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Background: There is a lack of empirical data on design effects (DEFF) for mortality rate for highly clustered data such as with Ebola virus disease (EVD), along with a lack of documentation of methodological limitations and operational utility of mortality estimated from cluster-sampled studies when the DEFF is high., Objectives: The objectives of this paper are to report EVD mortality rate and DEFF estimates, and discuss the methodological limitations of cluster surveys when data are highly clustered such as during an EVD outbreak., Methods: We analysed the outputs of two independent population-based surveys conducted at the end of the 2014-2016 EVD outbreak in Bo District, Sierra Leone, in urban and rural areas. In each area, 35 clusters of 14 households were selected with probability proportional to population size. We collected information on morbidity, mortality and changes in household composition during the recall period (May 2014 to April 2015). Rates were calculated for all-cause, all-age, under-5 and EVD-specific mortality, respectively, by areas and overall. Crude and adjusted mortality rates were estimated using Poisson regression, accounting for the surveys sample weights and the clustered design., Results: Overall 980 households and 6,522 individuals participated in both surveys. A total of 64 deaths were reported, of which 20 were attributed to EVD. The crude and EVD-specific mortality rates were 0.35/10,000 person-days (95%CI: 0.23-0.52) and 0.12/10,000 person-days (95%CI: 0.05-0.32), respectively. The DEFF for EVD mortality was 5.53, and for non-EVD mortality, it was 1.53. DEFF for EVD-specific mortality was 6.18 in the rural area and 0.58 in the urban area. DEFF for non-EVD-specific mortality was 1.87 in the rural area and 0.44 in the urban area., Conclusion: Our findings demonstrate a high degree of clustering; this contributed to imprecise mortality estimates, which have limited utility when assessing the impact of disease. We provide DEFF estimates that can inform future cluster surveys and discuss design improvements to mitigate the limitations of surveys for highly clustered data.

Background: Skeletal muscle injury in Ebola virus disease (EVD) has been reported, but its association with morbidity and mortality remains poorly defined., Methods: This retrospective study included patients admitted to 2 EVD treatment units over an 8-month period in 2019 during an EVD epidemic in the Democratic Republic of the Congo., Results: An overall 333 patients (median age, 30 years; 58% female) had at least 1 creatine kinase (CK) measurement (n = 2229; median, 5/patient [IQR, 1-11]). Among patients, 271 (81%) had an elevated CK level (>380 U/L); 202 (61%) had rhabdomyolysis (CK >1000 IU/L); and 45 (14%) had severe rhabdomyolysis (≥5000 U/L). Among survivors, the maximum CK level was a median 1600 (IQR, 550-3400), peaking 3.4 days after admission (IQR, 2.3-5.5) and decreasing thereafter. Among fatal cases, the CK rose monotonically until death, with a median maximum CK level of 2900 U/L (IQR, 1500-4900). Rhabdomyolysis at admission was an independent predictor of acute kidney injury (adjusted odds ratio, 2.2 [95% CI, 1.2-3.8]; P = .0065) and mortality (adjusted hazard ratio, 1.7 [95% CI, 1.03-2.9]; P = .037)., Conclusions: Rhabdomyolysis is associated with acute kidney injury and mortality in patients with EVD. These findings may inform clinical practice by identifying laboratory monitoring priorities and highlighting the importance of fluid management., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Ebola virus disease (EVD) is associated with multisystem organ failure and high mortality. Severe hypoglycaemia is common, life-threatening, and correctable in critically ill patients, but glucose monitoring may be limited in EVD treatment units., Methods: We conducted a retrospective review of patients admitted to EVD treatment units in Butembo and Katwa, Eastern DRC. Glucose measurements were done using a handheld glucometer at the bedside or using the Piccolo xpress Chemistry Analyzer on venous samples., Findings: 384 patients (median age 30 years (interquartile range, IQR, 20-45), 57% female) and 6422 glucose measurements (median 11 per patient, IQR 4-22) were included in the analysis. Severe hypoglycaemia (≤2.2 mmol/L) and hyperglycaemia (>10 mmol/L) were recorded at least once during the ETU admission in 97 (25%) and 225 (59%) patients, respectively. A total of 2004 infusions of glucose-containing intravenous solutions were administered to 302 patients (79%) with a median cumulative dose of 175g (IQR 100-411). The overall case fatality rate was 157/384 (41%) and was 2.2-fold higher (95% CI 1.3-3.8) in patients with severe hypoglycaemia than those without hypoglycaemia (p = 0.0042). In a multivariable Cox proportional hazards model, periods of severe hypoglycaemia (adjusted hazard ratio (aHR) 6.2, 95% CI 3.2-12, p < 0.0001) and moderate hypoglycaemia (aHR 3.0, 95% CI 1.9-4.8, p < 0.0001) were associated with elevated mortality., Interpretation: Hypoglycaemia is common in EVD, requires repeated correction with intravenous dextrose solutions, and is associated with mortality., Funding: This study was not supported by any specific funding., Competing Interests: Declaration of interests SM is employed by Ridgeback Biotherapeutics, and is listed as inventor on the patent application for mAb 114, US Application No.62/087, 087 (PCT Application No. PCT/US2015/060,733) related to anti-Ebola virus antibodies and their use. SM receives royalties paid by the NIH Office of Financial Management (OFM)., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: The rVSVΔG-ZEBOV-GP vaccine constitutes a valuable tool to control Ebola virus disease outbreaks. This retrospective cohort study aimed to assess the protective effect of the vaccine against death among patients with confirmed Ebola virus disease., Methods: In this retrospective cohort analysis of patients with confirmed Ebola virus disease admitted to Ebola health facilities in the Democratic Republic of the Congo between July 27, 2018, and April 27, 2020, we performed univariate and multivariate analyses to assess case fatality risk and cycle threshold for nucleoprotein according to vaccination status, Ebola virus disease-specific treatments (eg, mAb114 and REGN-EB3), and other risk factors., Findings: We analysed all 2279 patients with confirmed Ebola virus disease. Of these 2279 patients, 1300 (57%) were female and 979 (43%) were male. Vaccination significantly lowered case fatality risk (vaccinated: 25% [106/423] vs not vaccinated: 56% [570/1015]; p<0·0001). In adjusted analyses, vaccination significantly lowered the risk of death compared with no vaccination, with protection increasing as time elapsed from vaccination to symptom onset (vaccinated ≤2 days before onset: 27% [27/99], adjusted relative risk 0·56 [95% CI 0·36-0·82, p=0·0046]; 3-9 days before onset: 20% [28/139], 0·44 [0·29-0·65, p=0·0001]; ≥10 days before onset: 18% [12/68], 0·40 [0·21-0·69; p=0·0022]; vaccination date unknown: 33% [39/117], 0·69 [0·48-0·96; p=0·0341]; and vaccination status unknown: 52% [441/841], 0·80 [0·70-0·91, p=0·0011]). Longer time from symptom onset to admission significantly increased risk of death (49% [1117/2279], 1·03 [1·02-1·05; p<0·0001]). Cycle threshold values for nucleoprotein were significantly higher-indicating lower viraemia-among patients who were vaccinated compared with those who were not vaccinated; the highest difference was observed among those vaccinated 21 days or longer before symptom onset (median 30·0 cycles [IQR 24·6-33·7]) compared with patients who were not vaccinated (21·4 cycles [18·4-25·9], p<0·0001)., Interpretation: To our knowledge, this is the first observational study describing the protective effect of rVSVΔG-ZEBOV-GP vaccination against death among patients with confirmed Ebola virus disease admitted to an Ebola health facility. Vaccination was protective against death for all patients, even when adjusted for Ebola virus disease-specific treatment, age group, and time from symptom onset to admission., Funding: Médecins Sans Frontières., Translation: For the French translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Ebola virus (EBOV) is a negative single-stranded RNA virus within the Filoviridae family and the causative agent of Ebola virus disease (EVD). Nonhuman primates (NHPs), including cynomolgus and rhesus macaques, are considered the gold standard animal model to interrogate mechanisms of EBOV pathogenesis. However, despite significant genetic similarity (>90%), NHP species display different clinical presentation following EBOV infection, notably a ∼1-2 days delay in disease progression. Consequently, evaluation of therapeutics is generally conducted in rhesus macaques, whereas cynomolgus macaques are utilized to determine efficacy of preventative treatments, notably vaccines. This observation is in line with reported differences in disease severity and host responses between these two NHP following infection with simian varicella virus, influenza A and SARS-CoV-2. However, the molecular underpinnings of these differential outcomes following viral infections remain poorly defined. In this study, we compared published transcriptional profiles obtained from cynomolgus and rhesus macaques infected with the EBOV-Makona Guinea C07 using bivariate and regression analyses to elucidate differences in host responses. We report the presence of a shared core of differentially expressed genes (DEGs) reflecting EVD pathology, including aberrant inflammation, lymphopenia, and coagulopathy. However, the magnitudes of change differed between the two macaque species. These findings suggest that the differential clinical presentation of EVD in these two species is mediated by altered transcriptional responses.

Ebola virus (EBOV), belonging to the species Zaire ebolavirus in the genus Ebolavirus , causes a severe febrile illness in humans with case fatality rates (CFRs) up to 90%. While there have been six virus species classified, which each have a single type virus in the genus Ebolavirus , CFRs of ebolavirus infections vary among viruses belonging to each distinct species. In this review, we aim to define the ebolavirus species-specific virulence on the basis of currently available laboratory and experimental findings. In addition, this review will also cover the variant-specific virulence of EBOV by referring to the unique biological and pathogenic characteristics of EBOV variant Makona, a new EBOV variant isolated from the 2013-2016 EBOV disease outbreak in West Africa. A better definition of species-specific and variant-specific virulence of ebolaviruses will facilitate our comprehensive knowledge on genus Ebolavirus biology, leading to the development of therapeutics against well-focused pathogenic mechanisms of each Ebola disease.

Background: Machine learning (ML) algorithms are now increasingly used in infectious disease epidemiology. Epidemiologists should understand how ML algorithms behave within the context of outbreak data where missingness of data is almost ubiquitous., Methods: Using simulated data, we use a ML algorithmic framework to evaluate data imputation performance and the resulting case fatality ratio (CFR) estimates, focusing on the scale and type of data missingness (i.e., missing completely at random-MCAR, missing at random-MAR, or missing not at random-MNAR)., Results: Across ML methods, dataset sizes and proportions of training data used, the area under the receiver operating characteristic curve decreased by 7% (median, range: 1%-16%) when missingness was increased from 10% to 40%. Overall reduction in CFR bias for MAR across methods, proportion of missingness, outbreak size and proportion of training data was 0.5% (median, range: 0%-11%)., Conclusion: ML methods could reduce bias and increase the precision in CFR estimates at low levels of missingness. However, no method is robust to high percentages of missingness. Thus, a datacentric approach is recommended in outbreak settings-patient survival outcome data should be prioritised for collection and random-sample follow-ups should be implemented to ascertain missing outcomes., Competing Interests: The authors have declared that no competing interest exist.

Background: Detailed longitudinal studies of HIV-positive individuals in West Africa are lacking. Here the HIV prevalence, incidence, all-cause mortality, and the proportion of individuals receiving treatment with cART in two cohorts of participants in Ebola-related studies are described., Setting: Individuals of all ages were enrolled and followed at four sites in the area of Monrovia, Liberia., Methods: Two cohorts identified in response to the Ebola epidemic are described to provide insights into the current state of the HIV epidemic. HIV testing was performed at baseline for participants in both cohorts and during follow-up in one cohort., Results: Prevalence and incidence of HIV (prevalence of 3.1% for women and 1.4% for men and incidence of 3.3 per 1,000) were higher in these cohorts compared to 2018 national estimates (prevalence of 1.3% and incidence of 0.39 per 1,000). Most participants testing positive did not know their status prior to testing. Of those who knew they were HIV positive, 7.9% reported being on antiretroviral treatment. The death rate among those with HIV was 12.3% compared to 1.9% in HIV-negative individuals (adjusted odds ratio of 6.87). While higher levels of d-dimer were associated with increased mortality, this was not specific to those with HIV, however lower hemoglobin levels were associated with increased mortality among those with HIV., Conclusion: These findings point to a need to perform further research studies aimed at fulfilling these knowledge gaps and address current shortcomings in the provision of care for those living with HIV in Liberia., Competing Interests: The authors have declared that no competing interests exist.

Ebolaviruses Bundibugyo virus (BDBV) and Ebola virus (EBOV) cause fatal hemorrhagic disease in humans and nonhuman primates. While the host response to EBOV is well characterized, less is known about BDBV infection. Moreover, immune signatures that mediate natural protection against all ebolaviruses remain poorly defined. To explore these knowledge gaps, we transcriptionally profiled BDBV-infected rhesus macaques, a disease model that results in incomplete lethality. This approach enabled us to identify prognostic indicators. As expected, survival (∼60%) correlated with reduced clinical pathology and circulating infectious virus, although peak viral RNA loads were not significantly different between surviving and nonsurviving macaques. Survivors had higher anti-BDBV antibody titers and transcriptionally derived cytotoxic T cell-, memory B cell-, and plasma cell-type quantities, demonstrating activation of adaptive immunity. Conversely, a poor prognosis was associated with lack of an appropriate adaptive response, sustained innate immune signaling, and higher expression of myeloid-derived suppressor cell (MDSC)-related transcripts ( S100A8 , S100A9 , CEBPB , PTGS2 , CXCR1 , and LILRA3 ). MDSCs are potent immunosuppressors of cellular and humoral immunity, and therefore, they represent a potential therapeutic target. Circulating plasminogen activator inhibitor 1 (PAI-1) and tissue plasminogen activator (tPA) levels were also elevated in nonsurvivors and in survivors exhibiting severe illness, emphasizing the importance of maintaining coagulation homeostasis to control disease progression. IMPORTANCE Bundibugyo virus (BDBV) and Ebola virus (EBOV) are ebolaviruses endemic to Africa that cause severe, often fatal hemorrhagic disease. BDBV is considered a less pathogenic ebolavirus due to its reduced lethality during human outbreaks, as well as in experimentally infected nonhuman primates. The reduced mortality of BDBV in NHP models, resulting in a pool of survivors, afforded us the unique opportunity of identifying immune correlates that confer protection against ebolaviruses. In this study, we discovered that the survival of BDBV-infected nonhuman primates (NHPs) was dependent on early development of adaptive (memory) immune responses and reduced myeloid-derived suppressor cell (MDSC)-related signaling. MDSCs are a heterogenous group of immune cells implicated in a number of diseases that are powerful immunosuppressors of cellular and humoral immunity. Thus, MDSCs represent a novel therapeutic target to prevent ebolavirus disease. To our knowledge, this is the first study to link increased morbidity with recruitment of these potent immunosuppressive cells.

The unprecedented 2013-2016 West Africa Ebola outbreak accelerated several medical countermeasures (MCMs) against Ebola virus disease (EVD). Several investigational products (IPs) were used throughout the outbreak but were not conclusive for efficacy results. Only the Randomized Controlled Trial (RCT) on ZMapp was promising but inconclusive. More recently, during the second-largest Ebola outbreak in North Kivu and Ituri provinces, Democratic Republic of the Congo (DRC), four IPs, including one small molecule (Remdesivir), two monoclonal antibody (mAb) cocktails (ZMapp and REGN-EB3) and a single mAb (mAb114), were evaluated in an RCT, the Pamoja Tulinde Maisha (PALM) study. Two products (REGN-EB3 and mAb114) demonstrated efficacy as compared to the control arm, ZMapp. There were remarkably few side effects recorded in the trial. The FDA approved both medications in this scientifically sound study, marking a watershed moment in the field of EVD therapy. These products can be produced relatively inexpensively and can be stockpiled. The administration of mAbs in EVD patients appears to be safe and effective, while several critical knowledge gaps remain; the impact of early administration of Ebola-specific mAbs on developing a robust immune response for future Ebola virus exposure is unknown. The viral mutation escape, leading to resistance, presents a potential limitation for single mAb therapy; further improvements need to be explored. Understanding the contribution of Fc-mediated antibody functions such as antibody-dependent cellular cytotoxicity (ADCC) of those approved mAbs is still critical. The potential merit of combination therapy and post-exposure prophylaxis (PEP) need to be demonstrated. Furthermore, the PALM trial has accounted for 30% of mortality despite the administration of specific treatments. The putative role of EBOV soluble Glycoprotein (sGP) as a decoy to the immune system, the virus persistence, and relapses might be investigated for treatment failure. The development of pan-filovirus or pan-species mAbs remains essential for protection. The interaction between FDA-approved mAbs and vaccines remains unclear and needs to be investigated. In this review, we summarize the efficacy and safety results of the PALM study and review current research questions for the further development of mAbs in pre-exposure or emergency post-exposure use., Competing Interests: OTM is employed by Leidos Biomedical Research. SM is employed by Ridgeback Biotherapeutics, and is listed as inventor on the patent application for mAb 114, US Application No.62/087, 087 (PCT Application No. PCT/US2015/060733) related to anti-Ebola virus antibodies and their use. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Tshiani Mbaya, Mukumbayi and Mulangu.)

Pandemics have been recognized as a serious global threat to humanity. To effectively prevent the spread and outbreak of the epidemic disease, theoretical models intended to depict the disease dynamics have served as the main tools to understand its underlying mechanisms and thus interrupt its transmission. Two commonly-used models are mean-field compartmental models and agent-based models (ABM). The former ones are analytically tractable for describing the dynamics of subpopulations by cannot explicitly consider the details of individual movements. The latter one is mainly used to the spread of epidemics at a microscopic level but have limited simulation scale for the randomness of the results. To overcome current limitations, a hierarchical hybrid modeling and simulation method, combining mean-field compartmental model and ABM, is proposed in this paper. Based on this method, we build a hybrid model, which takes both individual heterogeneity and the dynamics of sub-populations into account. The proposed model also investigates the impact of combined interventions (i. e. vaccination and pre-deployment training) for healthcare workers (HCWs) on the spread of disease. Taking the case of 2014-2015 Ebola Virus Disease (EVD) in Sierra Leone as an example, we examine its spreading mechanism and evaluate the effect of prevention by our parameterized and validated hybrid model. According to our simulation results, an optimal combination of pre-job training and vaccination deployment strategy has been identified. To conclude, our hybrid model helps informing the synergistic disease control strategies and the corresponding hierarchical hybrid modeling and simulation method can further be used to understand the individual dynamics during epidemic spreading in large scale population and help inform disease control strategies for different infectious disease., Competing Interests: The authors have declared that no competing interests exist.

Background: Ebola virus disease (EVD) is an often-fatal infection where the effectiveness of medical countermeasures is uncertain. During the West African outbreak (2013-2016), several patients were treated with different types of anti-viral therapies including monoclonal antibody-based cocktails that had the potential to neutralise Ebola virus (EBOV). However, at the time, the efficacy of these therapies was uncertain. Given the scale of the outbreak, several clinical phenotypes came to the forefront including the ability of the same virus to cause recrudescence in the same patient-perhaps through persisting in immune privileged sites. Several key questions remained including establishing if monoclonal antibody therapy was effective in humans with severe EVD, whether virus escape mutants were selected during treatment, and what is the potential mechanism(s) of persistence. This was made possible through longitudinal samples taken from a UK patient with EVD., Methods: Several different sample types, plasma and cerebrospinal fluid, were collected and sequenced using Illumina-based RNAseq. Sequence reads were mapped both to EBOV and the human genome and differential gene expression analysis used to identify changes in the abundance of gene transcripts as infection progressed. Digital Cell Quantitation analysis was used to predict the immune phenotype in samples derived from blood., Results: The findings were compared to equivalent data from West African patients. The study found that both virus and host markers were predictive of a fatal outcome. This suggested that the extensive supportive care, and most likely the application of the medical countermeasure ZMab (a monoclonal antibody cocktail), contributed to survival of the UK patient. The switch from progression to a 'fatal' outcome to a 'survival' outcome could be seen in both the viral and host markers. The UK patient also suffered a recrudescence infection 10 months after the initial infection. Analysis of the sequencing data indicated that the virus entered a period of reduced or minimal replication, rather than other potential mechanisms of persistence-such as defective interfering genomes., Conclusions: The data showed that comprehensive supportive care and the application of medical countermeasures are worth pursuing despite an initial unfavourable prognosis.

During Sierra Leone's 2014-2015 Ebola virus disease (EVD) epidemic, early reports warned of health system collapse and potential effects on other-cause mortality. These same warnings are reverberating during the COVID-19 pandemic. Consideration of the impacts of EVD on maternal and child health services from facility data can be instructive during COVID-19. We surveyed all peripheral healthcare units (PHUs) in Sierra Leone in October 2014 and March 2015 to assess closures, staffing, amenities, medicines, supplies, and service utilization during May 2014-January 2015 and October 2013-January 2014. We report PHU characteristics and service utilization changes for equivalent 4-month periods during the epidemic and the prior year. We present utilization changes by district and service type, and model excess child mortality. PHU closures (-8%) and staff attrition (-3%) were limited, but many facilities lacked amenities, medicines, and supplies. Utilization of preventive and scheduled services fell more than individualized, clinical care interventions, aside from malaria treatment which declined significantly. Ebola virus disease intensity in districts was weakly associated with utilization, aside from two districts that were severely affected. Modeling suggests utilization declines resulted in 6,782 excess under-five deaths (an increase of 21%) between 2014 and 2015. Ebola virus disease negatively affected service provision, but utilization declined relatively more, particularly for preventive and scheduled interventions. Although these findings are specific to Sierra Leone's EVD epidemic, they illustrate the magnitude of possible effects in other settings due to COVID-19-induced service disruptions, where collateral impacts on child mortality from other preventable causes may far outweigh COVID-19 mortality.

Patients and physicians worldwide are facing tremendous health care hazards that are caused by the ongoing severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) pandemic. Remdesivir (GS-5734) is the first approved treatment for severe coronavirus disease 2019 (COVID-19). It is a novel nucleoside analog with a broad antiviral activity spectrum among RNA viruses, including ebolavirus (EBOV) and the respiratory pathogens Middle East respiratory syndrome coronavirus (MERS-CoV), SARS-CoV, and SARS-CoV-2. First described in 2016, the drug was derived from an antiviral library of small molecules intended to target emerging pathogenic RNA viruses. In vivo , remdesivir showed therapeutic and prophylactic effects in animal models of EBOV, MERS-CoV, SARS-CoV, and SARS-CoV-2 infection. However, the substance failed in a clinical trial on ebolavirus disease (EVD), where it was inferior to investigational monoclonal antibodies in an interim analysis. As there was no placebo control in this study, no conclusions on its efficacy in EVD can be made. In contrast, data from a placebo-controlled trial show beneficial effects for patients with COVID-19. Remdesivir reduces the time to recovery of hospitalized patients who require supplemental oxygen and may have a positive impact on mortality outcomes while having a favorable safety profile. Although this is an important milestone in the fight against COVID-19, approval of this drug will not be sufficient to solve the public health issues caused by the ongoing pandemic. Further scientific efforts are needed to evaluate the full potential of nucleoside analogs as treatment or prophylaxis of viral respiratory infections and to develop effective antivirals that are orally bioavailable., (Copyright © 2020 American Society for Microbiology.)

Objective: To study Ebola virus disease (EVD) in children aged 15 years and below, and to identify risk factors associated with death., Patients and Methods: Retrospective, multicenter, descriptive, and analytical study of files of children aged 15 years and below in Ebola treatment centers (ETC) of Donka from March 2014 to May 2015. We included all files of children aged 15 years and below hospitalized for EVD in the two ETCs., Results: A total of 739 patients hospitalized in both ETCs, 146 children aged 15 years and below (20%) were registered during the study period. The mean age of children was 6.73±4.26 years. Most children were aged above five years (65.8%) and the mean time to consultation was 4.34±3.21 days. The main clinical signs were asthenia (78.8%), fever (75.3%), anorexia (53.4%), headache (45.9%), vomiting (41.8%), abdominal pain (29.5%), and diarrhea (28.8%). The case fatality was 48%, including 54.3% in Coyah and 45% in Conakry. Older age (aOR=0.83, 95% CI [0.76-0.95]), fever (aOR=3.28, 95% CI [1.22-8.87]), diarrhea (aOR=2.98, 95% CI [1.19-4.48]), and hemorrhage (aOR=3.13, 95% CI [1.00-10.38]) were independently associated with death due to EVD., Conclusion: EVD remains serious especially in children, with high case fatality. Risk factors independently associated with death were young age, diarrhea, hemorrhage, and fever. Particular attention to these risk factors and vaccination will contribute to improving the prognosis of EVD in children., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

The conduct of clinical trials during the West Africa Ebola outbreak in 2014 highlighted many ethical challenges. How these challenges were addressed, what clinical studies were conducted during that outbreak, and the lessons learned for dealing with future outbreaks were the subject of a National Academy of Medicine committee report titled Integrating Clinical Research into Epidemic Response: The Ebola Experience . This report suggested improvements for research during subsequent emerging or re-emerging outbreaks and is summarized in this review. We also discuss the current Ebola outbreak in the Democratic Republic of the Congo and highlight how the dialogue has changed and how successful clinical trials have been implemented. We conclude with a description of productive efforts to include pregnant women and children in therapeutic and vaccine trials during outbreaks that are currently ongoing.

Purpose: Sierra Leone recorded the highest incidence rate for the 2013-2016 West African Ebola outbreak. In this investigation, we used the medical records of Ebola patients with different sociodemographic and clinical features to determine the factors that are associated with Ebola treatment outcome during the 2013-2016 West African Ebola outbreak in Sierra Leone and constructed a predictive in-facility mortality score., Methods: We used the anonymized medical records of 1077 laboratory-confirmed pediatric and adult patients with EVD who received treatment at the 34 Military Hospital and the Police Training School Ebola Treatment Centers in Sierra Leone between the period of June 2014 and April 2015. We later determined the in-facility case fatality rates for Ebola, the odds of dying during Ebola treatment, and later constructed a predictive in-facility mortality score for these patients based on their clinical and sociodemographic characteristics., Results: We constructed a model that partitioned the study population into three mortality risk groups of equal patient numbers, based on risk scoring: low (score ≤ -5), medium (score -4 to 1), and high-risk group (score ≥ 2). The CFR of patients with EVD belonging to the low- (≤-5), medium (-4 to 1), and high- (≥2) risk groups were 0.56%, 9.75%, and 67.41%, respectively., Conclusions: We succeeded in designing an in-facility mortality risk score that reflects EVD clinical severity and can assist in the clinical prioritization of patients with EVD., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Sierra Leone experienced the largest documented epidemic of Ebola Virus Disease in 2014-2015. The government implemented a national tollfree telephone line (1-1-7) for public reporting of illness and deaths to improve the detection of Ebola cases. Reporting of deaths declined substantially after the epidemic ended. To inform routine mortality surveillance, we aimed to describe the trends in deaths reported to the 1-1-7 system and to quantify people's motivations to continue reporting deaths after the epidemic., Methods: First, we described the monthly trends in the number of deaths reported to the 1-1-7 system between September 2014 and September 2019. Second, we conducted a telephone survey in April 2017 with a national sample of individuals who reported a death to the 1-1-7 system between December 2016 and April 2017. We described the reported deaths and used ordered logistic regression modeling to examine the potential drivers of reporting motivations., Findings: Analysis of the number of deaths reported to the 1-1-7 system showed that 12% of the expected deaths were captured in 2017 compared to approximately 34% in 2016 and over 100% in 2015. We interviewed 1,291 death reporters in the survey. Family members reported 56% of the deaths. Nearly every respondent (94%) expressed that they wanted the 1-1-7 system to continue. The most common motivation to report was to obey the government's mandate (82%). Respondents felt more motivated to report if the decedent exhibited Ebola-like symptoms (adjusted odds ratio 2.3; 95% confidence interval 1.8-2.9)., Conclusions: Motivation to report deaths that resembled Ebola in the post-outbreak setting may have been influenced by knowledge and experiences from the prolonged epidemic. Transitioning the system to a routine mortality surveillance tool may require a robust social mobilization component to match the high reporting levels during the epidemic, which exceeded more than 100% of expected deaths in 2015., Competing Interests: The authors have declared that no competing interests exist.

The outbreak of Ebola virus disease (EVD) that raged between 2014 and 2016 in the West African sub-region was one of the global epidemics that spiked international public health concern in the last decade. Since the discovery of ebolavirus in 1976, the 2014-2016 epidemics have been the worst with significant case fatality rates and socioeconomic impact in the affected countries. This review looks at important health determinants that directly accounted for the spatial events of rapid spread and severity of EVD in West Africa, with consequent high fatality rates. It also brings up a time-point health determinant model to conceptualize understanding of this important outbreak with a view to enlightening the public andproviding valuable recommendations that may be crucial to preventing or curtailing any future outbreak of the disease., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The outbreaks of Ebola virus between 2014 and 2020 have drawn attention to knowledge gaps related to Ebola virus disease in pregnant women. The aim of this study was to systematically evaluate available data on pregnant and lactating women with acute Ebola virus disease or following recovery. We searched MEDLINE, Embase, Cochrane Library (CENTRAL), Web of Science Core Collection, CINAHL, POPLINE, Global Health, and WHO Global Index Medicus, in addition to grey literature, for relevant articles. Studies of all types and published between database inception and Aug 19, 2019, were eligible (PROSPERO 129335). We identified 1060 records, of which 52 studies met our inclusion criteria. Overall, mortality in 274 pregnant women with Ebola virus disease was 72% (197 women died); mortality for pregnant women with Ebola virus disease were not higher than those in the general population of patients with Ebola virus disease. Nearly all women with Ebola virus disease had adverse pregnancy outcomes. Among survivors, Ebola virus RNA was detected by RT-PCR in amniotic fluid up to 32 days after maternal clearance of Ebola virus from the blood and in breastmilk 26 days after symptom onset. A risk of transmission of Ebola virus from pregnancy-related fluids and breastmilk probably exists, and precautions should be taken., (Copyright © 2020 World Health Organization. Published by Elsevier Ltd. All rights reserved. Published by Elsevier Ltd.. All rights reserved.)

Competing Interests: Competing interests: The authors completed the ICMJE Unified Competing Interest form (available upon request from the corresponding author), and declare no conflicts of interest.

Background: The 2018-2019 Ebola virus disease (EVD) outbreak in North Kivu and Ituri provinces in the Democratic Republic of the Congo (DRC) is the largest ever recorded in the DRC. It has been declared a Public Health Emergency of International Concern. The outbreak emerged in a region of chronic conflict and insecurity, and directed attacks against health care workers may have interfered with disease response activities. Our study characterizes and quantifies the broader conflict dynamics over the course of the outbreak by pairing epidemiological and all available spatial conflict data., Methods: We build a set of conflict variables by mapping the spatial locations of all conflict events and their associated deaths in each of the affected health zones in North Kivu and Ituri, eastern DRC, before and during the outbreak. Using these data, we compare patterns of conflict before and during the outbreak in affected health zones and those not affected. We then test whether conflict is correlated with increased EVD transmission at the health zone level., Findings: The incidence of conflict events per capita is ~ 600 times more likely in Ituri and North Kivu than for the rest of the DRC. We identified 15 time periods of substantial uninterrupted transmission across 11 health zones and a total of 120 bi-weeks. We do not find significant short-term associations between the bi-week reproduction numbers and the number of conflicts. However, we do find that the incidence of conflict per capita was correlated with the incidence of EVD per capita at the health zone level for the entire outbreak (Pearson's r = 0.33, 95% CI 0.05-0.57). In the two provinces, the monthly number of conflict events also increased by a factor of 2.7 in Ebola-affected health zones (p value < 0.05) compared to 2.0 where no transmission was reported and 1.3 in the rest of the DRC, in the period between February 2019 and July 2019., Conclusion: We characterized the association between variables documenting broad conflict levels and EVD transmission. Such assessment is important to understand if and how such conflict variables could be used to inform the outbreak response. We found that while these variables can help characterize long-term challenges and susceptibilities of the different regions they provide little insight on the short-term dynamics of EVD transmission.

Background: The 2013-2016 West Africa Ebola Virus Disease (EVD) outbreak recorded the highest incidence and mortality since the discovery of the virus in Zaire in 1976; with more than 28,000 probable and confirmed EVD cases and 11,000 deaths. Studies relating to previous outbreaks usually involved small sample sizes. In this study we are set to identify those sociodemographic and clinical features that predict in-facility mortality among EVD patients using a large sample size., Methods: We analysed the anonymized medical records of 938 laboratory-confirmed EVD patients 15 years old and above who received treatment at The 34 Military Hospital and The Police Training School EVD Treatment Centers in Sierra Leone in the period June 2014 to April 2015. We used both univariable and multivariable logistic regression to determine the predictors for in-facility mortality of these patients based on their sociodemographic and clinical characteristics., Results: The median age of the EVD cases was 33 years (interquartile range = 25 to 40 years). The majority of the EVD cases were male (59.0%) and had secondary level education (79.3%). We reported a low overall in-facility case fatality rate of 26.4%. The associations between case fatality rates and EVD patients who reported fever, abdominal pain, cough, diarrhoea, vomiting, fatigue, haemorrhage, dysphagia, conjunctival injection, dyspnea, and skin rash at the time of admission were all statistically significant (p <  0.05). Our preferred model with the age group 65 years and above alongside the following clinical symptoms; diarrhoea, vomiting, fatigue, dysphagia, conjunctival injection, dyspnea and cough produced a receiver operating characteristic (ROC) curve with an AUC (area under the curve) value of 0.93., Conclusions: We constructed a simple model that can be optimally used alongside other rapid EVD diagnostic tools to identify EVD in-facility treatment mortality predictors based on the sociodemographic characteristics and clinical symptoms of adult EVD patients. We also reported low EVD cases among patients with secondary and tertiary education. These subpopulations of our patients who are generally informed about the signs and symptoms of EVD, alongside our treatment regimen may have been responsible for our comparatively lower case fatality rate.

The epidemic of Coronavirus disease 2019 (COVID-19) in China caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has become a global concern and subsequently labeled a pandemic by the World Health Organization on March 11th. As the world mobilizes to contain the COVID-19, scientists and public health experts are increasingly alarmed about the potentially catastrophic effects of an outbreak in Africa. The establishment of Africa Centres for Disease Control and Prevention by the Africa Union in 2017 was an unprecedented move toward strengthening national responses, so far enabling all fifty member states with confirmed cases of COVID-19 to adequately respond, break chains of transmission and effectively contain the spread of SARS-CoV-2. We enter an uncertain and challenging period that may severely test the preparedness, organizational resource and resilience of African states and the fabric of their societies. However, we speculate that the fear associated with COVID-19 may also lead to some of the long-standing messages about simple measures to reduce the spread, such as hand washing, finally becoming absorbed and more universally adopted by health workers and the public. Is it possible that regardless of the terrible threat posed by SARS-CoV-2, the increased adoption of these health protection measures may result in a reduction in the spread of other infectious diseases?, Competing Interests: The authors declare no competing interests., (© Raoul Emeric Guetiya Wadoum et al.)

Objective: To evaluate the association between oral third-generation cephalosporin antibiotic treatment and mortality in Ebola virus disease (EVD)., Methods: This retrospective cohort studied EVD-infected patients admitted to five Ebola Treatment Units in Sierra Leone and Liberia during 2014-15. Empiric treatment with cefixime 400 mg once daily for five days was the clinical protocol; however, due to resource variability, only a subset of patients received treatment. Data on sociodemographics, clinical characteristics, malaria status and Ebola viral loads were collected. The primary outcome was mortality compared between cases treated with cefixime within 48 h of admission to those not treated within 48 h. Propensity scores were derived using clinical covariates. Mortality between treated and untreated cases was compared using propensity-matched conditional logistic regression and bootstrapped log-linear regression analyses to calculate an odds ratio (OR) and relative risk (RR), respectively, with associated 95% confidence intervals (CI)., Results: Of 424 cases analysed, 360 (84.9%) met the cefixime treatment definition. The mean age was 30.5 years and 40.3% were male. Median cefixime treatment duration was 4 days (IQR: 3, 5). Among cefixime-treated patients, mortality was 54.7% (95% CI: 49.6-59.8%) vs. 73.4% (95% CI: 61.5-82.7%) in untreated patients. In conditional logistic regression, mortality likelihood was significantly lower among cases receiving cefixime (OR = 0.48, 95% CI: 0.32-0.71; P = 0.01). In the bootstrap analysis, a non-significant risk reduction was found with cefixime treatment (RR = 0.82, 95% CI: 0.64-1.16, P = 0.11)., Conclusion: Early oral cefixime may be associated with reduced mortality in EVD and warrants further investigation., (© 2020 John Wiley & Sons Ltd.)

Background: For the 2013-2016 Ebola epidemic in West Africa, the largest Ebola virus disease (EVD) epidemic to date, we aim to analyse the patient mix in detail to characterise key sources of spatiotemporal heterogeneity in the case fatality ratios (CFR)., Methods: We applied a non-parametric Boosted Regression Trees (BRT) imputation approach for patients with missing survival outcomes and adjusted for model imperfection. Semivariogram analysis and kriging were used to investigate spatiotemporal heterogeneities., Results: CFR estimates varied significantly between districts and over time over the course of the epidemic. BRT modelling accounted for most of the spatiotemporal variation and interactions in CFR, but moderate spatial autocorrelation remained for distances up to approximately 90 km. Combining district-level CFR estimates and kriged district-level residuals provided the best linear unbiased predicted map of CFR accounting for the both explained and unexplained spatial variation. Temporal autocorrelation was not observed in the district-level residuals from the BRT estimates., Conclusions: This study provides new insight into the epidemiology of the 2013-2016 West African Ebola epidemic with a view of informing future public health contingency planning, resource allocation and impact assessment. The analytical framework developed in this analysis, coupled with key domain knowledge, could be deployed in real time to support the response to ongoing and future outbreaks., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The second largest Ebolavirus disease (EVD) outbreak ever recorded is currently ongoing in Eastern Democratic Republic of the Congo (DRC). This is the first outbreak for which the recombinant Vesicular Stomatitis Virus - Zaire Ebolavirus (rVSV-ZEBOV) candidate vaccine has been widely administered, using a ring vaccination strategy. We examined whether prior vaccination with rVSV-ZEBOV impacts viral load, organ impairment, and survival among patients with EVD admitted to Ebola Treatment Units (ETUs) in the DRC. We conducted a retrospective observational study of patients admitted to the ETUs in Butembo and Katwa, Eastern DRC, between 30 March and 10 August 2019. We included 257 patients, of whom 44 had been vaccinated prior to admission and 213 were unvaccinated. Vaccinated patients were admitted to hospital sooner than unvaccinated patients (median 2 days (IQR 1.8-4) versus 4 days (IQR 3-6), p < 0.001). Vaccinated patients had a lower viral load at admission compared to those who were unvaccinated: 6.0 log 10 cp/mL (IQR 5.0-7.1) versus 6.9 log 10 cp/mL (IQR 5.4-7.6), p = 0.017. In a longitudinal analysis of daily viral load measurements, vaccinated patients had an overall viremia 1.32 log 10 cp/mL (95% CI 0.58-2.1) lower than unvaccinated patients over the course of their infection. Acute kidney injury at admission was less common in vaccinated patients: OR 0.44 (95% CI 0.20-0.94), p = 0.027. Mortality in vaccinated patients was 10/44 (23%) compared to 117/213 (55%) unvaccinated patients (OR 0.24, 95% CI 0.11-0.51, p < 0.001). In conclusion, prior rVSV-ZEBOV vaccination was associated with reduced severity of infection and improved survival among patients with confirmed EVD treated at ETUs in Eastern DRC. These findings support the efficacy of the rVSV-ZEBOV vaccine in modulating EVD severity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: TKM-130803 is a specific anti-EBOV therapeutic comprised of two small interfering RNAs (siRNA) siLpol-2 and siVP35-2. The pharmacokinetics (PK) of these siRNAs was defined in Ebola virus disease (EVD) patients, with reference to efficacy (ET) and toxicology thresholds (TT). The relationship between PK and patient survival was explored., Methods: Pharmacokinetic (PK) and pharmacodynamic (PD) data were available for seven participants with EVD in Sierra Leone who received 0·3 mg/kg of TKM-130803 by intravenous infusion over 2 h daily for up to 7 days. Plasma concentration of siRNA was compared to survival at 14 days. PK data were fitted to two-compartment models then Monte Carlo simulated PK profiles were compared to ET (Cmax 0·04-0·57 ng/mL and mean concentration 1·43 ng/mL), and TT (3000 ng/mL)., Findings: Viral loads (VL) were not significantly different at treatment onset or during treatment (p = 0·1) in subjects who survived or died. siRNA was in quantitative excess of virus genomes throughout treatment, but the 95% percentile exceeded TT. The maximum AUC for which the 95% percentile remained under TT was a continuous infusion of 0·15 mg/kg/day. Plasma concentration of both siRNAs were higher in subjects who died compared to subjects who survived (p<0·025 both siRNAs)., Interpretation: TKM-130803 was circulating in molar excess of circulating virus; a level considered needed for efficacy. Given extremely high viral loads it seems likely that the patients died because they were physiologically beyond the point of no return. Subjects who died exhibited some indication of impaired drug clearance, justifying caution in dosing strategies for such patients. This analysis has given a useful insight into the pharmacokinetics of the siRNA in the disease state and illustrates the value of designing PKPD studies into future clinical trials in epidemic situations., Funding: This work was supported by the Wellcome Trust of Great Britain (grant number 106491/Z/14/Z and 097997/Z/11/A) and by the EU FP7 project PREPARE (602525). The PHE laboratory was funded by the UK Department for International Development. The funders had no role in trial design, data collection or analysis. The views expressed are those of the authors and not necessarily those of Public Health England, the Department of Health, or the EU., Trial Registration: Pan African Clinical Trials Registry PACTR201501000997429., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Recent Ebola virus (EBOV) outbreaks in West Africa and the Democratic Republic of the Congo have highlighted the urgent need for approval of medical countermeasures for treatment and prevention of EBOV disease (EVD). Until recently, when successes were achieved in characterizing the efficacy of multiple experimental EVD therapeutics in humans, the only feasible way to obtain data regarding potential clinical benefits of candidate therapeutics was by conducting well-controlled animal studies. Nonclinical studies are likely to continue to be important tools for screening and development of new candidates with improved pharmacological properties. Here, we describe a natural history study to characterize the time course and order of progression of the disease manifestations of EVD in rhesus monkeys. In 12 rhesus monkeys exposed by the intramuscular route to 1000 plaque-forming units of EBOV, multiple endpoints were monitored for 28 days following exposure. The disease progressed rapidly with mortality events occurring 7-10 days after exposure. Key disease manifestations observed consistently across the infected animals included, but were not limited to, viremia, fever, systemic inflammation, coagulopathy, lymphocytolysis, renal tubular necrosis with mineralization, and hepatocellular degeneration and necrosis.

Background: Although several experimental therapeutics for Ebola virus disease (EVD) have been developed, the safety and efficacy of the most promising therapies need to be assessed in the context of a randomized, controlled trial., Methods: We conducted a trial of four investigational therapies for EVD in the Democratic Republic of Congo, where an outbreak began in August 2018. Patients of any age who had a positive result for Ebola virus RNA on reverse-transcriptase-polymerase-chain-reaction assay were enrolled. All patients received standard care and were randomly assigned in a 1:1:1:1 ratio to intravenous administration of the triple monoclonal antibody ZMapp (the control group), the antiviral agent remdesivir, the single monoclonal antibody MAb114, or the triple monoclonal antibody REGN-EB3. The REGN-EB3 group was added in a later version of the protocol, so data from these patients were compared with those of patients in the ZMapp group who were enrolled at or after the time the REGN-EB3 group was added (the ZMapp subgroup). The primary end point was death at 28 days., Results: A total of 681 patients were enrolled from November 20, 2018, to August 9, 2019, at which time the data and safety monitoring board recommended that patients be assigned only to the MAb114 and REGN-EB3 groups for the remainder of the trial; the recommendation was based on the results of an interim analysis that showed superiority of these groups to ZMapp and remdesivir with respect to mortality. At 28 days, death had occurred in 61 of 174 patients (35.1%) in the MAb114 group, as compared with 84 of 169 (49.7%) in the ZMapp group (P = 0.007), and in 52 of 155 (33.5%) in the REGN-EB3 group, as compared with 79 of 154 (51.3%) in the ZMapp subgroup (P = 0.002). A shorter duration of symptoms before admission and lower baseline values for viral load and for serum creatinine and aminotransferase levels each correlated with improved survival. Four serious adverse events were judged to be potentially related to the trial drugs., Conclusions: Both MAb114 and REGN-EB3 were superior to ZMapp in reducing mortality from EVD. Scientifically and ethically sound clinical research can be conducted during disease outbreaks and can help inform the outbreak response. (Funded by the National Institute of Allergy and Infectious Diseases and others; PALM ClinicalTrials.gov number, NCT03719586.)., (Copyright © 2019 Massachusetts Medical Society.)

The paper considers local responses to the introduction of an Ebola Treatment Centre in eastern Sierra Leone during the West African epidemic of 2014-15. Our study used qualitative methods consisting of focus groups and interviews, to gather responses from patients, members of the families of survivors and deceased victims of the disease, social liaison workers from the centre, and members of the general public. The data indicate that scepticism and resistance were widespread at the outset, but that misconceptions were replaced, in the minds of those directly affected by the disease, by more positive later assessments. Social workers, and social contacts of families with workers in the centre, helped reshape these perceptions, but a major factor was direct experience of the disease. This is apparent in the positive endorsements by survivors and families who had members taken to the facility. Even relatives of deceased victims agreed that the case-handling centre was valuable. However, we also present evidence of continuing scepticism in the minds of members of the general public, who continue to suspect that Ebola was a crisis manufactured for external benefit. Our conclusions stress the importance of better connectivity between communities and Ebola facilities to facilitate experiential learning. There is also a need to address the wider cognitive shock caused by a well-funded Ebola health initiative arriving in communities with a long history of inadequate health care. Restoring trust in medicine requires Ebola Virus Disease to be re-contextualized within a broader framework of concern for the health of all citizens., Competing Interests: The authors have declared that no competing interests exist.

Ebola virus disease (EVD), caused by Ebola viruses, resulted in more than 11 500 deaths according to a recent 2018 WHO report. With mortality rates up to 90%, it is nowadays one of the most deadly infectious diseases. However, no Food and Drug Administration-approved Ebola drugs or vaccines are available yet with the mainstay of therapy being supportive care. The high fatality rate and absence of effective treatment or vaccination make Ebola virus a category-A biothreat pathogen. Fortunately, a series of investigational countermeasures have been developed to control and prevent this global threat. This review summarizes the recent therapeutic advances and ongoing research progress from research and development to clinical trials in the development of small-molecule antiviral drugs, small-interference RNA molecules, phosphorodiamidate morpholino oligomers, full-length monoclonal antibodies, and vaccines. Moreover, difficulties are highlighted in the search for effective countermeasures against EVD with additional focus on the interplay between available in silico prediction methods and their evidenced potential in antiviral drug discovery., (© 2018 Wiley Periodicals, Inc.)

Recent Ebola virus disease outbreaks affirm the dire need for treatments with proven efficacy. Randomized controlled clinical trials remain the gold standard but, during disease outbreaks, may be difficult to conduct due to ethical concerns and challenging field conditions. In the absence of a randomized control group, statistical modeling to create a control group could be a possibility. Such a model-based reference control would only be credible if it had the same mortality risk as that of the experimental group in the absence of treatment. One way to test this counterfactual assumption is to evaluate whether reasonable similarity exists across nonrandomized control groups from different clinical studies, which might suggest that a future control group would be similarly homogeneous. We evaluated similarity across six clinical studies conducted during the 2013-2016 West Africa outbreak of Ebola virus disease. These studies evaluated favipiravir, the biologic ZMapp, the antimalarial drug amodiaquine, or administration of convalescent plasma or convalescent whole blood. We compared the nonrandomized control groups of these six studies comprising 1147 individuals infected with Ebola virus. We found considerable heterogeneity, which did not disappear after statistical modeling to adjust for prognostic variables. Mortality risk varied widely (31 to 66%) across the nonrandomized control arms of these six studies. Models adjusting for baseline covariates (age, sex, and cycle threshold, a proxy for viral load) failed to sufficiently recalibrate these studies and showed that heterogeneity remained. Our findings highlight concerns about making invalid conclusions when comparing nonrandomized control groups to cohorts receiving experimental treatments., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

The Ebola virus is unparalleled in its charismatic ability to ignite fear, anxiety and disgust at a scale grossly disproportionate to the number of lives it claims. As an archetypal 'Emerging Infectious Disease' (EID), this designation and the politics that have encircled it have provided Ebola with a conceptual space in which epidemiology and geography to splice together in the genesis and maintenance of its charismatic valence. Even before the West African outbreak of 2013-2016, Ebola was an 'exceptional' and 'master status' disease around which media attention mobilised to an unparalleled degree and effect. This paper argues that even if never directly conceptualised as such, Ebola is uniquely charismatic among EIDs and, more, this charisma can be understood geographically. To do so, the paper proceeds in three parts to explore how Ebola's geographic charisma emerges from: (i) it being fixed 'in place' as something innately African; (ii) fears about the virus moving 'out of place' and (iii) its 'potential energy' or the persistent unease generated by the uncertainty of when and where the virus's potential geographies will become actual., (© 2019 Foundation for the Sociology of Health & Illness.)

Background: Micronutrient supplementation is recommended in Ebola virus disease (EVD); however, there are limited data on therapeutic impacts of specific micronutrients., Objective: To evaluate the association between vitamin A supplementation and mortality in EVD., Methods: This retrospective cohort included patients with EVD admitted to 5 International Medical Corps Ebola Treatment Units (ETUs) in 2 countries during 2014-2015. Protocolized treatments with micronutrients were used at all ETUs: however, because of resource constraints, only a subset of patients received vitamin A. Standardized data on demographics, clinical characteristics, malaria status, and Ebola viral loads (cycle threshold values) were collected. The outcome of interest was mortality between cases treated with 200,000 IU of vitamin A on care days 1 and/or 2, and those not. Propensity scores based on the first 48 h of care were derived using covariates of age, ETU duration, malaria status, cycle threshold values, and clinical symptoms. Patients were matched 1:1 using nearest neighbors with replacement. Mortality between cases treated and not treated with vitamin A was compared using generalized estimating equations to calculate RR with associated 95% CI., Results: There were 424 cases analyzed, of which 330 (77.8%) were treated with vitamin A. The mean age was 30.5 y and 40.3% were men. The most common symptoms were diarrhea (85.6%), anorexia (80.7%), and abdominal pain (76.9%). Mortality proportions among cases treated and not treated with vitamin A were 55.0% and 71.9%, respectively. In the propensity-matched analysis, mortality was significantly lower among cases receiving vitamin A (RR = 0.77, 95% CI: 0.59, 0.99; P = 0.041). In a subgroup analysis of patients treated with multivitamins already containing vitamin A, additional vitamin A supplementation did not impact mortality., Conclusion: Early vitamin A supplementation was associated with reduced mortality in patients with EVD, and should be further studied and considered for use in future epidemics., (Copyright © American Society for Nutrition 2019.)

The Ebola virus is a pathogen that causes high morbidity and mortality in epidemic events during which health personnel are frequently infected. Such an epidemic occurred in West Africa, prompting WHO to issue a call in 2014 for health personnel to be dispatched to affected countries. Cuba responded and signed an assistance agreement under which 265 Cuban health professionals, members of the Henry Reeve Emergency Medical Contingent, volunteered their services in the Republic of Guinea, Sierra Leone and Liberia. This article presents Cuba's strategy of medical aid and organization of the three medical teams formed; refers to the teams' contribution to epidemic control in treatment centers where they worked alongside other personnel; and describes measures taken in Cuba to prevent the virus from entering the country through returning volunteers or other means. In the centers where Cuban medical teams worked with other health professionals in West Africa, case fatality decreased from 80%-90% to 24%, contributing to control of the epidemic; no Ebola outbreaks occurred in Cuba. During the epidemic, two Cuban health professionals died of malaria and one physician fell ill with Ebola. This paper includes an overview of the treatment and evolution of the latter case, a doctor who contracted the disease in Sierra Leone and was treated in Geneva and Havana. KEYWORDS Ebola virus, treatment, strategy, followup, medical collaboration, Republic of Guinea, Sierra Leone, Liberia, Cuba.

Background: It is well established that Ebola Survivors experience a myriad of physical and psychological sequelae. However, little is known about how they seek care to address their health needs. Our study determines the current healthcare seeking behaviour among Ebola survivors and determines the prevalence, pattern of use and correlates of traditional and complementary medicine (T&CM) use among Ebola survivors in Sierra Leone., Methods: We conducted a nationwide questionnaire survey among a cross-sectional sample of Ebola Survivors in Sierra Leone between January and August 2018. We employed descriptive statistics, chi-square test, Fisher exact two-tailed test and backward stepwise binary regression analysis for data analysis. A p-value less than 0.05 was considered statistically significant., Results: Ebola Survivors who participated in our study (n = 358), visited a healthcare provider (n = 308, 86.0%), self-medicated with conventional medicines (n = 255, 71.2%) and visited a private pharmacy outlet (n = 141, 39.4%). Survivors also self-medicated with T&CM products (n = 107, 29.9%), concurrently self-medicated with conventional and T&CM products (n = 62, 17.3%), and visited a T&CM practitioner (n = 41, 11.5%). Almost half of (n = 163, 45.5%) Ebola survivors reported using T&CM treatments for post ebola related symptoms and non-Ebola related symptoms since their discharge from an Ebola treatment centre. Ebola survivors who considered their health to be fair or poor (AOR = 4.08; 95%CI: 2.22-7.50; p<0.01), presented with arthralgia (AOR = 2.52; 95%CI: 1.11-5.69, p = 0.026) and were discharged three years or less (AOR = 3.14; 95%CI: 1.13-8.73, p = 0.028) were more likely to use T&CM. Family (n = 101,62.0%) and friends (n = 38,23.3%) were the common sources of T&CM information. Abdominal pain (n = 49, 30.1%) followed by joint pain (n = 46, 28.2%) and back pain (n = 43, 26.4%) were the most cited post-Ebola indications for T&CM use. More than three-quarters of T&CM users (n = 135, 82.8%) failed to disclose their use of T&CM to their healthcare providers., Conclusion: Ebola survivors in Sierra Leone employ a myriad of healthcare options including T&CM in addressing their healthcare needs. Researchers, health policy makers and healthcare providers should be aware of the substantial role of T&CM in the health seeking of survivors, and this topic that should be factored into future research, policy formulation and implementation as well as routine practice regarding Ebola survivors., Competing Interests: The authors have declared that no competing interests exist.

Background: Between 8 May 2018 and 27 May 2019, cumulatively there were 1286 deaths from Ebola Virus Disease (EVD) in the Democratic Republic of Congo (DRC). The objective of this study was to estimate the monetary value of human lives lost through EVD in DRC., Methods: Human capital approach was applied to monetarily value years of life lost due to premature deaths from EVD. The future losses were discounted to their present values at 3% discount rate. The model was reanalysed using 5 and 10% discount rates. The analysis was done alternately using the average life expectancies for DRC, the world, and the Japanese females to assess the effect on the monetary value of years of life lost (MVYLL)., Results: The 1286 deaths resulted in a total MVYLL of Int$17,761,539 assuming 3% discount rate and DRC life expectancy of 60.5 years. The average monetary value per EVD death was of Int$13,801. About 44.7 and 48.6% of the total MVYLL was borne by children aged below 9 years and adults aged between 15 years and 59 years, respectively. Re-estimation of the algorithm with average life expectancies of the world (both sexes) and Japanese females, holding discount rate constant at 3%, increased the MVYLL by Int$ 3,667,085 (20.6%) and Int$ 7,508,498 (42.3%), respectively. The application of discount rates of 5 and 10%, holding life expectancy constant at 60.5 years, reduced the MVYLL by Int$ 4,252,785 (- 23.9%) and Int$ 9,658,195 (- 54.4%) respectively., Conclusion: The EVD outbreak in DRC led to a considerable MVYLL. There is an urgent need for DRC government and development partners to disburse adequate resources to strengthen the national health system and other systems that address social determinants of health to end recurrence of EVD outbreaks.

Quinacrine hydrochloride is a small-molecule, orally bioavailable drug that has been used clinically as an antimalarial and for many other applications. A machine learning model trained on Ebola virus (EBOV) screening data identified quinacrine as a potent (nanomolar) in vitro inhibitor. In the current study, quinacrine 25 mg/kg was shown to protect 70% of mice (statistically significant) from a lethal challenge with mouse-adapted EBOV with once-daily intraperitoneal dosing for 8 days., (Copyright © 2019 American Society for Microbiology.)

Use of the vesicular stomatitis virus (VSV)-based Ebola virus vaccine during outbreaks and the potential use of a similar VSV-based Lassa virus vaccine has raised questions about the vaccines' stability should the cold chain fail. We demonstrated that current cold chain conditions might tolerate significant variances without affecting efficacy.

Uganda suffered four Ebola and five Marburg virus outbreaks from 2000 to 2012 with significant health worker mortality. This paper describes findings from 41 interviews with health workers from three outbreaks. Interviewees frequently encountered stigma from their communities, sometimes accompanied by mistrust and violence. These difficulties were defined as 'challenges of society.' Health workers also suffered emotional trauma, depressive symptoms, and fear classified as 'challenges of psyche.' As the incidence of such outbreaks will likely increase due to ecological and economic trends, health workers require greater access to personal protective equipment (PPE) and knowledge of viral containment. Such improvements would create an optimal psychosocial climate for managing infectious patients ultimately decreasing the severity of future outbreaks.