A single-dose live-attenuated YF17D-vectored SARS-CoV-2 vaccine candidate.

The expanding pandemic of coronavirus disease 2019 (COVID-19) requires the development of safe, efficacious and fast-acting vaccines. Several vaccine platforms are being leveraged for a rapid emergency response1. Here we describe the development of a candidate vaccine (YF-S0) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that uses live-attenuated yellow fever 17D (YF17D) vaccine as a vector to express a noncleavable prefusion form of the SARS-CoV-2 spike antigen. We assess vaccine safety, immunogenicity and efficacy in several animal models. YF-S0 has an excellent safety profile and induces high levels of SARS-CoV-2 neutralizing antibodies in hamsters (Mesocricetus auratus), mice (Mus musculus) and cynomolgus macaques (Macaca fascicularis), and-concomitantly-protective immunity against yellow fever virus. Humoral immunity is complemented by a cellular immune response with favourable T helper 1 polarization, as profiled in mice. In a hamster model2 and in macaques, YF-S0 prevents infection with SARS-CoV-2. Moreover, a single dose conferred protection from lung disease in most of the vaccinated hamsters within as little as 10 days. Taken together, the quality of the immune responses triggered and the rapid kinetics by which protective immunity can be attained after a single dose warrant further development of this potent SARS-CoV-2 vaccine candidate.

Very high epilepsy prevalence in rural Southern Rwanda: The underestimated burden of epilepsy in sub-Saharan Africa.

OBJECTIVES: Up to 85% of people living with epilepsy (PwE) reside in low-and middle-income countries. In sub-Saharan Africa, the lifetime prevalence of epilepsy is 16 per 1000 persons. In Northern rural Rwanda, a 47.7 per 1000 prevalence has been reported. As variations in prevalence across geographical areas have been observed, we studied the prevalence in Southern rural Rwanda using the same robust methodology as applied in the North. METHODS: We conducted a three-stage, cross-sectional, door-to-door survey in two rural villages in Southern Rwanda from June 2022 to April 2023. First, trained enumerators administered the validated Limoges questionnaire for epilepsy screening. Second, neurologists examined the persons who had screened positively to confirm the epilepsy diagnosis. Third, cases with an inconclusive assessment were separately reexamined by two neurologists to reevaluate the diagnosis. RESULTS: Enumerators screened 1745 persons (54.4% female, mean age: 24 ± 19.3 years), of whom 304 (17.4%) screened positive. Epilepsy diagnosis was confirmed in 133 (52.6% female, mean age: 30 ± 18.2 years) and active epilepsy in 130 persons. Lifetime epilepsy prevalence was 76.2 per 1000 (95% CI: 64.2-89.7‰). The highest age-specific rate occurred in the 29-49 age group. No gender-specific differences were noted. In 22.6% of the PwE, only non-convulsive seizures occurred. The treatment gap was 92.2%, including a diagnosis gap of 79.4%. CONCLUSION: We demonstrated a very high epilepsy prevalence in Southern rural Rwanda, with over 20% of cases having only non-convulsive seizures, which are often underdiagnosed in rural Africa. In line with previous Rwandan reports, we reiterate the high burden of the disease in the country. Geographic variation in prevalence throughout Africa may result from differences in risk and aetiological factors. Case-control studies are underway to understand such differences and propose adapted health policies for epilepsy prevention.

Challenges to epilepsy management in Rwandan women living with epilepsy.

BACKGROUND AND PURPOSE: In Rwanda, epilepsy prevalence ranges between 29‰ and 49‰. Many women living with epilepsy (WwE) are of childbearing age. Epilepsy characteristics and management, contraception, pregnancy, puerperium and stigma in WwE presenting at the neurology clinic of Ndera, Rwanda, were investigated. METHODS: This prospective cross-sectional study investigated demographics, epilepsy characteristics, treatment, contraception, folic acid use, pregnancy, puerperium and stigma in WwE aged ≥18 years. Subgroups were analysed by status of any pregnancy and time of epilepsy diagnosis relative to pregnancy, with significant differences expected. RESULTS: During December 2020 and January 2021, a hundred WwE were enrolled (range 18-67 years). Fifty-two women had never been pregnant, 39 women had epilepsy onset before pregnancy and nine were diagnosed after pregnancy. No significant differences in age, marital status or occupation were observed. Contraception was used by 27%, of whom 50% were taking enzyme-inducing anti-epileptic medication. Valproate was used by 46% of WwE of reproductive age. Thirty-nine women with epilepsy onset before pregnancy reported 91 pregnancies, with 14% spontaneous abortions. None used folic acid before conception, and 59% only during pregnancy. Five of 78 newborns were preterm. No offspring had major congenital malformations. Nearly 25% of WwE were not compliant with their anti-epileptic medication schedule during pregnancy or breastfeeding. Internalized stigma was observed in more than 60%. Up to 25% had been discriminated against at school or work. CONCLUSION: A comprehensive strategy considering the reproductive health and societal challenges of WwE is needed to drive optimal epilepsy management, reproductive health outcomes and societal inclusion.

Association of depression and epilepsy in Rwanda: A prospective longitudinal study.

INTRODUCTION: Depression is the most common psychiatric comorbidity for persons living with epilepsy. In Rwanda, the prevalence of epilepsy and depression are high, with 4,9% and 13.0% respectively. This prospective interventional study aimed to determine the prevalence and incidence of depression and the outcome of persons living with epilepsy (PwE) with depression attending the outpatient neurology department of a tertiary center. METHODS: Persons living with epilepsy enrolled between February and June 2018 in a screening cohort with a 12-month follow-up. At every 3-month study visit, PwE were screened for depression using the Patient Health Questionnaire (PHQ-9) questionnaire. Any positively screened subject was administered the Hamilton Depression Rating Scale (HDRS) to confirm the diagnosis and severity of depression. Subjects with moderate to severe depression (MSD), were started on treatment and were followed for another year. We describe the prevalence and incidence of depression, baseline characteristics, epilepsy and depression outcomes, and changes in PGI-C. RESULTS: Of 572 PwE enrolled, 46 were diagnosed with MSD in a twelve-month period, resulting in an incidence of MSD of 32.7/1000 patient-years. The prevalence of any depression and MSD was 14.2% and 4.7%, respectively. Longer epilepsy duration and seizure status at baseline were associated with MSD. Significant improvements in PGI-C and seizure frequency were observed after treatment optimization. CONCLUSION: The use of PHQ-9 and HDRS proved successful in identifying depression in PwE. Combined treatment of epilepsy and depression resulted in improved outcomes, warranting the implementation of depression screening every six months in daily neurology practice.

A near full-length HIV-1 genome from 1966 recovered from formalin-fixed paraffin-embedded tissue.

With very little direct biological data of HIV-1 from before the 1980s, far-reaching evolutionary and epidemiological inferences regarding the long prediscovery phase of this pandemic are based on extrapolations by phylodynamic models of HIV-1 genomic sequences gathered mostly over recent decades. Here, using a very sensitive multiplex RT-PCR assay, we screened 1,645 formalin-fixed paraffin-embedded tissue specimens collected for pathology diagnostics in Central Africa between 1958 and 1966. We report the near-complete viral genome in one HIV-1 positive specimen from Kinshasa, Democratic Republic of Congo (DRC), from 1966 ("DRC66")-a nonrecombinant sister lineage to subtype C that constitutes the oldest HIV-1 near full-length genome recovered to date. Root-to-tip plots showed the DRC66 sequence is not an outlier as would be expected if dating estimates from more recent genomes were systematically biased; and inclusion of the DRC66 sequence in tip-dated BEAST analyses did not significantly alter root and internal node age estimates based on post-1978 HIV-1 sequences. There was larger variation in divergence time estimates among datasets that were subsamples of the available HIV-1 genomes from 1978 to 2014, showing the inherent phylogenetic stochasticity across subsets of the real HIV-1 diversity. Our phylogenetic analyses date the origin of the pandemic lineage of HIV-1 to a time period around the turn of the 20th century (1881 to 1918). In conclusion, this unique archival HIV-1 sequence provides direct genomic insight into HIV-1 in 1960s DRC, and, as an ancient-DNA calibrator, it validates our understanding of HIV-1 evolutionary history.

1970s and 'Patient 0' HIV-1 genomes illuminate early HIV/AIDS history in North America.

The emergence of HIV-1 group M subtype B in North American men who have sex with men was a key turning point in the HIV/AIDS pandemic. Phylogenetic studies have suggested cryptic subtype B circulation in the United States (US) throughout the 1970s and an even older presence in the Caribbean. However, these temporal and geographical inferences, based upon partial HIV-1 genomes that postdate the recognition of AIDS in 1981, remain contentious and the earliest movements of the virus within the US are unknown. We serologically screened >2,000 1970s serum samples and developed a highly sensitive approach for recovering viral RNA from degraded archival samples. Here, we report eight coding-complete genomes from US serum samples from 1978-1979-eight of the nine oldest HIV-1 group M genomes to date. This early, full-genome 'snapshot' reveals that the US HIV-1 epidemic exhibited extensive genetic diversity in the 1970s but also provides strong evidence for its emergence from a pre-existing Caribbean epidemic. Bayesian phylogenetic analyses estimate the jump to the US at around 1970 and place the ancestral US virus in New York City with 0.99 posterior probability support, strongly suggesting this was the crucial hub of early US HIV/AIDS diversification. Logistic growth coalescent models reveal epidemic doubling times of 0.86 and 1.12 years for the US and Caribbean, respectively, suggesting rapid early expansion in each location. Comparisons with more recent data reveal many of these insights to be unattainable without archival, full-genome sequences. We also recovered the HIV-1 genome from the individual known as 'Patient 0' (ref. 5) and found neither biological nor historical evidence that he was the primary case in the US or for subtype B as a whole. We discuss the genesis and persistence of this belief in the light of these evolutionary insights.

Effectiveness of community health workers on identification and mobilization of persons living with epilepsy in rural Rwanda using a validated screening tool.

INTRODUCTION: Engagement and training of community health workers (CHWs) have demonstrated their value in different conditions. Despite repeat epilepsy trainings of CHWs in Northern Rwanda, the treatment gap remained high. We hypothesized that effectiveness of CHWs on mobilization of patients living with epilepsy (PwE) could be improved using a validated tool for epilepsy screening. METHODS: CHWs associated with health centers (HCs) of Gataraga, Kimonyi and Karwasa attended a 1-day training on epilepsy and Limoges epilepsy screening questionnaire (Kinyarwanda version). Thereafter, CHWs screened households in their villages for persons with one or more positive answer. CHWs then accompanied positively screened persons to a consultation for clinical evaluation and diagnosis by neurologists, and demographic data were collected. CHW variables were collected retrospectively. RESULTS: A total of 1308 persons were screened positive by 281 CHWs. Clinical diagnosis of epilepsy was confirmed in 589 and in 93 additional unscreened PwE, presenting voluntarily at the consultation. Pre-intervention number of 48 PwE increased to 682 after, a 14.2-fold increase. The overall treatment gap amounted to 93.0%. The age distribution of male PwE preponderance at younger age inverted to females at older age. CHW characteristics showed non-significant differences within and across HCs. Logistic regression did not relate CHW age, gender, and experience to screening results. DISCUSSION: Equipping CHWs with a validated screening tool was effective in identifying and mobilizing PwE in a short time frame and offers opportunity for future scaling. Nonetheless, barriers to sustainability of care will need to be addressed before.

Patient satisfaction and its health provider-related determinants in primary health facilities in rural China.

BACKGROUND: Patient satisfaction is an important outcome measure of health service and is one of the main reasons for the gradual deterioration of doctor-patient relationships in China. This study used the standardized patient (SP) method to explore patient satisfaction and its health provider-related determinants among primary health facilities in rural China. METHODS: The dataset comprised 1138 clinic cases in 728 rural primary health facilities in 31 counties, spread across four provinces. Information regarding the consultation interaction between the unannounced SPs and primary physicians was recorded. Patient satisfaction was gathered from the feedback of SPs after the visit. RESULTS: The overall average score of SP satisfaction with rural primary health facilities was only 13.65 (SD = 3.22) out of 20. The SP scores were found to be consistent with those of real patients. After controlling variances in patient population via the SP method, the regression analysis demonstrated that health provider-related factors, such as physician-level characteristics, consultation process, affordability, and convenience, have a significant correlation with patient satisfaction among primary physicians. Among factors relating to physician-level characteristics, affordability, convenience and the consultation process of the visit, the quality of the consultation process (e.g., consultation time, proactively providing necessary instructions and other crucial information) were found to be the prominent determinants. CONCLUSIONS: This study revealed the need to improve patient satisfaction in primary health facilities in rural China. To solve this issue, we recommend that policies to increase medical service quality be implemented in rural primary healthcare systems.

Systems biology approach predicts immunogenicity of the yellow fever vaccine in humans.

A major challenge in vaccinology is to prospectively determine vaccine efficacy. Here we have used a systems biology approach to identify early gene 'signatures' that predicted immune responses in humans vaccinated with yellow fever vaccine YF-17D. Vaccination induced genes that regulate virus innate sensing and type I interferon production. Computational analyses identified a gene signature, including complement protein C1qB and eukaryotic translation initiation factor 2 alpha kinase 4-an orchestrator of the integrated stress response-that correlated with and predicted YF-17D CD8(+) T cell responses with up to 90% accuracy in an independent, blinded trial. A distinct signature, including B cell growth factor TNFRS17, predicted the neutralizing antibody response with up to 100% accuracy. These data highlight the utility of systems biology approaches in predicting vaccine efficacy.

Stakeholder views of the practical and cultural barriers to epilepsy care in Uganda.

OBJECTIVE: Epilepsy is one of the most prevalent, treatable neurological diseases globally. In sub-Saharan Africa, people with epilepsy (PWE) frequently seek treatment from traditional or pastoral healers, who are more accessible than biomedical care providers. This often contributes to the substantial time delay in obtaining adequate biomedical care for these patients. In Uganda, the few biomedical providers who can treat epilepsy cannot meet the great need for epilepsy care. Additionally, patients are often hesitant to seek biomedical care, often preferring the easily accessible and trusted sociocultural treatment options. This study sought to elucidate the barriers to biomedical care for PWE as well as identify potential solutions to overcome these barriers from various stakeholder perspectives. METHODS: This study used qualitative research methods. Semistructured interviews and focus group discussions were conducted with four major stakeholder groups: PWE or family members of PWE, neurologists and psychiatrists, traditional healers, and pastoral healers. All interviews and focus group discussions that were in English were audio recorded and transcribed verbatim. Those that were not in English were translated live and audio recorded. A translator later translated the non-English portion of audio recording to ensure proper interpretation. Two independent coders coded the dataset and conducted an inter-rater reliability (IRR) assessment to ensure reliable coding of the data. Thematic analysis was then performed to discern themes from the data and compare nuances between each of the study design groups. RESULTS: Participants discussed several different causes of epilepsy ranging from spiritual to biological causes, often incorporating elements of both. Commonly endorsed spiritual causes of epilepsy included witchcraft and ancestral spirits. Commonly endorsed biological causes included genetics, fever, malaria, and brain injury. For patients and families, beliefs about the cause of epilepsy often played a role in whom they chose to seek treatment from. Three major barriers to biomedical care were discussed: practical barriers, medical infrastructure barriers, and barriers related to stigma. Practical barriers related to issues such as transportation, cost of medical care, and distance to the nearest healthcare facility. Under medical infrastructure, drug stock-outs and lack of access to antiepileptic drugs (AEDs) were the most consistent problems stated among patients. Stigma was heavily discussed and brought up by nearly every participant. Additionally, three significant solutions to improving epilepsy care in Uganda were highlighted by participants: collaboration among treatment providers, community sensitization efforts to address stigma, and building medical infrastructure. Within building infrastructure, all participant types, except traditional healers, proposed the development of an epilepsy clinic designed to specifically treat epilepsy. CONCLUSIONS: Based on these findings, there are four critical interventions that should be considered for improving epilepsy care in Uganda: the creation of dedicated epilepsy clinics, infrastructure strengthening to address medication stock-outs, community outreach programs for sensitization, and collaboration between biomedical providers and traditional healers. This article is part of the Special Issue "The Intersection of Culture, Resources, and Disease: Epilepsy Care in Uganda".

Leveraging the lessons learned from studies on the cultural context of epilepsy care in Uganda: Opportunities and future directions.

In this summary paper, we review the body of research contained in this special issue, The Intersection of Culture, Resources, and Disease: Epilepsy Care in Uganda, and corollary recommendations for a way forward. We review key findings and conclusions for the studies, which tell a story of culture and care-seeking through discussions and data gleaned from a rich research landscape traversing community village dwellings, shared communal areas, churches, and urban hospitals. The voices and perspectives of over 16,000 study participants inclusive of people living with epilepsy, their neighbors and healthcare workers, traditional healers, and faith leaders are reported. From this, we synthesize findings and prioritize a set of recommendations to advance epilepsy care in Uganda. Progress will require infrastructure strengthening, multilevel educational investments, and an ambitious, extensive program of community sensitization. These proposed priorities and actions outline a way forward through formidable but surmountable challenges but require harmonized efforts by government and other relevant stakeholders, scholars, clinicians, and community leaders. This article is part of the Special Issue "The Intersection of Culture, Resources, and Disease: Epilepsy Care in Uganda".

Healthcare provider perspectives regarding epilepsy care in Uganda.

OBJECTIVE: Epilepsy is the most common chronic neurological disorder in the world and imposes a large economic burden on global healthcare systems, especially in low-income settings and rural areas as is found in sub-Saharan Africa (SSA). Despite the high epilepsy prevalence, there are no systematic descriptions of healthcare provider (HCP) perceptions and needs in managing people with epilepsy (PWE) in Uganda. Identifying these perceptions and needs is crucial for understanding community priorities, thereby enhancing the development of culturally sensitive communications, interventions, and research approaches. METHODS: In this qualitative study, we used semistructured interview guides to conduct focus group discussions that explored the perspectives of 32 providers of epilepsy care from health facilities around Mbarara, Uganda. Our sample included nonspecialized general physicians (n = 3), medical residents (n = 8), medical clinical officers (n = 3), psychiatric clinical nurses (n = 6), medical nurses and nursing assistants (n = 9), and other providers (n = 3), who were loosely grouped into discussion groups based on level or type of training. Self-assessed proficiency ratings were also administered to gain a better understanding of participants' confidence in their training, preparedness, and capabilities regarding epilepsy care. Thematic analysis of the focus group transcripts was conducted to ascertain commonly occurring themes about perceptions and challenges in epilepsy care. RESULTS: Our analyses identified nine major themes that dominated the perspectives of the study participants: care management, medications, diagnostics, HCP training, human resources, location, patient education, social support, and community knowledge and beliefs. Proficiency ratings prioritized areas of confidence as knowledge related to referrals, psychosocial impacts, and seizure neurophysiology. Areas of need were revealed as knowledge of diagnostic tools and antiepileptic drug (AED) regimens. CONCLUSIONS: Our findings delineate the perspectives of providers caring for PWE, with consistent recognition of challenges centering around resource augmentation, infrastructure strengthening, and education. Participants emphasized the urgent need to augment these resources to address limitations in medication types and access, trained human resources, and diagnostic tools. They overwhelmingly recognized the need for infrastructure strengthening to address human, diagnostic, medicinal, and capital resource limitations that place undue burden on patients with epilepsy and physicians. Providers indicated a clear desire to learn more about different diagnostic tools and medical management practices, potentially through continuing education, specialized training, or more intentional in-school diagnostic preparation. They also advocated for the powerful influence of patient and family education and clearly articulated the need for community sensitization and support. This article is part of the Special Issue "The Intersection of Culture, Resources, and Disease: Epilepsy Care in Uganda".

Sociocultural determinants and patterns of healthcare utilization for epilepsy care in Uganda.

OBJECTIVE: Epilepsy is a global public health concern, with the majority of cases occurring in lower- and middle-income countries where the treatment gap remains formidable. In this study, we simultaneously explore how beliefs about epilepsy causation, perceived barriers to care, seizure disorder characteristics, and demographics influence the initial choice of healthcare for epilepsy and its impact on attaining biomedical care (BMC). METHODS: This study utilized the baseline sample (n = 626) from a prospective cohort study of people with epilepsy (PWE) attending three public hospitals in Uganda (Mulago National Referral Hospital, Butabika National Referral Mental Hospital, and Mbarara Regional Referral Hospital) for epilepsy care. Patient and household demographics, clinical seizure disorder characteristics, and sociocultural questionnaires were administered. Logistic regression and principal component analyses (PCA) were conducted to examine associations with the choice of primary seizure treatment. RESULTS: The sample was 49% female, and 24% lived in rural settings. A biomedical health facility was the first point of care for 355 (56.7%) participants, while 229 (36.6%) first sought care from a traditional healer and 42 (6.7%) from a pastoral healer. Preliminary inspection of candidate predictors using relaxed criteria for significance (p < 0.20) identified several factors potentially associated with a greater odds of seeking BMC first. Demographic predictors included older caredriver (decision-maker for the participant) age (odds ratio [OR]: 1.01, 95% confidence interval [CI]: [0.99, 1.02], p-value: 0.09), greater caredriver education level (OR = 1.21, 95% CI: [1.07, 1.37], p-value = 0.003), and lower ratio of sick to healthy family members (OR = 0.77 [0.56, 1.05], P = 0.097). For clinical predictors, none of the proposed predictors associated significantly with seeking BMC first. Self-report causation predictors associated with a greater odds of seeking BMC first included higher belief in biological causes of epilepsy (OR = 1.31 [0.92, 1.88], P = 0.133) and lower belief in socio-spiritual causes of epilepsy (OR = 0.68 [0.56, 0.84], P < 0.001). In the multivariate model, only higher caredriver education (OR = 1.19 [1.04, 1.36], P = 0.009) and lower belief in socio-spiritual causes of epilepsy (OR = 0.69 [0.56, 0.86], P < 0.01) remained as predictors of seeking BMC first. Additionally, PCA revealed a pattern which included high income with low beliefs in nonbiological causes of epilepsy as being associated with seeking BMC first (OR = 1.32 [1.12, 1.55], p = 0.001). Despite reaching some form of care faster, individuals seeking care from traditional or pastoral healers experienced a significant delay to eventual BMC (P < 0.001), with an average delay of more than two years (traditional healer: 2.53 years [1.98, 3.24]; pastoral care: 2.18 [1.21, 3.91]). CONCLUSIONS: Coupled with low economic and educational status, belief in spiritual causation of epilepsy is a dominant determinant of opting for traditional or pastoral healing over BMC, regardless of concurrent belief in biological etiologies. There is a prolonged delay to eventual BMC for PWE who begin their treatment seeking with nonallopathic providers, and although nonallopathic healers provide PWE with benefits not provided by BMC, this notable delay likely prevents earlier administration of evidence-based care with known efficacy. Based on these findings, initiatives to increase public awareness of neurobiological causes of epilepsy and effectiveness of biomedical drug treatments may be effective in preventing delays to care, as would programs designed to facilitate cooperation and referral among traditional, faith-based, and biomedical providers. This article is part of the Special Issue "The Intersection of Culture, Resources, and Disease: Epilepsy Care in Uganda".

Measurements of quality of village-level care and patients' healthcare-seeking behaviors in rural China.

BACKGROUND: Although the progress in global health initiatives has improved the availability of primary health care (PHC), unqualified healthcare remains a serious challenge in low- and middle-income countries, where PHC is often underutilized. This study examines factors associated with patients' healthcare-seeking behaviors in rural Chin-seeking healthcare at village-level PHC providers, at higher-level health facilities, self-medicating, and refraining from seeking medical help. We focus on provider-side factors, including (1) the unobservable quality indicator, (2) the observable quality indicator, and (3) the observable signal indicator. METHODS: We analyzed 1578 episodes of healthcare-seeking behaviors of patients with diarrhea or cough/runny nose symptom from surveys conducted in July 2017 and January 2018 in 114 villages of the Yunnan province. We investigated the correlation between quality-related factors with patients' healthcare-seeking behaviors by multinomial logit regression. RESULTS: We found that rural patients were insensitive to the unobservable quality of healthcare providers, as measured by standardized clinical vignettes, which might be attributable to the credence nature of PHC. The observable quality indicator, whether the clinician has received full-time junior college formal medical education, was associated with patients' healthcare choices. Patients, however, were more likely to select healthcare based on the observable signal indicator, which was measured by the availability of medicines. Additionally, the observable signal indicator had no significant association with two quality indicators. Notably, socioeconomically-disadvantaged patients relied more on the village-level PHC, which emphasized the role of PHC in promoting the welfare of rural populations. CONCLUSIONS: Our study found an inconsistency between objective quality of healthcare provided by providers and subjective quality perceived by patients. Patients could not identify the actual quality of PHC precisely, while they were more likely to make decisions based on the observable signal indicator. Therefore, the quality of PHC should be more observable to patients. This study not only supplements the literature on healthcare-seeking choices by examining four types of behaviors simultaneously but also clarifies rural patients' perceptions of the quality of PHC for policy decision-making on increasing the utilization of PHC and improving the medical welfare of the vulnerable.

Addressing the treatment gap and societal impact of epilepsy in Rwanda--Results of a survey conducted in 2005 and subsequent actions.

This study, supported by the Rwandan Ministry of Health and the World Health Organization, was conducted in 2005 to determine the prevalence of epilepsy and its sociocultural perception in Rwanda, as well as epilepsy-related knowledge and practices of health-care professionals (HCPs). A cross-sectional, nationally representative survey was conducted throughout Rwanda by trained investigators. Participants were recruited by random cluster sampling based on the organization of administrative units in the country. Overall, 1137 individuals (62% from rural areas) were interviewed. The prevalence of epilepsy was estimated to be 49 per 1000 people or 41 per 1000 for active epilepsy. Onset of epilepsy before the age of 2years was reported in 32% of the cases. Family history of epilepsy, head trauma, and premature delivery were reported in 53%, 50%, and 68% of the cases, respectively. Most (68%) patients did not receive any medical treatment for epilepsy; 21.5% had received some form of traditional treatment. According to responses from the general population, people with epilepsy should not be entitled to schooling (according to 66%), to work (according to 72%), to the use of public places (according to 69%), or to marriage (according to 66%). Furthermore, 50% believed that epilepsy was untreatable, and 40% thought that it was transmissible. Of the 29 HCPs interviewed, the majority knew the definition of epilepsy and status epilepticus, as well as basic treatment options and side effects. However, 90% believed that treatment was only necessary in the first week after a seizure. Living with epilepsy was associated heavily with stigma, and a significant treatment gap (68%) was identified. Following this study, numerous actions have been taken by the Rwandan government, the Rwandan League Against Epilepsy, and several nongovernmental organizations to increase awareness about epilepsy and to close the treatment gap. An overview of these activities is provided.

Direct evidence of extensive diversity of HIV-1 in Kinshasa by 1960.

Human immunodeficiency virus type 1 (HIV-1) sequences that pre-date the recognition of AIDS are critical to defining the time of origin and the timescale of virus evolution. A viral sequence from 1959 (ZR59) is the oldest known HIV-1 infection. Other historically documented sequences, important calibration points to convert evolutionary distance into time, are lacking, however; ZR59 is the only one sampled before 1976. Here we report the amplification and characterization of viral sequences from a Bouin's-fixed paraffin-embedded lymph node biopsy specimen obtained in 1960 from an adult female in Léopoldville, Belgian Congo (now Kinshasa, Democratic Republic of the Congo (DRC)), and we use them to conduct the first comparative evolutionary genetic study of early pre-AIDS epidemic HIV-1 group M viruses. Phylogenetic analyses position this viral sequence (DRC60) closest to the ancestral node of subtype A (excluding A2). Relaxed molecular clock analyses incorporating DRC60 and ZR59 date the most recent common ancestor of the M group to near the beginning of the twentieth century. The sizeable genetic distance between DRC60 and ZR59 directly demonstrates that diversification of HIV-1 in west-central Africa occurred long before the recognized AIDS pandemic. The recovery of viral gene sequences from decades-old paraffin-embedded tissues opens the door to a detailed palaeovirological investigation of the evolutionary history of HIV-1 that is not accessible by other methods.

Epilepsy-Related Direct Medical and Direct Non-Medical Cost in Adult Patients Living with Epilepsy at a Tertiary Neurology Center in Rwanda.

Objective: Up to one in four patients living with epilepsy (PwE) mentions financial constraints as a reason for loss to follow-up at the Ndera tertiary neuropsychiatry hospital. Therefore, we evaluated the annual direct medical cost (DMC) and direct non-medical cost (DnMC) of epilepsy and calculated costs assuming different follow-up frequency. Materials and Methods: DMC data were obtained from a descriptive retrospective study of medical records, pharmacy dispensation and hospital logs of PwE, following their initial consultation in 2018 and who adhered to the normal clinical practice of monthly consultations for one year. DnMC data were collected through structured interviews of PwE in a cross-sectional cohort in August 2020. DnMC included biomedical care costs (eg, transportation, hospitality) and non-biomedical costs (traditional healer visits). We report weighted means for total costs, health insurance costs, and out-of-pocket costs (OoP). Results: Mean annual total cost was 389.4 US$, of which 226.2 US$ was covered by the Rwandan Health Insurance co-payment for DMC and 163.2 US$ was OoP paid by patients. Mean weighted annual DMC (n = 55) was 248.9 US$. Mean weighted annual DMC for medical consultations and antiseizure medication accounted for 30.7 US$ and 161.7 US$, respectively. Based on structured interviews (n = 69), mean weighted annual DnMC for biomedical care was 73.0 US$. Mean DnMC for traditional healer care was 67.6 US$. Weighted annual total OoP was 163.2 US$ or 20% of the GDP per capita. OoP consisted of 14% DMC co-payment, 45% biomedical DnMC, and 41% traditional healer DnMC. Conclusion: Epilepsy-related costs at a tertiary center are an important economic burden for PwE and Rwandan Health Insurance. Biomedical and traditional healer DnMC constitute 86% of total OoP. Future prospective studies should evaluate outcomes and costs of reduced visit frequency, indirect costs, and costs of comorbidities.

Corrigendum: Long-Term Impact of Single Epilepsy Training on Knowledge, Attitude and Practices: Comparison of Trained and Untrained Rwandan Community Health Workers.

[This corrects the article DOI: 10.3389/ijph.2021.645598.].

Irrational Use of Medicine in the Treatment of Presumptive Asthma Among Rural Primary Care Providers in Southwestern China.

Poor knowledge, scarce resources, and lack of or misaligned incentives have been widely documented as drivers of the irrational use of medicine (IUM), which significantly challenges the efficiency of health systems across the globe. However, there is limited understanding of the influence of each factor on IUM. We used detailed data on provider treatment of presumptive asthma cases in rural China to assess the contributions of provider knowledge, resource constraints, and provider behavior on IUM. This study enrolled 370 village providers from southwest China. All providers responded to a clinical vignette to test their knowledge of how to treat presumptive asthma. Resource constraints ("capacity") were defined as the availability of the prescribed medicines in vignette. To measure provider behavior ("performance"), a subset of providers (104 of 370) were randomly selected to receive unannounced visits by standardized patients (SPs) who performed of presumptive asthma symptoms described in the vignette. We found that, 54% (201/370) of providers provided the vignette-based patients with prescriptions. Moreover, 67% (70/104) provided prescriptions for the SPs. For the vignette, only 10% of the providers prescribed the correct medicines; 38% prescribed only unnecessary medicines (and did not provide correct medicine); 65% prescribed antibiotics (although antibiotics were not required); and 55% prescribed polypharmacy prescriptions (that is, they prescribed five or more different types of drugs). For the SP visits, the numbers were 12%, 51%, 63%, and 0%, respectively. The lower number of medicines in the SP visits was due, in part, to the injections' not being allowed based on ethical considerations (in response to the vignette, however, 65% of providers prescribed injections). The difference between provider knowledge and capacity is insignificant, while a significant large gap exists between provider performance and knowledge/capacity (for 11 of 17 indicators). Our analysis indicated that capacity constraints play a minor role in driving IUM compared to provider performance in the treatment of asthma cases in rural China. If similar findings hold for other disease cases, this suggests that policies to reduce the IUM in rural China have largely been unsuccessful, and alternatives for improving aligning provider incentives with appropriate drug use should be explored.

Biodistribution and environmental safety of a live-attenuated YF17D-vectored SARS-CoV-2 vaccine candidate.

New platforms are needed for the design of novel prophylactic vaccines and advanced immune therapies. Live-attenuated yellow fever vaccine YF17D serves as a vector for several licensed vaccines and platform for novel candidates. On the basis of YF17D, we developed an exceptionally potent COVID-19 vaccine candidate called YF-S0. However, use of such live RNA viruses raises safety concerns, such as adverse events linked to original YF17D (yellow fever vaccine-associated neurotropic disease [YEL-AND] and yellow fever vaccine-associated viscerotropic disease [YEL-AVD]). In this study, we investigated the biodistribution and shedding of YF-S0 in hamsters. Likewise, we introduced hamsters deficient in signal transducer and activator of transcription 2 (STAT2) signaling as a new preclinical model of YEL-AND/AVD. Compared with YF17D, YF-S0 showed improved safety with limited dissemination to brain and visceral tissues, absent or low viremia, and no shedding of infectious virus. Considering that yellow fever virus is transmitted by Aedes mosquitoes, any inadvertent exposure to the live recombinant vector via mosquito bites is to be excluded. The transmission risk of YF-S0 was hence compared with readily transmitting YF-Asibi strain and non-transmitting YF17D vaccine, with no evidence for productive infection of mosquitoes. The overall favorable safety profile of YF-S0 is expected to translate to other vaccines based on the same YF17D platform.