Safety and efficacy of a three-dose regimen of Plasmodium falciparum sporozoite vaccine in adults during an intense malaria transmission season in Mali: a randomised, controlled phase 1 trial.

BACKGROUND: WHO recently approved a partially effective vaccine that reduces clinical malaria in children, but increased vaccine activity is required to pursue malaria elimination. A phase 1 clinical trial was done in Mali, west Africa, to assess the safety, immunogenicity, and protective efficacy of a three-dose regimen of Plasmodium falciparum sporozoite (PfSPZ) Vaccine (a metabolically active, non-replicating, whole malaria sporozoite vaccine) against homologous controlled human malaria infection (CHMI) and natural P falciparum infection. METHODS: We recruited healthy non-pregnant adults aged 18-50 years in Donéguébougou, Mali, and surrounding villages (Banambani, Toubana, Torodo, Sirababougou, Zorokoro) for an open-label, dose-escalation pilot study and, thereafter, a randomised, double-blind, placebo-controlled main trial. Pilot study participants were enrolled on an as-available basis to one group of CHMI infectivity controls and three staggered vaccine groups receiving: one dose of 4·5 × 105, one dose of 9 × 105, or three doses of 1·8 × 106 PfSPZ via direct venous inoculation at approximately 8 week intervals, followed by homologous CHMI 5 weeks later with infectious PfSPZ by direct venous inoculation (PfSPZ Challenge). Main cohort participants were stratified by village and randomly assigned (1:1) to receive three doses of 1·8 × 106 PfSPZ or normal saline at 1, 13, and 19 week intervals using permuted block design by the study statistician. The primary outcome was safety and tolerability of at least one vaccine dose; the secondary outcome was vaccine efficacy against homologous PfSPZ CHMI (pilot study) or against naturally transmitted P falciparum infection (main study) measured by thick blood smear. Combined artesunate and amodiaquine was administered to eliminate pre-existing parasitaemia. Outcomes were analysed by modified intention to treat (mITT; including all participants who received at least one dose of investigational product; safety and vaccine efficacy) and per protocol (vaccine efficacy). This trial is registered with ClinicalTrials.gov, number NCT02627456. FINDINGS: Between Dec 20, 2015, and April 30, 2016, we enrolled 56 participants into the pilot study (five received the 4·5 × 105 dose, five received 9 × 105, 30 received 1·8 × 106, 15 were CHMI controls, and one withdrew before vaccination) and 120 participants into the main study cohort with 60 participants assigned PfSPZ Vaccine and 60 placebo in the main study. Adverse events and laboratory abnormalities post-vaccination in all dosing groups were few, mainly mild, and did not differ significantly between vaccine groups (all p>0·05). Unexpected severe transaminitis occured in four participants: one participant in pilot phase that received 1·8 × 106 PfSPZ Vaccine, one participant in main phase that received 1·8 × 106 PfSPZ Vaccine, and two participants in the main phase placebo group. During PfSPZ CHMI, approximately 5 weeks after the third dose of 1·8 × 106 PfSPZ, none of 29 vaccinees and one of 15 controls became positive on thick blood smear; subsequent post-hoc PCR analysis for submicroscopic blood stage infections detected P falciparum parasites in none of the 29 vaccine recipients and eight of 15 controls during CHMI. In the main trial, 32 (58%) of 55 vaccine recipients and 42 (78%) of 54 controls became positive on thick blood smear during 24-week surveillance after vaccination. Vaccine efficacy (1-hazard ratio) was 0·51 per protocol (95% CI 0·20-0·70; log-rank p=0·0042) and 0·39 by mITT (0·04-0·62; p=0·033); vaccine efficacy (1-risk ratio) was 0·24 per-protocol (0·02-0·41; p=0·031) and 0·22 mITT (0·01-0·39; p=0·041). INTERPRETATION: A three-dose regimen of PfSPZ Vaccine was safe, well tolerated, and conferred 51% vaccine efficacy against intense natural P falciparum transmission, similar to 52% vaccine efficacy reported for a five-dose regimen in a previous trial. FUNDING: US National Institute of Allergy and Infectious Diseases, National Institutes of Health, Sanaria. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Epilepsy stigma in the Republic of Guinea and its socioeconomic and clinical associations: A cross-sectional analysis.

OBJECTIVE: We aim to quantify the degree of epilepsy stigma perceived by people living with epilepsy (PLWE) in the Republic of Guinea (2019 gross national income per capita, 930 USD) and analyze the demographic, social, and clinical factors associated with epilepsy stigma in this setting. METHODS: A prospective convenience cohort of PLWE was recruited at the Ignace Deen Hospital in Conakry and evaluated by U.S. and Guinean neurology-trained physicians. A survey instrument exploring demographic, social, and clinical variables was designed and administered. The primary outcome measure was the Stigma Scale of Epilepsy (SSE), a 24-item scale with scores ranging from 0 (least stigma)-100 (most). Regression models were fit to assess associations between SSE score and pre-selected demographic, social, and clinical variables of interest. RESULTS: 249 PLWE (112 female; mean age 20.0 years; 22 % from rural locales; 14 % of participants >16 years old with no formal schooling; 11 % seizure-free for >=6 months) had an average SSE score of 46.1 (standard deviation = 14.5) points. Children had an average SSE score of 45.2, and adults had an average score of 47.0. There were no significant differences between self- and guardian-reported SSE scores (means = 45.8 and 46.5, respectively), p = .86. In univariate analyses, higher stigma scores were associated with more seizures (p = .005), more depressive symptoms (p = .01), and lower household wealth (p = .03). In a multivariable model including sex, educational level, household wealth, generalized tonic-clonic seizures, seizure frequency, and seizure-related burns, only higher seizure frequency (ß = -2.34, p = .03) and lower household wealth (ß = 4.05, p = .03) were significantly associated with higher SSE scores. CONCLUSION: In this Guinean cohort of people living with poorly-controlled epilepsy, there was a moderate degree of perceived stigma on average. Stigma was associated with higher seizure frequency and lower household wealth-both potentially modifiable factors.

Prevalence, severity, and associations of depression in people with epilepsy in Guinea: A single-center study.

BACKGROUND AND OBJECTIVE: Depression has long been recognized as a comorbidity of epilepsy in high-income countries, ranging from 17 to 49% of people with epilepsy (PWE). Of the limited studies from sub-Saharan Africa (SSA), where most people have uncontrolled seizures, an even higher prevalence of depression is reported among PWE at times exceeding 80%. We sought to assess the prevalence and severity of depression and its associated factors among PWE in Guinea, a sub-Saharan West African country where most PWE have poorly controlled seizures. METHODS: People with epilepsy from the community, age 16 years old and above, were consecutively recruited into a convenience cohort at the Ignace Deen Hospital in the capital city, Conakry, in summer 2018 as part of a larger study characterizing PWE in Guinea. Each participant was evaluated by a team of Guinean physicians and a U.S.-based neurologist to confirm the diagnosis of epilepsy. Inperson interviews were performed to measure demographic, clinical, socioeconomic, and related variables. Depression was measured via the Patient Health Questionniare-9 in the language of the participant's preference with a cutoff of 5 or more points being categorized as depressed. Regression analyses were performed to measure the associations between explanatory variables with the outcome of depression. RESULT: Of 140 PWE (age range: 16-66 years old; 64 female; 64% taking an antiseizure medication including 28% carbamazepine, 16% phenobarbital, and 14% valproic acid; duration of epilepsy: 11 years; 71% with one or more seizures in the past month; 17% never treated with an antiseizure medication; 90% with loss of consciousness during seizures; 10% without formal education; 31% with university level education; 62% using tap water; 48% with a serious seizure-related injury), the point prevalence of depression was 66% (95% confidence interval [CI]: 58%-74%): 43% of PWE had mild depression, 19% moderate, 4% moderate to severe, and 0.1% severe. In a multivariate analysis, the occurrence of a seizure in the past month (odds ratio: 3.03, 95% CI: 2.63-3.48, p = 0.01) was associated with depression, while gender, self-perceived stigma score, serious injuries, and the number of antiseizure medications taken were not statistically significantly associated (p > 0.05). Twenty-five percent of all participants endorsed thoughts of self-harm or suicidality. CONCLUSION: Two-thirds of PWE in Guinea had depression in this single-institution convenience cohort. The presence of a seizure in the last month was the factor most associated with depression and is modifiable in many PWE. The high prevalance of depression suggests that screening and addressing depressive symptoms should be incorporated into routine epilepsy care in Guinea.

Rous Sarcoma Virus Genomic RNA Dimerization Capability In Vitro Is Not a Prerequisite for Viral Infectivity.

Retroviruses package their full-length, dimeric genomic RNA (gRNA) via specific interactions between the Gag polyprotein and a "Ψ" packaging signal located in the gRNA 5'-UTR. Rous sarcoma virus (RSV) gRNA has a contiguous, well-defined Ψ element, that directs the packaging of heterologous RNAs efficiently. The simplicity of RSV Ψ makes it an informative model to examine the mechanism of retroviral gRNA packaging, which is incompletely understood. Little is known about the structure of dimerization initiation sites or specific Gag interaction sites of RSV gRNA. Using selective 2'-hydroxyl acylation analyzed by primer extension (SHAPE), we probed the secondary structure of the entire RSV 5'-leader RNA for the first time. We identified a putative bipartite dimerization initiation signal (DIS), and mutation of both sites was required to significantly reduce dimerization in vitro. These mutations failed to reduce viral replication, suggesting that in vitro dimerization results do not strictly correlate with in vivo infectivity, possibly due to additional RNA interactions that maintain the dimers in cells. UV crosslinking-coupled SHAPE (XL-SHAPE) was next used to determine Gag-induced RNA conformational changes, revealing G218 as a critical Gag contact site. Overall, our results suggest that disruption of either of the DIS sequences does not reduce virus replication and reveal specific sites of Gag-RNA interactions.

Socioeconomic associations of poorly controlled epilepsy in the Republic of Guinea: cross-sectional study.

OBJECTIVE: To explore the socioeconomic factors associated with epilepsy in the Republic of Guinea. METHODS: People living with epilepsy (PLWE) were prospectively recruited at Ignace Deen Hospital, Conakry, in 2018. An instrument exploring household assets as a measure of wealth was designed and administered. Multivariate logistic regression models with fixed effects were fitted to assess the associations of sociodemographic and microeconomic factors with self-reported frequency of seizures in the prior month and regular intake of antiseizure medications (ASMs). Participants were stratified by age group: children (<13 years), adolescents (13-21) and adults (>21). RESULTS: A total of 285 participants (mean age 19.5 years; 129 females; 106 children, 72 adolescents, 107 adults, median household size 8) had an average of 4.2 seizures in the prior month. 64% were regularly taking ASMs. Direct costs of epilepsy were similar across income strata, averaging 60 USD/month in the lowest and 75 USD/month in the highest wealth quintiles (P = 0.42). The poorest PLWE were more likely to spend their money on traditional treatments (average 35USD/month) than on medical consultations (average 11 USD/month) (P = 0.01), whereas the wealthiest participants were not. Higher seizure frequency was associated with a lower household education level in adolescents and children (P = 0.028; P = 0.026) and with being male (P = 0.009) in children. Adolescents in higher-educated households were more likely to take ASMs (P = 0.004). Boys were more likely to regularly take ASMs than girls (P = 0.047). CONCLUSIONS: Targeted programming for children and adolescents in the households with the lowest education and for girls would help improve epilepsy care in Guinea.

OBJECTIF: Explorer les facteurs socioéconomiques associés à l'épilepsie en République de Guinée. MÉTHODES: Des personnes vivant avec l'épilepsie (PVE) ont été recrutées prospectivement à l'hôpital Ignace Deen, à Conakry, en 2018. Un outil explorant les actifs des ménages en tant que mesure de la richesse a été conçu et administré. Des modèles de régression logistique multivariée avec des effets fixes ont été ajustés pour évaluer les associations de facteurs sociodémographiques et microéconomiques avec la fréquence autodéclarée des crises au cours du mois précédent et la prise régulière de médicaments antiépileptiques (MAE). Les participants ont été stratifiés par groupe d'âge: enfants (<13 ans), adolescents (13-21) et adultes (> 21). RÉSULTATS: 285 participants (âge moyen 19,5 ans; 129 femmes; 106 enfants, 72 adolescents, 107 adultes, taille médiane du ménage 8) ont eu en moyenne 4,2 crises au cours du mois précédent. 64% prenaient régulièrement des MAE. Les coûts directs de l'épilepsie étaient similaires dans toutes les strates de revenus, atteignant en moyenne 60 USD/mois dans les quintiles de richesse les plus bas et 75 USD/mois dans les quintiles de richesse les plus élevés (p = 0,42). Les PVE les plus pauvres étaient plus susceptibles de dépenser leur argent pour des traitements traditionnels (35 USD/mois en moyenne) que pour des consultations médicales (11 USD/mois en moyenne) (p = 0,01), contrairement aux participants les plus riches. Une fréquence de crises plus élevée était associée à un niveau d'éducation du ménage plus faible chez les adolescents et les enfants (p = 0,028; p = 0,026) et au fait d'être de sexe masculin (p = 0,009) chez les enfants. Les adolescents des ménages avec un niveau d'éducation plus élevé étaient plus susceptibles de prendre des MAE (p = 0,004). Les garçons étaient plus susceptibles de prendre régulièrement des MAE que les filles (p = 0,047). CONCLUSIONS: Des programmes ciblés pour les enfants et les adolescents dans les ménages les moins scolarisés et pour les filles aideraient à améliorer les soins de l'épilepsie en Guinée.

Cerebrovascular accidents indicative of COVID-19 infection: about 4 observations in Guinea.

INTRODUCTION: Coronavirus is a virus with potential to target the nervous and respiratory systems. The aim of this work is to establish the prevalence of strokes in COVID19 positive patients in Guinea. METHODS: All patients with stroke confirmed by brain imaging and COVID-positive PCR were included in this study. Retrospective patient data were obtained from medical records. Informed consent was obtained. RESULTS: The RT-PCR confirmed the initial diagnosis and the chest CT scan provided a good diagnostic orientation. Brain imaging identified ischemic brain lesions. We report the case of four patients with stroke and a COVID-19 incidental finding in Guinea. CONCLUSION: This work shows that the onset of ischemic stroke associated with COVID-19 is generally delayed, but can occur both early and late in the course of the disease. More attention is needed because the early symptoms of viral attack are not just pulmonary.

Minimal Setting Stroke Unit in a Sub-Saharan African Public Hospital.

Introduction: Sub-Saharan Africa (SSA) has the highest stroke prevalence along with a case fatality that amounts to 40%. We aimed to assess the effect of a minimal setting stroke unit in SSA Public hospital on stroke mortality and main medical complications. Materials and Methods: The study was set in Conakry, Guinea, Ignace Deen public referral hospital. Clinical characteristics, hospital mortality and main medical stroke complications rates (pneumonia, urinary tract infections, sores and venous thromboembolism) of admitted stroke patients after the installation of a minimal stroke unit equipped with heart rate, blood pressure and blood oxygen saturation monitoring and portable oxygen concentrator (POST) were compared to a similar number of stroke patients admitted before the stroke unit creation (PRE). Results: PRE (n = 318) and POST (n = 361) stroke, patients were comparable in term of age (61 ± 14 vs. 60 ± 14.8 years, p = 0.24), sex (56 vs. 50% males, p = 0.09), High blood pressure rate (76.7 vs. 79%, p = 0.44), stroke subtype (ischemic in 72 vs. 78% of cases, p = 0.05) and NIHSS (11 ± 4 vs. 11 ± 4, p = 0.85). Diabetes was more frequent in the PRE group (19 vs. 9%, p < 0.001). Mortality was significantly lower in the POST group (7.2 vs. 22.3%, p < 0.0001) as well as medical complications (4.1 vs. 27.7%, p < 0.001) and lower pneumonia rate (3.3 vs. 14.5%, p < 0.001). Conclusions: Minimally equipped stroke units significantly reduce stroke mortality and main medical complications in SSA.

School status and its associations among children with epilepsy in the Republic of Guinea.

BACKGROUND: In low-income countries (LICs), there are multiple barriers for children with epilepsy (CWE) to attend school. We examined potentially modifiable associations with poor school performance in CWE in the West African Republic of Guinea. METHODS: Children with epilepsy of school age were recruited using public announcements and a clinical register of people with epilepsy at the Ignace Deen Hospital in Conakry in 2018. A team of Guinean and U.S. neurologists and neurologists-in-training interviewed each CWE and parent for his/her epilepsy history, household finances, educational attainment level, and perceived stigma using the Stigma Scale of Epilepsy (SSE). Each child was also tested using the Wechsler Nonverbal Scale of Ability (WNV). Low school performance was defined as either not attending school or being held back a grade level at least once. Potential predictors of low school performance were analyzed. FINDINGS: Of 128 CWE (mean age: 11.6 years, 48.4% female), 11.7% (n = 15) never attended school, 23.3% (n = 30) dropped out, and 64.8% (n = 83) were currently enrolled. Of CWE attending school, 46.9% (n = 39) were held back a grade level. Overall, 54 children were defined as low performers (LPs) (42%). ;Greater than 100 lifetime seizures (odds ratio (OR) = 8.81; 95% confidence interval (CI) = 2.51, 37.4; p = 0.001) and lower total WNV score (OR = 0.954; 95% CI = 0.926, 0.977; p < 0.001) were significantly associated with poor school performance in separate models, when controlling for potential confounders. Given the strong relationship between seizure freedom and school performance, we estimated that 38 additional CWE (33.6%) could become high performers (HPs) if all CWE were adequately treated to achieve the lifetime seizure category of <10 seizures and could be cognitively intact again. Models examining SSE and household wealth quintile were not significantly associated with school performance. CONCLUSIONS: Higher lifetime seizures and lower WNV score were significantly associated with low school performance in CWE in Guinea. In spite of our conservative definition of high school performance (attending without failing) and risk of referral bias at an academic center where patients were allowed to self-refer, we demonstrate that seizure control in this setting could increase the number of CWE who could attend and stay in school.

Smartphone EEG and remote online interpretation for children with epilepsy in the Republic of Guinea: Quality, characteristics, and practice implications.

PURPOSE: Children with epilepsy in low-income countries often go undiagnosed and untreated. We examine a portable, low-cost smartphone-based EEG technology in a heterogeneous pediatric epilepsy cohort in the West African Republic of Guinea. METHODS: Children with epilepsy were recruited at the Ignace Deen Hospital in Conakry, 2017. Participants underwent sequential EEG recordings with an app-based EEG, the Smartphone Brain Scanner-2 (SBS2) and a standard Xltek EEG. Raw EEG data were transmitted via Bluetooth™ connection to an Android™ tablet and uploaded for remote EEG specialist review and reporting via a new, secure web-based reading platform, crowdEEG. The results were compared to same-visit Xltek 10-20 EEG recordings for identification of epileptiform and non-epileptiform abnormalities. RESULTS: 97 children meeting the International League Against Epilepsy's definition of epilepsy (49 male; mean age 10.3 years, 29 untreated with an antiepileptic drug; 0 with a prior EEG) were enrolled. Epileptiform discharges were detected on 21 (25.3%) SBS2 and 31 (37.3%) standard EEG recordings. The SBS2 had a sensitivity of 51.6% (95%CI 32.4%, 70.8%) and a specificity of 90.4% (95%CI 81.4%, 94.4%) for all types of epileptiform discharges, with positive and negative predictive values of 76.2% and 75.8% respectively. For generalized discharges, the SBS2 had a sensitivity of 43.5% with a specificity of 96.2%. CONCLUSIONS: The SBS2 has a moderate sensitivity and high specificity for the detection of epileptiform abnormalities in children with epilepsy in this low-income setting. Use of the SBS2+crowdEEG platform permits specialist input for patients with previously poor access to clinical neurophysiology expertise.

Epilepsy and traditional healers in the Republic of Guinea: A mixed methods study.

PURPOSE: The purpose of this study was to characterize the reasons, extent, and impact of traditional medicine use among people with epilepsy (PWE) in the Republic of Guinea. METHODS: Guinea is a low-income country in sub-Saharan Africa (SSA) with limited healthcare resources. People with epilepsy and their caregivers were seen at a public referral hospital in Conakry, the capital city, where they completed semi-structured interviews with physicians regarding their beliefs about epilepsy, medical care, and engagement with traditional healers. RESULTS: Of 132 participants (49% children, 44% female, 55% with a university-educated head of household), 79% had seen a traditional healer, and 71% saw a traditional healer before seeing a medical provider for their epilepsy. Participants were treated by a traditional healer for a mean of 39 months before seeing a medical provider. By contrast, 58% of participants reported taking antiepileptic drugs (AEDs) regularly; 46% reported having undergone a head computed tomography (CT) scan; 58% reported having had an electroencephalogram, and 4% reported having had a brain magnetic resonance imaging (MRI) scan. CONCLUSIONS: Traditional healers in Guinea provide frontline care for PWE in Guinea with considerable delays in AED initiation, even among a cohort of PWE actively seeking medical care. Engaging with these healers is critical for both influencing community perceptions and appropriately managing epilepsy throughout the country.

Medullar Kock without Pott: 13 cases observed at the university hospital center of Conakry, Guinea.

Background: The diagnostic certainty of medullar tuberculosis (TB) without Pott disease is difficult to establish in a tropical environment with the large group of infectious, parasitic, and systemic myelopathies, despite the increasing availability of magnetic resonance imaging (MRI) data and improvement of biological exploration platforms. Methods: We retrospectively analyzed the files of 186 patients hospitalized in the Department of Neurology and Neurosurgery of the University Hospital Center of Conakry, Guinea, between 2008 and 2016 for the management of non-compressive and compressive myelopathy. Biological evidence of TB infection was demonstrated for 13 (6.9%) patients. Results: Infectious clinical picture prior to the development of neurological signs was reported in 11 patients (84.6%). The neurological signs were summed up by the existence of a sensitivo-motor semiology of progressive evolution (100% of cases) with sphincter disorders in 11 patients (84.6%) and a medullary compression symptomatology with a lesion and under lesion syndrome from the outset in 4 patients (30.8%). Medullary MRI revealed an extensive intramedullary hypersignal in 9 patients with non-compressive myelopathy and in 4 cases, the lesions appeared in T1 hypersignal and T2 isosignal were localized. Lumbar puncture (LP) revealed lymphocytic pleocytosis, hypoglucorrhage (0.3 to 0.5 g/l), and leukocytosis. Conclusion: This study reveals a classic clinical, biological, neuroradiological, and evolutionary profile of compressive and non-compressive myelopathies. These results are important for the therapeutic and evolutionary discussion of TB myelopathies for good management.

Correlates of condom use among sex workers and their boyfriends in three West African countries.

The aim of this study was to identify correlates associated with condom use at last intercourse between sex workers (SW) and their boyfriends (BF). The sample was derived as a convenience sample recruited through existing HIV prevention organizations in Benin, Guinea and Senegal. The Theory of Planned Behavior served as the conceptual framework. A total of 406 individuals (220 SW and 186 BF) participated in the study. Socio-demographic, behavioral and psychological variables were collected through a face-to-face administered questionnaire. Condom use at last intercourse was significantly associated with intention and perceived control among SW as well as their BF. With respect to intention, perceived control, attitude and moral norm explained 82 and 74% of intention of SW and BF, respectively. These results suggest that promoting condom use among SW and BF should be based primarily on the development of personal ability to overcome obstacles to condom use.

Activation of the cytokine network and unfavorable outcome in patients with yellow fever.

To study the contribution of inflammatory mediators to the pathogenesis of yellow fever (YF), the serum levels of several cytokines and chemokines were measured in 7 patients with fatal YF (f-YF), 11 patients with nonfatal hemorrhagic YF (nf/h-YF), and 18 patients with nonfatal nonhemorrhagic YF (nf/nh-YF). The levels of interleukin (IL)-6, monocyte chemoattractant protein-1, interferon-inducible protein (IP)-10, tumor necrosis factor- alpha , and IL-1 receptor antagonist (IL-1RA) were all statistically significantly higher in the patients with f-YF than in those with nf/nh-YF. In patients with nf/h-YF, only levels of IP-10 and IL-1RA were significantly elevated. The high levels of pro- and anti-inflammatory cytokines and chemokines in serum from patients with f-YF are reminiscent of those seen in patients with bacterial sepsis. This finding has implications for the understanding of the pathophysiology of YF and the development of therapeutic strategies.