Direct therapeutic effect of sulfadoxine-pyrimethamine on nutritional deficiency-induced enteric dysfunction in a human Intestine Chip.

BACKGROUND: Sulfadoxine-pyrimethamine (SP) antimalarial therapy has been suggested to potentially increase the birth weight of infants in pregnant women in sub-Saharan Africa, independently of malarial infection. Here, we utilized female intestinal organoid-derived cells cultured within microfluidic Organ Chips to investigate whether SP could directly impact intestinal function and thereby improve the absorption of essential fats and nutrients crucial for fetal growth. METHODS: Using a human organ-on-a-chip model, we replicated the adult female intestine with patient organoid-derived duodenal epithelial cells interfaced with human intestinal endothelial cells. Nutrient-deficient (ND) medium was perfused to simulate malnutrition, resulting in the appearance of enteric dysfunction indicators such as villus blunting, reduced mucus production, impaired nutrient absorption, and increased inflammatory cytokine secretion. SP was administered to these chips in the presence or absence of human peripheral blood mononuclear cells (PBMCs). FINDINGS: Our findings revealed that SP treatment effectively reversed multiple intestinal absorptive abnormalities observed in malnourished female Intestine Chips, as validated by transcriptomic and proteomic analyses. SP also reduced the production of inflammatory cytokines and suppressed the recruitment of PBMCs in ND chips. INTERPRETATION: Our results indicate that SP could potentially increase birth weights by preventing enteric dysfunction and suppressing intestinal inflammation. This underscores the potential of SP as a targeted intervention to improve maternal absorption, subsequently contributing to healthier fetal growth. While SP treatment shows promise in addressing malabsorption issues that can influence infant birth weight, we did not model pregnancy in our chips, and thus its usefulness for treatment of malnourished pregnant women requires further investigation through clinical trials. FUNDING: The Bill and Melinda Gates Foundation, and the Wyss Institute for Biologically Inspired Engineering at Harvard University, and the HDDC Organoid Core of the P30 DK034854.

Improving coverage of antenatal iron and folic acid supplementation and malaria prophylaxis through targeted information and home deliveries in Côte d'Ivoire: a cluster randomised controlled trial.

INTRODUCTION: Coverage of antenatal iron and folic acid (IFA) supplementation and malaria chemoprophylaxis remains low in many low-income and middle-income settings. We assessed the effectiveness of personal information (INFO) sessions and personal information session plus home deliveries (INFO+DELIV) to increase coverage of IFA supplementation and intermittent preventive treatment in pregnancy (IPTp), and their effectiveness on postpartum anaemia and malaria infection. METHODS: We included 118 clusters randomised to a control (39), INFO (39) and INFO+DELIV (40) arm, in a trial conducted between 2020 and 2021 with pregnant women (age ≥15 years) in their first or second trimester of pregnancy in Taabo, Côte d'Ivoire. We used generalised linear regression models to assess intervention impact in postpartum anaemia and malaria parasitaemia, and displayed resulting estimates as prevalence ratios. RESULTS: Overall, 767 pregnant women were enrolled and 716 (93.3%) were followed up after delivery. Neither intervention had an impact on postpartum anaemia, with estimated adjusted prevalence ratios (aPRs) of 0.97 (95% CI 0.79 to 1.19, p=0.770) for INFO and 0.87 (95% CI 0.70 to 1.09, p=0.235) for INFO+DELIV. While INFO had no effect on malaria parasitaemia (aPR=0.95, 95% CI 0.39 to 2.31, p=0.915), INFO+DELIV reduced malaria parasitaemia by 83% (aPR=0.17, 95% CI 0.04 to 0.75, p=0.019). No improvements in antenatal care (ANC) coverage (aPR=1.05, 95% CI 0.81 to 1.36, p=0.692), IFA (aPR=2.00, 95% CI 0.89 to 4.46, p=0.093) and IPTp (aPR=1.03, 95% CI 0.87 to 1.21, p=0.728) compliance were found for INFO. INFO+DELIV increased ANC attendance (aPR=1.35, 95% CI 1.02 to 1.78, p=0.037) and compliance with IPTp (aPR=1.60, 95% CI 1.41 to 1.80, p<0.001) and IFA recommendations (aPR=7.06, 95% CI 3.68 to 13.51, p<0.001). CONCLUSIONS: INFO+DELIV can substantially increase compliance with IFA supplementation and improve malaria prevention. However, the increases in IFA supplementation are likely insufficient to address the prevalence of often severe anaemia in this population. TRIAL REGISTRATION NUMBER: NCT04250428.

Optimization of HPLC-MS/MS method for determination of antimalarial adulterants in herbal products.

The use of herbal products is booming all over the world because of being believed as safer than conventional drugs and free of side effects. However, there are untrustworthy manufacturers who adulterate herbal products by adding conventional drugs which might eventually lead to microbial resistance and herb-to-drug interactions. There is a need to develop methods for detecting adulterants in herbal products. A high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method for simultaneous identification and determination of conventional antimalarials (chloroquine, quinine, sulfadoxine, pyrimethamine, mefloquine, lumefantrine, amodiaquine, artemisinin, dihydroartemisinin, artesunate and artemether) in herbal products was developed. Stable isotopically labelled compounds (artemether-d3, quindine-d3, and sulfadoxine-d3) were used as internal standards (ISs) for quantitative analysis. Extraction of analytes was performed using methanol: water: formic acid (90:10:0.1, v/v) and chromatographic separation was done in a gradient mode using mobile phase A: Ultrapure water containing 0.1% formic acid and 1 mM ammonium formate and mobile phase B: Acetonitrile/methanol (50:50) containing 0.1% formic acid and 1 mM ammonium formate. The calibration curves were linear (r2 ≥ 0.991) over the range of 0.001-0.3 µg mL-1 for all compounds. The limit of detection (LOD) ranged from 0.002 to 0.02 µg mL-1 while the limit of quantification (LOQ) ranged from 0.006 to 0.08 µg mL-1. Accuracy, expressed as recovery of spiked herbal products ranged from 52 to 128%. The precision, expressed as percent relative standard deviation (%RSD) at two concentration levels, ranged from 1.0 to 13.8%. The matrix effect expressed as the matrix factor (MF) ranged from 0.77 to 0.97. The developed method was used to identify and quantify conventional antimalarials in herbal product samples from Tanzania. Ten out of 50 herbal products were found to contain amodiaquine, sulfadoxine, pyrimethamine, mefloquine, dihydroartemisinin, artemether and lumefantrine. The developed method is considered a valuable tool for getting a better understanding of the adulteration of conventional antimalarials in herbal products.

Folic acid supplementation and malaria susceptibility and severity among people taking antifolate antimalarial drugs in endemic areas.

BACKGROUND: Description of the condition Malaria, an infectious disease transmitted by the bite of female mosquitoes from several Anopheles species, occurs in 87 countries with ongoing transmission (WHO 2020). The World Health Organization (WHO) estimated that, in 2019, approximately 229 million cases of malaria occurred worldwide, with 94% occurring in the WHO's African region (WHO 2020). Of these malaria cases, an estimated 409,000 deaths occurred globally, with 67% occurring in children under five years of age (WHO 2020). Malaria also negatively impacts the health of women during pregnancy, childbirth, and the postnatal period (WHO 2020). Sulfadoxine/pyrimethamine (SP), an antifolate antimalarial, has been widely used across sub-Saharan Africa as the first-line treatment for uncomplicated malaria sTo examine the effects of folic acid supplementation, at various doses, on malaria susceptibility (risk of infection) and severity among people living in areas with various degrees of malaria endemicity. We will examine the interaction between folic acid supplements and antifolate antimalarial drugs. Specifically, we will aim to answer the following. Among uninfected people living in malaria endemic areas, who are taking or not taking antifolate antimalarials for malaria prophylaxis, does taking a folic acid-containing supplement increase susceptibility to or severity of malaria infection? Among people with malaria infection who are being treated with antifolate antimalarials, does folic acid supplementation increase the risk of treatment failure?Criteria for considering studies for this review Types of studies Inclusion criteria Randomized controlled trials (RCTs) Quasi-RCTs with randomization at the individual or cluster level conducted in malaria-endemic areas (areas with ongoing, local malaria transmission, including areas approaching elimination, as listed in the World Malaria Report 2020) (WHO 2020) Exclusion criteria Ecological studies Observational studies In vivo/in vitro studies Economic studies Systematic literature reviews and meta-analyses (relevant systematic literature reviews and meta-analyses will be excluded but flagged for grey literature screening) Types of participants Inclusion criteria Individuals of any age or gender, living in a malaria endemic area, who are taking antifolate antimalarial medications (inclu

Malaria in pregnancy control and pregnancy outcomes: a decade's overview using Ghana's DHIMS II data.

BACKGROUND: Malaria in pregnancy control interventions have been implemented through antenatal care services for more than 2 decades in Ghana. The uptake of these interventions has seen steady improvement over the years. This has occurred within the context of decreasing global trends of malaria infection confirmed by decreasing malaria in pregnancy prevalence in Ghana. However, not much is known about how these improvements in interventions uptake and reduction in malaria infection prevalence have impacted pregnancy outcomes in the country. This study aimed at describing trends of maternal anaemia and low birth weight prevalence and uptake of malaria in pregnancy control interventions over the last decade using data from Ghana's District Health Information Management System (DHIMS II). METHODS: Data from Ghana's DHIMS II on variables of interest covering the period 2012 to 2021 was analysed descriptively using Microsoft Excel 365. Results were computed as averages and percentages and presented in tables and graphs. RESULTS: The prevalence of maternal anaemia at booking and at term and low birth weight increased marginally from 31.0%, 25.5% and 8.5% in 2012 to 36.6%, 31.9% and 9.5% in 2021 respectively. Severe anaemia prevalence at booking and at term remained under 2% over the study period. Women making at least 4 ANC visits, receiving at least 3 doses of intermittent preventive treatment of malaria and an insecticide-treated net increased from 77.0%, 41.4% and 4.1% in 2012 to 82%, 55.0% and 93.3% in 2021, respectively. Malaria test positivity rate reduced from 54.0% to 34.3% between 2014 and 2021 while women receiving iron and folate supplementation for 3 and 6 months rose from 43.0% and 25.5% to 89.7% and 61.8%, respectively between 2017 and 2021. CONCLUSION: Maternal anaemia and low birth weight prevalence showed marginal upward trends over the last decade despite reduced malaria infection rate and improved uptake of malaria in pregnancy control interventions. There is room for improvement in current intervention implementation levels but the complex and multi-factorial aetiologies of maternal anaemia and low birth weight need urgent investigation and quantification to inform policy and practice.

Sulfadoxine-pyrimethamine parasitological efficacy against Plasmodium falciparum among pregnant women and molecular markers of resistance in Zambia: an observational cohort study.

BACKGROUND: The World Health Organization recommends the provision of intermittent preventive treatment during pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) at 4-week intervals from gestational week 13 to delivery in areas of moderate to high malaria transmission intensity. However, the effect of IPTp-SP has been compromised in some areas due to parasite resistance, raising the importance of parasitological and chemoprophylactic surveillance, and monitoring SP-resistance markers in the Plasmodium falciparum population. METHODS: Between November 2013 and April 2014 in Nchelenge, Zambia, 1086 pregnant women received IPTp-SP at antenatal-care bookings. Blood samples were collected on day 0, and on day 28 post-treatment to test for malaria parasites and to estimate SP parasitological efficacy in the treatment and prevention of parasitaemia. A random sample of 96, day 0 malaria-positive samples were analysed to estimate the prevalence of SP-resistance markers in the P. falciparum population. RESULTS: The overall parasitological and prophylactic failure among women who had paired day 0 and day 28 blood slides was 18.6% (95% CI 15.5, 21.8; 109 of 590). Among pregnant women who had asymptomatic parasitaemia on day 0, the day 28 PCR-uncorrected parasitological failure was 30.0% (95% CI 23.7, 36.2; 62 of 207) and the day 28 PCR-corrected parasitological failure was 15.6% (95% CI: 10.6, 20.6; 32 of 205). Among women who tested negative at day 0, 12.3% (95% CI: 9.0, 15.6; 47 of 383) developed parasitaemia at day 28. Among the 96 malaria-positive samples assayed from day 0, 70.8% (95% CI: 60.8, 79.2) contained the DHPS double (Gly-437 + Glu-540) mutation and 92.7% (95% CI: 85.3, 96.5) had the DHFR triple (Asn-108 + Ile-51 + Arg-59) mutation. The quintuple mutation (DHFR triple + DHPS double) and the sextuple mutant (DHFR triple + DHPS double + Arg-581) were found among 68.8% (95% CI: 58.6, 77.3) and 9.4% (95% CI: 4.2, 16.0) of samples, respectively. CONCLUSION: The parasitological and chemoprophylactic failure of SP, and the prevalence of resistance markers in Nchelenge is alarmingly high. Alternative therapies are urgently needed to safeguard pregnant women against malarial infection.

Effects of Malaria Interventions During Pregnancy on Low Birth Weight in Malawi.

INTRODUCTION: In malaria-endemic countries, malaria during pregnancy is associated with adverse birth outcomes, including low birth weight (i.e., <2.5 kg). However, the effects of the widely promoted and recommended approaches of intermittent preventive treatment for malaria in pregnancy and insecticide-treated nets for pregnant women on low birth weight have been insufficiently examined. This analysis investigates the independent and combined effects of intermittent preventive treatment for malaria in pregnancy and insecticide-treated nets on low birth weight among Malawian children. METHODS: Using pooled data sets from 2004, 2010, and 2015-2016 Malawi Demographic and Health Surveys, a total of 18,285 births were analyzed between August and December 2019. Binomial generalized linear regression models with a log-link function explored the associations under consideration. RESULTS: The overall low birth weight prevalence was 10.3%. Prevalence was lower in children whose mothers used adequate intermittent preventive treatment for malaria in pregnancy (adjusted prevalence ratio=0.88, 95% CI=0.79, 0.99) or used insecticide-treated nets (adjusted prevalence ratio=0.89, 95% CI=0.79, 0.99) than their respective counterparts. Low birth weight was 20.0% lower among children whose mothers adequately used both intermittent preventive treatment for malaria in pregnancy and insecticide-treated nets than those without these approaches (adjusted prevalence ratio=0.80, 95% CI=0.68, 0.93). Iron supplement consumption and survey year were significant effect modifiers on the relationship between intermittent preventive treatment for malaria in pregnancy and low birth weight. CONCLUSIONS: There were evident benefits of independent and combined use of intermittent preventive treatment for malaria in pregnancy and insecticide-treated nets on low birth weight, thereby supporting the use of these interventions during pregnancy. The reduced protective effects of intermittent preventive treatment for malaria in pregnancy over time highlight the need for innovative preventive methods against malaria in pregnancy.

GM2 Gangliosidoses: Clinical Features, Pathophysiological Aspects, and Current Therapies.

GM2 gangliosidoses are a group of pathologies characterized by GM2 ganglioside accumulation into the lysosome due to mutations on the genes encoding for the ß-hexosaminidases subunits or the GM2 activator protein. Three GM2 gangliosidoses have been described: Tay-Sachs disease, Sandhoff disease, and the AB variant. Central nervous system dysfunction is the main characteristic of GM2 gangliosidoses patients that include neurodevelopment alterations, neuroinflammation, and neuronal apoptosis. Currently, there is not approved therapy for GM2 gangliosidoses, but different therapeutic strategies have been studied including hematopoietic stem cell transplantation, enzyme replacement therapy, substrate reduction therapy, pharmacological chaperones, and gene therapy. The blood-brain barrier represents a challenge for the development of therapeutic agents for these disorders. In this sense, alternative routes of administration (e.g., intrathecal or intracerebroventricular) have been evaluated, as well as the design of fusion peptides that allow the protein transport from the brain capillaries to the central nervous system. In this review, we outline the current knowledge about clinical and physiopathological findings of GM2 gangliosidoses, as well as the ongoing proposals to overcome some limitations of the traditional alternatives by using novel strategies such as molecular Trojan horses or advanced tools of genome editing.

"They Merely Prescribe and I Merely Swallow": Perceptions of Antenatal Pharmaceuticals and Nutritional Supplements Among Pregnant Women in Bamako, Mali.

OBJECTIVES: New international guidelines for antenatal care (ANC) will likely result in an increase in nutritional supplements and preventative medications for pregnant women in low and middle-income countries. Our objective was to understand how pregnant women in Mali perceive and experience multi-drug regimens in ANC in order to reveal factors that may influence uptake and adherence. METHODS: We conducted 29 semi-structured interviews and three focus groups with 21 pregnant women in two urban ANC sites in Bamako, Mali. Interviews focused on perception of purpose of ANC pharmaceuticals (particularly iron supplements, sulfadoxine-pyrimethamine as intermittent prevention of malaria and antiretroviral therapy for HIV), beliefs regarding efficacy and risk, and understanding of dosage and regimen. Transcripts were inductively coded and analyzed using the 'Framework' method. RESULTS: Participant descriptions of medication purpose, understanding of dosing, and beliefs about risks and efficacy varied widely, revealing that many pregnant women lack complete information about their medications. While some were burdened by side effects or complex regimens, women generally held favorable attitudes toward ANC medications. Responses suggest major barriers to adherence lie in the health system, namely insufficient patient-provider communication and inconsistent prescribing practices. CONCLUSIONS FOR PRACTICE: National health programs looking to improve maternal and child health with ANC pharmaceuticals need to place greater attention on patient counseling and consistent implementation of administration guidelines. Communication that positions pharmaceuticals as beneficial to mother and child, while presenting understandable information about purpose, dosing and potential side effects can promote uptake of multi-drug regimens and ANC services in general.

Patient and treatment pathways for toxoplasmosis in the United States: data analysis of the Vizient Health Systems Data from 2011 to 2017.

Toxoplasmosis causes substantial morbidity and mortality in the United States (US). Clinical manifestations to toxoplasmosis vary and there is limited information on incidence or treatment patterns in the US. Treatment pathways for pyrimethamine-based regimens and trimethoprim-sulfamethoxazole (TMP-SMX) for toxoplasmosis hospitalizations were investigated using the Vizient Health Systems inpatient and outpatient data. Between January 1st, 2011 and December 31st, 2017, 10,273 hospital visits from 4,736 unique patients received a primary or secondary ICD-9/ICD-10 diagnosis for toxoplasmosis. The projected annual hospital visits with a diagnosis of toxoplasmosis was 68,821, corresponding to a total annual incidence of 9,832 comprising ocular toxoplasmosis of 2,169, toxoplasmic encephalitis of 1,399, unspecified toxoplasmosis of 4,368, congenital toxoplasmosis of 381, multisystemic toxoplasmosis of 69 and other toxoplasmosis of 1,446. Only 16.3% of the study population received treatment with pyrimethamine-based regimens or TMP-SMX. Pyrimethamine-based regimens were used significantly more often than TMP-SMX in toxoplasmic encephalitis (88.7% vs 79.6%, p = 0.01), other toxoplasmosis (85.0% vs 79.2%, p = 0.04), and unspecified toxoplasmosis (87.6% vs 77.9%, p = 0.03) in hospitals with 300 beds or more. A significantly higher percentage of visits with TMP-SMX as first-line treatment switched to pyrimethamine-based regimens compared to visits initiated on pyrimethamine-based treatments (26.7% vs 4.1%, p < .001). Ocular toxoplasmosis patients receiving pyrimethamine-based therapy were more likely to be discharged home compared to TMP-SMC at rates of 72.4% and 55.2%, respectively. Our analysis of commercial insurance records suggest toxoplasmosis is undertreated. Overall, pyrimethamine-based regimens are favored over TMP-SMX, have higher rates of discharge home, and have lower switch rates.

Adverse Reactions in Antifolate-Treated Toxoplasmic Retinochoroiditis.

This study seeks to define factors affecting the development of adverse reactions to intensive therapy of toxoplasmic retinochoroiditis with antifolate agents (pyrimethamine/sulfadoxine) and antibiotics followed by secondary antifolate prophylaxis. The study was of retrospective and observational nature. Medical files were reviewed of 551 patients suffering from ocular toxoplasmosis during 1994-2013. All patients were treated with the same protocol: 3-week intensive pyrimethamine/sulfadoxine plus antibiotic/steroid therapy. Three hundred and fourteen out of the 551 patients qualified for the subsequent 6-month long secondary antifolate prophylaxis. The type and occurrence rate of adverse reactions were taken into account. The probability of an adverse reaction during the intensive therapy phase was 33.4%. Hypertransaminasemia was the most common event observed in 24.6% of the patients, but it assumed a severe character in just 0.9%, with male gender and age over 25 years being the predisposing factors. Less common adverse effects included thrombocytopenia (8.3%), hypersensitivity skin reactions (3.0%), and abdominal pain (1.4%). The adverse effects of secondary antifolate prophylaxis, most commonly hypersensitivity skin reactions and hypertransaminasemia, followed by thrombocytopenia and abdominal pain, were observed in 4.9% of the patients. Ten of them (2.7%) had to discontinue the treatment while eight others continued with pyrimethamine alone without further adverse effects, which suggests that discontinuation of the sulfonamide decreased the propensity for adverse reactions. The treatment strategy in these patients differed from previous reports in that it used lower doses of pyrimethamine/sulfonamide, with no folinic acid supplementation. Nonetheless, the rate and severity of adverse events were no greater than those noticed with traditional regimens, with higher antifolate doses and folinic acid supplementation. We conclude that the dose and drug-mitigated treatment strategy we employed deserves consideration as a promising alternative to traditional treatments for ocular toxoplasmosis.

Intermittent screening and treatment with artemether-lumefantrine versus intermittent preventive treatment with sulfadoxine-pyrimethamine for malaria in pregnancy: a facility-based, open-label, non-inferiority trial in Nigeria.

BACKGROUND: The spread of SP resistance may compromise the effectiveness of intermittent preventive treatment of malaria in pregnancy (MiP) with sulfadoxine-pyrimethamine (IPTp-SP) across Africa. However, there is no recommended alternative medicine for IPTp or alternative strategy for prevention of MiP. This poses problems for the prevention of MiP. This study investigated, whether screening with a rapid diagnostic test for malaria at routine antenatal clinic attendances and treatment of only those who are positive (intermittent screening and treatment) with artemether-lumefantrine is as effective and safe as IPTp-SP in pregnant women. METHODS: During antenatal clinic sessions at the General Hospital Calabar, Nigeria, held between October 2013 and November 2014, 459 pregnant women were randomized into either the current standard IPTp-SP or intermittent screening and treatment with artemether-lumefantrine (ISTp-AL). All women received a long-lasting insecticide-treated net at enrolment. Study women had a maximum of four scheduled visits following enrolment. Haemoglobin concentration and peripheral parasitaemia were assessed in the third trimester (36-40 weeks of gestation). Birth weight was documented at delivery or within a week for babies delivered at home. RESULTS: In the third trimester, the overall prevalence of severe anaemia (Hb < 8 g/dl) and moderate (8-10.9 g/dl) anaemia was 0.8 and 27.7%, respectively, and was similar in both treatment groups (p = 0.204). The risk of third-trimester severe anaemia did not differ significantly between both treatment arms (risk difference - 1.75% [95% CI - 4.16 to 0.66]) although the sample was underpowered for this outcome due to several participants being unavailable to give a blood sample. The risk of third-trimester maternal parasitaemia was significantly lower in the ISTp-AL arm (RD - 3.96% [95% CI - 7.76 to - 0.16]). The risk of low birthweight was significantly lower in the ISTp-AL arm after controlling for maternal age, gravidity and baseline parasitaemia (risk difference - 1.53% [95% CI - 1.54 to - 1.15]). Women in the ISTp-AL arm complained of fever more frequently compared to women in the IPTp-SP arm (p = 0.022). CONCLUSIONS: The trial results suggest that in an area of high malaria transmission with moderate sulfadoxine-pyrimethamine resistance, ISTp with artemether-lumefantrine may be an effective strategy for controlling malaria in pregnancy. Trial registration PACTR, PACTR201308000543272. Registered 29 April 2013, http://www.pactr.org/ATMWeb/appmanager/atm/atmregistry?dar=true&tNo=PACTR201308000543272.

High folate levels are not associated with increased malaria risk but with reduced anaemia rates in the context of high-dosed folate supplements and intermittent preventive treatment against malaria in pregnancy with sulphadoxine-pyrimethamine in Benin.

OBJECTIVES: To investigate whether high-dosed folate supplements might diminish the efficacy of malaria intermittent preventive treatment in pregnancy (IPTp) with sulphadoxine-pyrimethamine (SP) in a cohort of pregnant women in Benin, where malaria is holoendemic. METHODS: We followed 318 women during the entire pregnancy and analysed haematological and Plasmodium falciparum indicators in the context of an intermittent preventive treatment trial in Benin. During the follow-up, women received two-dose IPTp (1500/75 mg of SP per dose) at the maternity clinic and 600 mg of albendazole, 200 mg ferrous sulphate and 5 mg folic acid per day for home treatment. RESULTS: High folate levels were not associated with increased malaria risk (adjusted OR (aOR) = 0.51 (95% CI: 0.17; 1.56, P-value = 0.24)), nor with increased P. falciparum density (beta coefficient = -0.26 (95% CI: -0.53; 0.02), P-value = 0.07) in a randomised trial of IPTp in Benin. On the contrary, higher iron levels were statistically associated with increased odds of a positive blood smear (aOR = 1.7 95% CI (1.2; 2.3), P-value < 0.001) and P. falciparum parasite density (beta coefficient = 0.2 95% CI (0.1; 0.3), P-value < 0.001). High folate levels were statistically associated with decreased odds of anaemia (aOR = -0.30 95% CI (0.10; 0.88), P-value = 0.03). CONCLUSIONS: High folate levels are not associated with increased malarial risk in a prospective longitudinal cohort in the context of both iron and high-dosed folate supplements and IPTp. They are associated with reduced risk of anaemia, which is particularly important because iron, also given to treat anaemia, might be associated with increased malaria risk.

Factors Influencing Anti-Malarial Prophylaxis and Iron Supplementation Non-Compliance among Pregnant Women in Simiyu Region, Tanzania.

Malaria and iron-deficient anemia during pregnancy pose considerable risks for the mother and newborn. Intermittent Preventive Treatment during pregnancy with sulphadoxine-pyrimethamine (IPTp-SP) and iron supplement to prevent anemia to all pregnant women receiving antenatal care (ANC) services is highly recommended. However, their compliance remains low. This study aimed at identifying factors influencing non-compliance of medications among pregnant women. A descriptive cross-sectional study was conducted in Simiyu region in northwest Tanzania using a structured questionnaire to collect data from 430 women who were pregnant or gave birth 12 months prior to data collection. Data were analyzed using non-parametric statistical analysis with STATA 10. Overall, 284 (66%) and 195 (45%) of interviewed women received IPTp-SP and iron supplementation during their ANC visits, respectively. The majority (85%) of women whom received medications were aware if they had received IPTp-SP or iron supplementation. Of those received IPTp-SP, only 11% took all the three doses, while the remaining 89% took only two doses or one dose. For women who received iron supplementation, 29% reported that they did not take any dose at all. Reasons given for not complying with regiments included not liking the medications and disapproval from male partners. Our findings suggest that IPTp-SP and iron supplement compliance among pregnant women in Simiyu region is low. Intensification of community education, further qualitative research and administration of medication through directly-observed therapy (DOT) are recommended to address the problem.

Effects of Thymus vulgaris ethanolic extract on chronic toxoplasmosis in a mouse model.

The current work was undertaken to investigate the potential effectiveness of Thymus vulgaris ethanolic extract (TVE) against Toxoplasma gondii infection in chronic experimental toxoplasmosis. To evaluate prophylactic effects, mice received 500 mg/kg TVE for 5 days before they were infected by an avirulent Me49 T. gondii strain. To investigate the therapeutic effects of the extract postinfection, daily treatment with TVE was initiated at 6 weeks postinfection and continued for 10 days. The following groups of animals were used as controls: uninfected/non-treated, infected/non-treated, and infected/treated with a combination of pyrimethamine and sulfadiazine. Brain cyst count and histopathological changes using H&E and Feulgen stains were used to evaluate the efficacy of TVE. The mean number of brain cysts was significantly decreased by 24 % in mice treated prophylactically with TVE. TVE also significantly reduced the mean number of brain cysts when administered to animals already chronically infected with T. gondii. The effect of TVE was comparable to that of treatment with a mixture of sulfadiazine and pyrimethamine (46 and 51 % reduction, respectively). Moreover, considerable amelioration of the pathological lesions in the brain and retina was observed. The results demonstrate the potential efficacy of T. vulgaris as a new natural therapeutic and prophylactic agent for use in the treatment of chronic toxoplasmosis.

Effect of Nigella sativa oil on experimental toxoplasmosis.

Toxoplasmosis is a parasitic infection caused by Toxoplasma gondii protozoon. It is most commonly treated by pyrimethamine (PYR); however, this was intolerable by many patients. The aim of this study was to assess therapeutic effects of Nigella sativa oil (NSO) alone and combined with pyrimethamine (PYR) compared to a previous combination of clindamycin (CLN) and (PYR). One hundred Albino mice were used in the current study and were equally divided into five groups: normal (I), infected untreated control (II); infected, treated with NSO-only (III); infected, treated with NSO + PYR (IV); and infected, treated with CLN + PYR (V). The virulent RH Toxoplasma strain was used in infection survival rates estimation, impression smears from liver and spleen, and histopathological and ultrastructural studies were done. Liver malondialdehyde (MDA) level and total antioxidant capacity (TAC) were determined. Interferon-γ and specific IgM were also measured in sera by ELISA. Results showed that NSO alone has no direct anti-Toxoplasma effect, whereas its combination with PYR produced potent effect that is comparable to CLN + PYR. It significantly increased the survival rate and decreased the parasite density and pathological insult in both liver and spleen. Also, significant increase in interferon-γ level denotes stimulation of cellular immunity. NSO + PYR combination markedly improved the antioxidant capacity of Toxoplasma infected mice compared to the infected untreated ones and to CLN/PYR. In conclusion, although NSO, if administered alone, has significant immunostimulant and antioxidant properties, it failed to decrease tachyzoite counts. Combination of NSO and PYR had synergistic effect in treatment of toxoplasmosis.

The effect of iron-fortified complementary food and intermittent preventive treatment of malaria on anaemia in 12- to 36-month-old children: a cluster-randomised controlled trial.

BACKGROUND: Iron deficiency (ID) and malaria co-exist in tropical regions and both contribute to high rates of anaemia in young children. It is unclear whether iron fortification combined with intermittent preventive treatment (IPT) of malaria would be an efficacious strategy for reducing anaemia in young children. METHODS: A 9-month cluster-randomised, single-blinded, placebo-controlled intervention trial was carried out in children aged 12-36 months in south-central Côte d'Ivoire, an area of intense and perennial malaria transmission. The study groups were: group 1: normal diet and IPT-placebo (n = 125); group 2: consumption of porridge, an iron-fortified complementary food (CF) with optimised composition providing 2 mg iron as NaFeEDTA and 3.8 mg iron as ferrous fumarate 6 days per week (CF-FeFum) and IPT-placebo (n = 126); group 3: IPT of malaria at 3-month intervals, using sulfadoxine-pyrimethamine and amodiaquine and no dietary intervention (n = 127); group 4: both CF-FeFum and IPT (n = 124); and group 5: consumption of porridge, an iron-fortified CF with the composition currently on the Ivorian market providing 2 mg iron as NaFeEDTA and 3.8 mg iron as ferric pyrophosphate 6 days per week (CF-FePP) and IPT-placebo (n = 127). The primary outcome was haemoglobin (Hb) concentration. Linear and logistic regression mixed-effect models were used for the comparison of the five study groups, and a 2 × 2 factorial analysis was used to assess treatment interactions of CF-FeFum and IPT (study groups 1-4). RESULTS: After 9 months, the Hb concentration increased in all groups to a similar extent with no statistically significant difference between groups. In the 2 × 2 factorial analysis after 9 months, no treatment interaction was found on Hb (P = 0.89). The adjusted differences in Hb were 0.24 g/dl (95 % CI -0.10 to 0.59; P = 0.16) in children receiving IPT and -0.08 g/dl (95 % CI -0.42 to 0.26; P = 0.65) in children receiving CF-FeFum. At baseline, anaemia (Hb <11.0 g/dl) was 82.1 %. After 9 months, IPT decreased the odds of anaemia (odds ratio [OR], 0.46 [95 % CI 0.23-0.91]; P = 0.023), whereas iron-fortified CF did not (OR, 0.85 [95 % CI 0.43-1.68]; P = 0.68), although ID (plasma ferritin <30 µg/l) was decreased markedly in children receiving iron fortified CF (OR, 0.19 [95 % CI 0.09-0.40]; P < 0.001). CONCLUSIONS: IPT alone only modestly decreased anaemia, but neither IPT nor iron fortified CF significantly improved Hb concentration after 9 months. Additionally, IPT did not augment the effect of the iron fortified CF. CF fortified with highly bioavailable iron improved iron status but not Hb concentration, despite three-monthly IPT of malaria. Thus, further research is necessary to develop effective combination strategies to prevent and treat anaemia in malaria endemic regions. TRIAL REGISTRATION: http://www.clinicaltrials.gov ; identifier NCT01634945; registered on July 3, 2012.

A Systematic Review and Meta-Analysis of the Efficacy of Anti-Toxoplasma gondii Medicines in Humans.

No effective drug and definitive "gold standard" treatment for Toxoplasma gondii (T. gondii) infection has been available so far, though some medicines have been commonly used in the treatment of T. gondii infection, such as spiramycin, azithromycin, traditional Chinese medicine (TCM), pyrimethamine- sulfadiazine (P-S), trimethoprim-sulfamethoxazole (TMP-SMX), and pyrimethamine-clindamycin (P-C). A systematic review and meta-analysis were performed to compare the efficacies of these conventional medicines in the treatment. Cohort studies for the treatment of acute T. gondii infection were searched from PubMed, Google Scholar, ect. All the cases number for different group extracted from each included literature were input to meta-analysis 3.13 software to calculate the pooled negative conversion rate (NCR), cure rate (CR) or vertical transmission rate based on their sample size and weight. The pooled NCR with 95% confidence intervals (CI) was used to evaluate the overall rate of a diagnosis positive result conversion to a negative result after treatment, which of spiramycin, azithromycin and TCM were 83.4% (95%CI, 72.1%-90.8%), 82.5% (95%CI, 75.9%-87.6%), and 85.5% (95%CI, 71.3%-93.3%) respectively, with no statistical difference between them. The pooled CR with 95% CI was used to evaluate the overall rate of complete disappearance of clinical symptoms for toxoplasmic encephalitis after therapy, which of P-S, TMP-SMX, and P-C were 49.8% (95%CI, 38. 8% -60.8%), 59.9% (95%CI, 48.9%-70.0%), and 47.6% (95%CI, 24.8%-71.4%) respectively, with no statistical difference between them. Primary T. gondii infection in pregnancy was treated mainly with spiramycin alone or combined with other drugs, and the pooled rate of vertical transmission was about 9.9% (95%CI, 5.9%-16.2%) after therapy. Toxoplasmic encephalitis in AIDS patients was usually treated with sulfonamides combined with other drugs and the pooled CR was 49.4% (95%CI, 37.9%-60.9%).

Perspectives of health care providers on the provision of intermittent preventive treatment in pregnancy in health facilities in Malawi.

BACKGROUND: Nearly 20 years after the adoption by the government of Malawi of the provision of intermittent preventive treatment in pregnancy (IPTp) for malaria, only 55% of pregnant women received at least two doses of sulfadoxine-pyrimethamine (SP) in 2010. Although several reasons for the low coverage have been suggested, few studies have examined the views of health care providers. This study examined the experiences of the nurses and midwives in providing antenatal care (ANC) services. METHODS: This study was conducted in health facilities in Malawi that provide routine ANC services. Providers of ANC in Malawi were selected from in eight health care facilities of Malawi. Selected providers were interviewed using a semi-structured interview guide designed to address a series of themes related to their working conditions and their delivery of IPTp. RESULTS: Nurses displayed detailed knowledge of ANC services and the rationale behind them. Nurses understood that they should provide two doses of IPTp during a pregnancy, but they did not agree on the timing of the doses. Nurses gave SP as directly observed therapy (DOT) at the clinic. Nurses did not give SP pills to women to take home with them because they did not trust that women would take the pills. Women who resisted taking SP explained they do not take drugs if they had not eaten, or they feared side effects, or they were not sick. Reasons for not giving the first or second dose of SP included a delay in the first ANC visit, testing positive for HIV, and presenting with malaria. None of the nurses were able to show any specific written guidelines on when to give SP. The challenges faced by the nurses include being overworked and persuading women to take SP under observation. CONCLUSION: The findings show that the nurses had gained the knowledge and technical skills to provide appropriate ANC services. With regard to IPTp, nurses need guidelines that would be available at the health facility about how and when to give SP. The adoption of the WHO guidelines and their diffusion to health care facilities could help increase the coverage of IPTp2 (at least two doses of sulfadoxine-pyrimethamine) in Malawi.

Impact of intermittent preventive treatment in pregnancy with azithromycin-containing regimens on maternal nasopharyngeal carriage and antibiotic sensitivity of Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus: a cross-sectional survey at delivery.

Sulfadoxine-pyrimethamine (SP) plus azithromycin (AZ) (SPAZ) has the potential for intermittent preventive treatment of malaria in pregnancy (IPTp), but its use could increase circulation of antibiotic-resistant bacteria associated with severe pediatric infections. We evaluated the effect of monthly SPAZ-IPTp compared to a single course of SP plus chloroquine (SPCQ) on maternal nasopharyngeal carriage and antibiotic susceptibility of Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus at delivery among 854 women participating in a randomized controlled trial in Papua New Guinea. Serotyping was performed, and antibiotic susceptibility was evaluated by disk diffusion and Etest. Potential risk factors for carriage were examined. Nasopharyngeal carriage at delivery of S. pneumoniae (SPAZ, 7.2% [30/418], versus SPCQ, 19.3% [84/436]; P<0.001) and H. influenzae (2.9% [12/418] versus 6.0% [26/436], P=0.028), but not S. aureus, was significantly reduced among women who had received SPAZ-IPTp. The number of macrolide-resistant pneumococcal isolates was small but increased in the SPAZ group (13.3% [4/30], versus SPCQ, 2.2% [2/91]; P=0.033). The proportions of isolates with serotypes covered by the 13-valent pneumococcal conjugate vaccine were similar (SPAZ, 10.3% [3/29], versus SPCQ, 17.6% [16/91]; P=0.352). Although macrolide-resistant isolates were rare, they were more commonly detected in women who had received SPAZ-IPTp, despite the significant reduction of maternal carriage of S. pneumoniae and H. influenzae observed in this group. Future studies on SPAZ-IPTp should evaluate carriage and persistence of macrolide-resistant S. pneumoniae and other pathogenic bacteria in both mothers and infants and assess the clinical significance of their circulation.