Dhfr and dhps mutations in Plasmodium falciparum isolates in Mlandizi, Kibaha,

Sulfadoxine-pyrimethamine (SP), the current first line antimalarial drug in Tanzania, is compromised by evolution and spread of mutations in the parasite's dhfr and dhps genes. In the present study we established the baseline frequencies of Plasmodium falciparum dihydrofolate reductase (pfdhfr) and dihydropteroate synthase (pfdhps) mutant genotypes and their potential for predicting the in vivo efficacy of SP in Mlandizi, Tanzania. The efficacy of SP treatment was by following 116 children with uncomplicated falciparum malaria for 14 days after treatment. Infected blood samples were collected on filter paper at days 0, 3, 7 and 14. Parasite genomic DNA was extracted and point mutations at positions 51, 59, 108 and 164 of the dhfr gene and at 581, 540 and 437 of the dhps gene were analysed by nested Polymerase Chain Reaction/ Restriction Fragment Length Polymorphism. Out of 116 children enrolled, 98 (86%) of eligible children demonstrated an adequate clinical response by day 14. There were 7.3 % early and 6.7% late therapeutic failures. At day 0, only 8.0% (4/50) the parasites showed no mutation at the dhfr locus; for dhps this was 73%. Triple mutant dhfr alleles (Ile 51, Arg 59, Asn 108) occurred in 47%, double mutant dhps (Gly 437, Glu 540) alleles in 7.9%. No mutation was detected at codon 164 of the dhfr gene. The presence of triple dhfr mutant alleles was related to clinical failure, but did not show significant association (Fisher exact test, P=0.166, OR 2.15 0.776.20). The higher rates of mutation on the dhfr do not spell a bright future for SP treatment in Tanzania. It is rational to think of an alternative first line antimalarial drug, while retaining SP for malaria intermittent treatment in regnancy. Keywords: Plasmodium falciparum, sulfadoxine-pyrimethamine, dhfr, dhps, TanzaniaTanzania Health Research Bulletin Vol. 8 (2) 2006: pp. 50-5

Heterogeneity in transmissibility and shedding SARS-CoV-2 via droplets and aerosols

Background: Which virological factors mediate overdispersion in the transmissibility of emerging viruses remains a longstanding question in infectious disease epidemiology. Methods: Here, we use systematic review to develop a comprehensive dataset of respiratory viral loads (rVLs) of SARS-CoV-2, SARS-CoV-1 and influenza A(H1N1)pdm09. We then comparatively meta-analyze the data and model individual infectiousness by shedding viable virus via respiratory droplets and aerosols. Results: The analyses indicate heterogeneity in rVL as an intrinsic virological factor facilitating greater overdispersion for SARS-CoV-2 in the COVID-19 pandemic than A(H1N1)pdm09 in the 2009 influenza pandemic. For COVID-19, case heterogeneity remains broad throughout the infectious period, including for pediatric and asymptomatic infections. Hence, many COVID-19 cases inherently present minimal transmission risk, whereas highly infectious individuals shed tens to thousands of SARS-CoV-2 virions/min via droplets and aerosols while breathing, talking and singing. Coughing increases the contagiousness, especially in close contact, of symptomatic cases relative to asymptomatic ones. Infectiousness tends to be elevated between 1-5 days post-symptom onset. Conclusions: Intrinsic case variation in rVL facilitates overdispersion in the transmissibility of emerging respiratory viruses. Our findings present considerations for disease control in the COVID-19 pandemic as well as future outbreaks of novel viruses.</p

Saleability of Anti-malarials in Private Drug Shops in Muheza, Tanzania: A Baseline study in an era of assumed Artemisinin Ccombination Therapy (ACT).

Artemether-lumefantrine (ALu) replaced sulphadoxine-pymimethamine (SP) as the official first-line anti-malarial in Tanzania in November 2006. So far, artemisinin combination therapy (ACT) is contra-indicated during pregnancy by the national malaria treatment guidelines, and pregnant women depend on SP for Intermittent Preventive Treatment (IPTp) during pregnancy. SP is still being dispensed by private drug stores, but it is unknown to which extent. If significant, it may undermine its official use for IPTp through induction of resistance. The main study objective was to perform a baseline study of the private market for anti-malarials in Muheza town, an area with widespread anti-malarial drug resistance, prior to the implementation of a provider training and accreditation programme that will allow accredited drug shops to sell subsidized ALu. All drug shops selling prescription-only anti-malarials, in Muheza town, Tanga Region voluntarily participated from July to December 2009. Qualitative in-depth interviews were conducted with owners or shopkeepers on saleability of anti-malarials, and structured questionnaires provided quantitative data on drugs sales volume. All surveyed drug shops illicitly sold SP and quinine (QN), and legally amodiaquine (AQ). Calculated monthly sale was 4,041 doses, in a town with a population of 15,000 people. Local brands of SP accounted for 74% of sales volume, compared to AQ (13%), QN (11%) and ACT (2%). In community practice, the saleability of ACT was negligible. SP was best-selling, and use was not reserved for IPTp, as stipulated in the national anti-malarial policy. It is a major reason for concern that such drug-pressure in the community equals de facto intermittent presumptive treatment. In an area where SP drug resistance remains high, unregulated SP dispensing to people other than pregnant women runs the risk of eventually jeopardizing the effectiveness of the IPTp strategy. Further studies are recommended to find out barriers for ACT utilization and preference for self-medication and to train private drug dispensers

A comparative effectiveness study of the breaking the cycle and Maxxine Wright intervention programs for substance-involved mothers and their children: study protocol

Abstract Background Children of substance-involved mothers are at especially high risk for exposure to adverse childhood experiences (ACEs) and poor mental health and development. Early interventions that support mothers, children, and the mother-child relationship have the greatest potential to reduce exposure to early adversity and the mental health problems associated with these exposures. Currently, there is a lack of evidence from the real-world setting demonstrating effectiveness and return on investment for intervention programs that focus on the mother-child relationship in children of substance-involved mothers. Methods One hundred substance-involved pregnant and/or parenting women with children between the ages of 0–6 years old will be recruited through the Breaking the Cycle and Maxxine Wright intervention programs, in Toronto, Ontario, Canada and Surrey, British Columbia, Canada, respectively. Children’s socioemotional development and exposure to risk and protective factors, mothers’ mental health and history of ACEs, and mother-child relationship quality will be assessed in both intervention programs. Assessments will occur at three time points: pre-intervention, 12-, and 24-months after engagement in the intervention program. Discussion There is a pressing need to identify interventions that promote the mental health of infants and young children exposed to early adversity. Bringing together an inter-disciplinary research team and community partners, this study aligns with national strategies to establish strong evidence for infant mental health interventions that reduce child exposure to ACEs and support the mother-child relationship. This study was registered with clinicaltrials.gov (NCT05768815) on March 14, 2023

Malaria-related mortality based on verbal autopsy in an area of low endemicity in a predominantly rural population in Ethiopia

<p>Abstract</p> <p>Background</p> <p>Although malaria is one of the most important causes of death in Ethiopia, measuring the magnitude of malaria-attributed deaths at community level poses a considerable difficulty. Nevertheless, despite its low sensitivity and specificity, verbal autopsy (VA) has been the most important technique to determine malaria-specific cause of death for community-based studies. The present study was undertaken to assess the magnitude of malaria mortality in a predominantly rural population of Ethiopia using VA technique at Butajira Rural Health Programme (BRHP) Demographic Surveillance Site (DSS).</p> <p>Methods</p> <p>A verbal autopsy was carried out for a year from August 2003 to July 2004 for all deaths identified at BRPH-DSS. Two trained physicians independently reviewed each VA questionnaire and indicated the most likely causes of death. Finally, all malaria related deaths were identified and used for analysis.</p> <p>Results</p> <p>A verbal autopsy study was successfully conducted in 325 deaths, of which 42 (13%) were attributed to malaria. The majority of malaria deaths (47.6%) were from the rural lowlands compared to those that occurred in the rural highlands (31%) and urban (21.4%) areas. The proportional mortality attributable to malaria was not statistically significant among the specific age groups and ecological zones. Mortality from malaria was reckoned to be seasonal; 57% occurred during a three-month period at the end of the rainy season between September and November. About 71% of the deceased received some form of treatment before death, while 12 (28.6%) of those who died neither sought care from a traditional healer nor were taken to a conventional health facility before death. Of those who sought treatment, 53.3% were first taken to a private clinic, 40% sought care from public health facilities, and the remaining two (6.7%) received traditional medicine. Only 11.9% of the total malaria-related deaths received some sort of treatment within 24h after the onset of illness.</p> <p>Conclusion</p> <p>The results of this study suggest that malaria plays a considerable role as a cause of death in the study area. Further data on malaria mortality with a relatively large sample size for at least two years will be needed to substantially describe the burden of malaria mortality in the study area.</p

Use and limitations of malaria rapid diagnostic testing by community health workers in war-torn Democratic Republic of Congo

<p>Abstract</p> <p>Background</p> <p>Accurate and practical malaria diagnostics, such as immunochromatographic rapid diagnostic tests (RDTs), have the potential to avert unnecessary treatments and save lives. Volunteer community health workers (CHWs) represent a potentially valuable human resource for expanding this technology to where it is most needed, remote rural communities in sub-Saharan Africa with limited health facilities and personnel. This study reports on a training programme for CHWs to incorporate RDTs into their management strategy for febrile children in the Democratic Republic of Congo, a tropical African setting ravaged by human conflict.</p> <p>Methods</p> <p>Prospective cohort study, satisfaction questionnaire and decision analysis.</p> <p>Results</p> <p>Twelve CHWs were trained to safely and accurately perform and interpret RDTs, then successfully implemented rapid diagnostic testing in their remote community in a cohort of 357 febrile children. CHWs were uniformly positive in evaluating RDTs for their utility and ease of use. However, high malaria prevalence in this cohort (93% by RDTs, 88% by light microscopy) limited the cost-effectiveness of RDTs compared to presumptive treatment of all febrile children, as evidenced by findings from a simplified decision analysis.</p> <p>Conclusions</p> <p>CHWs can safely and effectively use RDTs in their management of febrile children; however, cost-effectiveness of RDTs is limited in zones of high malaria prevalence.</p

Malaria Rapid Testing by Community Health Workers Is Effective and Safe for Targeting Malaria Treatment: Randomised Cross-Over Trial in Tanzania

Early diagnosis and prompt, effective treatment of uncomplicated malaria is critical to prevent severe disease, death and malaria transmission. We assessed the impact of rapid malaria diagnostic tests (RDTs) by community health workers (CHWs) on provision of artemisinin-based combination therapy (ACT) and health outcome in fever patients. Twenty-two CHWs from five villages in Kibaha District, a high-malaria transmission area in Coast Region, Tanzania, were trained to manage uncomplicated malaria using RDT aided diagnosis or clinical diagnosis (CD) only. Each CHW was randomly assigned to use either RDT or CD the first week and thereafter alternating weekly. Primary outcome was provision of ACT and main secondary outcomes were referral rates and health status by days 3 and 7. The CHWs enrolled 2930 fever patients during five months of whom 1988 (67.8%) presented within 24 hours of fever onset. ACT was provided to 775 of 1457 (53.2%) patients during RDT weeks and to 1422 of 1473 (96.5%) patients during CD weeks (Odds Ratio (OR) 0.039, 95% CI 0.029-0.053). The CHWs adhered to the RDT results in 1411 of 1457 (96.8%, 95% CI 95.8-97.6) patients. More patients were referred on inclusion day during RDT weeks (10.0%) compared to CD weeks (1.6%). Referral during days 1-7 and perceived non-recovery on days 3 and 7 were also more common after RDT aided diagnosis. However, no fatal or severe malaria occurred among 682 patients in the RDT group who were not treated with ACT, supporting the safety of withholding ACT to RDT negative patients. RDTs in the hands of CHWs may safely improve early and well-targeted ACT treatment in malaria patients at community level in Africa.\ud \ud \ud \u

Effectiveness of artemether-lumefantrine provided by community health workers in under-five children with uncomplicated malaria in rural Tanzania: an open label prospective study

\ud Home-management of malaria (HMM) strategy improves early access of anti-malarial medicines to high-risk groups in remote areas of sub-Saharan Africa. However, limited data are available on the effectiveness of using artemisinin-based combination therapy (ACT) within the HMM strategy. The aim of this study was to assess the effectiveness of artemether-lumefantrine (AL), presently the most favoured ACT in Africa, in under-five children with uncomplicated Plasmodium falciparum malaria in Tanzania, when provided by community health workers (CHWs) and administered unsupervised by parents or guardians at home. An open label, single arm prospective study was conducted in two rural villages with high malaria transmission in Kibaha District, Tanzania. Children presenting to CHWs with uncomplicated fever and a positive rapid malaria diagnostic test (RDT) were provisionally enrolled and provided AL for unsupervised treatment at home. Patients with microscopy confirmed P. falciparum parasitaemia were definitely enrolled and reviewed weekly by the CHWs during 42 days. Primary outcome measure was PCR corrected parasitological cure rate by day 42, as estimated by Kaplan-Meier survival analysis. This trial is registered with ClinicalTrials.gov, number NCT00454961. A total of 244 febrile children were enrolled between March-August 2007. Two patients were lost to follow up on day 14, and one patient withdrew consent on day 21. Some 141/241 (58.5%) patients had recurrent infection during follow-up, of whom 14 had recrudescence. The PCR corrected cure rate by day 42 was 93.0% (95% CI 88.3%-95.9%). The median lumefantrine concentration was statistically significantly lower in patients with recrudescence (97 ng/mL [IQR 0-234]; n = 10) compared with reinfections (205 ng/mL [114-390]; n = 92), or no parasite reappearance (217 [121-374] ng/mL; n = 70; p ≤ 0.046). Provision of AL by CHWs for unsupervised malaria treatment at home was highly effective, which provides evidence base for scaling-up implementation of HMM with AL in Tanzania.\u

Area 5 Influences Excitability within the Primary Motor Cortex in Humans

In non-human primates, Brodmann's area 5 (BA 5) has direct connectivity with primary motor cortex (M1), is largely dedicated to the representation of the hand and may have evolved with the ability to perform skilled hand movement. Less is known about human BA 5 and its interaction with M1 neural circuits related to hand control. The present study examines the influence of BA 5 on excitatory and inhibitory neural circuitry within M1 bilaterally before and after continuous (cTBS), intermittent (iTBS), and sham theta-burst stimulation (sham TBS) over left hemisphere BA 5. Using single and paired-pulse TMS, measurements of motor evoked potentials (MEPs), short interval intracortical inhibition (SICI), and intracortical facilitation (ICF) were quantified for the representation of the first dorsal interosseous muscle. Results indicate that cTBS over BA 5 influences M1 excitability such that MEP amplitudes are increased bilaterally for up to one hour. ITBS over BA 5 results in an increase in MEP amplitude contralateral to stimulation with a delayed onset that persists up to one hour. SICI and ICF were unaltered following TBS over BA 5. Similarly, F-wave amplitude and latency were unaltered following cTBS over BA 5. The data suggest that BA 5 alters M1 output directed to the hand by influencing corticospinal neurons and not interneurons that mediate SICI or ICF circuitry. Targeting BA 5 via cTBS and iTBS is a novel mechanism to powerfully modulate activity within M1 and may provide an avenue for investigating hand control in healthy populations and modifying impaired hand function in clinical populations