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The MORDOR trial in Niger, Malawi, and Tanzania found that biannual mass distribution of azithromycin to children younger than 5 years led to a 13.5% reduction in all-cause mortality (NCT02048007). To help elucidate the mechanism for mortality reduction, we report IgG responses to 11 malaria, bacterial, and protozoan pathogens using a multiplex bead assay in pre-specified substudy of 30 communities in the rural Niger placebo-controlled trial over a three-year period ( n  = 5642 blood specimens, n  = 3814 children ages 1–59 months). Mass azithromycin reduces Campylobacter spp. force of infection by 29% (hazard ratio = 0.71, 95% CI: 0.56, 0.89; P  = 0.004) but serological measures show no significant differences between groups for other pathogens against a backdrop of high transmission. Results align with a recent microbiome study in the communities. Given significant sequelae of Campylobacter infection among preschool aged children, our results support an important mechanism through which biannual mass distribution of azithromycin likely reduces mortality in Niger. In a randomized placebo-controlled trial in rural Niger, biannual azithromycin distribution to children 1-59 months reduced all-cause mortality. Based on serology, Arzika et al . here report a reduction of Campylobacter infection, supporting one mechanism for the intervention’s impact on mortality.

Cryptosporidium spp are well recognised as causes of diarrhoeal disease during waterborne epidemics and in immunocompromised hosts. Studies have also drawn attention to an underestimated global burden and suggest major gaps in optimum diagnosis, treatment, and immunisation. Cryptosporidiosis is increasingly identified as an important cause of morbidity and mortality worldwide. Studies in low-resource settings and high-income countries have confirmed the importance of cryptosporidium as a cause of diarrhoea and childhood malnutrition. Diagnostic tests for cryptosporidium infection are suboptimum, necessitating specialised tests that are often insensitive. Antigen-detection and PCR improve sensitivity, and multiplexed antigen detection and molecular assays are underused. Therapy has some effect in healthy hosts and no proven efficacy in patients with AIDS. Use of cryptosporidium genomes has helped to identify promising therapeutic targets, and drugs are in development, but methods to assess the efficacy in vitro and in animals are not well standardised. Partial immunity after exposure suggests the potential for successful vaccines, and several are in development; however, surrogates of protection are not well defined. Improved methods for propagation and genetic manipulation of the organism would be significant advances.

The objective of this clinical trial was to evaluate the effectiveness of zinc supplementation on diarrhea and average daily weight gain (ADG) in pre-weaned dairy calves. A total of 1,482 healthy Holstein heifer and bull calves from a large California dairy were enrolled at 24 to 48 hours of age until hutch exit at approximately 90 days of age. Calves were block-randomized by time to one of three treatments: 1) placebo, 2) zinc methionine (ZM), or 3) zinc sulfate (ZS) administered in milk once daily for 14 days. Serum total protein at enrollment and body weight at birth, treatment end, and hutch exit were measured. Fecal consistency was assessed daily for 28 days post-enrollment. For a random sample of 127 calves, serum zinc concentrations before and after treatment and a fecal antigen ELISA at diarrhea start and resolution for Escherichia coli K99, rotavirus, coronavirus, and Cryptosporidium parvum were performed. Linear regression showed that ZM-treated bull calves had 22 g increased ADG compared to placebo-treated bulls (P = 0.042). ZM-treated heifers had 9 g decreased ADG compared to placebo-treated heifers (P = 0.037), after adjusting for average birth weight. Sex-stratified models showed that high birth weight heifers treated with ZM gained more than placebo-treated heifers of the same birth weight, which suggests a dose-response effect rather than a true sex-specific effect of ZM on ADG. Cox regression showed that ZM and ZS-treated calves had a 14.7% (P = 0.015) and 13.9% (P = 0.022) reduced hazard of diarrhea, respectively, compared to placebo-treated calves. Calves supplemented for at least the first five days of diarrhea with ZM and ZS had a 21.4% (P = 0.027) and 13.0% (P = 0.040) increased hazard of cure from diarrhea, respectively, compared to placebo-treated calves. Logistic regression showed that the odds of microbiological cure at diarrhea resolution for rotavirus, C. parvum, or any single fecal pathogen was not different between treatment groups. Zinc supplementation delayed diarrhea and expedited diarrhea recovery in pre-weaned calves. Additionally, zinc improved weight gain differentially in bulls compared to heifers, indicating a research need for sex-specific dosing.

Gastrointestinal disease caused by the apicomplexan parasite Cryptosporidium parvum is one of the most important diseases of young ruminant livestock, particularly neonatal calves. Infected animals may suffer from profuse watery diarrhoea, dehydration and in severe cases death can occur. At present, effective therapeutic and preventative measures are not available and a better understanding of the host–pathogen interactions is required. Cryptosporidium parvum is also an important zoonotic pathogen causing severe disease in people, with young children being particularly vulnerable. Our knowledge of the immune responses induced by Cryptosporidium parasites in clinically relevant hosts is very limited. This review discusses the impact of bovine cryptosporidiosis and describes how a thorough understanding of the host–pathogen interactions may help to identify novel prevention and control strategies.

Cryptosporidiosis, a parasitic zoonosis caused by the genus Cryptosporidium (C.), currently lacks a vaccine or fully effective treatment. Nitazoxanide (NTZ), the only medication approved by the US Food and Drug Administration for treating cryptosporidiosis, exhibits limited efficacy in immunosuppressed hosts. Thymoquinone (THQ), the active component of Nigella sativa, possesses immunomodulatory, antitumor, hepatoprotective, antioxidant, antimicrobial, and antiprotozoal properties. This study evaluated the therapeutic effects of THQ alone or loaded onto chitosan nanoparticles (CsNPs) against Cryptosporidium parvum infection compared to NTZ. Chitosan nanoparticles were synthesized and characterized using X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), zeta potential analysis, and scanning electron microscopy. The cytotoxicity of CsNPs, THQ/CsNPs, and NTZ/CsNPs was evaluated on HT-29 cells. Mice were divided into seven groups to assess treatment efficacy through parasitological analysis of oocyst shedding, histopathological examination of intestinal, hepatic, and splenic tissues, immunohistochemical analysis using cyclin D1 staining of intestinal tissue, and immunological analysis measuring IFN-γ and IL-10 cytokine levels. Additionally, pharmacokinetic profiles of THQ and NTZ in free and nanoparticle-loaded forms were analyzed. XRD confirmed changes in peak position, shape, and intensity following the loading of THQ and NTZ into CsNPs. FTIR spectra demonstrated distinct differences in peak patterns between loaded nanoparticles and individual components, confirming successful drug encapsulation. Moreover, cytotoxicity studies showed dose-dependent effects on cell viability, with NTZ/CsNPs exhibiting the highest cytotoxicity. Regarding oocyst shedding reduction, THQ demonstrated greater efficacy than NTZ (77% vs. 54%), which was further enhanced when loaded onto CsNPs (89% for THQ/CsNPs vs. 78% for NTZ/CsNPs). Histopathological analysis revealed the restoration of structural alterations in intestinal, hepatic, and splenic tissues in treated groups. Cyclin D1 immunohistochemical staining showed a significant reduction in immunoreactivity in the THQ/CsNP-treated group compared to other treatments. Furthermore, immune responses were modulated by nanoparticle therapies, with significantly lower IFN-γ levels and higher IL-10 levels in treated groups. Pharmacokinetic analysis demonstrated that CsNP formulations significantly improved drug bioavailability by achieving higher peak plasma concentrations (Cmax), earlier time to peak concentration (Tmax), and prolonged half-life (t1/2) compared to free drugs. Thymoquinone demonstrated significant potential as an anti-cryptosporidiosis therapeutic agent, with enhanced efficacy when loaded onto chitosan nanoparticles. Chitosan-based nanoparticle formulations improved the pharmacokinetic profiles of both THQ and NTZ, offering a promising strategy for enhancing drug bioavailability and retention while reducing parasitic burden and modulating immune responses effectively.

Cryptosporidium and Giardia are important causes of diarrhoeal illness. Adequate knowledge of the molecular diversity and geographical distribution of these parasites and the environmental and climatic variables that influence their prevalence is important for effective control of infection in at-risk populations, yet relatively little is known about the epidemiology of these parasites in Africa. Cryptosporidium is associated with moderate to severe diarrhoea and increased mortality in African countries and both parasites negatively affect child growth and development. Malnutrition and HIV status are also important contributors to the prevalence of Cryptosporidium and Giardia in African countries. Molecular typing of both parasites in humans, domestic animals and wildlife to date indicates a complex picture of both anthroponotic, zoonotic and spill-back transmission cycles that requires further investigation. For Cryptosporidium , the only available drug (nitazoxanide) is ineffective in HIV and malnourished individuals and therefore more effective drugs are a high priority. Several classes of drugs with good efficacy exist for Giardia , but dosing regimens are suboptimal and emerging resistance threatens clinical utility. Climate change and population growth are also predicted to increase both malnutrition and the prevalence of these parasites in water sources. Dedicated and co-ordinated commitments from African governments involving “One Health” initiatives with multidisciplinary teams of veterinarians, medical workers, relevant government authorities, and public health specialists working together are essential to control and prevent the burden of disease caused by these parasites.

Cryptosporidium is increasingly recognized as one of the major causes of moderate to severe diarrhoea in developing countries. With treatment options limited, control relies on knowledge of the biology and transmission of the members of the genus responsible for disease. Currently, 26 species are recognized as valid on the basis of morphological, biological and molecular data. Of the nearly 20 Cryptosporidium species and genotypes that have been reported in humans, Cryptosporidium hominis and Cryptosporidium parvum are responsible for the majority of infections. Livestock, particularly cattle, are one of the most important reservoirs of zoonotic infections. Domesticated and wild animals can each be infected with several Cryptosporidium species or genotypes that have only a narrow host range and therefore have no major public health significance. Recent advances in next-generation sequencing techniques will significantly improve our understanding of the taxonomy and transmission of Cryptosporidium species, and the investigation of outbreaks and monitoring of emerging and virulent subtypes. Important research gaps remain including a lack of subtyping tools for many Cryptosporidium species of public and veterinary health importance, and poor understanding of the genetic determinants of host specificity of Cryptosporidium species and impact of climate change on the transmission of Cryptosporidium.

In 2010, a Cryptosporidium hominis outbreak resulted in 27,000 clinical cryptosporidiosis cases (45% of the population) in Östersund, Sweden. Long-term abdominal and joint symptoms are common following cryptosporidiosis in adults, and it can affect the development of children in low-income countries. We investigated the potential consequences for children in a high-income setting. In 2011, we prospectively surveyed 600 randomly selected children aged 0–5 years from Östersund. Cases were defined as respondents reporting new episodes of diarrhoea during the outbreak. After 10 years, respondents received a follow-up questionnaire about long-term symptoms ( n  = 423). We used X 2 and Mann–Whitney U tests to assess between-group differences in demographics and the mean number of symptoms. Logistic regressions adjusted for sex, age, and prior issues with loose stools were used to examine associations between case status and symptoms reported at follow-up. We retrieved data on healthcare visits from patient records. In total, 121 cases and 174 non-cases responded to the follow-up questionnaire (69.7%). Cases reported 1.74 (median 1.00, range 0–14) symptoms and non-cases 1.37 (median 0.00, range 0–11) symptoms ( p  = 0.029). Cases were more likely to report joint symptoms (aOR 4.0, CI 1.3–12.0) and fatigue (aOR 1.9, CI 1.1–3.4), but numbers were generally low. We found no between-group differences in abdominal symptoms, healthcare utilization, or disease diagnoses. Children aged 0–5 years from high-income countries may experience long-term symptoms after cryptosporidiosis, but may not be affected to the same extent as adults or their peers living in low-income countries.

Cryptosporidiosis is a zoonotic protozoan disease in which diarrhea is the main clinical manifestation. Cryptosporidium spp. is an important opportunistic pathogenic protozoan. Inadequate clinical knowledge of the disease can easily lead to underdiagnosis. This study reports the case of a patient with recurrent pancreatitis and primary Sjögren’s syndrome who was found to be infected with Cryptosporidium spp. After appropriate treatment, the patient’s symptoms improved. Clinicians should be aware of the symptoms of cryptosporidiosis and screen for it because it is easily overlooked.

The chemical diversity and known safety profiles of drugs previously tested in humans make them a valuable set of compounds to explore potential therapeutic utility in indications outside those originally targeted, especially neglected tropical diseases. This practice of “drug repurposing” has become commonplace in academic and other nonprofit drug-discovery efforts, with the appeal that significantly less time and resources are required to advance a candidate into the clinic. Here, we report a comprehensive open-access, drug repositioning screening set of 12,000 compounds (termed ReFRAME; Repurposing, Focused Rescue, and Accelerated Medchem) that was assembled by combining three widely used commercial drug competitive intelligence databases (Clarivate Integrity, GVK Excelra GoStar, and Citeline Pharmaprojects), together with extensive patent mining of small molecules that have been dosed in humans. To date, 12,000 compounds (∼80% of compounds identified from data mining) have been purchased or synthesized and subsequently plated for screening. To exemplify its utility, this collection was screened against Cryptosporidium spp., a major cause of childhood diarrhea in the developing world, and two active compounds previously tested in humans for other therapeutic indications were identified. Both compounds, VB-201 and a structurally related analog of ASP-7962, were subsequently shown to be efficacious in animal models of Cryptosporidium infection at clinically relevant doses, based on available human doses. In addition, an open-access data portal (https://reframedb.org) has been developed to share ReFRAME screen hits to encourage additional follow-up and maximize the impact of the ReFRAME screening collection.