An updated list of eumycetoma causative agents and their differences in grain formation and treatment response.

SUMMARYIn 2023, the World Health Organization designated eumycetoma causative agents as high-priority pathogens on its list of fungal priority pathogens. Despite this recognition, a comprehensive understanding of these causative agents is lacking, and potential variations in clinical manifestations or therapeutic responses remain unclear. In this review, 12,379 eumycetoma cases were reviewed. In total, 69 different fungal species were identified as causative agents. However, some were only identified once, and there was no supporting evidence that they were indeed present in the grain. Madurella mycetomatis was by far the most commonly reported fungal causative agent. In most studies, identification of the fungus at the species level was based on culture or histology, which was prone to misidentifications. The newly used molecular identification tools identified new causative agents. Clinically, no differences were reported in the appearance of the lesion, but variations in mycetoma grain formation and antifungal susceptibility were observed. Although attempts were made to explore the differences in clinical outcomes based on antifungal susceptibility, the lack of large clinical trials and the inclusion of surgery as standard treatment posed challenges in drawing definitive conclusions. Limited case series suggested that eumycetoma cases caused by Fusarium species were less responsive to treatment than those caused by Madurella mycetomatis. However, further research is imperative for a comprehensive understanding.

The short-term impact of Schistosoma mansoni infection on health-related quality of life: implications for current elimination policies.

The WHO aims to eliminate schistosomiasis as a public health problem by 2030. However, standard morbidity measures poorly correlate to infection intensities, hindering disease monitoring and evaluation. This is exacerbated by insufficient evidence on Schistosoma's impact on health-related quality of life (HRQoL). We conducted community-based cross-sectional surveys and parasitological examinations in moderate-to-high Schistosoma mansoni endemic communities in Uganda. We calculated parasitic infections and used EQ-5D instruments to estimate and compare HRQoL utilities in these populations. We further employed Tobit/linear regression models to predict HRQoL determinants. Two-thirds of the 560 participants were diagnosed with parasitic infection(s), 49% having S. mansoni. No significant negative association was observed between HRQoL and S. mansoni infection status/intensity. However, severity of pain urinating (ß = -0.106; s.e. = 0.043) and body swelling (ß = -0.326; s.e. = 0.005), increasing age (ß = -0.016; s.e. = 0.033), reduced socio-economic status (ß = 0.128; s.e. = 0.032), and being unemployed predicted lower HRQoL. Symptom severity and socio-economic status were better predictors of short-term HRQoL than current S. mansoni infection status/intensity. This is key to disentangling the link between infection(s) and short-term health outcomes, and highlights the complexity of correlating current infection(s) with long-term morbidity. Further evidence is needed on long-term schistosomiasis-associated HRQoL, health and economic outcomes to inform the case for upfront investments in schistosomiasis interventions.

Interventions can shift the thermal optimum for parasitic disease transmission.

Temperature constrains the transmission of many pathogens. Interventions that target temperature-sensitive life stages, such as vector control measures that kill intermediate hosts, could shift the thermal optimum of transmission, thereby altering seasonal disease dynamics and rendering interventions less effective at certain times of the year and with global climate change. To test these hypotheses, we integrated an epidemiological model of schistosomiasis with empirically determined temperature-dependent traits of the human parasite Schistosoma mansoni and its intermediate snail host (Biomphalaria spp.). We show that transmission risk peaks at 21.7 °C (Topt ), and simulated interventions targeting snails and free-living parasite larvae increased Topt by up to 1.3 °C because intervention-related mortality overrode thermal constraints on transmission. This Topt shift suggests that snail control is more effective at lower temperatures, and global climate change will increase schistosomiasis risk in regions that move closer to Topt Considering regional transmission phenologies and timing of interventions when local conditions approach Topt will maximize human health outcomes.

Evaluating the World Health Organization's SkinNTDs App as a Training Tool for Skin Neglected Tropical Diseases in Ghana and Kenya: Cross-Sectional Study.

BACKGROUND: Neglected tropical diseases (NTDs) affect over 1.5 billion people worldwide, primarily impoverished populations in low- and middle-income countries. Skin NTDs, a significant subgroup, manifest primarily as skin lesions and require extensive diagnosis and treatment resources, including trained personnel and financial backing. The World Health Organization has introduced the SkinNTDs app, a mobile health tool designed to train and be used as a decision support tool for frontline health care workers. As most digital health guidelines prioritize the thorough evaluation of mobile health interventions, it is essential to conduct a rigorous and validated assessment of this app. OBJECTIVE: This study aims to assess the usability and user experience of World Health Organization SkinNTDs app (version 3) as a capacity-building tool and decision-support tool for frontline health care workers. METHODS: A cross-sectional study was conducted in Ghana and Kenya. Frontline health care workers dealing with skin NTDs were recruited through snowball sampling. They used the SkinNTDs app for at least 5 days before completing a web-based survey containing demographic variables and the user version of the Mobile Application Rating Scale (uMARS), a validated scale for assessing health apps. A smaller group of participants took part in semistructured interviews and one focus group. Quantitative data were analyzed using SPSS with a 95% CI and P≤.05 for statistical significance and qualitative data using ATLAS.ti to identify attributes, cluster themes, and code various dimensions that were explored. RESULTS: Overall, 60 participants participated in the quantitative phase and 17 in the qualitative phase. The SkinNTDs app scored highly on the uMARS questionnaire, with an app quality mean score of 4.02 (SD 0.47) of 5, a subjective quality score of 3.82 (SD 0.61) of 5, and a perceived impact of 4.47 (SD 0.56) of 5. There was no significant association between the app quality mean score and any of the categorical variables examined, according to Pearson correlation analysis; app quality mean score vs age (P=.37), sex (P=.70), type of health worker (P=.35), country (P=.94), work context (P=.17), frequency of dealing with skin NTDs (P=.09), and dermatology experience (P=.63). Qualitative results echoed the quantitative outcomes, highlighting the ease of use, the offline functionality, and the potential utility for frontline health care workers in remote and resource-constrained settings. Areas for improvement were identified, such as enhancing the signs and symptoms section. CONCLUSIONS: The SkinNTDs app demonstrates notable usability and user-friendliness. The results indicate that the app could play a crucial role in improving capacity building of frontline health care workers dealing with skin NTDs. It could be improved in the future by including new features such as epidemiological context and direct contact with experts. The possibility of using the app as a diagnostic tool should be considered. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/39393.

Drug Repurposing in the Chemotherapy of Infectious Diseases.

Repurposing is a universal mechanism for innovation, from the evolution of feathers to the invention of Velcro tape. Repurposing is particularly attractive for drug development, given that it costs more than a billion dollars and takes longer than ten years to make a new drug from scratch. The COVID-19 pandemic has triggered a large number of drug repurposing activities. At the same time, it has highlighted potential pitfalls, in particular when concessions are made to the target product profile. Here, we discuss the pros and cons of drug repurposing for infectious diseases and analyze different ways of repurposing. We distinguish between opportunistic and rational approaches, i.e., just saving time and money by screening compounds that are already approved versus repurposing based on a particular target that is common to different pathogens. The latter can be further distinguished into divergent and convergent: points of attack that are divergent share common ancestry (e.g., prokaryotic targets in the apicoplast of malaria parasites), whereas those that are convergent arise from a shared lifestyle (e.g., the susceptibility of bacteria, parasites, and tumor cells to antifolates due to their high rate of DNA synthesis). We illustrate how such different scenarios can be capitalized on by using examples of drugs that have been repurposed to, from, or within the field of anti-infective chemotherapy.

Sandalwood Oils of Different Origins Are Active In Vitro against Madurella mycetomatis, the Major Fungal Pathogen Responsible for Eumycetoma.

In the search for new bioactive agents against the infectious pathogen responsible for the neglected tropical disease (NTD) mycetoma, we tested a collection of 27 essential oils (EOs) in vitro against Madurella mycetomatis, the primary pathogen responsible for the fungal form of mycetoma, termed eumycetoma. Among this series, the EO of Santalum album (Santalaceae), i.e., East Indian sandalwood oil, stood out prominently with the most potent inhibition in vitro. We, therefore, directed our research toward 15 EOs of Santalum species of different geographical origins, along with two samples of EOs from other plant species often commercialized as "sandalwood oils". Most of these EOs displayed similar strong activity against M. mycetomatis in vitro. All tested oils were thoroughly analyzed by GC-QTOF MS and most of their constituents were identified. Separation of the sandalwood oil into the fractions of sesquiterpene hydrocarbons and alcohols showed that its activity is associated with the sesquiterpene alcohols. The major constituents, the sesquiterpene alcohols (Z)-α- and (Z)-ß-santalol were isolated from the S. album oil by column chromatography on AgNO3-coated silica. They were tested as isolated compounds against the fungus, and (Z)-α-santalol was about two times more active than the ß-isomer.

Diabetes Fever.

While diabetes manifests multiple clinical presentations, complications and comorbidities, most modern discourse focuses on the cardiovascular aspects of the syndrome. In this communication, we explore the vast spectrum of fever and diabetes. We highlight the bidirectional interactions between febrile illness and diabetes, as well as drug-drug interactions. These multifaceted connections must be understood by all health care professionals who manage diabetes and/or fever.

Machine learning and drug discovery for neglected tropical diseases.

Neglected tropical diseases affect millions of individuals and cause loss of productivity worldwide. They are common in developing countries without the financial resources for research and drug development. With increased availability of data from high throughput screening, machine learning has been introduced into the drug discovery process. Models can be trained to predict biological activities of compounds before working in the lab. In this study, we use three publicly available, high-throughput screening datasets to train machine learning models to predict biological activities related to inhibition of species that cause leishmaniasis, American trypanosomiasis (Chagas disease), and African trypanosomiasis (sleeping sickness). We compare machine learning models (tree based models, naive Bayes classifiers, and neural networks), featurizing methods (circular fingerprints, MACCS fingerprints, and RDKit descriptors), and techniques to deal with the imbalanced data (oversampling, undersampling, class weight/sample weight).

Crimean-Congo hemorrhagic fever: Immunopathogenesis and recent advances in the development of vaccines.

Crimean-Congo hemorrhagic fever is a serious vector-borne zoonotic viral infection which leads to severe illness and fatalities in people living in endemic regions and becoming infected sporadically. Hyalomma ticks are responsible for the transmission of the virus which belongs to the family Nairoviridae. This disease spreads through ticks bite, infected tissues, or blood of viremic animals, and from infected humans to others. Serological studies also indicate the presence of the virus in various domestic and wild animals to be a risk factor for the transmission of the disease. Crimean-Congo hemorrhagic fever virus elicits many immune responses during the infection including inflammatory, innate, and adaptive immune responses. The development of an effective vaccine could be a promising method for the control and prevention of disease in endemic areas. The purpose of this review is to highlight the importance of CCHF, its mode of transmission, the interaction of the virus with the hosts and ticks, immunopathogenesis, and advances in immunization.

The abundance and morphology of human large intestinal goblet and tuft cells during chronic schistosomiasis.

Schistosomiasis affects nearly 240 million people in predominately low- and middle-income countries and ranks second in the number of cases and socio-economic burden among all parasitic diseases. Despite the enormous burden posed by schistosomes, our understanding of how schistosomiasis impacts infected human tissues remains limited. Intestinal schistosomiasis in animal models leads to goblet cell hyperplasia, likely increasing mucus production and reflecting an intestinal type 2 immune response. However, it is unknown whether these same changes occur in schistosome-infected humans. Using immunofluorescence and light microscopy, we compared the abundance and morphology of goblet cells in patients diagnosed with schistosomiasis to uninfected controls. The mucin-containing vesicles in goblet cells from schistosome-infected patients were significantly larger (hypertrophic) than uninfected individuals, although goblet cell hyperplasia was absent in chronic human schistosomiasis. In addition, we examined tuft cells in the large intestinal epithelium of control and schistosome-infected patients. Tuft cell numbers expand during helminth infection in mice, but these cells have not been characterized in human parasite infections. We found no evidence of tuft cell hyperplasia during human schistosome infection. Thus, our study provides novel insight into schistosome-associated changes to the intestinal epithelium in humans, suggesting an increase in mucus production by large intestinal goblet cells but relatively minor effects on tuft cell numbers.

Cutaneous melioidosis: An updated review and primer for the dermatologist.

Melioidosis is an emerging infection with increasing endemic foci and global distribution. It is underrecognized and underdiagnosed because of factors including limited awareness of the disease, nonspecific clinical presentation, lack of diagnostic facilities in some locations, misidentification in laboratories inexperienced with culture, and identification of Burkholderia pseudomallei. Cutaneous findings are reported in approximately 10% to 20% of melioidosis cases and dermatologists may play a significant role in its recognition and management. The most dynamic situation of melioidosis recognition and/or expansion currently is in the United States. Global modeling had predicted that B. pseudomallei were potentially endemic in the southern United States and endemicity with local cases of melioidosis was confirmed in 2022. With the distribution and prevalence of melioidosis increasing globally and with this recent recognition that melioidosis is now endemic in the southern United States, it is important for dermatologists to maintain high clinical suspicion in appropriate patients and be familiar with its diagnosis and treatment. Here we review the available literature on cutaneous melioidosis to evaluate its epidemiology, etiology, pathophysiology and clinical presentation and provide guidance for diagnosis and management in dermatology practice.

Unpacking the impact of integrating the neglected tropical disease supply chain into the national supply chain system: illustrative evidence from Liberia.

Effective supply chain management is a critical pillar of well-functioning health systems ensuring that medical commodities reach those in need. In Liberia, the national neglected tropical disease (NTD) programme supports health systems strengthening for case management of NTDs. Integration of NTD commodities into the national health system supply chain is central to the integrated approach; however, there is minimal evidence on enablers and barriers. Drawing on qualitative evaluation data, we illustrate that perceived benefits and strengths to integrating NTD commodities into the supply chain include leveraged storage and management capacities capitalized at lower system levels; the political will to integrate based on cost-saving and capacity strengthening potential and positive progress integrating paper-based reporting tools. Challenges remain, specifically the risk of reliance on donor funding; difficulty in accessing commodities due to bureaucratic bottlenecks; lack of inclusion of NTD commodities within electronic data tools and poor coordination leading to an inability to meet demand. Collectively, the negative consequences of ineffective integration of NTD commodities into the supply chain has a detrimental impact on health workers (including community health workers) unable to deliver the quality of care to patients. Trust between affected populations and the health system is compromised when treatments are unavailable.

Report of Weil's disease with a fatal course triggered by Jarisch-Herxheimer reaction.

Leptospirosis, a zoonotic disease characterized by a spectrum of influenza-like symptoms, can manifest as severe cases so called Weil's disease. Early diagnosis and treatment are crucial to avoid the potentially fatal course of the disease. Within 24 hours of the initial administration of antibiotics, patients may experience the Jarisch-Herxheimer reaction (JHR), characterized by chills, fever, hypotension, and impaired consciousness. The Okinawa Prefecture, where our hospital is situated, boasts the highest incidence rate of leptospirosis among all regions in Japan. This reports our encounter with the initial leptospirosis case after a period of 16 years within the Okinawa Prefecture. This case exhibited JHR and required the utilization of noradrenaline (NA). Despite evidence indicating that JHR does not correlate with mortality, we contend that diagnosis of Weil's disease necessitates admission to an intensive care unit (ICU) and vigilant monitoring for JHR, as it may result in impairment of general condition and fatal outcome, as observed in our case.

Adoption of community-based strategies for sustainable vector control and prevention.

Community engagement strategies provide tools for sustainable vector-borne disease control. A previous cluster randomized control trial engaged nine intervention communities in seven participatory activities to promote management of the domestic and peri-domestic environment to reduce risk factors for vector-borne Chagas disease. This study aims to assess the adoption of this innovative community-based strategy, which included chickens' management, indoor cleaning practices, and domestic rodent infestation control, using concepts from the Diffusion of Innovations Theory. We used questionnaires and semi-structured interviews to understand perceptions of knowledge gained, intervention adoption level, innovation attributes, and limiting or facilitating factors for adoption. The analysis process focused on five innovation attributes proposed by the Diffusion of Innovations Theory: relative advantage, compatibility, complexity, trialability, and observability. Rodent management was highly adopted by participants, as it had a relative advantage regarding the use of poison and was compatible with local practices. The higher complexity was reduced by offering several types of trapping systems and having practical workshops allowed trialability. Observability was limited because the traps were indoors, but information and traps were shared with neighbors. Chicken management was not as widely adopted due to the higher complexity of the method, and lower compatibility with local practices. Using the concepts proposed by the Diffusion of Innovations Theory helped us to identify the enablers and constraints in the implementation of the Chagas vector control strategy. Based on this experience, community engagement and intersectoral collaboration improve the acceptance and adoption of novel and integrated strategies to improve the prevention and control of neglected diseases.

Predicting the potential nationwide distribution of the snail vector, Oncomelania hupensis quadrasi, in the Philippines using the MaxEnt algorithm.

Schistosomiasis remains a major public health concern affecting approximately 12 million people in the Philippines due to inadequate information about the disease and limited prevention and control efforts. Schistosoma japonicum, one of the causative agents of the disease, requires an amphibious snail Oncomelania hupensis quadrasi (O. h. quadrasi) to complete its life cycle. Using the geographical information system (GIS) and maximum entropy (MaxEnt) algorithm, this study aims to predict the potential high-risk habitats of O. h. quadrasi driven by environmental factors in the Philippines. Based on the bioclimatic determinants, a very high-performance model was generated (AUC = 0.907), with the mean temperature of the driest quarter (25.3%) contributing significantly to the prevalence of O. h. quadrasi. Also, the snail vector has a high focal distribution, preferring areas with a pronounced wet season and high precipitation throughout the year. However, the findings provided evidence for snail adaptation to different environmental conditions. High suitability of snail habitats was found in Quezon, Camarines Norte, Camarines Sur, Albay, Sorsogon, Northern Samar, Eastern Samar, Leyte, Bohol, Surigao del Norte, Surigao del Sur, Agusan del Norte, Davao del Norte, North Cotabato, Lanao del Norte, Misamis Occidental, and Zamboanga del Sur. Furthermore, snail habitat establishment includes natural and man-made waterlogged areas, with the progression of global warming and climate change predicted to be drivers of increasing schistosomiasis transmission zones in the country.

A health-systems journey towards more people-centred care: lessons from neglected tropical disease programme integration in Liberia.

BACKGROUND: Neglected tropical diseases (NTDs) are associated with high levels of morbidity and disability as a result of stigma and social exclusion. To date, the management of NTDs has been largely biomedical. Consequently, ongoing policy and programme reform within the NTD community is demanding the development of more holistic disease management, disability and inclusion (DMDI) approaches. Simultaneously, integrated, people-centred health systems are increasingly viewed as essential to ensure the efficient, effective and sustainable attainment of Universal Health Coverage. Currently, there has been minimal consideration of the extent to which the development of holistic DMDI strategies are aligned to and can support the development of people-centred health systems. The Liberian NTD programme is at the forefront of trying to establish a more integrated, person-centred approach to the management of NTDs and provides a unique learning site for health systems decision makers to consider how shifts in vertical programme delivery can support overarching systems strengthening efforts that are designed to promote the attainment of health equity. METHODS: We use a qualitative case study approach to explore how policy and programme reform of the NTD programme in Liberia supports systems change to enable the development of integrated people-centred services. RESULTS: A cumulation of factors, catalysed by the shock to the health system presented by the Ebola epidemic, created a window of opportunity for policy change. However, programmatic change aimed at achieving person-centred practice was more challenging. Deep reliance on donor funding for health service delivery in Liberia limits the availability of flexible funding, and the ongoing funding prioritization towards specific disease conditions limits flexibility in health systems design that can shape more person-centred care. CONCLUSION: Sheikh et al.'s four key aspects of people centred health systems, that is, (1) putting peoples voices and needs first; (2) people centredness in service delivery; (3) relationships matter: health systems as social institutions; and (4) values drive people centred health systems, enable the illumination of varying push and pull factors that can facilitate or hinder the alignment of DMDI interventions with the development of people-centred health systems to support disease programme integration and the attainment of health equity.

Antifungal Activity of Natural Naphthoquinones and Anthraquinones against Madurella mycetomatis.

Eumycetoma, the fungal form of the neglected tropical disease mycetoma, is a crippling infectious disease with low response rates to currently available antifungal drugs. In this study, a series of natural naphthoquinones and anthraquinones was evaluated for their activity against Madurella mycetomatis, which is the most common causative agent of eumycetoma. The metabolic activity of Madurella mycetomatis as well as the viability of Galleria mellonella larvae upon treatment with quinones was investigated. Several hydroxy-substituted naphthoquinones exhibited activity against Madurella mycetomatis. In particular, naphthazarin (5,8-dihydroxy-1,4-naphthoquinone) was identified as a considerably active antifungal compound against Madurella mycetomatis (IC50 =1.4 µM), while it showed reduced toxicity to Galleria mellonella larvae, which is a well-established in vivo invertebrate model for mycetoma drug studies.

Delayed Compression Paralysis Following an Iliopsoas Hematoma 30 Days After Saw-Scaled Viper (Echis carinatus sochureki) Envenoming: A Case Report.

Snakebite envenoming is a neglected tropical disease disproportionately affecting the rural and marginalized population in low-middle-income countries. The saw-scaled viper (Echis carinatus) is a clinically important snake that causes serious morbidity and mortality in the Indian subcontinent. Even though it is within the so-called big-four snakes against which polyvalent antivenom is available throughout India, reports of antivenom ineffectiveness are emerging in saw-scaled viper envenoming, especially around Jodhpur, Rajasthan, India. This case report highlights a patient with saw-scaled viper envenoming with an ineffective antivenom response complicated by acute kidney injury as well as local and systemic bleeding complications, which subsequently resulted in a pelvic hematoma that compressed the lumbosacral nerves, causing lower-limb weakness and sensory deficits. He was successfully managed with hematoma aspiration and supportive care. This case brings into focus the challenges of managing saw-scaled viper envenoming in this region with antivenom ineffectiveness, resulting in delayed and significant coagulopathy and its complications leading to prolonged hospital stay and morbidity. Our report spotlights less emphasized aspects of long-term morbidity in snakebite survivors, such as loss of working days and productivity. We also highlight the need for an organized system of long-term follow-up of snakebite survivors to screen for possible complications and manage them early.

A geochemical and mineralogical characterization of soils associated with podoconiosis.

Podoconiosis is a disease that causes swelling and disfiguration of the lower legs found in several developing countries where shoes are not regularly worn. The current model for the etiology of the disease proposes that mineralogical agents enter the lymph system through the skin leading to inflammation that causes swelling of the feet and legs. We collected 125 soil samples from 21 towns associated with podoconiosis, 8 towns unassociated with Podoconiosis as controls, and 3 towns of unknown status. Data collected for each soil sample included color, particle size, mineralogy, and geochemistry to distinguish unique components within the podoconiosis-associated soils. Our results indicate podoconiosis-associated soils are more highly weathered than non-podoconiosis associated soils. The enrichment of kaolinite and gibbsite suggests that these minerals, their surface chemistry, and trace elements associated with them should be prioritized in future podoconiosis research. In addition, we found that color may be a valuable tool to identify soils at greater risk for inducing podoconiosis.

Genomics of Ocular Chlamydia trachomatis After 5 Years of SAFE Interventions for Trachoma in Amhara, Ethiopia.

BACKGROUND: To eliminate trachoma as a public health problem, the World Health Organization recommends the SAFE (surgery, antibiotics, facial cleanliness, and environmental improvement) strategy. As part of the SAFE strategy in the Amhara Region, Ethiopia, the Trachoma Control Program distributed >124 million doses of antibiotics between 2007 and 2015. Despite this, trachoma remained hyperendemic in many districts and a considerable level of Chlamydia trachomatis (Ct) infection was evident. METHODS: We utilized residual material from Abbott m2000 Ct diagnostic tests to sequence 99 ocular Ct samples from Amhara and investigated the role of Ct genomic variation in continued transmission of Ct. RESULTS: Sequences were typical of ocular Ct at the whole-genome level and in tissue tropism-associated genes. There was no evidence of macrolide resistance in this population. Polymorphism around the ompA gene was associated with village-level trachomatous inflammation-follicular prevalence. Greater ompA diversity at the district level was associated with increased Ct infection prevalence. CONCLUSIONS: We found no evidence for Ct genomic variation contributing to continued transmission of Ct after treatment, adding to evidence that azithromycin does not drive acquisition of macrolide resistance in Ct. Increased Ct infection in areas with more ompA variants requires longitudinal investigation to understand what impact this may have on treatment success and host immunity.