Assessing attitudes towards violence against women and girls, their determinants and health-seeking behaviour among women and men in South Sudan: a cross-sectional national survey.

OBJECTIVE: Investigating attitudes accepting two categories of violence against women and girls (VAWG) (intimate partner violence-IPV-and other expressions of VAWG) and their association with seven demographic/social determinants and health-seeking behaviours in South Sudan. DESIGN: Cross-sectional study using data from the South Sudan National Household Survey 2020. SETTING: South Sudan. PARTICIPANTS AND METHODS: 1741 South Sudanese women and 1739 men aged 15-49 years; data captured between November 2020 and February 2021 and analysed using binary logistic regression. RESULTS: People with secondary or higher education displayed attitudes rejecting acceptance of IPV (OR 0.631, 95% CI 0.508 to 0.783). Women and men living in states with more numerous internally displaced people (IDP) or political/military violence had attitudes accepting IPV more than residents of less violence-affected regions (OR 1.853, 95% CI 1.587 to 2.164). Women had a higher odd of having attitudes accepting IPV than men (OR 1.195, 95% CI 1.014 to 1.409). People knowing where to receive gender-based violence healthcare and psychological support (OR 0.703, 95% CI 0.596 to 0.830) and with primary (OR 0.613, 95% CI 0.515 to 0.729), secondary or higher education (OR 0.596, 95% CI 0.481 to 0.740) displayed attitudes rejecting acceptance of other expressions of VAWG. People residing in states with proportionately more IDP and who accepted IPV were more likely to have attitudes accepting other expressions of VAWG (OR 1.699, 95% CI 1.459 to 1.978; OR 3.195, 95% CI 2.703 to 3.775, respectively). CONCLUSION: Attitudes towards accepting VAWG in South Sudan are associated with women's and men's education, gender, residence and knowledge about health-seeking behaviour. Prioritising women's empowerment and gender transformative programming in the most conflict-affected areas where rates of VAWG are higher should be prioritised along with increasing girls' access to education. A less feasible strategy to decrease gender inequalities is reducing insecurity, military conflict, and displacement, and increasing economic stability.

Transmissibility and severity of COVID-19 in a humanitarian setting: First few X investigation of cases and contacts in Juba, South Sudan, 2020.

BACKGROUND: The first few 'X' (FFX) studies provide evidence to guide public health decision-making and resource allocation. The adapted WHO Unity FFX protocol for COVID-19 was implemented to gain an understanding of the clinical, epidemiological, virological and household transmission dynamics of the first cases of COVID-19 infection detected in Juba, South Sudan. METHODS: Laboratory-confirmed COVID-19 cases were identified through the national surveillance system, and an initial visit was conducted with eligible cases to identify all close contacts. Consenting cases and close contacts were enrolled between June 2020 and December 2020. Demographic, clinical information and biological samples were taken at enrollment and 14-21 days post-enrollment for all participants. RESULTS: Twenty-nine primary cases and 82 contacts were included in the analyses. Most primary cases (n = 23/29, 79.3%) and contacts (n = 61/82, 74.4%) were male. Many primary cases (n = 18/29, 62.1%) and contacts (n = 51/82, 62.2%) were seropositive for SARS-CoV-2 at baseline. The secondary attack rate among susceptible contacts was 12.9% (4/31; 95% CI: 4.9%-29.7%). All secondary cases and most (72%) primary cases were asymptomatic. Reported symptoms included coughing (n = 6/29, 20.7%), fever or history of fever (n = 4/29, 13.8%), headache (n = 3/29, 10.3%) and shortness of breath (n = 3/29, 10.3%). Of 38 cases, two were hospitalised (5.3%) and one died (2.6%). CONCLUSIONS: These findings were used to develop the South Sudanese Ministry of Health surveillance and contract tracing protocols, informing local COVID-19 case definitions, follow-up protocols and data management systems. This investigation demonstrates that rapid FFX implementation is critical in understanding the emerging disease and informing response priorities.

Limited awareness of HIV Status hinders uptake of treatment among female sex workers and sexually exploited adolescents in Wau and Yambio, South Sudan.

BACKGROUND: Several factors determine uptake of HIV testing services (HTS) by female sex workers (FSW), including their knowledge of HIV and their awareness of services supporting people who are HIV-positive. HTS provided entry into the UNAIDS 90-90-90 cascade of care. We conducted a cross-sectional biobehavioural survey (BBS) to determine HIV prevalence and progress towards UNAIDS 90-90-90 cascade targets among this population in South Sudan. METHODS: Respondent-driven sampling (RDS) was used to recruit women and sexually exploited girls aged 13-18 years who exchanged sex for goods or money in the past 6 months and resided in the town for at least 1 month. Consenting participants were interviewed and tested for HIV and, if positive, they were also tested for their viral load (VL). Data were weighted in RDS Analyst and analyzed with Stata 13. RESULTS: A total of 1,284 participants were recruited. The overall HIV cascade coverages were 64.8% aware of their HIV-positive status; 91.0% of those aware of their positive status were on ART; and VL suppression among those on ART was 93.0%. CONCLUSION: Being unaware of their HIV-positive status limits, the uptake of HIV treatment among FSW in South Sudan. This underscores the importance of optimized case-finding approaches to increase HTS among FSW and sexually exploited minors.

Progress toward the UNAIDS 90-90-90 targets among female sex workers and sexually exploited female adolescents in Juba and Nimule, South Sudan.

BACKGROUND: Little is known about HIV in South Sudan and even less about HIV among female sex workers (FSW). We characterized progress towards UNAIDS 90-90-90 targets among female sex workers (FSW) and sexually exploited female adolescents in Juba and Nimule, South Sudan. METHODS: We conducted a biobehavioral survey of FSW and sexually exploited female adolescents using respondent-driven sampling (RDS) in Juba (November 2015-March 2016) and in Nimule (January-March 2017) to estimate achievements toward the UNAIDS 90-90-90 targets (90% of HIV-positive individuals know their status; of these, 90% are receiving antiretroviral therapy [ART]; and of these, 90% are virally suppressed). Eligibility criteria were girls and women who were aged ≥15 years; spoke English, Juba Arabic, or Kiswahili; received money, goods, or services in exchange for sex in the past 6 months; and resided, worked, or socialized in the survey city for ≥1 month. Data were weighted for RDS methods. RESULTS: We sampled 838 FSW and sexually exploited female adolescents in Juba (HIV-positive, 333) and 409 in Nimule (HIV-positive, 108). Among HIV-positive FSW and sexually exploited female adolescents living in Juba, 74.8% self-reported being aware of their HIV status; of these, 73.3% self-reported being on ART; and of these, 62.2% were virally suppressed. In Nimule, 79.5% of FSW and sexually exploited female adolescents living with HIV self-reported being aware of their HIV status; of these, 62.9% self-reported being on ART; and of these, 75.7% were virally suppressed. CONCLUSIONS: Although awareness of HIV status is the lowest of the 90-90-90 indicators in many countries, treatment uptake and viral suppression were lowest among FSW and sexually exploited female adolescents in South Sudan. Differentiated service delivery facilitate linkage to and retention on treatment in support of attainment of viral suppression.

Transmission of SARS-CoV-2 in standardised first few X cases and household transmission investigations: A systematic review and meta-analysis.

We aimed to estimate the household secondary infection attack rate (hSAR) of SARS-CoV-2 in investigations aligned with the WHO Unity Studies Household Transmission Investigations (HHTI) protocol. We conducted a systematic review and meta-analysis according to PRISMA 2020 guidelines. We searched Medline, Embase, Web of Science, Scopus and medRxiv/bioRxiv for "Unity-aligned" First Few X cases (FFX) and HHTIs published 1 December 2019 to 26 July 2021. Standardised early results were shared by WHO Unity Studies collaborators (to 1 October 2021). We used a bespoke tool to assess investigation methodological quality. Values for hSAR and 95% confidence intervals (CIs) were extracted or calculated from crude data. Heterogeneity was assessed by visually inspecting overlap of CIs on forest plots and quantified in meta-analyses. Of 9988 records retrieved, 80 articles (64 from databases; 16 provided by Unity Studies collaborators) were retained in the systematic review; 62 were included in the primary meta-analysis. hSAR point estimates ranged from 2% to 90% (95% prediction interval: 3%-71%; I 2 = 99.7%); I 2 values remained >99% in subgroup analyses, indicating high, unexplained heterogeneity and leading to a decision not to report pooled hSAR estimates. FFX and HHTI remain critical epidemiological tools for early and ongoing characterisation of novel infectious pathogens. The large, unexplained variance in hSAR estimates emphasises the need to further support standardisation in planning, conduct and analysis, and for clear and comprehensive reporting of FFX and HHTIs in time and place, to guide evidence-based pandemic preparedness and response efforts for SARS-CoV-2, influenza and future novel respiratory viruses.

SARS-CoV-2 Variants, South Sudan, January-March 2021.

As the coronavirus pandemic continues, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequence data are required to inform vaccine efforts. We provide SARS-CoV-2 sequence data from South Sudan and document the dominance of SARS-CoV-2 lineage B.1.525 (Eta variant) during the country's second wave of infection.

Macrophage migration inhibitory factor in Nodding syndrome.

Nodding syndrome (NS) is a catastrophic and enigmatic childhood epilepsy, accompanied by multiple neurological impairments and neuroinflammation. Of all the infectious, environmental and psychological factors associated with NS, the major culprit is Onchocerca Volvulus (Ov)-a parasitic worm transmitted to human by blackflies. NS seems to be an 'Autoimmune Epilepsy' in light of the recent findings of deleterious autoimmune antibodies to Glutamate receptors and to Leiomodin-I in NS patients. Moreover, we recently found immunogenetic fingerprints in HLA peptide-binding grooves associate with protection or susceptibility to NS. Macrophage migration inhibitory factor (MIF) is an immune-regulatory cytokine playing a central role in modulating innate and adaptive immunity. MIF is also involved in various pathologies: infectious, autoimmune and neurodegenerative diseases, epilepsy and others. Herein, two functional polymorphisms in the MIF gene, a -794 CATT5-8 microsatellite repeat and a -173 G/C single-nucleotide polymorphism, were assessed in 49 NS patients and 51 healthy controls from South Sudan. We also measured MIF plasma levels in established NS patients and healthy controls. We discovered that the frequency of the high-expression MIF -173C containing genotype was significantly lower in NS patients compared to healthy controls. Interestingly however, MIF plasma levels were significantly elevated in NS patients than in healthy controls. We further demonstrated that the HLA protective and susceptibility associations are dominant over the MIF association with NS. Our findings suggest that MIF might have a dual role in NS. Genetically controlled high-expression MIF genotype is associated with disease protection. However, elevated MIF in the plasma may contribute to the detrimental autoimmunity, neuroinflammation and epilepsy.

Seroprevalence of Severe Acute Respiratory Syndrome Coronavirus 2 IgG in Juba, South Sudan, 20201.

Relatively few coronavirus disease cases and deaths have been reported from sub-Saharan Africa, although the extent of its spread remains unclear. During August 10-September 11, 2020, we recruited 2,214 participants for a representative household-based cross-sectional serosurvey in Juba, South Sudan. We found 22.3% of participants had severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor binding domain IgG titers above prepandemic levels. After accounting for waning antibody levels, age, and sex, we estimated that 38.3% (95% credible interval 31.8%-46.5%) of the population had been infected with SARS-CoV-2. At this rate, for each PCR-confirmed SARS-CoV-2 infection reported by the Ministry of Health, 103 (95% credible interval 86-126) infections would have been unreported, meaning SARS-CoV-2 has likely spread extensively within Juba. We also found differences in background reactivity in Juba compared with Boston, Massachusetts, USA, where the immunoassay was validated. Our findings underscore the need to validate serologic tests in sub-Saharan Africa populations.

Lessons learned from implementation of a national hotline for Ebola virus disease emergency preparedness in South Sudan.

BACKGROUND: The world's second largest Ebola outbreak occurred in the Democratic Republic of Congo from 2018 to 2020. At the time, risk of cross-border spread into South Sudan was very high. Thus, the South Sudan Ministry of Health scaled up Ebola preparedness activities in August 2018, including implementation of a 24-h, toll-free Ebola virus disease (EVD) hotline. The primary purpose was the hotline was to receive EVD alerts and the secondary goal was to provide evidence-based EVD messages to the public. METHODS: To assess whether the hotline augmented Ebola preparedness activities in a protracted humanitarian emergency context, we reviewed 22 weeks of call logs from January to June 2019. Counts and percentages were calculated for all available data. RESULTS: The hotline received 2114 calls during the analysis period, and an additional 1835 missed calls were documented. Callers used the hotline throughout 24-h of the day and were most often men and individuals living in Jubek state, where the national capital is located. The leading reasons for calling were to learn more about EVD (68%) or to report clinical signs or symptoms (16%). Common EVD-related questions included EVD signs and symptoms, transmission, and prevention. Only one call was documented as an EVD alert, and there was no documentation of reported symptoms or whether the person met the EVD case definition. CONCLUSIONS: Basic surveillance information was not collected from callers. To trigger effective outbreak investigation from hotline calls, the hotline should capture who is reporting and from where, symptoms and travel history, and whether this information should be further investigated. Electronic data capture will enhance data quality and availability of information for review. Additionally, the magnitude of missed calls presents a major challenge. When calls are answered, there is potential to provide health communication, so risk communication needs should be considered. However, prior to hotline implementation, governments should critically assess whether their hotline would yield actionable data and if other data sources for surveillance or community concerns are available.

Response to Malnutrition Treatment in Low Weight-for-Age Children: Secondary Analyses of Children 6-59 Months in the ComPAS Cluster Randomized Controlled Trial.

Weight-for-age z-score (WAZ) is not currently an admission criterion to therapeutic feeding programs, and children with low WAZ at high risk of mortality may not be admitted. We conducted a secondary analysis of RCT data to assess response to treatment according to WAZ and mid-upper arm circumference (MUAC) and type of feeding protocol given: a simplified, combined protocol for severe and moderate acute malnutrition (SAM and MAM) vs. standard care that treats SAM and MAM, separately. Children with a moderately low MUAC (11.5-12.5 cm) and a severely low WAZ (<-3) respond similarly to treatment in terms of both weight and MUAC gain on either 2092 kJ (500 kcal)/day of therapeutic or supplementary food. Children with a severely low MUAC (<11.5 cm), with/without a severely low WAZ (<-3), have similar recovery with the combined protocol or standard treatment, though WAZ gain may be slower in the combined protocol. A limitation is this analysis was not powered for these sub-groups specifically. Adding WAZ < -3 as an admission criterion for therapeutic feeding programs admitting children with MUAC and/or oedema may help programs target high-risk children who can benefit from treatment. Future work should evaluate the optimal treatment protocol for children with a MUAC < 11.5 and/or WAZ < -3.0.

Seroprevalence of anti-SARS-CoV-2 IgG antibodies in Juba, South Sudan: a population-based study.

BACKGROUND: Relatively few COVID-19 cases and deaths have been reported through much of sub-Saharan Africa, including South Sudan, although the extent of SARS-CoV-2 spread remains unclear due to weak surveillance systems and few population-representative serosurveys. METHODS: We conducted a representative household-based cross-sectional serosurvey in Juba, South Sudan. We quantified IgG antibody responses to SARS-CoV-2 spike protein receptor-binding domain and estimated seroprevalence using a Bayesian regression model accounting for test performance. RESULTS: We recruited 2,214 participants from August 10 to September 11, 2020 and 22.3% had anti-SARS-CoV-2 IgG titers above levels in pre-pandemic samples. After accounting for waning antibody levels, age, and sex, we estimated that 38.5% (32.1 - 46.8) of the population had been infected with SARS-CoV-2. For each RT-PCR confirmed COVID-19 case, 104 (87-126) infections were unreported. Background antibody reactivity was higher in pre-pandemic samples from Juba compared to Boston, where the serological test was validated. The estimated proportion of the population infected ranged from 30.1% to 60.6% depending on assumptions about test performance and prevalence of clinically severe infections. CONCLUSIONS: SARS-CoV-2 has spread extensively within Juba. Validation of serological tests in sub-Saharan African populations is critical to improve our ability to use serosurveillance to understand and mitigate transmission.

Analyses of the performance of the Ebola virus disease alert management system in South Sudan: August 2018 to November 2019.

South Sudan implemented Ebola virus disease preparedness interventions aiming at preventing and rapidly containing any importation of the virus from the Democratic Republic of Congo starting from August 2018. One of these interventions was a surveillance system which included an Ebola alert management system. This study analyzed the performance of this system. A descriptive cross-sectional study of the Ebola virus disease alerts which were reported in South Sudan from August 2018 to November 2019 was conducted using both quantitative and qualitative methods. As of 30 November 2019, a total of 107 alerts had been detected in the country out of which 51 (47.7%) met the case definition and were investigated with blood samples collected for laboratory confirmation. Most (81%) of the investigated alerts were South Sudanese nationals. The alerts were identified by health workers (53.1%) at health facilities, at the community (20.4%) and by screeners at the points of entry (12.2%). Most of the investigated alerts were detected from the high-risk states of Gbudwe (46.9%), Jubek (16.3%) and Torit (10.2%). The investigated alerts commonly presented with fever, bleeding, headache and vomiting. The median timeliness for deployment of Rapid Response Team was less than one day and significantly different between the 6-month time periods (K-W = 7.7567; df = 2; p = 0.0024) from 2018 to 2019. Strengths of the alert management system included existence of a dedicated national alert hotline, case definition for alerts and rapid response teams while the weaknesses were occasional inability to access the alert toll-free hotline and lack of transport for deployment of the rapid response teams which often constrain quick response. This study demonstrates that the Ebola virus disease alert management system in South Sudan was fully functional despite the associated challenges and provides evidence to further improve Ebola preparedness in the country.

High HIV and syphilis prevalence among female sex workers in Juba, South Sudan.

HIV prevalence is estimated to be 2.7% in South Sudan; however, little is known about the young country's epidemic. We conducted a respondent-driven sampling biobehavioral survey in Juba of female sex workers (FSW) aged ≥15 years who sold or exchanged sex in the last 6 months to learn more about this population. We enrolled 838 FSW from November 2015 to March 2016 and estimated HIV prevalence to be 37.8%. Prevalence of active syphilis was 7.3%. FSW were from South Sudan and most neighboring countries. Comprehensive knowledge of HIV was 11.1% and 64.2% of FSW had never spoken with an outreach worker. In multivariable analysis, HIV was associated with being from Uganda (aOR: 3.3, 95% CI: 1.7-6.1) or Kenya (aOR: 4.3, 95% CI: 1.5-13.0) versus from South Sudan. Our survey suggests that FSW may play a critical role in South Sudan's HIV epidemic and highlights the importance of tailoring services to the unique needs of FSW of all nationalities in Juba.

Protection or susceptibility to devastating childhood epilepsy: Nodding Syndrome associates with immunogenetic fingerprints in the HLA binding groove.

Nodding syndrome (NS) is a devastating and enigmatic childhood epilepsy. NS is accompanied by multiple neurological impairments and neuroinflammation, and associated with the parasite Onchocerca volvulus (Ov) and other environmental factors. Moreover, NS seems to be an 'Autoimmune Epilepsy' since: 1. ~50% of NS patients have neurotoxic cross-reactive Ov/Leimodin-I autoimmune antibodies. 2. Our recently published findings: Most (~86%) of NS patients have glutamate-receptor AMPA-GluR3B peptide autoimmune antibodies that bind, induce Reactive Oxygen Species, and kill both neural cells and T cells. Furthermore, NS patient's IgG induce seizures, brain multiple damage alike occurring in brains of NS patients, and elevation of T cells and activated microglia and astrocytes, in brains of normal mice. Human Leukocyte antigen (HLA) class I and II molecules are critical for initiating effective beneficial immunity against foreign microorganisms and contributing to proper brain function, but also predispose to detrimental autoimmunity against self-peptides. We analyzed seven HLA loci, either by next-generation-sequencing or Sequence-Specific-Oligonucleotide-Probe, in 48 NS patients and 51 healthy controls from South Sudan. We discovered that NS associates significantly with both protective HLA haplotype: HLA-B*42:01, C*17:01, DRB1*03:02, DQB1*04:02 and DQA1*04:01, and susceptible motif: Ala24, Glu63 and Phe67, in the HLA-B peptide-binding groove. These amino acids create a hydrophobic and sterically closed peptide-binding HLA pocket, favoring proline residue. Our findings suggest that immunogenetic fingerprints in HLA peptide-binding grooves tentatively associate with protection or susceptibility to NS. Accordingly, different HLA molecules may explain why under similar environmental factors, only some children, within the same families, tribes and districts, develop NS, while others do not.

Dual-Targeted Autoimmune Sword in Fatal Epilepsy: Patient's glutamate receptor AMPA GluR3B peptide autoimmune antibodies bind, induce Reactive Oxygen Species (ROS) in, and kill both human neural cells and T cells.

Nodding Syndrome (NS) is a fatal pediatric epilepsy of unknown etiology, accompanied by multiple neurological impairments, and associated with Onchocerca volvulus (Ov), malnutrition, war-induced trauma, and other insults. NS patients have neuroinflammation, and ~50% have cross-reactive Ov/Leiomodin-1 neurotoxic autoimmune antibodies. RESULTS: Studying 30 South Sudanese NS patients and a similar number of healthy subjects from the same geographical region, revealed autoimmune antibodies to 3 extracellular peptides of ionotropic glutamate receptors in NS patients: AMPA-GluR3B peptide antibodies (86%), NMDA-NR1 peptide antibodies (77%) and NMDA-NR2 peptide antibodies (87%) (in either 1:10, 1:100 or 1:1000 serum dilution). In contrast, NS patients did not have 26 other well-known autoantibodies that target the nervous system in several autoimmune-mediated neurological diseases. We demonstrated high expression of both AMPA-GluR3 and NMDA-NR1 in human neural cells, and also in normal human CD3+ T cells of both helper CD4+ and cytotoxic CD8+ types. Patient's GluR3B peptide antibodies were affinity-purified, and by themselves precipitated short 70 kDa neuronal GluR3. NS patient's affinity-purified GluR3B peptide antibodies also bound to, induced Reactive Oxygen Species (ROS) in, and killed both human neural cells and T cells within 1-2 hours only. NS patient's purified IgGs, or serum (1:10 or 1:30), induced similar effects. In vivo video EEG experiments in normal mice, revealed that when NS patient's purified IgGs were released continuously (24/7 for 1 week) in normal mouse brain, they induced all the following: 1.Seizures, 2. Cerebellar Purkinje cell loss, 3. Degeneration in the hippocampus and cerebral cortex, and 4. Elevation of CD3+ T cells, and of activated Mac-2+microglia and GFAP+astrocytes in both the gray and white matter of the cerebral cortex, hippocampus, corpus calossum and cerebellum of mice. NS patient's serum cytokines: IL-1ß, IL-2, IL-6, IL-8, TNFα, IFNγ, are reduced by 85-99% compared to healthy subjects, suggesting severe immunodeficiency in NS patients. This suspected immunodeficiency could be caused by combined effects of the: 1. Chronic Ov infection, 2. Malnutrition, 3. Killing of NS patient's T cells by patient's own GluR3B peptide autoimmune antibodies (alike the killing of normal human T cells by the NS patient's GluR3B peptide antibodies found herein in vitro). CONCLUSIONS: Regardless of NS etiology, NS patients suffer from 'Dual-targeted Autoimmune Sword': autoimmune AMPA GluR3B peptide antibodies that bind, induce ROS in, and kill both neural cells and T cells. These neurotoxic and immunotoxic GluR3B peptide autoimmune antibodies, and also NS patient's NMDA-NR1/NR2A and Ov/Leiomodin-1 autoimmune antibodies, must be silenced or removed. Moreover, the findings of this study are relevant not only to NS, but also to many more patients with other types of epilepsy, which have GluR3B peptide antibodies in serum and/or CSF. This claim is based on the following facts: 1. The GluR3 subunit is expressed in neural cells in crucial brains regions, in motor neurons in the spinal cord, and also in other cells in the body, among them T cells of the immune system, 2. The GluR3 subunit has diverse neurophysiological role, and its deletion or abnormal function can: disrupt oscillatory networks of both sleep and breathing, impair motor coordination and exploratory activity, and increase the susceptibility to generate seizures, 3. GluR3B peptide antibodies were found so far in ~27% of >300 epilepsy patients worldwide, which suffer from various other types of severe, intractable and enigmatic epilepsy, and which turned out to be 'Autoimmune Epilepsy'. Furthermore, the findings of this study could be relevant to different neurological diseases besides epilepsy, since other neurotransmitter-receptors autoantibodies are present in other neurological and psychiatric diseases, e.g. autoimmune antibodies against other GluRs, Dopamine receptors, GABA receptors, Acetylcholine receptors and others. These neurotransmitter-receptors autoimmune autoantibodies might also act as 'Dual-targeted Autoimmune Sword' and damage both neural cells and T cells (as the AMPA-GluR3B peptide antibodies induced in the present study), since T cells, alike neural cells, express most if not all these neurotransmitter receptors, and respond functionally to the respective neurotransmitters - a scientific and clinical topic we coined 'Nerve-Driven Immunity'.

Is development aid to strengthen health systems during protracted conflict a useful investment? The case of South Sudan, 2011-2015.

Introduction: Is achievement of Sustainable Development Goal (SDG) 16 (building peaceful societies) a precondition for achieving SDG 3 (health and well-being in all societies, including conflict-affected countries)? Do health system investments in conflict-affected countries waste resources or benefit the public's health? To answer these questions, we examine the maternal, newborn, child and reproductive health (MNCRH) service provision during protracted conflicts and economic shocks in the Republic of South Sudan between 2011 (at independence) and 2015. Methods: We conducted two national cross-sectional probability surveys in 10 states (2011) and nine states (2015). Trained state-level health workers collected data from households randomly selected using probability proportional to size sampling of villages in each county. County data were weighted by their population sizes to measure state and national MNCRH services coverage. A two-sample, two-sided Z-test of proportions tested for changes in national health service coverage between 2011 (n=11 800) and 2015 (n=10 792). Results: Twenty-two of 27 national indicator estimates (81.5%) of MNCRH service coverage improved significantly. Examples: malaria prophylaxis in pregnancy increased by 8.6% (p<0.001) to 33.1% (397/1199 mothers, 95% CI ±2.9%), institutional deliveries by 10.5% (p<0.001) to 20% (230/1199 mothers, ±2.6%) and measles vaccination coverage in children aged 12-23 months by 11.2% (p<0.001) to 49.7% (529/1064 children, ±2.3%). The largest increase (17.7%, p<0.001) occurred for mothers treating diarrhoea in children aged 0-59 months with oral rehydration salts to 51.4% (635/1235 children, ±2.9%). Antenatal and postnatal care, and contraceptive prevalence did not change significantly. Child vitamin A supplementation decreased. Despite significant increases, coverage remained low (median of all indicators = 31.3%, SD = 19.7). Coverage varied considerably by state (mean SD for all indicators and states=11.1%). Conclusion: Health system strengthening is not a uniform process and not necessarily deterred by conflict. Despite the conflict, health system investments were not wasted; health service coverage increased.

What did we learn from preparing for cross-border transmission of Ebola virus disease into a complex humanitarian setting - The Republic of South Sudan?

BACKGROUND: Following the West Africa Ebola virus disease (EVD) outbreak (2013-2016), WHO developed a preparedness checklist for its member states. This checklist is currently being applied for the first time on a large and systematic scale to prepare for the cross border importation of the ongoing EVD outbreak in the Democratic Republic of Congo hence the need to document the lessons learnt from this experience. This is more pertinent considering the complex humanitarian context and weak health system under which some of the countries such as the Republic of South Sudan are implementing their EVD preparedness interventions. MAIN TEXT: We identified four main lessons from the ongoing EVD preparedness efforts in the Republic South Sudan. First, EVD preparedness is possible in complex humanitarian settings such as the Republic of South Sudan by using a longer-term health system strengthening approach. Second, the Republic of South Sudan is at risk of both domestic and cross border transmission of EVD and several other infectious disease outbreaks hence the need for an integrated and sustainable approach to outbreak preparedness in the country. Third, a phased and well-prioritized approach is required for EVD preparedness in complex humanitarian settings given the costs associated with preparedness and the difficulties in the accurate prediction of outbreaks in such settings. Fourth, EVD preparedness in complex humanitarian settings is a massive undertaking that requires effective and decentralized coordination. CONCLUSION: Despite a very challenging context, the Republic of South Sudan made significant progress in its EVD preparedness drive demonstrating that it is possible to rapidly scale up preparedness efforts in complex humanitarian contexts if appropriate and context-specific approaches are used. Further research, systematic reviews and evaluation of the ongoing preparedness efforts are required to ensure comprehensive documentation and application of the lessons learnt for future EVD outbreak preparedness and response efforts.

Case Definitions Used During the First 6 Months of the 10th Ebola Virus Disease Outbreak in the Democratic Republic of the Congo - Four Neighboring Countries, August 2018-February 2019.

On August 1, 2018, the Democratic Republic of the Congo (DRC) declared its 10th Ebola virus disease (Ebola) outbreak in an area with a high volume of cross-border population movement to and from neighboring countries. The World Health Organization (WHO) designated Rwanda, South Sudan, and Uganda as the highest priority countries for Ebola preparedness because of the high risk for cross-border spread from DRC (1). Countries might base their disease case definitions on global standards; however, historical context and perceived risk often affect why countries modify and adapt definitions over time, moving toward or away from regional harmonization. Discordance in case definitions among countries might reduce the effectiveness of cross-border initiatives during outbreaks with high risk for regional spread. CDC worked with the ministries of health (MOHs) in DRC, Rwanda, South Sudan, and Uganda to collect MOH-approved Ebola case definitions used during the first 6 months of the outbreak to assess concordance (i.e., commonality in category case definitions) among countries. Changes in MOH-approved Ebola case definitions were analyzed, referencing the WHO standard case definition, and concordance among the four countries for Ebola case categories (i.e., community alert, suspected, probable, confirmed, and case contact) was assessed at three dates (2). The number of country-level revisions ranged from two to four, with all countries revising Ebola definitions by February 2019 after a December 2018 peak in incidence in DRC. Case definition complexity increased over time; all countries included more criteria per category than the WHO standard definition did, except for the "case contact" and "confirmed" categories. Low case definition concordance and lack of awareness of regional differences by national-level health officials could reduce effectiveness of cross-border communication and collaboration. Working toward regional harmonization or considering systematic approaches to addressing country-level differences might increase efficiency in cross-border information sharing.

The first sixty days of COVID-19 in a humanitarian response setting: a descriptive epidemiological analysis of the outbreak in South Sudan.

INTRODUCTION: the coronavirus disease 2019 (COVID-19) was declared a pandemic on March 11, 2020. South Sudan, a low-income and humanitarian response setting, reported its first case of COVID-19 on April 5, 2020. We describe the socio-demographic and epidemiologic characteristics of COVID-19 cases in this setting. METHODS: we conducted a cross-sectional descriptive analysis of data for 1,330 confirmed COVID-19 cases from the first 60 days of the outbreak. RESULTS: among the 1,330 confirmed cases, the mean age was 37.1 years, 77% were male, 17% were symptomatic with 95% categorized as mild, and the case fatality rate was 1.1%. Only 24.7% of cases were detected through alerts and sentinel site surveillance, with 95% of the cases reported from the capital, Juba. Epidemic doubling time averaged 9.8 days (95% confidence interval [CI] 7.7 - 13.4), with an attack rate of 11.5 per 100,000 population. Test positivity rate was 18.2%, with test rate per 100,000 population of 53 and mean test turn-around time of 9 days. The case to contact ratio was 1: 2.2. CONCLUSION: this 2-month initial period of COVID-19 in South Sudan demonstrated mostly young adults and men affected, with most cases reported as asymptomatic. Systems´ limitations highlighted included a small proportion of cases detected through surveillance, low testing rates, low contact elicitation, and long collection to test turn-around times limiting the country´s ability to effectively respond to the outbreak. A multi-pronged response including greater access to testing, scale-up of surveillance, contact tracing and community engagement, among other interventions are needed to improve the COVID-19 response in this setting.

Measuring health system resilience in a highly fragile nation during protracted conflict: South Sudan 2011-15.

Health systems resilience (HSR) is defined as the ability of a health system to continue providing normal services in response to a crisis, making it a critical concept for analysis of health systems in fragile and conflict-affected settings (FCAS). However, no consensus for this definition exists and even less about how to measure HSR. We examine three current HSR definitions (maintaining function, improving function and achieving health system targets) using real-time data from South Sudan to develop a data-driven understanding of resilience. We used 14 maternal, newborn and child health (MNCH) coverage indicators from household surveys in South Sudan collected at independence (2011) and following 2 years of protracted conflict (2015), to construct a resilience index (RI) for 9 of the former 10 states and nationally. We also assessed health system stress using conflict-related indicators and developed a stress index. We cross tabulated the two indices to assess the relationship of resilience and stress. For maintaining function for 80% of MNCH indicators, seven state health systems were resilient, compared with improving function for 50% of the indicators (two states were resilient). Achieving the health system national target of 50% coverage in half of the MNCH indicators displayed no resilience. MNCH coverage levels were low, with state averages ranging between 15% and 44%. Central Equatoria State displayed high resilience and high system stress. Lakes and Northern Bahr el Ghazal displayed high resilience and low stress. Jonglei and Upper Nile States had low resilience and high stress. This study is the first to investigate HSR definitions using a resilience metric and to simultaneously measure health system stress in FCAS. Improving function is the HSR definition detecting the greatest variation in the RI. HSR and health system stress are not consistently negatively associated. HSR is highly complex warranting more in-depth analyses in FCAS.