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Background Follow-up for 28–42 days is recommended by the World Health Organization to assess antimalarial drug efficacy for nonpregnant populations. This study aimed to determine the optimal duration for pregnant women, as no specific guidance currently exists. Methods The distributions of time to recrudescence (treatment failure), confirmed by polymerase chain reaction genotyping for different antimalarial drugs in pregnancy, were analyzed by accelerated failure time models using secondary data on microscopically confirmed recurrent falciparum malaria collected in prospective studies on the Thailand–Myanmar border between 1994 and 2010. Results Of 946 paired isolates from 703 women, the median duration of follow-up for each genotyped recurrence (interquartile range) was 129 (83–174) days, with 429 polymerase chain reaction–confirmed recrudescent. Five different treatments were evaluated, and 382 Plasmodium falciparum recrudescences were identified as eligible. With log-logistic models adjusted for baseline parasitemia, the predicted cumulative proportions of all the recrudescences that were detected by 28 days were 70% (95% confidence interval [CI], 65%–74%) for quinine monotherapy (n = 295), 66% (95% CI, 53%–76%) for artesunate monotherapy (n = 43), 62% (95% CI, 42%–79%) for artemether–lumefantrine (AL; n = 19), 46% (95% CI, 26%–67%) for artesunate with clindamycin (n = 19), and 34% (95% CI, 11%–67%) for dihydroartemisinin–piperaquine (DP; n = 6). Corresponding figures by day 42 were 89% (95% CI, 77%–95%) for AL and 71% (95% CI, 38%–91%) for DP. Follow-up for 63 days was predicted to detect ≥95% of all recrudescence, except for DP. Conclusions In low-transmission settings, antimalarial drug efficacy assessments in pregnancy require longer follow-up than for nonpregnant populations.

Objective Dizziness is associated with hypertension but there are numerous other causes. The aims of the present study were to describe the characteristics and the clinical correlates of dizziness in a large cohort of hypertensive patients, and to test its prognostic value for all-cause, cardiovascular, and stroke mortality. Methods A total of 1716 individuals from the OLD-HTA Lyon's cohort of hypertensive patients recruited in the 1970s were categorized according to the absence or the presence of dizziness. The dizziness group was subdivided into vertigo and other dizziness excluding vertigo. Results Multiple regression analysis demonstrated that presence of dizziness was predicted by age, female sex, coronary artery disease, and the absence of microalbuminuria. During 30 years of follow-up, we observed 956 deaths, 508 of which with a cardiovascular cause, and 114 fatal acute strokes. In the multivariate Cox regression model, the presence of dizziness had no impact on the risk for all-cause mortality [hazard ratio 0.91; 95% CI (0.78-1.06)], cardiovascular mortality [hazard ratio 0.86; 95% CI (0.70-1.05)], or stroke mortality [hazard ratio 1.27; 95% CI (0.85-1.90)]. In an analysis of the different subgroups of dizziness, only vertigo had a prognostic impact. The increased risk was particularly marked on stroke death with a hazard ratio of 2.43 (95% CI 1.33-4.46) vs. patients without dizziness and 2.22 (95% CI 1.21-4.06) vs. patients with dizziness excluding vertigo. Conclusion Hypertensive patients with dizziness did not have a high-risk profile at baseline, but those with vertigo must be carefully followed over years because of the higher stroke mortality.

Background Plasmodium falciparum infections with slow parasite clearance following artemisinin-based therapies are widespread in the Greater Mekong Subregion. A molecular marker of the slow clearance phenotype has been identified: single genetic changes within the propeller region of the Kelch13 protein (pfk13; Pf3D7_1343700). Global searches have identified almost 200 different non-synonymous mutant pfk13 genotypes. Most mutations occur at low prevalence and have uncertain functional significance. To characterize the impact of different pfk13 mutations on parasite clearance, we conducted an individual patient data meta-analysis of the associations between parasite clearance half-life (PC1/2) and pfk13 genotype based on a large set of individual patient records from Asia and Africa. Methods A systematic literature review following the PRISMA protocol was conducted to identify studies published between 2000 and 2017 which included frequent parasite counts and pfk13 genotyping. Four databases (Ovid Medline, PubMed, Ovid Embase, and Web of Science Core Collection) were searched. Eighteen studies (15 from Asia, 2 from Africa, and one multicenter study with sites on both continents) met inclusion criteria and were shared. Associations between the log transformed PC1/2 values and pfk13 genotype were assessed using multivariable regression models with random effects for study site. Results Both the pfk13 genotypes and the PC1/2 were available from 3250 (95%) patients (n = 3012 from Asia (93%), n = 238 from Africa (7%)). Among Asian isolates, all pfk13 propeller region mutant alleles observed in five or more specific isolates were associated with a 1.5- to 2.7-fold longer geometric mean PC1/2 compared to the PC1/2 of wild type isolates (all p ≤ 0.002). In addition, mutant allele E252Q located in the P. falciparum region of pfk13 was associated with 1.5-fold (95%CI 1.4–1.6) longer PC1/2. None of the isolates from four countries in Africa showed a significant difference between the PC1/2 of parasites with or without pfk13 propeller region mutations. Previously, the association of six pfk13 propeller mutant alleles with delayed parasite clearance had been confirmed. This analysis demonstrates that 15 additional pfk13 alleles are associated strongly with the slow-clearing phenotype in Southeast Asia. Conclusion Pooled analysis associated 20 pfk13 propeller region mutant alleles with the slow clearance phenotype, including 15 mutations not confirmed previously.

Background Considering the uncertainty of safety of anti-malarial drugs in pregnancy, efficacy studies are one of the few sources of clinical safety data. Complete safety evaluation is not usually incorporated in efficacy studies due to financial and human resource constraints. This review reports the methods used for the assessment of safety of artemisinin-based and quinine-based treatments in efficacy studies in pregnancy. Methods Methodology of assessment and reporting of safety in efficacy studies of artemisinin-based and quinine-based treatment in pregnancy was reviewed using seven databases and two clinical trial registries. The protocol was registered to PROSPERO (CRD42017054808). Results Of 48 eligible efficacy studies the method of estimation of gestational age was reported in only 32 studies (67%, 32/48) and ultrasound was used in 18 studies (38%, 18/48). Seventeen studies (35%, 17/48) reported parity, 9 (19%, 9/48) reported gravidity and 13 (27%, 13/48) reported both. Thirty-eight studies (79%, 38/48) followed participants through to pregnancy outcome. Fetal loss was assessed in 34 studies (89%, 34/38), but the definition of miscarriage and stillbirth were defined only in 11 (32%, 11/34) and 7 (21%, 7/34) studies, respectively. Preterm birth was assessed in 26 studies (68%, 26/38) but was defined in 16 studies (62%, 16/26). Newborn weight was assessed in 30 studies (79%, 30/38) and length in 10 studies (26%, 10/38). Assessment of birth weight took gestational age into account in four studies (13%, 4/30). Congenital abnormalities were reported in 32 studies (84%, 32/38). Other common risk factors for adverse pregnancy outcomes were not well-reported. Conclusion Incomplete reporting and varied methodological assessment of pregnancy outcomes in anti-malarial drug efficacy studies limits comparison across studies. A standard list of minimal necessary parameters to assess and report the safety component of efficacy studies of anti-malarials in pregnancy is proposed. Electronic supplementary material The online version of this article (10.1186/s12936-017-2136-x) contains supplementary material, which is available to authorized users.

National audience; BACKGROUND:The aim of this study was to describe a tool based on vaccine sales to estimate vaccination coverage against seasonal influenza in near real-time in the French population aged 65 and over.METHODS:Vaccine sales data available on sale-day +1 came from a stratified sample of 3004 pharmacies in metropolitan France. Vaccination coverage rates were estimated between 2009 and 2014 and compared with those obtained based on vaccination refund data from the general health insurance scheme.RESULTS:The seasonal vaccination coverage estimates were highly correlated with those obtained from refund data. They were also slightly higher, which can be explained by the inclusion of non-reimbursed vaccines and the consideration of all individuals aged 65 and over. We have developed an online tool that provides estimates of daily vaccination coverage during each vaccination campaign.CONCLUSION:The developed tool provides a reliable and near real-time estimation of vaccination coverage among people aged 65 and over. It can be used to evaluate and adjust public health messages.; Position du problèmeL’objectif de cette étude est de décrire un outil permettant d’estimer en quasi-temps réel la couverture vaccinale contre la grippe saisonnière chez les 65 ans et plus à partir des ventes de vaccins en pharmacie.MéthodesLes données de ventes de vaccins proviennent d’un échantillon stratifié de 3004 pharmacies en France métropolitaine et sont disponibles le jour suivant les ventes. Les couvertures vaccinales estimées entre 2009 et 2014 ont été comparées avec celles obtenues à partir des données de remboursements aux affiliés du Régime général.RésultatsLes couvertures vaccinales saisonnières estimées sont très corrélées à celles obtenues avec les données de remboursements. Elles sont aussi légèrement supérieures, ce qui peut s’expliquer par l’inclusion de vaccins non remboursés et la prise en compte de l’ensemble des 65 ans et plus, tous régimes confondus. Nous avons développé un outil accessible en ligne permettant d’accéder quotidiennement à une estimation de la couverture vaccinale des 65 ans et plus lors de chaque campagne de vaccination.ConclusionL’outil développé permet de fournir une information fiable et en quasi-temps réel sur la couverture vaccinale des 65 ans et plus. Il peut être utilisé pour évaluer et ajuster les messages de santé publique.

BACKGROUND: Altered sensitivity to multiple antimalarial drugs is mediated by polymorphisms in pfmdr1, which encodes the Plasmodium falciparum multidrug resistance transporter. In Africa the N86Y and D1246Y polymorphisms have been shown to be selected by treatment, with artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP) selecting for wild-type and mutant alleles, respectively. However, there has been little study of pfmdr1 haplotypes, in part because haplotype analyses are complicated by multiclonal infections. METHODS: We fit a haplotype frequency estimation model, which accounts for multiclonal infections, to the polymorphic pfmdr1 N86Y, Y184F, and D1246Y alleles in samples from a longitudinal trial comparing AL and DP to treat uncomplicated P falciparum malaria in Tororo, Uganda from 2007 to 2012. We regressed estimates onto covariates of trial arm and selective drug pressure. RESULTS: Yearly trends showed increasing frequency estimates for haplotypes with wild type pfmdr1 N86 and D1246 alleles and decreasing frequency estimates for haplotypes with the mutant pfmdr1 86Y allele. Considering days since prior therapy, we saw evidence suggestive of selection by AL for haplotypes with N86 combined with 184F, D1246, or both, and against all haplotypes with 86Y, and evidence suggestive of selection by DP for 86Y only when combined with Y184 and 1246Y (haplotype YYY) and against haplotypes NFD and NYY. CONCLUSIONS: Based on our model, AL selected several haplotypes containing N86, whereas DP selection was haplotype specific, demonstrating the importance of haplotype analyses. Inverse selective pressure of AL and DP on the complementary haplotypes NFD and YYY suggests that rotating artemisinin-based antimalarial combination regimens may be the best treatment option to prevent resistance selection.

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IntroductionThere are growing concerns about the emergence of resistance to artemisinin-based combination therapies (ACTs). Since the widespread adoption of ACTs, there has been a decrease in the systematic surveillance of antimalarial drug resistance in many malaria-endemic countries. The aim of this work was to test whether data on travellers returning from Africa with malaria could serve as an additional surveillance system of local information sources for the emergence of drug resistance in endemic-countries.MethodologyData were collected from travellers with symptomatic Plasmodium falciparum malaria returning from Senegal (n = 1,993), Mali (n = 2,372), Cote d'Ivoire (n = 4,778) or Cameroon (n = 3,272) and recorded in the French Malaria Reference Centre during the period 1996-2011. Temporal trends of the proportion of parasite isolates that carried the mutant genotype, pfcrt 76T, a marker of resistance to chloroquine (CQ) and pfdhfr 108N, a marker of resistance to pyrimethamine, were compared for travellers and within-country surveys that were identified through a literature review in PubMed. The in vitro response to CQ was also compared between these two groups for parasites from Senegal.ResultsThe trends in the proportion of parasites that carried pfcrt 76T, and pfdhfr 108N, were compared for parasites from travellers and patients within-country using the slopes of the curves over time; no significant differences in the trends were found for any of the 4 countries. These results were supported by in vitro analysis of parasites from the field in Senegal and travellers returning to France, where the trends were also not significantly different.ConclusionThe results have not shown different trends in resistance between parasites derived from travellers or from parasites within-country. This work highlights the value of an international database of drug responses in travellers as an additional tool to assess the emergence of drug resistance in endemic areas where information is limited.

Nowadays, the development of cloning and ICSI (Intracytoplasmic Sperm Injection) techniques associated with the diversification of cryopreservation methods of the animal genetic resources require to focus on the quality of oocytes used. However, the oocyte viability is very difficult to assess and, contrary to the embryos, can’t be limited to the single morphological evaluation. The aim of this paper was to present the state of the art of the different existing approaches to evaluate the quality of rabbit mature oocytes after ovulation (MII stage). It was underlined that the viability of MII oocytes has been few studied in rabbit species. Experiments made in other species show that we are unable to assess oocytes quality with a single and unique tool and that this evaluation requires the combined use of several morphological, structural and metabolic criteria., Aujourd’hui, le développement des techniques de clonage et d’ICSI (Intracytoplasmic Sperm Injection) ainsi que la diversification des voies de cryoconservation des ressources génétiques chez le lapin nécessitent de s’intéresser d’une manière plus précise à la qualité des ovocytes utilisés. La viabilité de l’ovocyte est délicate à évaluer et, contrairement à l’embryon, ne peut se cantonner à la seule évaluation morphologique. L’objectif de ce papier est de faire un état des lieux des différentes approches existantes pour évaluer la qualité des ovocytes ovulés, matures (stade MII) chez la lapine. Il a été mis en évidence qu’il existe actuellement peu de travaux sur l’évaluation de la qualité ovocytaire chez la lapine. Les études menées chez les autres espèces montrent qu’aucun outil ne peut prédire à lui seul la qualité de l’ovocyte et que son appréciation passe obligatoirement par l’utilisation combinée de plusieurs critères morphologiques, structuraux et métaboliques.

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In patients successfully operated for coarctation of the aorta, the prevalence of hypertension is higher than that observed in the general population although the exact mechanism is not known. The hypothesis of increased arterial rigidity despite satisfactory correction of the coarctation has been proposed. The authors undertook 24 hour ambulatory blood pressure monitoring coupled with measurement of the QKD interval (pulse wave velocity) in order to evaluate the rigidity of the large arteries. These results were compared with those obtained in control patients paired with respect to gender, age, height and weight. Twenty-six patients with an average age of 14.5 +/- 2.9 years were included (age at time of surgery 6.3 +/- 3.7 years). The statistical data confirmed a higher systolic blood pressure (p0.05) in the operated patients compared with controls. The results confirm the hypothesis of increased residual arterial rigidity in children operated for coarctation of the aorta which could predispose to secondary hypertension, especially on effort. In the long term, this could be an unquestionable cardiovascular risk factor explaining the increased cardiovascular morbid-mortality compared with the general population.

COVID-19 has put each and every one at test. Cardiological clinics are facing constrained resources, limiting timely treatment of patients as usual. Patients with valvular heart disease are one of the most time sensitive patient populations, with delayed therapy possible leading to increased morbidity and mortality. Identifying and allocating the available resources to the most vulnerable patients is crucial in providing optimal patient care with prioritization of essential surgical or percutaneous procedures for valvular heart disease. Implementing telemedicine approaches might help to minimize non-essential physician-to-patient contact to ensure safety, for both patients and lastly but not least the treating physicians.

Pregnant women are particularly susceptible to malaria, which is the leading cause of mortality and morbidity of the mother and fetus in the tropics. The current World Health Organization (WHO) recommended study design for assessing antimalarial efficacy excludes pregnant women, which has resulted in fewer studies on treatment efficacy and greater variability of study designs in pregnant women. Based on limited evidence, WHO has recommended quinine (with clindamycin, if available) for first-trimester and artemisinin-based combination therapy (ACT) for second- and third-trimester women since 2015. The data on the safety of artemisinin-derivatives in the first trimester have been collected, mostly from inadvertent treatments, over two decades, and form reassuring evidence of safety, strikingly different to animal-based reproductive health studies. This thesis aims to summarize the evidence on the efficacy of antimalarials for uncomplicated falciparum malaria in pregnancy and to improve future research in tropical infectious diseases in pregnancy. Secondary data from prospective studies that assessed antimalarial efficacy by polymerase chain reaction were sought. Individual patient data of 4968 pregnant women (92% of all published work) from 19 studies in ten countries were pooled in a standardized format and analysed. These confirmed that quinine is less effective and less tolerable than ACTs. Quinine is also less suitable for elimination because of a higher risk of gametocyte development. Among ACTs, artemether-lumefantrine (AL) showed a slightly lower efficacy. In the second and third trimesters, the risks of congenital abnormality, miscarriage, stillbirth, preterm birth and small-for-gestational-age were similar among the four major ACTs (namely, AL, artesunate-amodiaquine, artesunate-mefloquine and dihydroartemisinin-piperaquine). Study designs need to be tailored for pregnant women. It is probably necessary to follow up pregnant women for longer to assess efficacy accurately, but proof can only be obtained by including them alongside non-pregnant reproductive-age women. To assess pregnancy outcomes, precise and reliable estimates of gestational age and longitudinal recording of repetitive malaria episodes through to delivery are essential. Quinine monotherapy should be replaced with ACTs for treating uncomplicated Plasmodium falciparum malaria in pregnant women. For AL, the most commonly used compound, dose optimization studies are needed. Investigations to find safe and effective drugs for pregnant women should be continued as every effort to prevent and reduce recurrence contributes to health of the mother and fetus.

Data Management (DM) is a critical, yet often neglected step of research studies, essential to guarantee the integrity of data and validity of conclusions derived from it. To enable meaningful data use (and re-use), investigators and their institutes must therefore be equipped with appropriate DM capacity. Little empirical research so far has explored DM practices in clinical research or the barriers and enablers of their implementation, especially in Low and Middle Income Countries (LMICs). Using a mixed-methods design, this thesis addresses this important and timely gap. A systematic review and meta-analysis of schistosomiasis treatment efficacy studies first demonstrates the pitfalls of aggregated data for re-use, and uncovers varied data management and analysis practices within this research community. The case of schistosomiasis (a neglected, under-researched tropical disease) is contrasted with that of malaria. Through its well-established data-sharing platform, the World- Wide Antimalarial Resistance Network (WWARN) enables an in-depth exploration of datasets and accompanying study documentation from 108 antimalarial trials performed in Africa. This exploratory analysis shows that DM capacity development needs particularly concern comprehensive annotation and transparent handling of study datasets. Two qualitative case studies in Dakar, Senegal and Brazzaville, Republic of the Congo complement this systematic description of DM across Africa. Through indepth interviews and observations of local practices, I examine clinical research staff's knowledge, attitudes, experiences and perceptions of DM, as well as the constraints within which they operate DM systems (DMS). Findings confirm that robust DMS depend on adequate financing and strong infrastructure, but also on an overall enabling environment where the importance of DM is recognised. Results from this work highlight priority areas for clinical research DM capacity strengthening in LMICs, emphasising the necessity to raise awareness of DM's complexity and to establish DM as a valued professional role.

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