Leveraging the power of partnerships: spreading the vision for a population health care delivery model in western Kenya.

BACKGROUND: The Academic Model Providing Access to Healthcare (AMPATH) has been a model academic partnership in global health for nearly three decades, leveraging the power of a public-sector academic medical center and the tripartite academic mission - service, education, and research - to the challenges of delivering health care in a low-income setting. Drawing our mandate from the health needs of the population, we have scaled up service delivery for HIV care, and over the last decade, expanded our focus on non-communicable chronic diseases, health system strengthening, and population health more broadly. Success of such a transformative endeavor requires new partnerships, as well as a unification of vision and alignment of strategy among all partners involved. Leveraging the Power of Partnerships and Spreading the Vision for Population Health. We describe how AMPATH built on its collective experience as an academic partnership to support the public-sector health care system, with a major focus on scaling up HIV care in western Kenya, to a system poised to take responsibility for the health of an entire population. We highlight global trends and local contextual factors that led to the genesis of this new vision, and then describe the key tenets of AMPATH's population health care delivery model: comprehensive, integrated, community-centered, and financially sustainable with a path to universal health coverage. Finally, we share how AMPATH partnered with strategic planning and change management experts from the private sector to use a novel approach called a 'Learning Map®' to collaboratively develop and share a vision of population health, and achieve strategic alignment with key stakeholders at all levels of the public-sector health system in western Kenya. CONCLUSION: We describe how AMPATH has leveraged the power of partnerships to move beyond the traditional disease-specific silos in global health to a model focused on health systems strengthening and population health. Furthermore, we highlight a novel, collaborative tool to communicate our vision and achieve strategic alignment among stakeholders at all levels of the health system. We hope this paper can serve as a roadmap for other global health partners to develop and share transformative visions for improving population health globally.

Comparative analysis of the secretome from a model filarial nematode (Litomosoides sigmodontis) reveals maximal diversity in gravid female parasites.

Filarial nematodes (superfamily Filarioidea) are responsible for an annual global health burden of ∼6.3 million disability-adjusted life-years, which represents the greatest single component of morbidity attributable to helminths affecting humans. No vaccine exists for the major filarial diseases, lymphatic filariasis and onchocerciasis; in part because research on protective immunity against filariae has been constrained by the inability of the human-parasitic species to complete their lifecycles in laboratory mice. However, the rodent filaria Litomosoides sigmodontis has become a popular experimental model, as BALB/c mice are fully permissive for its development and reproduction. Here, we provide a comprehensive analysis of excretory-secretory products from L. sigmodontis across five lifecycle stages and identifications of host proteins associated with first-stage larvae (microfilariae) in the blood. Applying intensity-based quantification, we determined the abundance of 302 unique excretory-secretory proteins, of which 64.6% were present in quantifiable amounts only from gravid adult female nematodes. This lifecycle stage, together with immature microfilariae, released four proteins that have not previously been evaluated as vaccine candidates: a predicted 28.5 kDa filaria-specific protein, a zonadhesin and SCO-spondin-like protein, a vitellogenin, and a protein containing six metridin-like ShK toxin domains. Female nematodes also released two proteins derived from the obligate Wolbachia symbiont. Notably, excretory-secretory products from all parasite stages contained several uncharacterized members of the transthyretin-like protein family. Furthermore, biotin labeling revealed that redox proteins and enzymes involved in purinergic signaling were enriched on the adult nematode cuticle. Comparison of the L. sigmodontis adult secretome with that of the human-infective filarial nematode Brugia malayi (reported previously in three independent published studies) identified differences that suggest a considerable underlying diversity of potential immunomodulators. The molecules identified in L. sigmodontis excretory-secretory products show promise not only for vaccination against filarial infections, but for the amelioration of allergy and autoimmune diseases.

'Acceleration' of the food delivery marketplace: Perspectives of local authority professionals in the North-East of England on temporary COVID regulations.

In January 2021, we assessed the implications of temporary regulations in the United Kingdom allowing pubs and restaurants to operate on a takeaway basis without instigating a change of use. Local authorities (LAs) across the North-East of England were unaware of any data regarding the take-up of these regulations, partially due to ongoing capacity issues; participants also raised health concerns around takeaway use increasing significantly. One year on, we repeated the study aiming to understand the impact of these regulations on the policy and practice of key professional groups. Specifically, we wanted to understand if LAs were still struggling with staff capacity to address the regulations, whether professionals still had public health trepidations, and if any unexpected changes had occurred across the local food environment because of the pandemic. We conversed with 16 public health professionals, planners and environmental health officers across seven LAs throughout the North-East of England via focus groups and interviews. Data collated were analysed via an inductive and semantic, reflexive-thematic approach. Through analysis of the data, three themes were generated and are discussed throughout: popular online delivery services as a mediator to increased takeaway usage; potential long-term health implications and challenges; continued uncertainty regarding the temporary regulations. This paper highlights important changes to local food environments, which public health professionals should be aware of, so they are better equipped to tackle health inequalities across urban and sub-urban areas.

Fast acting allosteric phosphofructokinase inhibitors block trypanosome glycolysis and cure acute African trypanosomiasis in mice.

The parasitic protist Trypanosoma brucei is the causative agent of Human African Trypanosomiasis, also known as sleeping sickness. The parasite enters the blood via the bite of the tsetse fly where it is wholly reliant on glycolysis for the production of ATP. Glycolytic enzymes have been regarded as challenging drug targets because of their highly conserved active sites and phosphorylated substrates. We describe the development of novel small molecule allosteric inhibitors of trypanosome phosphofructokinase (PFK) that block the glycolytic pathway resulting in very fast parasite kill times with no inhibition of human PFKs. The compounds cross the blood brain barrier and single day oral dosing cures parasitaemia in a stage 1 animal model of human African trypanosomiasis. This study demonstrates that it is possible to target glycolysis and additionally shows how differences in allosteric mechanisms may allow the development of species-specific inhibitors to tackle a range of proliferative or infectious diseases.

A retrospective analysis of ketamine administration by critical care paramedics in a pre-hospital care setting.

OBJECTIVE: This project aims to describe pre-hospital use of ketamine in trauma by South East Coast Ambulance Service critical care paramedics and evaluate the occurrence of any side effects or adverse events. METHODS: A retrospective analysis of patients receiving pre-hospital ketamine for trauma between 16 March 2013 and 30 April 2017. Administrations were identified from Advanced Life Saving Interventions and Procedures reports submitted by the clinician and, later, from an electronic database. Each was scrutinised for patient demographics, doses and reports of side effects or adverse events. RESULTS: A total of 510 unique administrations were identified. Following the exclusion of 61 records, 449 (88.0%) administrations remained. The most common indication for administration of ketamine was lower limb injury, with 228 (50.8%) administrations. Ketamine was only administered intravenously, and the median dose of ketamine for all administrations was 30 mg (interquartile range 20-40 mg). The gender split was dominated by males who accounted for 302 (67.3%) administrations compared to 147 (32.7%) females. The median age of patients was 44 years (interquartile range 28-58 years), with women on average being older than men. Telephone calls to a consultant were made for 243/449 (54.1%) of the administrations, reflecting a need for sanctioning of the drug, advice on dosages or indications, for example. CONCLUSIONS: Critical care paramedics within a well governed system are able to safely administer ketamine within an approved dosing regimen under a Patient Group Direction. Median doses are in keeping with nationally approved guidelines. Reported side effects were within the described frequencies in the British National Formulary. Prospective studies are now needed in order to confirm the safety and efficacy of ketamine administration among the advanced paramedic population.

Phylogenomics and analysis of shared genes suggest a single transition to mutualism in Wolbachia of nematodes.

Wolbachia, endosymbiotic bacteria of the order Rickettsiales, are widespread in arthropods but also present in nematodes. In arthropods, A and B supergroup Wolbachia are generally associated with distortion of host reproduction. In filarial nematodes, including some human parasites, multiple lines of experimental evidence indicate that C and D supergroup Wolbachia are essential for the survival of the host, and here the symbiotic relationship is considered mutualistic. The origin of this mutualistic endosymbiosis is of interest for both basic and applied reasons: How does a parasite become a mutualist? Could intervention in the mutualism aid in treatment of human disease? Correct rooting and high-quality resolution of Wolbachia relationships are required to resolve this question. However, because of the large genetic distance between Wolbachia and the nearest outgroups, and the limited number of genomes so far available for large-scale analyses, current phylogenies do not provide robust answers. We therefore sequenced the genome of the D supergroup Wolbachia endosymbiont of Litomosoides sigmodontis, revisited the selection of loci for phylogenomic analyses, and performed a phylogenomic analysis including available complete genomes (from isolates in supergroups A, B, C, and D). Using 90 orthologous genes with reliable phylogenetic signals, we obtained a robust phylogenetic reconstruction, including a highly supported root to the Wolbachia phylogeny between a (A + B) clade and a (C + D) clade. Although we currently lack data from several Wolbachia supergroups, notably F, our analysis supports a model wherein the putatively mutualist endosymbiotic relationship between Wolbachia and nematodes originated from a single transition event.

Deletion of parasite immune modulatory sequences combined with immune activating signals enhances vaccine mediated protection against filarial nematodes.

BACKGROUND: Filarial nematodes are tissue-dwelling parasites that can be killed by Th2-driven immune effectors, but that have evolved to withstand immune attack and establish chronic infections by suppressing host immunity. As a consequence, the efficacy of a vaccine against filariasis may depend on its capacity to counter parasite-driven immunomodulation. METHODOLOGY AND PRINCIPAL FINDINGS: We immunised mice with DNA plasmids expressing functionally-inactivated forms of two immunomodulatory molecules expressed by the filarial parasite Litomosoides sigmodontis: the abundant larval transcript-1 (LsALT) and cysteine protease inhibitor-2 (LsCPI). The mutant proteins enhanced antibody and cytokine responses to live parasite challenge, and led to more leukocyte recruitment to the site of infection than their native forms. The immune response was further enhanced when the antigens were targeted to dendritic cells using a single chain Fv-αDEC205 antibody and co-administered with plasmids that enhance T helper 2 immunity (IL-4) and antigen-presenting cell recruitment (Flt3L, MIP-1α). Mice immunised simultaneously against the mutated forms of LsALT and LsCPI eliminated adult parasites faster and consistently reduced peripheral microfilaraemia. A multifactorial analysis of the immune response revealed that protection was strongly correlated with the production of parasite-specific IgG1 and with the numbers of leukocytes present at the site of infection. CONCLUSIONS: We have developed a successful strategy for DNA vaccination against a nematode infection that specifically targets parasite-driven immunosuppression while simultaneously enhancing Th2 immune responses and parasite antigen presentation by dendritic cells.

Laundry detergents as a source of heavy metals in Irish domestic wastewater.

Concentrations of Cd, Cu and Zn in 175 detergent samples representing twenty-one brands of washing powders were analysed. Mean concentrations of 3.03 (+/- 0.50) microg Cd/g, 2.61 (+/- 1.22) microg Cu/g and 15.23 (+/- 7.26) microg Zn/g were recorded. The concentration of cadmium was much lower than previously reported. The daily contribution of metals from laundry washing are in the order of 54.5 microg Cd/ca/d, 47.0 microg Cu/ca/d and 274.1 microg Zn/ca/d. In Irish municipal wastewater the contribution from detergents of these metals are 31.9% for Cd, 0.24% Cu and 0.30% for Zn. This has important implications for sewage sludge disposal.

A peritoneal dialysis patient with fatal culture-negative peritonitis.

Culture-negative peritoneal inflammation accounts for between 5 and 20% of cases of peritonitis in peritoneal dialysis patients. Diagnostic yields may be enhanced considerably by reculturing dialysate effluents using appropriate collection methods and optimal laboratory techniques (including prolonged low-temperature and anaerobic incubations). In patients with persistent culture-negative peritonitis, consideration should be given to the possibilities of unusual or fastidious microorganisms (especially fungi and mycobacteria) and non-infective causes (especially drug reactions, malignancy, visceral inflammation and retroperitoneal inflammation). In this paper, an illustrative case of persistent culture-negative peritonitis is presented followed by a discussion of the investigative approach to such patients, with particular emphasis on differential diagnosis and the limitations of currently available tests.