Effects of Electrical Stimulation on Wound Closure in Mice with Experimental Diabetes Mellitus

The purpose of the present study was to examine the effect of electrical stimulation (ES) on the closure of full-thickness excisional wounds in mice with type-1 experimental diabetes mellitus (DM). Alloxon monohydrate (100mg/kg) was used to induce experimental DM in mole CD-1 mice (n = 88). Full-thickness skin excisions (1cm2) in diabetic (urine glucose \u3e 0) and non-diabetic (urine glucose = 0) mice were administered 1, 3, or 5 treatments of ES (200μs, 200 Hz) for 15 minutes, at 0 (sham), 5, 10, or 12.5 volts. Alloxon injection resulted in a positive urine glucose test in 48 mice yielding an induction rate for DM of 54.5 percent. All groups exhibited decreases in wound length, perimeter, and surface area between days 2 and 16 following the creation of wounds. Non-diabetic wounds treated with ES hod the greatest percentage (60%) of closure. Diabetic wounds treated with ES hod a greater percentage of clo­sure (36%) compared with sham-treated diabetic animals (12.5%). Treatment of wounds with the highest voltage of ES (12.5V) produced significant (P \u3c 0.01) decreases in the surface area, and significant (P \u3c 0.01) changes in the shapes of wounds in both diabetic and non-diabetic animals compared with sham-treated animals. These results support the clinical use of this adjunctive therapy to accelerate the closure of ulcers due to OM

Differential detection and distribution of microglial and hematogenous macrophage populations in the injured spinal cord of lys-EGFP-ki transgenic mice

The acute inflammatory response that follows spinal cord injury (SCI) contributes to secondary injury that results in the expansion of the lesion and further loss of neurologic function. A cascade of receptor-mediated signaling events after SCI leads to activation of innate immune responses including the migration of microglia and active recruitment of circulating leukocytes. Because conventional techniques do not always distinguish macrophages derived from CNS-resident microglia from blood-derived monocytes, the role that each macrophage type performs cannot be assessed unambiguously in these processes. We demonstrate that, in the normal and spinal cord-injured lys-EGFP-ki transgenic mouse, enhanced green fluorescent protein (EGFP) is expressed only in mature hematopoietic granulomyelomonocytic cells and not in microglia. This allowed us to assess the temporal and spatial relationships between microglia-derived and hematogenous macrophages as well as neutrophils during a period of 6 weeks after clip compression SCI. Within the lesion, EGFP-positive monocyte-derived macrophages were found at the epicenter surrounded by EGFP-negative-activated microglia and microglia-derived macrophages. Neutrophils were not present when EGFP-positive monocyte-derived macrophages were depleted, indicating that neutrophil persistence in the lesion depended on the presence of these monocytes. Thus, these 2 distinct macrophage populations can be independently identified and tracked, thereby allowing their roles in acute and chronic stages of SCI-associated inflammation to be defined. Copyright © 2012 by the American Association of Neuropathologists, Inc

Sub-national tailoring of malaria interventions in Mainland Tanzania: simulation of the impact of strata-specific intervention combinations using modelling

BACKGROUND: To accelerate progress against malaria in high burden countries, a strategic reorientation of resources at the sub-national level is needed. This paper describes how mathematical modelling was used in mainland Tanzania to support the strategic revision that followed the mid-term review of the 2015-2020 national malaria strategic plan (NMSP) and the epidemiological risk stratification at the council level in 2018. METHODS: Intervention mixes, selected by the National Malaria Control Programme, were simulated for each malaria risk strata per council. Intervention mixes included combinations of insecticide-treated bed nets (ITN), indoor residual spraying, larval source management, and intermittent preventive therapies for school children (IPTsc). Effective case management was either based on estimates from the malaria indicator survey in 2016 or set to a hypothetical target of 85%. A previously calibrated mathematical model in OpenMalaria was used to compare intervention impact predictions for prevalence and incidence between 2016 and 2020, or 2022. RESULTS: For each malaria risk stratum four to ten intervention mixes were explored. In the low-risk and urban strata, the scenario without a ITN mass campaign in 2019, predicted high increase in prevalence by 2020 and 2022, while in the very-low strata the target prevalence of less than 1% was maintained at low pre-intervention transmission intensity and high case management. In the moderate and high strata, IPTsc in addition to existing vector control was predicted to reduce the incidence by an additional 15% and prevalence by 22%. In the high-risk strata, all interventions together reached a maximum reduction of 76%, with around 70% of that reduction attributable to high case management and ITNs. Overall, the simulated revised NMSP was predicted to achieve a slightly lower prevalence in 2020 compared to the 2015-2020 NMSP (5.3% vs 6.3%). CONCLUSION: Modelling supported the choice of intervention per malaria risk strata by providing impact comparisons of various alternative intervention mixes to address specific questions relevant to the country. The use of a council-calibrated model, that reproduces local malaria trends, represents a useful tool for compiling available evidence into a single analytical platform, that complement other evidence, to aid national programmes with decision-making processes

The use of routine health facility data for micro-stratification of malaria risk in mainland Tanzania

BACKGROUND: Current efforts to estimate the spatially diverse malaria burden in malaria-endemic countries largely involve the use of epidemiological modelling methods for describing temporal and spatial heterogeneity using sparse interpolated prevalence data from periodic cross-sectional surveys. However, more malaria-endemic countries are beginning to consider local routine data for this purpose. Nevertheless, routine information from health facilities (HFs) remains widely under-utilized despite improved data quality, including increased access to diagnostic testing and the adoption of the electronic District Health Information System (DHIS2). This paper describes the process undertaken in mainland Tanzania using routine data to develop a high-resolution, micro-stratification risk map to guide future malaria control efforts. METHODS: Combinations of various routine malariometric indicators collected from 7098 HFs were assembled across 3065 wards of mainland Tanzania for the period 2017-2019. The reported council-level prevalence classification in school children aged 5-16 years (PfPR(5-16)) was used as a benchmark to define four malaria risk groups. These groups were subsequently used to derive cut-offs for the routine indicators by minimizing misclassifications and maximizing overall agreement. The derived-cutoffs were converted into numbered scores and summed across the three indicators to allocate wards into their overall risk stratum. RESULTS: Of 3065 wards, 353 were assigned to the very low strata (10.5% of the total ward population), 717 to the low strata (28.6% of the population), 525 to the moderate strata (16.2% of the population), and 1470 to the high strata (39.8% of the population). The resulting micro-stratification revealed malaria risk heterogeneity within 80 councils and identified wards that would benefit from community-level focal interventions, such as community-case management, indoor residual spraying and larviciding. CONCLUSION: The micro-stratification approach employed is simple and pragmatic, with potential to be easily adopted by the malaria programme in Tanzania. It makes use of available routine data that are rich in spatial resolution and that can be readily accessed allowing for a stratification of malaria risk below the council level. Such a framework is optimal for supporting evidence-based, decentralized malaria control planning, thereby improving the effectiveness and allocation efficiency of malaria control interventions

Spatio-temporal modelling of routine health facility data for malaria risk micro-stratification in mainland Tanzania

As malaria transmission declines, the need to monitor the heterogeneity of malaria risk at finer scales becomes critical to guide community-based targeted interventions. Although routine health facility (HF) data can provide epidemiological evidence at high spatial and temporal resolution, its incomplete nature of information can result in lower administrative units without empirical data. To overcome geographic sparsity of data and its representativeness, geo-spatial models can leverage routine information to predict risk in un-represented areas as well as estimate uncertainty of predictions. Here, a Bayesian spatio-temporal model was applied on malaria test positivity rate (TPR) data for the period 2017-2019 to predict risks at the ward level, the lowest decision-making unit in mainland Tanzania. To quantify the associated uncertainty, the probability of malaria TPR exceeding programmatic threshold was estimated. Results showed a marked spatial heterogeneity in malaria TPR across wards. 17.7 million people resided in areas where malaria TPR was high (>/= 30; 90% certainty) in the North-West and South-East parts of Tanzania. Approximately 11.7 million people lived in areas where malaria TPR was very low (< 5%; 90% certainty). HF data can be used to identify different epidemiological strata and guide malaria interventions at micro-planning units in Tanzania. These data, however, are imperfect in many settings in Africa and often require application of geo-spatial modelling techniques for estimation

Spatio-temporal modelling of routine health facility data for malaria risk micro-stratification in mainland Tanzania

As malaria transmission declines, the need to monitor the heterogeneity of malaria risk at finer scales becomes critical to guide community-based targeted interventions. Although routine health facility (HF) data can provide epidemiological evidence at high spatial and temporal resolution, its incomplete nature of information can result in lower administrative units without empirical data. To overcome geographic sparsity of data and its representativeness, geo-spatial models can leverage routine information to predict risk in un-represented areas as well as estimate uncertainty of predictions. Here, a Bayesian spatio-temporal model was applied on malaria test positivity rate (TPR) data for the period 2017-2019 to predict risks at the ward level, the lowest decision-making unit in mainland Tanzania. To quantify the associated uncertainty, the probability of malaria TPR exceeding programmatic threshold was estimated. Results showed a marked spatial heterogeneity in malaria TPR across wards. 17.7 million people resided in areas where malaria TPR was high (≥ 30; 90% certainty) in the North-West and South-East parts of Tanzania. Approximately 11.7 million people lived in areas where malaria TPR was very low (< 5%; 90% certainty). HF data can be used to identify different epidemiological strata and guide malaria interventions at micro-planning units in Tanzania. These data, however, are imperfect in many settings in Africa and often require application of geo-spatial modelling techniques for estimation

Risk of imported malaria infections in Zanzibar: a cross-sectional study

BACKGROUND: Zanzibar has made substantial progress in malaria control with vector control, improved diagnosis, and artemisinin-based combination therapy. Parasite prevalence in the population has remained around 1% but imported infections from mainland Tanzania contribute to sustained local transmission. Understanding travel patterns between mainland Tanzania and Zanzibar, and the risk of malaria infection, may help to control malaria importation to Zanzibar. METHODS: A rolling cross-sectional survey linked to routine reactive case detection of malaria was carried out in Zanzibar between May 2017 and October 2018. Households of patients diagnosed with malaria at health facilities were surveyed and household members were tested for malaria using rapid diagnostic tests and a sub-sample by quantitative PCR (qPCR). Interviews elicited a detailed travel history of all household members who had travelled within the past two months, including trips within and outside of Zanzibar. We estimated the association of malaria infection with travel destinations in pre-defined malaria endemicity categories, trip duration, and other co-variates using logistic regression. RESULTS: Of 17,891 survey participants, 1177 (7%) reported a recent trip, of which 769 (65%) visited mainland Tanzania. Among travellers to mainland Tanzania with travel destination details and a qPCR result available, 241/378 (64%) reported traveling to districts with a 'high' malaria endemicity and for 12% the highest endemicity category was 'moderate'. Travelers to the mainland were more likely to be infected with malaria parasites (29%, 108/378) than those traveling within Zanzibar (8%, 16/206) or to other countries (6%, 2/17). Among travellers to mainland Tanzania, those visiting highly endemic districts had a higher odds of being qPCR-positive than those who travelled only to districts where malaria-endemicity was classified as low or very low (adjusted odd ratio = 7.0, 95% confidence interval: 1.9-25.5). Among travellers to the mainland, 110/378 (29%) never or only sometimes used a mosquito net during their travel. CONCLUSIONS: Strategies to reduce malaria importation to Zanzibar may benefit from identifying population groups traveling to highly endemic areas in mainland Tanzania. Targeted interventions to prevent and clear infections in these groups may be more feasible than attempting to screen and treat all travellers upon arrival in Zanzibar

Effect of HIV on the frequency and number of Mycobacterium tuberculosis-specific CD4+ T cells in blood and the airways in latent tuberculosis infection

HIV-1 infection substantially increases the risk of developing tuberculosis (TB). There is extensive depletion of Mycobacterium tuberculosis (M.tuberculosis)-specific CD4+ T cells in blood in early HIV infection, but little is known about responses in the lungs at this stage. Given that mucosal organs are a principal target for HIV-mediated CD4 destruction, we investigated M.tuberculosis-specific responses in bronchoalveolar lavage (BAL), in persons with latent TB infection and untreated HIV-1 co-infection with preserved CD4 counts. M.tuberculosis-specific CD4+ cytokine responses (IFN-, TNF- and IL-2) were discordant in frequency and function between BAL and blood. Responses in BAL were 15-fold lower in HIV-infected compared to uninfected persons (p=0.048), whilst blood responses were 2-fold lower (p=0.006). However, an increase in T cells in the airways in HIV-infected persons resulted in the overall number of M.tuberculosis-specific CD4+ cells in BAL being similar. Our study highlights the important insights gained from studying TB immunity at the site of disease during HIV infection

Efficacy, persistence and vector susceptibility to pirimiphos-methyl (Actellic® 300CS) insecticide for indoor residual spraying in Zanzibar

Background Indoor residual spraying (IRS) of households with insecticide is a principal malaria vector control intervention in Zanzibar. In 2006, IRS using the pyrethroid lambda-cyhalothrine was introduced in Zanzibar. Following detection of pyrethroid resistance in 2010, an insecticide resistance management plan was proposed, and IRS using bendiocarb was started in 2011. In 2014, bendiocarb was replaced by pirimiphos methyl. This study investigated the residual efficacy of pirimiphos methyl (Actellic® 300CS) sprayed on common surfaces of human dwellings in Zanzibar. Methods The residual activity of Actellic 300CS was determined over 9 months through bioassay tests that measured the mortality of female Anopheles mosquitoes, exposed to sprayed surfaces under a WHO cone. The wall surfaces included; mud wall, oil or water painted walls, lime washed wall, un-plastered cement block wall and stone blocks. Insecticide susceptibility testing was done to investigate the resistance status of local malaria vectors against Actellic 300CS using WHO protocols; Anopheline species were identified using PCR methods. Results Baseline tests conducted one-day post-IRS revealed 100 % mortality on all sprayed surfaces. The residual efficacy of Actellic 300CS was maintained on all sprayed surfaces up to 8 months post-IRS. However, the bioassay test conducted 9 months post-IRS showed the 24 h mortality rate to be ≤80 % for lime wash, mud wall, water paint and stone block surfaces. Only oil paint surface retained the recommended residual efficacy beyond 9 months post-IRS, with mortality maintained at ≥97 %. Results of susceptibility tests showed that malaria vectors in Zanzibar were fully (100 %) susceptible to Actellic 300CS. The predominant mosquito vector species was An. arabiensis (76.0 %) in Pemba and An. gambiae (83.5 %) in Unguja. Conclusion The microencapsulated formulation of pirimiphos methyl (Actellic 300CS) is a highly effective and appropriate insecticide for IRS use in Zanzibar as it showed a relatively prolonged residual activity compared to other products used for the same purpose. The insecticide extends the residual effect of IRS thereby making it possible to effectively protect communities with a single annual spray round reducing overall costs. The insecticide proved to be a useful alternative in insecticide resistance management plans

Implementation research of a cluster randomized trial evaluating the implementation and effectiveness of intermittent preventive treatment for malaria using dihydroartemisinin-piperaquine on reducing malaria burden in school-aged children in Tanzania: methodology, challenges, and mitigation

BACKGROUND: It has been more than 20 years since the malaria epidemiologic shift to school-aged children was noted. In the meantime, school-aged children (5-15 years) have become increasingly more vulnerable with asymptomatic malaria prevalence reaching up to 70%, making them reservoirs for subsequent transmission of malaria in the endemic communities. Intermittent Preventive Treatment of malaria in schoolchildren (IPTsc) has proven to be an effective tool to shrink this reservoir. As of 3(rd) June 2022, the World Health Organization recommends IPTsc in moderate and high endemic areas. Even so, for decision-makers, the adoption of scientific research recommendations has been stifled by real-world implementation challenges. This study presents methodology, challenges faced, and mitigations used in the evaluation of the implementation of IPTsc using dihydroartemisinin-piperaquine (DP) in three councils (Handeni District Council (DC), Handeni Town Council (TC) and Kilindi DC) of Tanga Region, Tanzania so as to understand the operational feasibility and effectiveness of IPTsc on malaria parasitaemia and clinical malaria incidence. METHODS: The study deployed an effectiveness-implementation hybrid design to assess feasibility and effectiveness of IPTsc using DP, the interventional drug, against standard of care (control). Wards in the three study councils were the randomization unit (clusters). Each ward was randomized to implement IPTsc or not (control). In all wards in the IPTsc arm, DP was given to schoolchildren three times a year in four-month intervals. In each council, 24 randomly selected wards (12 per study arm, one school per ward) were chosen as representatives for intervention impact evaluation. Mixed design methods were used to assess the feasibility and acceptability of implementing IPTsc as part of a more comprehensive health package for schoolchildren. The study reimagined an existing school health programme for Neglected Tropical Diseases (NTD) control include IPTsc implementation. RESULTS: The study shows IPTsc can feasibly be implemented by integrating it into existing school health and education systems, paving the way for sustainable programme adoption in a cost-effective manner. CONCLUSIONS: Through this article other interested countries may realise a feasible plan for IPTsc implementation. Mitigation to any challenge can be customized based on local circumstances without jeopardising the gains expected from an IPTsc programme. Trial registration clinicaltrials.gov, NCT04245033. Registered 28 January 2020, https://clinicaltrials.gov/ct2/show/NCT04245033