Eligible participants, children aged 1-9 years and people aged 15 years and older, were examined for trachoma using the World Health Organization simplified grading system. RESULTS: A total of 23,171 households were surveyed and 104,959 participants (92.3% of those enumerated) examined for trachoma signs. A total of 44,511 children aged 1-9 years and 65,255 people aged 15 years and older were examined for trachomatous inflammation-follicular (TF) and trichiasis, respectively. Prevalence of TF varied by district, ranging from 0.0% (95% confidence interval, CI 0.0-0.1%) in Mbinga to 11.8% (95% CI 6.8-16.5%) in Chunya. Trichiasis prevalence was lowest in Urambo (0.03%, 95% CI 0.00-0.24%) and highest in Kibaha (1.08%, 95% CI 0.74-1.43%). CONCLUSION: Only three districts qualified for mass drug administration with azithromycin. Trichiasis is still a public health problem in many districts, thus community-based trichiasis surgery should be considered to prevent blindness due to trachoma. These findings will facilitate achievement of trachoma elimination objectives.

Controlling Neglected Tropical Diseases (NTDs) in Haiti: Implementation Strategies and Evidence of Their Success.

Lymphatic filariasis (LF) and soil-transmitted helminths (STH) have been targeted since 2000 in Haiti, with a strong mass drug administration (MDA) program led by the Ministry of Public Health and Population and its collaborating international partners. By 2012, Haiti's neglected tropical disease (NTD) program had reached full national scale, and with such consistently good epidemiological coverage that it is now able to stop treatment for LF throughout almost all of the country. Essential to this success have been in the detail of how MDAs were implemented. These key programmatic elements included ensuring strong community awareness through an evidence-based, multi-channel communication and education campaign facilitated by voluntary drug distributors; strengthening community trust of the drug distributors by ensuring that respected community members were recruited and received appropriate training, supervision, identification, and motivation; enforcing a "directly observed treatment" strategy; providing easy access to treatment though numerous distribution posts and a strong drug supply chain; and ensuring quality data collection that was used to guide and inform MDA strategies. The evidence that these strategies were effective lies in both the high treatment coverage obtained- 100% geographical coverage reached in 2012, with almost all districts consistently achieving well above the epidemiological coverage targets of 65% for LF and 75% for STH-and the significant reduction in burden of infection- 45 communes having reached the target threshold for stopping treatment for LF. By taking advantage of sustained international financial and technical support, especially during the past eight years, Haiti's very successful MDA campaign resulted in steady progress toward LF elimination and development of a strong foundation for ongoing STH control. These efforts, as described, have not only helped establish the global portfolio of "best practices" for NTD control but also are poised to help solve two of the most important future NTD challenges-how to maintain control of STH infections after the community-based LF "treatment platform" ceases and how to ensure appropriate morbidity management for patients currently suffering from lymphatic filarial disease.