Artemether-lumefantrine with or without single-dose primaquine and sulfadoxine-pyrimethamine plus amodiaquine with or without single-dose tafenoquine to reduce Plasmodium falciparum transmission: a phase 2, single-blind, randomised clinical trial in Ouelessebougou, Mali.

BACKGROUND: Artemether-lumefantrine is widely used for uncomplicated Plasmodium falciparum malaria; sulfadoxine-pyrimethamine plus amodiaquine is used for seasonal malaria chemoprevention. We aimed to determine the efficacy of artemether-lumefantrine with and without primaquine and sulfadoxine-pyrimethamine plus amodiaquine with and without tafenoquine for reducing gametocyte carriage and transmission to mosquitoes. METHODS: In this phase 2, single-blind, randomised clinical trial conducted in Ouelessebougou, Mali, asymptomatic individuals aged 10-50 years with P falciparum gametocytaemia were recruited from the community and randomly assigned (1:1:1:1) to receive either artemether-lumefantrine, artemether-lumefantrine with a single dose of 0·25 mg/kg primaquine, sulfadoxine-pyrimethamine plus amodiaquine, or sulfadoxine-pyrimethamine plus amodiaquine with a single dose of 1·66 mg/kg tafenoquine. All trial staff other than the pharmacist were masked to group allocation. Participants were not masked to group allocation. Randomisation was done with a computer-generated randomisation list and concealed with sealed, opaque envelopes. The primary outcome was the median within-person percent change in mosquito infection rate in infectious individuals from baseline to day 2 (artemether-lumefantrine groups) or day 7 (sulfadoxine-pyrimethamine plus amodiaquine groups) after treatment, assessed by direct membrane feeding assay. All participants who received any trial drug were included in the safety analysis. This study is registered with ClinicalTrials.gov, NCT05081089. FINDINGS: Between Oct 13 and Dec 16, 2021, 1290 individuals were screened and 80 were enrolled and randomly assigned to one of the four treatment groups (20 per group). The median age of participants was 13 (IQR 11-20); 37 (46%) of 80 participants were female and 43 (54%) were male. In individuals who were infectious before treatment, the median percentage reduction in mosquito infection rate 2 days after treatment was 100·0% (IQR 100·0-100·0; n=19; p=0·0011) with artemether-lumefantrine and 100·0% (100·0-100·0; n=19; p=0·0001) with artemether-lumefantrine with primaquine. Only two individuals who were infectious at baseline infected mosquitoes on day 2 after artemether-lumefantrine and none at day 5. By contrast, the median percentage reduction in mosquito infection rate 7 days after treatment was 63·6% (IQR 0·0-100·0; n=20; p=0·013) with sulfadoxine-pyrimethamine plus amodiaquine and 100% (100·0-100·0; n=19; p<0·0001) with sulfadoxine-pyrimethamine plus amodiaquine with tafenoquine. No grade 3-4 or serious adverse events occurred. INTERPRETATION: These data support the effectiveness of artemether-lumefantrine alone for preventing nearly all mosquito infections. By contrast, there was considerable post-treatment transmission after sulfadoxine-pyrimethamine plus amodiaquine; therefore, the addition of a transmission-blocking drug might be beneficial in maximising its community impact. FUNDING: Bill & Melinda Gates Foundation.

Genome-wide genetic variation and molecular surveillance of drug resistance in Plasmodium falciparum isolates from asymptomatic individuals in Ouélessébougou, Mali.

Sequence analysis of Plasmodium falciparum parasites is informative in ensuring sustained success of malaria control programmes. Whole-genome sequencing technologies provide insights into the epidemiology and genome-wide variation of P. falciparum populations and can characterise geographical as well as temporal changes. This is particularly important to monitor the emergence and spread of drug resistant P. falciparum parasites which is threatening malaria control programmes world-wide. Here, we provide a detailed characterisation of genome-wide genetic variation and drug resistance profiles in asymptomatic individuals in South-Western Mali, where malaria transmission is intense and seasonal, and case numbers have recently increased. Samples collected from Ouélessébougou, Mali (2019-2020; n = 87) were sequenced and placed in the context of older Malian (2007-2017; n = 876) and African-wide (n = 711) P. falciparum isolates. Our analysis revealed high multiclonality and low relatedness between isolates, in addition to increased frequencies of molecular markers for sulfadoxine-pyrimethamine and lumefantrine resistance, compared to older Malian isolates. Furthermore, 21 genes under selective pressure were identified, including a transmission-blocking vaccine candidate (pfCelTOS) and an erythrocyte invasion locus (pfdblmsp2). Overall, our work provides the most recent assessment of P. falciparum genetic diversity in Mali, a country with the second highest burden of malaria in West Africa, thereby informing malaria control activities.

Persistence of Plasmodium falciparum HRP-2 antigenaemia after artemisinin combination therapy is not associated with gametocytes.

BACKGROUND: In some settings, sensitive field diagnostic tools may be needed to achieve elimination of falciparum malaria. To this end, rapid diagnostic tests (RDTs) based on the detection of the Plasmodium falciparum protein HRP-2 are being developed with increasingly lower limits of detection. However, it is currently unclear how parasite stages that are unaffected by standard drug treatments may contribute to HRP-2 detectability and potentially confound RDT results even after clearance of blood stage infection. This study assessed the detectability of HRP-2 in periods of post-treatment residual gametocytaemia. METHODS: A cohort of 100 P. falciparum infected, gametocyte positive individuals were treated with or without the gametocytocidal drug primaquine (PQ), alongside standard artemisinin-based combination therapy (ACT), in the context of a randomised clinical trial in Ouelessebougou, Mali. A quantitative ELISA was used to measure levels of HRP-2, and compared time to test negativity using a standard and ultra-sensitive RDT (uRDT) between residual gametocyte positive and negative groups. RESULTS: Time to test negativity was longest by uRDT, followed by ELISA and then standard RDT. No significant difference in time to negativity was found between the treatment groups with and without residual gametocytes: uRDT (HR 0.79 [95% CI 0.52-1.21], p = 0.28), RDT (HR 0.77 [95% CI 0.51-1.15], p = 0.20) or ELISA (HR 0.88 [95% CI 0.59-1.32], p = 0.53). Similarly, no difference was observed when adjusting for baseline asexual parasite density. Quantified levels of HRP-2 over time were similar between groups, with differences attributable to asexual parasite densities. Furthermore, no difference in levels of HRP-2 was found between individuals who were or were not infectious to mosquitoes (OR 1.19 [95% CI 0.98-1.46], p = 0.077). CONCLUSIONS: Surviving sexual stage parasites after standard ACT treatment do not contribute to the persistence of HRP-2 antigenaemia, and appear to have little impact on RDT results.

Single low-dose tafenoquine combined with dihydroartemisinin-piperaquine to reduce Plasmodium falciparum transmission in Ouelessebougou, Mali: a phase 2, single-blind, randomised clinical trial.

BACKGROUND: Tafenoquine was recently approved as a prophylaxis and radical cure for Plasmodium vivax infection, but its Plasmodium falciparum transmission-blocking efficacy is unclear. We aimed to establish the efficacy and safety of three single low doses of tafenoquine in combination with dihydroartemisinin-piperaquine for reducing gametocyte density and transmission to mosquitoes. METHODS: In this four-arm, single-blind, phase 2, randomised controlled trial, participants were recruited at the Clinical Research Unit of the Malaria Research and Training Centre of the University of Bamako in Mali. Eligible participants were aged 12-50 years, with asymptomatic P falciparum microscopy-detected gametocyte carriage, had a bodyweight of 80 kg or less, and had no clinical signs of malaria defined by fever. Participants were randomly assigned (1:1:1:1) to standard treatment with dihydroartemisinin-piperaquine, or dihydroartemisinin-piperaquine plus a single dose of tafenoquine (in solution) at a final dosage of 0·42 mg/kg, 0·83 mg/kg, or 1·66 mg/kg. Randomisation was done with a computer-generated randomisation list and concealed with sealed, opaque envelopes. Dihydroartemisinin-piperaquine was administered as oral tablets over 3 days (day 0, 1, and 2), as per manufacturer instructions. A single dose of tafenoquine was administered as oral solution on day 0 in parallel with the first dose of dihydroartemisinin-piperaquine. Tafenoquine dosing was based on bodyweight to standardise efficacy and risk variance. The primary endpoint, assessed in the per-protocol population, was median percentage change in mosquito infection rate 7 days after treatment compared with baseline. Safety endpoints included frequency and incidence of adverse events. The final follow-up visit was on Dec 23, 2021; the trial is registered with ClinicalTrials.gov, NCT04609098. FINDINGS: From Oct 29 to Nov 25, 2020, 1091 individuals were screened for eligibility, 80 of whom were enrolled and randomly assigned (20 per treatment group). Before treatment, 53 (66%) individuals were infectious to mosquitoes, infecting median 12·50% of mosquitoes (IQR 3·64-35·00). Within-group reduction in mosquito infection rate on day 7 was 79·95% (IQR 57·15-100; p=0·0005 for difference from baseline) following dihydroartemisinin-piperaquine only, 100% (98·36-100; p=0·0005) following dihydroartemisinin-piperaquine plus tafenoquine 0·42 mg/kg, 100% (100-100; p=0·0001) following dihydroartemisinin-piperaquine plus tafenoquine 0·83 mg/kg, and 100% (100-100; p=0·0001) following dihydroartemisinin-piperaquine plus tafenoquine 1·66 mg/kg. 55 (69%) of 80 participants had a total of 94 adverse events over the course of the trial; 86 (92%) adverse events were categorised as mild, seven (7%) as moderate, and one (1%) as severe. The most common treatment-related adverse event was mild or moderate headache, which occurred in 15 (19%) participants (dihydroartemisinin-piperaquine n=2; dihydroartemisinin-piperaquine plus tafenoquine 0·42 mg/kg n=6; dihydroartemisinin-piperaquine plus tafenoquine 0·83 mg/kg n=3; and dihydroartemisinin-piperaquine plus tafenoquine 1·66 mg/kg n=4). No serious adverse events occurred. No significant differences in the incidence of all adverse events (p=0·73) or treatment-related adverse events (p=0·62) were observed between treatment groups. INTERPRETATION: Tafenoquine was well tolerated at all doses and accelerated P falciparum gametocyte clearance. All tafenoquine doses showed improved transmission reduction at day 7 compared with dihydroartemisinin-piperaquine alone. These data support the case for further research on tafenoquine as a transmission-blocking supplement to standard antimalarials. FUNDING: Bill & Melinda Gates Foundation. TRANSLATIONS: For the French, Portuguese, Spanish and Swahili translations of the abstract see Supplementary Materials section.

Impact of ultrasound scanning on pregnant Women's compliance with attendance at antenatal care visits and supervised delivery at primary healthcare centres in northern Nigeria: Initial experiences.

INTRODUCTION: The world health organisation (WHO) recommends at least one ultrasound scan amidst eight antenatal care visits, however, most pregnant women in low and middle-income countries do not achieve this. This study aims to assess the impact of limited obstetrics ultrasound (LOUS) within primary healthcare centres in northern Nigeria. METHODS: A cross sectional study was conducted across selected primary healthcare centres in Bauchi and Kano States (northern Nigeria). The study protocol was approved by the Ministry of Health in each State. Within each State a total of nine primary healthcare centres were randomly selected. Information on all complete antenatal care (ANC) records of women who used the primary healthcare facility for 12 months prior to introduction of ultrasound (January 2016 to December 2016) and 12 months after (January 2018 to December 2018) were collected. Study data were analysed using descriptive (mean, standard deviations) and inferential statistics. Independent sample t-test were used to find out if there was a statistical difference between the pre and post-intervention data on women compliance to ANC visits, facility based delivery, maternal and child mortality. Data were analysed using the Statistical Package for Social Sciences and significance was set at p ≤ 0.05. RESULTS: There was a significant increase in the number of ANC visits and supervised facility delivery after introduction of ultrasound services (LOUS) in the primary healthcare centres. The number of ANC visits in Kano State was 2637.6 ± 972.0 before and 3793.0 ± 517.5 after the introduction of ultrasound services. The number of ANC visits in Bauchi State was 1866.6 ± 488.3 before and 2854.0 ± 631.3 after the introduction of ultrasound services. The number of supervised facility deliveries in Kano state was 520.1 ± 128.7 before and 1021.1 ± 217.0 after the introduction of LOUS. The number of supervised facility deliveries for Bauchi state was 553.1 ± 309.9 before and 1056.3 ± 295.4 after introduction of LOUS. A total of 2486 (11.0%) women were referred for further imaging due to equivocal ultrasound findings. A total of 2185 (9.7%) pregnant women were referred for appropriate care due to multiple gestations. CONCLUSION: This study found that LOUS, in resource scarce settings, has the potential of improving ANC visits, facility delivery rates and reduce maternal and child mortality. It also leads to change in patient management plans resulting in referrals for appropriate care. IMPLICATION FOR PRACTICE: Technological interventions using ultrasound have the potential to motivate pregnant women to attend ANC, give birth in a healthcare facility and thus reduce maternal and child morbidity and mortality. This is in line with the global drive to reduce maternal and child death by 2030 to less than 70 maternal deaths in 100,000 live births and neonatal mortality reduction to 12 in 1000 live births and under 5 mortality reduction to 25 in 1000 live births.

Pyronaridine-artesunate or dihydroartemisinin-piperaquine combined with single low-dose primaquine to prevent Plasmodium falciparum malaria transmission in Ouélessébougou, Mali: a four-arm, single-blind, phase 2/3, randomised trial.

BACKGROUND: Pyronaridine-artesunate is the most recently licensed artemisinin-based combination therapy. WHO has recommended that a single low dose of primaquine could be added to artemisinin-based combination therapies to reduce Plasmodium falciparum transmission in areas aiming for elimination of malaria or areas facing artemisinin resistance. We aimed to determine the efficacy of pyronaridine-artesunate and dihydroartemisinin-piperaquine with and without single low-dose primaquine for reducing gametocyte density and transmission to mosquitoes. METHODS: We conducted a four-arm, single-blind, phase 2/3, randomised trial at the Ouélessébougou Clinical Research Unit of the Malaria Research and Training Centre of the University of Bamako (Bamako, Mali). Participants were aged 5-50 years, with asymptomatic P falciparum malaria mono-infection and gametocyte carriage on microscopy, haemoglobin density of 9·5 g/dL or higher, bodyweight less than 80 kg, and no use of antimalarial drugs over the past week. Participants were randomly assigned (1:1:1:1) to one of four treatment groups: pyronaridine-artesunate, pyronaridine-artesunate plus primaquine, dihydroartemisinin-piperaquine, or dihydroartemisinin-piperaquine plus primaquine. Treatment allocation was concealed to all study staff other than the trial pharmacist and treating physician. Dihydroartemisinin-piperaquine and pyronaridine-artesunate were administered as per manufacturer guidelines over 3 days; primaquine was administered as a single dose in oral solution according to bodyweight (0·25 mg/kg; in 1 kg bands). The primary endpoint was percentage reduction in mosquito infection rate (percentage of mosquitoes surviving to dissection that were infected with P falciparum) at 48 h after treatment compared with baseline (before treatment) in all treatment groups. Data were analysed per protocol. This trial is now complete, and is registered with ClinicalTrials.gov, NCT04049916. FINDINGS: Between Sept 10 and Nov 19, 2019, 1044 patients were assessed for eligibility and 100 were enrolled and randomly assigned to one of the four treatment groups (n=25 per group). Before treatment, 66 (66%) of 100 participants were infectious to mosquitoes, with a median of 15·8% (IQR 5·4-31·9) of mosquitoes becoming infected. In individuals who were infectious before treatment, the median percentage reduction in mosquito infection rate 48 h after treatment was 100·0% (IQR 100·0 to 100·0) for individuals treated with pyronaridine-artesunate plus primaquine (n=18; p<0·0001) and dihydroartemisinin-piperaquine plus primaquine (n=15; p=0·0001), compared with -8·7% (-54·8 to 93·2) with pyronaridine-artesunate (n=17; p=0·88) and 50·4% (13·8 to 70·9) with dihydroartemisinin-piperaquine (n=16; p=0·13). There were no serious adverse events, and there were no significant differences between treatment groups at any point in the frequency of any adverse events (Fisher's exact test p=0·96) or adverse events related to study drugs (p=0·64). The most common adverse events were headaches (40 events in 32 [32%] of 100 participants), rhinitis (31 events in 30 [30%]), and respiratory infection (20 events in 20 [20%]). INTERPRETATION: These data support the use of single low-dose primaquine as an effective supplement to dihydroartemisinin-piperaquine and pyronaridine-artesunate for blocking P falciparum transmission. The new pyronaridine-artesunate plus single low-dose primaquine combination is of immediate relevance to regions in which the containment of partial artemisinin and partner-drug resistance is a growing concern and in regions aiming to eliminate malaria. FUNDING: The Bill & Melinda Gates Foundation. TRANSLATIONS: For the French, Spanish and Swahilil translations of the abstract see Supplementary Materials section.

Renal doppler indices and their correlation with laboratory indices of human immunodeficiency virus sero-positive adult individuals.

INTRODUCTION: Renal Doppler resistive index (RI) and pulsatility index (PI) values are potentially more sensitive at detecting renal abnormalities when compared to standard laboratory indices in patients with HIV/AIDS. To the best of our knowledge, there are no published research articles on renal Doppler indices and their correlation with laboratory indices of HIV sero-positive adult individuals. This study aimed to assess the renal function of HIV-sero-positive adults using RI and PI, and correlating these indices against laboratory values. METHODS: A prospective cross-sectional study was conducted from July 2019 to April 2020. A purposive sampling method was employed and included 396 HIV sero-positive adult individuals. Sampling for the renal RI and PI was performed at the level of the inter-lober arteries, in between the medullary pyramids. An RI value above 0.70 and a PI value above 1.56 were consider abnormal. Serum creatine and urea together with evidence of proteinuria were recorded at the time of scanning. RESULTS: Forty-three (10.9%) men had an abnormal RI, 32 (8.1%) had abnormal PI, five (2.5%) had abnormal creatinine, two (1%) abnormal urea and eight (4.1%) with proteinuria. In women, 29 (7.3%) had abnormal RI, 22 (5.6%) abnormal PI, four (2%) abnormal creatinine and urea and six (3%) had proteinuria. There was a statistically significant weak positive correlation between RI and PI and serum creatinine and urea (r > 0.2, P < 0.05). CONCLUSION: The proportion of patients with abnormal RI and PI was higher than the proportion of participants with abnormal serum urea, creatinine and proteinuria. Renal Doppler indices could be used be used in the early assessment of renal function in HIV sero-positive adults individuals. IMPLICATIONS FOR PRACTICE: Serum creatinine and urea are routinely used to evaluate renal function in patients with HIV/AIDS. Findings from this initial study show that RI and PI could be used detecting early renal abnormalities when compared to standard laboratory values.

Effect of 4 years of seasonal malaria chemoprevention on the acquisition of antibodies to Plasmodium falciparum antigens in Ouelessebougou, Mali.

BACKGROUND: More than 200 million people live in areas of highly seasonal malaria transmission where Seasonal Malaria Chemoprevention (SMC) with sulfadoxine-pyrimethamine (SP) and amodiaquine (AQ) was recommended in 2012 by WHO. This strategy is now implemented widely and protected more than 19 million children in 2018. It was previously reported that exposure to SMC reduced antibody levels to AMA1, MSP-142 and CSP, but the duration of exposure to SMC up to three 3 years, had no effect on antibody levels to MSP-142 and CSP. METHODS: In 2017, a cross-sectional survey was carried out 1 month after the last dose of SMC had been given to children aged 4-5 years randomly selected from areas where SMC had been given for 2 or 4 years during the malaria transmission season. A total of 461 children were enrolled, 242 children in areas where SMC had been implemented for 4 years and 219 children in areas where SMC had been implemented for 2 years. Antibody extracted from dry blood spots was used to measure IgG levels to the malaria antigens CSP, MSP-142 and AMA1 by ELISA. RESULTS: The prevalence of antibodies to MSP-142 was similar in children who had received SMC for 4 years compared to those who had received SMC for only 2 years (85.1 vs 86.0%, ajusted odd ratio (aOR) = 1.06, 95% confidence intervals (CI 0.62-1.80), p = 0.80). The prevalence of antibodies to AMA-1 and to CSP was not lower in children who received SMC for 4 years compared to those who had received SMC for only 2 years (95.3 vs 88.8%, aOR = 3.16, 95% CI 1.44-6.95, p = 0.004 for AMA-1; and 91.2 vs 81.9%, aOR = 3.14, 95% CI 1.70-5.76, p < 0.001 for CSP). Median antibody levels for anti-MSP-142 IgG were not significatively inferior in children who had received SMC for four rather than 2 years (0.88 (IQR: 0.64-1.15) and 0.95 ((0.68-1.15), respectively), anti-CSP (1.30 (1.00-1.56) and 1.17 (0.87-1.47)), and anti-AMA-1 (1.45 (1.24-1.68) and 1.41 (1.17-1.64)). CONCLUSION: In an area of high seasonal malaria transmission, children who had received SMC for 4 years did not had lower seropositivity or antibody levels to AMA1, MSP-142 and CSP compared to children who had received SMC for only 2 years suggesting that children who have received SMC for 4 years may not be more at risk of malaria after the cessation of SMC than children who have received SMC for a shorter period.

Clinical indication-based diagnostic reference levels for paediatric head computed tomography examinations in Kano Metropolis, northwestern Nigeria.

INTRODUCTION: Paediatric patients are recognised to be at higher risk of developing radiation-induced cancer than adults because of rapidly growing organs and tissues which are vulnerable to cellular damage. The aim of the study was to determine indication based Diagnostic Reference Levels (DRLCI) for paediatric head computed tomography (CT) examinations within Kano metropolis, Nigeria. METHODS: CT dose index (CTDIvol), dose length product (DLP) and other scan parameters were recorded for 113 paediatric undergoing CT head examinations. Different clinical indications were recorded and categorised in addition to patient age. Third quartile values (75th percentile) of the median dose were considered as DRLCI. Analysis of Variance (ANOVA) was used to test for differences between DRLCI, for different age groups, and variations among institutions. The Statistical Package for Social Sciences version 23.0 was used for analysis. Statistical significance was set at p < 0.05. RESULTS: DRLCI for Hydrocephalus for <5 years and 5-10 years was 28.10 mGy and 28.11 mGy with DLP of 1623.20 mGy cm and 1623.21 mGy cm, respectively. The 11-15 year group recorded 29.10 mGy and 1625.20 mGy cm. Indications of haemorrhage/trauma and post-seizure imaging all had same values for <5 years and 5-10 years (28.10 mGy and 1623.20 mGy cm) while the 11 to 15-year group recorded 39.60 mGy and 1626 mGy cm. Intracranial Space Occupying lesion had the same DRLCI value for < 5years and 5-10 years (29.0 mGy and 1600 mGy cm, respectively) the 11 to 15-year group recorded values of 46.20 mGy and 1663.4 mGy cm. There was no statistically significant difference between DRLCI for <5 years and 5 to 10-year age groups (p = 0.199), while different centres showed some statistically significant relationships (p = 0.02). CONCLUSION: The study noted dose differences between age groups less than 10 years and above ten years, there were some statistically significant relationship with DRLCI. Dose optimisation techniques for paediatric examinations together with selection of the right protocol for paediatric head CT are necessary. IMPLICATIONS FOR PRACTICE: The study has provided DRLCI for paediatric head CT examinations. These values can be used for future comparisons and as a potential dose optimisation tool. Such data can also guide radiographers when selecting appropriate parameters for indication-based CT examination to help achieve a low dose with acceptable image quality.

Hb Moscva [ß24(B6)Gly→Asp (GGT>GAT), HBB: c.74G>A]: An Unstable Hemoglobin Newly Detected as a De Novo Mutation in a Mauritanian Patient.

Unstable hemoglobins (Hbs) are a group of Hb disorders that could be the origin of chronic hemolytic anemia. Most of these disorders are caused by point mutations taking place in the globin genes and affecting the stability of the Hb molecule. They are inherited as autosomal dominant diseases and described worldwide. Herein we report a new observation of an unstable variant in the Mauritanian population. The patient was a young girl of Mauritanian origin. She presented with chronic hemolytic anemia with an unknown etiology after being referred to several medical centers. Laboratory investigations based on routine analyses, capillary electrophoresis (CE), cation exchange high performance liquid chromatography (HPLC) and DNA sequencing revealed an abnormal unstable Hb known as Hb Moscva [ß24(B6)Gly→Asp (GGT>GAT), HBB: c.74G>A] that occurred as a de novo mutation newly detected in an African girl of Mauritanian origin.

HLA class I (-A, -B, -C) and class II (-DR, -DQ) polymorphism in the Mauritanian population.

BACKGROUND: HLA antigens have been widely studied for their role in transplantation biology, human diseases and population diversity. The aim of this study was to provide the first profile of HLA class I and class II alleles in the Mauritanian population. METHODS: HLA typing was carried in 93 healthy Mauritanian blood donors, using single specific primer amplification (PCR-SSP). RESULTS: Occurrences of the main HLA class I (-A, -B, -C) and class II (-DR, -DQ) antigens in the general population showed that out of the 17 HLA-A allele groups detected, five main HLA-A allele groups: A*02 (18.42%), A*01 (14.04%), A*23 (14.04%), A*30 (13.16%) and A*29 (12.28%) were the most common identified along other 12 relatively minor allele groups. Twenty three allele groups were observed in the locus B of which B*07 (13.46%) was the most prevalent followed by B*15, B*35, B*08 and B*27 all, with a frequency between 7 to 8%. Three prevalent HLA-C allele groups (C*02: 35.09%, C*07: 20.19% and C*06: 13.6%) were detected. The main HLA class II observed allele groups were: DRB1*13 (27.42%), DRB1*03 (24.73%), DRB1*11 (13.98%), DQB1*03 (36.03%), DQB1*02 (22.06%) and DQB1*05 (18.8%). Except for few haplotype in class I (A*02-B*07: 4.45%, A*02-C02: 10%, A*23-C*02: 8.8%, B*07-C*02: 8.8%, B*15-C*02: 8.8%) and in class II (DRB1*13-DQB1*06: 11.94%, DRB1*03-DQB1*02:11.19% and DRB1*03-DQB1*03: 10.45%), the majority of locus combination were in the range of 2-3%. A single predominant haplotype C*02-DRB1*03 (16.67%) was found. CONCLUSIONS: These results, in agreement with previous data using different tissues markers, underlined the ethnic heterogeneity of the Mauritanian population.

Double-hybrid density-functional theory with meta-generalized-gradient approximations.

We extend the previously proposed one-parameter double-hybrid density-functional theory [K. Sharkas, J. Toulouse, and A. Savin, J. Chem. Phys. 134, 064113 (2011)] to meta-generalized-gradient-approximation (meta-GGA) exchange-correlation density functionals. We construct several variants of one-parameter double-hybrid approximations using the Tao-Perdew-Staroverov-Scuseria (TPSS) meta-GGA functional and test them on test sets of atomization energies and reaction barrier heights. The most accurate variant uses the uniform coordinate scaling of the density and of the kinetic energy density in the correlation functional, and improves over both standard Kohn-Sham TPSS and second-order Møller-Plesset calculations.

Hb S [ß6(A3)Glu→Val, GAG>GTG] and ß-globin gene cluster haplotype distribution in Mauritania.

Of 1050 Mauritanian blood donors screened from the two main racial groups, i.e., the Moors and Black Africans, 60 were found to carry Hb S [ß6(A3)Glu→Val, GAG>GTG], giving a global frequency of 5.71%. The prevalence observed in the Black African Mauritanians (10.69%) is almost five times that found in the Moor group (2.25%). Four of the five main ß(S) haplotypes were detected in this study: Senegal (77.8%), Benin (8.8%), Arab-Indian (5.5%) and Bantu (4.4%). These data showed that Hb S is a serious public health problem in Mauritania. They also confirm the ethnic heterogeneity of the Mauritanian population.

A novel strategy for evaluating the effects of an electronic test ordering alert message: Optimizing cardiac marker use.

BACKGROUND: Laboratory ordering functions within computerized provider order entry (CPOE) systems typically support the display of electronic alert messages to improve test utilization or implement new ordering policies. However, alert strategies have been shown to vary considerably in their success and the characteristics contributing to an alert's success are poorly understood. Improved methodologies are needed to evaluate alerts and their mechanisms of action. MATERIALS AND METHODS: Clinicians order inpatient and emergency department laboratory tests using our institutional CPOE system. We analyzed user interaction data captured by our CPOE system to evaluate how clinicians responded to an alert. We evaluated an alert designed to implement an institutional policy restricting the indications for ordering creatine kinase-MB (CKMB). RESULTS: Within 2 months of alert implementation, CKMB-associated searches declined by 79% with a corresponding decline in CKMB orders. Furthermore, while prior to alert implementation, clinicians searching for CKMB ultimately ordered this test 99% of the time, following implementation, only 60% of CKMB searches ultimately led to CKMB test orders. This difference presumably represents clinicians who reconsidered the need for CKMB in response to the alert, demonstrating the alert's just-in-time advisory capability. In addition, as clinicians repeatedly viewed the alert, there was a "dose-dependant" decrease in the fraction of searches without orders. This presumably reflects the alerting strategy's long-term educational component, as clinicians aware of the new policy will not search for CKMB when not indicated. CONCLUSIONS: Our analytic approach provides insight into the mechanism of a CPOE alert and demonstrates that alerts may act through a combination of just-in-time advice and longer term education. Use of this approach when implementing alerts may prove useful to improve the success of a given alerting strategy.

Radioprotective effect of American ginseng on human lymphocytes at 90 minutes postirradiation: a study of 40 cases.

BACKGROUND: Ionizing radiation (IR) initiates intracellular oxidative stress through enhanced formation of reactive oxygen species (ROS) that attack DNA leading to cell death. Because of the diversity of IR applied in medicine, agriculture, industry, and the growing threats of global terrorism, the acquisition of radioprotectors is an urgent need for the nation. However, the applicability of radioprotectors currently under investigation is limited due to their inherent toxicity. OBJECTIVE: This study investigated the effect of a standardized North American ginseng extract (NAGE, total ginsenoside content: 11.7%) on DNA damage in human lymphocytes at 90 minutes postirradiation. DESIGN: With the application of NAGE (250-1000 microg mL(-1)) at 90 minutes postirradiation (1 and 2 Gy), DNA damage in lymphocytes obtained from 40 healthy individuals was evaluated by cytokinesis-block micronucleus assay. Similar experiments were also performed in lymphocytes treated with WR-1065 (1 mmol/L or 3 mmol/L). In addition, before and after irradiation, lymphocytes obtained from 10 individuals were measured for their total antioxidant capacity (TAC) and the reactive oxygen species (ROS). RESULTS: The significant effect of NAGE against (137)Cs-induced micronuclei (MN) in lymphocytes is concentration dependent. NAGE (750 microg mL(-1)) reduced MN yield by 50.7% after 1 Gy and 35.9% after 2 Gy exposures, respectively; these results were comparable to that of WR-1065. Furthermore, we also found that NAGE reduces MN yield and ROS but increases TAC in lymphocytes. CONCLUSIONS: Our results suggest that NAGE is a relatively nontoxic natural compound that holds radioprotective potential in human lymphocytes even when applied at 90 minutes postirradiation. One of the radioprotective mechanisms may be mediated through the scavenging of free radicals and enhancement of the intracellular TAC.

A novel class of laboratory middleware. Promoting information flow and improving computerized provider order entry.

A central duty of the laboratory is to inform clinicians about the availability and usefulness of laboratory testing. In this report, we describe a new class of laboratory middleware that connects the traditional clinical laboratory information system with the rest of the enterprise, facilitating information flow about testing services. We demonstrate the value of this approach in efficiently supporting an inpatient order entry application. We also show that order entry monitoring and iterative middleware updates can enhance ordering efficiency and promote improved ordering practices. Furthermore, we demonstrate the value of algorithmic approaches to improve the accuracy and completeness of laboratory test searches. We conclude with a discussion of design recommendations for middleware applications and discuss the potential role of middleware as a sharable, centralized repository of laboratory test information.

Load elongation behavior of the canine anterior cruciate ligament.

This paper describes the results of an investigation on the mechanical properties of canine anterior cruciate ligaments. A total of 38 ligaments were tested. It is shown that the completely reversible (elastic) range of strain is limited to 14 percent elongation, corresponding to an applied load of 200 N. Within this range each specimen was tested at different strain rates varying from 0.12 percent/s to 220 percent/s and it is demonstrated that the mechanical behavior of the ligaments is not sensitive to strain rate in the range investigated. After completion of tests in the reversible range, of strain ten ligaments were frozen and similar tests were performed after thawing. It is shown that freezing produces alterations of the mechanical properties. The ligaments become more rigid than when they are tested in fresh conditions. From room temperature up to 45C, the load-elongation relationship is not significantly dependent upon test temperature.