BACKGROUND: During the ongoing outbreak of clade II monkeypox virus (MPXV), many U.S. patients were prescribed tecovirimat, an antiviral drug that was made available under an expanded access Investigational New Drug (EA-IND) program. We evaluated EA-IND data to summarize characteristics of treated patients, outcomes, and serious adverse events (SAEs). METHODS: We evaluated data from patients prescribed tecovirimat from May 29, 2022, through July 10, 2023. Baseline patient characteristics, clinical courses, and outcomes were evaluated via intake forms, outcome forms, and patient diaries. Data were summarized in aggregate by human immunodeficiency virus (HIV) status and by comorbidities of special interest. Reported SAEs were also compiled. RESULTS: Tecovirimat was prescribed for over 7100 patients in the United States, most often for lesions in sensitive anatomical areas, such as certain anogenital lesions (83.5%; 5135 out of 6148 patients), and pain (52.5%; 3227 out of 6148 patients). The demographic and clinical characteristics mirrored those of patients worldwide. Among the 7181 patients with returned intake forms, 1626 also had returned outcome forms (22.6%). Many patients with severe immunocompromise (e.g., HIV with CD4 counts <200 cells/μl) received multiple courses of tecovirimat (43.1%; 22 out of 51 patients), including intravenously, and often experienced poor outcomes (35.3%; 18 out of 51 patients). Overall, 223 SAEs and 40 deaths were reported. Most SAEs were among patients who were severely immunocompromised, one of whom experienced hallucinations after tecovirimat was administered at twice the standard dose. CONCLUSIONS: Tecovirimat was used extensively. The returned EA-IND data suggest that life-threatening or protracted infections occurred in persons who were severely immunocompromised. SAEs were not commonly reported. The EA-IND data are not definitive; controlled clinical trial data are essential to elucidating if and how tecovirimat should be used.

The U.S. Centers for Disease Control and Prevention in collaboration with the National Malaria Elimination Program and the African Field Epidemiology Network established the Malaria Frontline Project to provide innovative approaches to improve the malaria program implementation in Kano and Zamfara States, Nigeria. Innovative approaches such as malaria bulletin, malaria monitoring wall chart, conduct of ward level data validation meetings and malaria dashboard have helped improve the use of data for decision making at all levels. Innovative approaches deployed during the project implementation facilitated data analysis and a better understanding of malaria program performance and data utilization for decision making at all levels. These innovative approaches may improve malaria control program performance in Nigeria and other resource limited countries. © Adefisoye Adewole et al. Pan African Medical Journal (ISSN: 1937-8688).

With concerns about the efficacy of repeat annual influenza vaccination, it is important to better understand the impact of priming vaccine immunity and develop an effective vaccination strategy. Here, we determined the impact of heterologous prime-boost vaccination on inducing broader protective immunity compared to repeat vaccination with the same antigen. The primed mice that were intramuscularly boosted with a heterologous inactivated influenza A virus (H1N1, H3N2, H5N1, H7N9, H9N2) vaccine showed increased strain-specific hemagglutination inhibition titers against prime and boost vaccine strains. Heterologous prime-boost vaccination of mice with inactivated viruses was more effective in inducing high levels of IgG antibodies specific for groups 1 and 2 hemagglutinin stalk domains, as well as cross-protection, compared to homologous vaccination. Both humoral and T cell immunity were found to play a critical role in conferring cross-protection by heterologous prime-boost vaccination. These results support a strategy to enhance cross-protective efficacy by heterologous prime-boost influenza vaccination.

Salmonella enterica serovar (Salmonella Typhi) is the causative bacterial agent of typhoid fever. Environmental surveillance of wastewater and wastewater-impacted surface waters has proven effective in monitoring various pathogens and has recently been applied to Salmonella Typhi. This study evaluated eight sample collection and concentration methods with 12 variations currently being developed and used for Salmonella Typhi surveillance globally to better understand the performance of each method based on its ability to detect Salmonella Typhi and its feasibility. Salmonella Typhi strains Ty21a and Ty2 were seeded to influent wastewater at known concentrations to evaluate the following methods: grab sampling using electropositive filters, centrifugation, direct enrichment, or membrane filtration and trap sampling using Moore swabs. Concentrated samples underwent nucleic acid extraction and were detected and/or quantified via quantitative polymerase chain reaction (qPCR). Results suggest that all methods tested can be successful at concentrating Salmonella Typhi for subsequent detection by qPCR, although each method has its own strengths and weaknesses, including the Salmonella Typhi concentration it is best suited for, with a range of positive detections observed as low as 0.1-0.001 colony-forming units (CFU) Ty21a/mL and 0.01 CFU Ty2/mL. These factors should be considered when identifying a method for environmental surveillance and will greatly depend on the use case planned.

Salmonella enterica serovar (Salmonella Typhi) is the causative bacterial agent of Typhoid fever. Environmental surveillance of wastewater and wastewater-impacted surface waters has proven effective in monitoring various pathogens, and has recently been applied to Salmonella Typhi. This study evaluated eight sample collection and concentration methods with twelve variations currently being developed and used for Salmonella Typhi surveillance globally to better understand the performance of each method based on their ability to detect Salmonella Typhi and feasibility. Salmonella Typhi strains, Ty21a and Ty2, were seeded to influent wastewater at known concentrations to evaluate the following methods: grab sampling using electropositive filters, centrifugation, direct enrichment, or membrane filtration and trap sampling using Moore swabs. Concentrated samples underwent nucleic acid extraction and were detected and/or quantified via qPCR. Results suggest that all methods tested can be successful at concentrating Salmonella Typhi for subsequent detection by qPCR, although each method has its own strengths and weaknesses including the Salmonella Typhi concentrations they are best suited for with a range of positive detections observed as low as 0.1-0.001 CFU Ty21a/mL and 0.01 CFU Ty2/mL. These factors should be considered when identifying a method for environmental surveillance and will greatly depend on the use case planned. Copyright The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.

BACKGROUND: The Malaria Frontline Project (MFP) supported the National Malaria Elimination Program for effective program implementation in the high malaria-burden states of Kano and Zamfara adapting the National Stop Transmission of Polio (NSTOP) program elimination strategies. PROJECT IMPLEMENTATION: The MFP was implemented in 34 LGAs in the two states (20 out of 44 in Kano and all 14 in Zamfara). MFP developed training materials and job aids tailored to expected service delivery for primary and district health facilities and strengthened supportive supervision. Pre- and post-implementation assessments of intervention impacts were conducted in both states. RESULTS: A total of 158 (Kano:83; Zamfara:75) and 180 (Kano:100; Zamfara:80) healthcare workers (HCWs), were interviewed for pre-and post-implementation assessments, respectively. The proportions of HCWs with correct knowledge on diagnostic criteria were Kano: 97.5% to 92.0% and Zamfara: 94.7% to 98.8%; and knowledge of recommended first line treatment of uncomplicated malaria were Kano: 68.7% to 76.0% and Zamfara: 69.3% to 65.0%. The proportion of HCWs who adhered to national guidelines for malaria diagnosis and treatment increased in both states (Kano: 36.1% to 73.0%; Zamfara: 39.2% to 67.5%) and HCW knowledge to confirm malaria diagnosis slightly decreased in Kano State but increased in Zamfara State (Kano: 97.5% to 92.0%; Zamfara: 94.8% to 98.8%). HCWs knowledge of correct IPTp drug increased in both states (Kano: 81.9% to 94.0%; Zamfara: 85.3% to 97.5%). CONCLUSION: MFP was successfully implemented using tailored training materials, job aids, supportive supervision, and data use. The project strategy can likely be adapted to improve the effectiveness of malaria program implementation in other Nigerian states, and other malaria endemic countries.

Nigeria had a confirmed case of COVID-19 on February 28, 2020. On March 17, 2020, the Nigerian Government inaugurated the Presidential Task Force (PTF) on COVID-19 to coordinate the country's multisectoral intergovernmental response. The PTF developed the National COVID-19 Multisectoral Pandemic Response Plan as the blueprint for implementing the response plans. The PTF provided funding, coordination, and governance for the public health response and executed resource mobilization and social welfare support, establishing the framework for containment measures and economic reopening. Despite the challenges of a weak healthcare infrastructure, staff shortages, logistic issues, commodity shortages, currency devaluation, and varying state government cooperation, high-level multisectoral PTF coordination contributed to minimizing the effects of the pandemic through early implementation of mitigation efforts, supported by a strong collaborative partnership with bilateral, multilateral, and private-sector organizations. We describe the lessons learned from the PTF COVID-19 for future multisectoral public health response.

To investigate animal reservoirs of monkeypox virus in Nigeria, we sampled 240 rodents during 2018-2019. Molecular (real-time PCR) and serologic (IgM) evidence indicated orthopoxvirus infections, but presence of monkeypox virus was not confirmed. These results can be used to develop public health interventions to reduce human infection with orthopoxviruses.

Pyrethroid resistance in the malaria vector Anopheles albimanus presents an obstacle to malaria elimination in the Americas. Here, An. albimanus CYP6P5 (the most overexpressed P450 in a Peruvian population) was functionally characterized. Recombinant CYP6P5 metabolized the type II pyrethroids, deltamethrin and α-cypermethrin with comparable affinities (K(M) of 3.3 μM ± 0.4 and 3.6 μM ± 0.5, respectively), but exhibited a 2.7-fold higher catalytic rate for α-cypermethrin (k(cat) of 6.02 min(-1) ± 0.2) versus deltamethrin (2.68 min(-1) ± 0.09). Time-course assays revealed progressive depletion of the above pyrethroids with production of four HPLC-detectable metabolites. Low depletion was obtained with type I pyrethroid, permethrin. Transgenic expression in Drosophila melanogaster demonstrated that overexpression of CYP6P5 alone conferred type II pyrethroid resistance, with only 16% and 55.3% mortalities in flies exposed to 0.25% α-cypermethrin and 0.15% deltamethrin, respectively. Synergist bioassays using P450 inhibitor piperonylbutoxide significantly recovered susceptibility (mortality = 73.6%, p < 0.001) in synergized flies exposed to 4% piperonylbutoxide, plus 0.25% α-cypermethrin, compared to non-synergized flies (mortality = 4.9%). Moderate resistance was also observed towards 4% DDT. These findings established the preeminent role of CYP6P5 in metabolic resistance in An. albimanus, highlighting challenges associated with deployment of insecticide-based control tools in the Americas.

BACKGROUND: Bacillus anthracis, the causative agent for anthrax, poses a potential bioterrorism threat and is capable of causing mass morbidity and mortality. Antimicrobials are the mainstay of postexposure prophylaxis (PEP) and treatment of anthrax. We conducted this safety review of 24 select antimicrobials to identify any new or emerging serious or severe adverse events (AEs) to help inform their risk-benefit evaluation for anthrax. METHODS: Twenty-four antimicrobials were included in this review. Tertiary data sources (e.g. Lactmed, Micromedex, REPROTOX) were reviewed for safety information and summarized to evaluate the known risks of these antimicrobials. PubMed was also searched for published safety information on serious or severe AEs with these antimicrobials; AEs that met inclusion criteria were abstracted and reviewed. RESULTS: A total of 1316 articles were reviewed. No consistent observations or patterns were observed among the abstracted AEs for a given antimicrobial; therefore, the literature review did not reveal evidence of new or emerging AEs that would add to the risk-benefit profiles already known from tertiary data sources. CONCLUSIONS: The reviewed antimicrobials have known and/or potential serious or severe risks that may influence selection when recommending an antimicrobial for PEP or treatment of anthrax. Given the high fatality rate of anthrax, the risk-benefit evaluation favors use of these antimicrobials for anthrax. The potential risks of antimicrobials should not preclude these reviewed antimicrobials from clinical consideration for anthrax but rather guide appropriate antimicrobial selection and prioritization across different patient populations with risk mitigation measures as warranted.

Since its emergence in China, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide including Pakistan. During the pandemic, whole genome sequencing has played an important role in understanding the evolution and genomic diversity of SARS-CoV-2. Although an unprecedented number of SARS-CoV-2 full genomes have been submitted in GISAID and NCBI, data from Pakistan is scarce. We report the sequencing, genomic characterization, and phylogenetic analysis of five SARS-CoV-2 strains isolated from patients in Pakistan. The oropharyngeal swabs of patients that were confirmed positive for SARS-CoV-2 through real-time RT-PCR at National Institute of Health, Pakistan, were selected for whole-genome sequencing. Sequencing was performed using NEBNext Ultra II Directional RNA Library Prep kit for Illumina (NEW ENGLAND BioLabs Inc., MA, US) and Illumina iSeq 100 instrument (Illumina, San Diego, US). Based on whole-genome analysis, three Pakistani SARS-CoV-2 strains clustered into the 20A (GH) clade along with the strains from Oman, Slovakia, United States, and Pakistani strain EPI_ISL_513925. The two 19B (S)-clade strains were closely related to viruses from India and Oman. Overall, twenty-nine amino acid mutations were detected in the current study genome sequences, including fifteen missense and four novel mutations. Notably, we have found a D614G (aspartic acid to glycine) mutation in spike protein of the sequences from the GH clade. The G614 variant carrying the characteristic D614G mutation has been shown to be more infectious that lead to its rapid spread worldwide. This report highlights the detection of GH and S clade strains and G614 variant from Pakistan warranting large-scale whole-genome sequencing of strains prevalent in different regions to understand virus evolution and to explore their genetic diversity.

The novel coronavirus disease 2019, COVID-19, which is caused by severe acute respiratory syndrome virus 2 (SARS-CoV-2) [1] was first reported in December 2019 by Chinese Health Authorities following an outbreak of pneumonia of unknown origin in Wuhan, Hubei Province [2,3]. SARS-CoV-2 is likely of zoonotic origin, similar to SARS and Middle East Respiratory Syndrome (MERS), and transmitted between humans through respiratory droplets and fomites. Since its emergence, it has rapidly spread globally [4].

BACKGROUND: Arboviral diseases, including dengue and chikungunya, are major public health concerns in Bangladesh where there have been unprecedented levels of transmission reported in recent years. The primary approach to control these diseases is to control the vector Aedes aegypti using pyrethroid insecticides. Although chemical control has long been practiced, no comprehensive analysis of Ae. aegypti susceptibility to insecticides has been conducted to date. The aim of this study was to determine the insecticide resistance status of Ae. aegypti in Bangladesh and investigate the role of detoxification enzymes and altered target site sensitivity as resistance mechanisms. METHODS: Eggs of Aedes mosquitoes were collected using ovitraps from five districts across Bangladesh and in eight neighborhoods of the capital city Dhaka, from August to November 2017. CDC bottle bioassays were conducted for permethrin, deltamethrin, malathion, and bendiocarb using 3- to 5-day-old F(0)-F(2) non-blood-fed female mosquitoes. Biochemical assays were conducted to detect metabolic resistance mechanisms, and real-time PCR was performed to determine the frequencies of the knockdown resistance (kdr) mutations Gly1016, Cys1534, and Leu410. RESULTS: High levels of resistance to permethrin were detected in all Ae. aegypti populations, with mortality ranging from 0 to 14.8% at the diagnostic dose. Substantial resistance continued to be detected against higher (2×) doses of permethrin (5.1-44.4% mortality). Susceptibility to deltamethrin and malathion varied between populations while complete susceptibility to bendiocarb was observed in all populations. Significantly higher levels of esterase and oxidase activity were detected in most of the test populations as compared to the susceptible reference Rockefeller strain. A significant association was detected between permethrin resistance and the presence of Gly1016 and Cys1534 homozygotes. The frequency of kdr (knockdown resistance) alleles varied across the Dhaka Aedes populations. Leu410 was not detected in any of the tested populations. CONCLUSIONS: The detection of widespread pyrethroid resistance and multiple resistance mechanisms highlights the urgency for implementing alternate Ae. aegypti control strategies. In addition, implementing routine monitoring of insecticide resistance in Ae. aegypti in Bangladesh will lead to a greater understanding of susceptibility trends over space and time, thereby enabling the development of improved control strategies.

BACKGROUND: Globally, noroviruses are recognized as an important cause of acute gastroenteritis (AGE), but data from low and middle-income countries are limited. AIMS: To examine the epidemiology and strain diversity of norovirus infections among children hospitalized for AGE in Bangladesh. METHODS: We implemented active surveillance of children <5 years of age hospitalized with AGE at 8 geographically dispersed tertiary care hospitals in Bangladesh from July 2012 to June 2016. We tested random samples of AGE cases stratified by site and age group for norovirus by real-time RT-PCR. Noro-positive specimens were genotyped. Coinfection with rotavirus was assessed based on prior EIA testing. RESULTS: We enrolled 5622 total AGE cases, of which 1008 were tested for norovirus. Total of 137 (14%) AGE cases tested positive for norovirus (range, 11%-17% by site). Most (94%) norovirus-associated hospitalizations were among children less than 2 years of age. Norovirus was detected year-round, with higher detection from March to June (20%-38%) and November to January (9%-18%). Genogroup II (GII) noroviruses were detected in 96% of cases, and the most frequent genotypes were GII.4 Sydney [P4 New Orleans] (33%), GII.3 [P16] (20%), and GII.4 Sydney [P16] (11%). The proportion of norovirus-positive specimens was significantly greater among rotavirus-negative AGE patients compared with rotavirus-positive AGE patients (27% vs. 5%, P < 0.001). As measured by the Vesikari severity score, a similar proportion of norovirus and rotavirus positive AGE patients were considered severe (68% vs. 70%, P = 0.86). CONCLUSIONS: Norovirus is an important cause of AGE hospitalization in Bangladeshi children with most infections caused by GII viruses.

Currently, the whole world is facing a COVID-19 pandemic. As of now, approximately 0.15 million people around the globe are infected with the novel coronavirus. In the last decade, two strains of the coronavirus family, SARS-CoV, MERS-CoV also resulted in epidemics in south Asian and the Middle Eastern countries with high mortality rate. This scenario demands the development of a putative vaccine which may provide immunity against all current and new evolving coronavirus strains. In this study, we design an epitope-based vaccine using an immunoinformatic approach. This vaccine may protect against all coronavirus strains. The vaccine is developed by considering the geographical distribution of coronavirus strains and host genetics (Chinese population). Nine experimentally validated epitopes sequences from coronavirus strains were used to derive the variants considering the conservancy in all strains. Further, the binding affinities of all derived variants were checked with most abundant HLA alleles in the Chinese population. Three MHC class-I epitopes from Spike glycoprotein and Nucleoprotein showed sufficient binding while one MHC class-II epitope from Spike glycoprotein found to be an effective binder. A cocktail of these epitopes gave more than 95% population coverage in the Chinese population. Moreover, MD simulation also supported the above-mentioned predictions. Further, in vivo studies are needed to confirm the immunogenic potential of these vaccines. This article is protected by copyright. All rights reserved.

The objective of this study was to describe the epidemiology of COVID-19 in Nigeria with a view of generating evidence to enhance planning and response strategies. A national surveillance dataset between 27 February and 6 June 2020 was retrospectively analysed, with confirmatory testing for COVID-19 done by real-time polymerase chain reaction (RT-PCR). The primary outcomes were cumulative incidence (CI) and case fatality (CF). A total of 40 926 persons (67% of total 60 839) had complete records of RT-PCR test across 35 states and the Federal Capital Territory, 12 289 (30.0%) of whom were confirmed COVID-19 cases. Of those confirmed cases, 3467 (28.2%) had complete records of clinical outcome (alive or dead), 342 (9.9%) of which died. The overall CI and CF were 5.6 per 100 000 population and 2.8%, respectively. The highest proportion of COVID-19 cases and deaths were recorded in persons aged 31-40 years (25.5%) and 61-70 years (26.6%), respectively; and males accounted for a higher proportion of confirmed cases (65.8%) and deaths (79.0%). Sixty-six per cent of confirmed COVID-19 cases were asymptomatic at diagnosis. In conclusion, this paper has provided an insight into the early epidemiology of COVID-19 in Nigeria, which could be useful for contextualising public health planning.

BACKGROUND: In 2013, the Nigeria Federal Ministry of Health established a Master Health Facility List (MHFL) as recommended by WHO. Since then, some health facilities (HFs) have ceased functioning and new facilities were established. We updated the MHFL and assessed service delivery parameters in the Malaria Frontline Project implementing areas in Kano and Zamfara States. METHODS: We assessed all HFs in each of the 34 project local government areas (LGAs) between July and September 2017. Project staff administered a semi-structured questionnaire developed for this assessment to heads of HFs about the type of facility, category and number of staff working at the facility and to record geo-coordinates of facility. RESULTS: In the Kano State project area, 726 HFs were identified and geo-located: 31 were new facilities, 608 (84%), 116 (16%) and two (0.3%) were Primary Health Care (PHC), secondary and tertiary facilities respectively. Using the national definition, there were 710 (98%) functional facilities and 644 (91%) of these reported to the national health information platform, District Health Information System, version 2 (DHIS2). The Zamfara project area had 739 HFs: eight were new, 715 (97%), 22 (3.0%) and two (0.2%) PHCs, secondary and tertiary facilities respectively. There were 695 (94%) functional facilities with 656 (94%) of these reporting to DHIS2. Using national criteria for primary health care designation, only 95 (9%) of all PHCs in the two States met the minimum human resource requirements. CONCLUSION: Most HFs were functional and reported to DHIS2. A comprehensive MHFL having all the important parameters that should be established and updated regularly by authorities to make it more useful for health services administration and management. Most functional facilities are understaffed.

In March 2020, following the annual International Committee on Taxonomy of Viruses (ICTV) ratification vote on newly proposed taxa, the phylum Negarnaviricota was amended and emended. At the genus rank, 20 new genera were added, two were deleted, one was moved, and three were renamed. At the species rank, 160 species were added, four were deleted, ten were moved and renamed, and 30 species were renamed. This article presents the updated taxonomy of Negarnaviricota as now accepted by the ICTV.

Background: In Pakistan and other countries using oral polio vaccine (OPV), immunity to type 2 poliovirus is now maintained by a single dose of inactivated polio vaccine (IPV) in routine immunization, supplemented in outbreak settings by monovalent OPV type 2 (mOPV2) and IPV. While well-studied in clinical trials, population protection against poliovirus type 2 achieved in routine and outbreak settings is generally unknown. Methods: We conducted two phases of a population-based serological survey of 7940 children aged 6-11 months old, between November 2016 and October 2017 from 13 polio high-risk locations in Pakistan. Results: Type 2 seroprevalence was 50% among children born after trivalent OPV (tOPV) withdrawal (April 2016), with heterogeneity across survey areas. Supplementary immunization activities (SIAs) with mOPV2 followed by IPV improved population immunity, varying from 89% in Pishin to 64% in Killa Abdullah, with little observed marginal benefit of subsequent campaigns. In the other high-risk districts surveyed, a single SIA with IPV was conducted and appeared to improve immunity to 57% in Karachi to 84% in Khyber. Conclusions: Our study documents declining population immunity following trivalent OPV withdrawal in Pakistan, and wide heterogeneity in the population impact of supplementary immunization campaigns. Differences between areas, attributable to vaccination campaign coverage, were far more important for type 2 humoral immunity than the number of vaccination campaigns or vaccines used. This emphasizes the importance of immunization campaign coverage for type 2 outbreak response in the final stages of polio eradication. Given the declining type 2 immunity in new birth cohorts it is also recommended that 2 or more doses of IPV should be introduced in the routine immunization program of Pakistan.

BACKGROUND: Avian hepatitis E virus (aHEV) has been associated with hepatitis-splenomegaly syndrome (HSS) in chickens along with asymptomatic subclinical infection in many cases. So far, four genotypes have been described, which cause infection in chickens, specifically in broiler breeders and layer chickens. In the present study, we isolated and identified two novel aHEV strains from the bile of layer chickens in Pakistan evincing clinical symptoms related to HSS. METHODOLOGY: Histology of liver and spleen tissues was carried out to observe histopathological changes in these tissues. Bile fluid and fecal suspensions were used for viral RNA isolation through MegNA pure and Trizol method which was further used for viral genome detection and characterization by cDNA synthesis and amplification of partial open reading frame (ORF) 1, ORF2 and complete ORF3. The bioinformatics tools; Molecular Evolutionary Genetics Analysis version 6.0 (MEGA 6), Mfold and ProtScale were used for phylogenic analysis, RNA secondary structure prediction and protein hydropathy analysis, respectively. RESULTS: Sequencing and phylogenetic analysis on the basis of partial methyltranferase (MeT), helicase (Hel) domain, ORF2 and complete ORF3 sequence suggests these Pakistani aHEV (Pak aHEV) isolates may belong to a Pakistani specific clade. The overall sequence similarity between the Pak aHEV sequences was 98-100%. The ORF1/ORF3 intergenic region contains a conserved cis-reactive element (CRE) and stem-loop structure (SLS). Analysis of the amino acid sequence of ORF3 indicated two hydrophobic domains (HD) and single conserved proline-rich domain (PRD) PREPSAPP (PXXPXXPP) with a single PSAP motif found in C-terminal. Amino acid changes S15 T, A31T, Q35H and G46D unique to the Pak aHEV sequences were found in the N-terminal region of ORF3. CONCLUSIONS: Our data suggests that Pak aHEV isolates may represent a novel Pakistani clade and high sequence homology to each other support the supposition they may belong to a monophyletic clade circulating in the region around Pakistan. The data presented in this study provide further information for aHEV genetic diversity, genotype mapping, global distribution and epidemiology.

BACKGROUND: In September, 2017, human monkeypox re-emerged in Nigeria, 39 years after the last reported case. We aimed to describe the clinical and epidemiological features of the 2017-18 human monkeypox outbreak in Nigeria. METHODS: We reviewed the epidemiological and clinical characteristics of cases of human monkeypox that occurred between Sept 22, 2017, and Sept 16, 2018. Data were collected with a standardised case investigation form, with a case definition of human monkeypox that was based on previously established guidelines. Diagnosis was confirmed by viral identification with real-time PCR and by detection of positive anti-orthopoxvirus IgM antibodies. Whole-genome sequencing was done for seven cases. Haplotype analysis results, genetic distance data, and epidemiological data were used to infer a likely series of events for potential human-to-human transmission of the west African clade of monkeypox virus. FINDINGS: 122 confirmed or probable cases of human monkeypox were recorded in 17 states, including seven deaths (case fatality rate 6%). People infected with monkeypox virus were aged between 2 days and 50 years (median 29 years [IQR 14]), and 84 (69%) were male. All 122 patients had vesiculopustular rash, and fever, pruritus, headache, and lymphadenopathy were also common. The rash affected all parts of the body, with the face being most affected. The distribution of cases and contacts suggested both primary zoonotic and secondary human-to-human transmission. Two cases of health-care-associated infection were recorded. Genomic analysis suggested multiple introductions of the virus and a single introduction along with human-to-human transmission in a prison facility. INTERPRETATION: This study describes the largest documented human outbreak of the west African clade of the monkeypox virus. Our results suggest endemicity of monkeypox virus in Nigeria, with some evidence of human-to-human transmission. Further studies are necessary to explore animal reservoirs and risk factors for transmission of the virus in Nigeria. FUNDING: None.

A guanine mononucleotide repeat in the rpsA (tp0279) gene was evaluated for improved strain discrimination using 72 Treponema pallidum-positive specimens. The tandem repeat combined with the enhanced Centers for Disease Control and Prevention typing system resulted in increased discrimination and should be useful for molecular epidemiologic studies on syphilis especially in outbreaks and among men who have sex with men.

OBJECTIVE: To assess PCV10 effectiveness against invasive pneumococcal disease (IPD) due to vaccine serotypes of Streptococcus pneumoniae (Sp) post introduction of vaccine in routine immunization program of Pakistan. METHODS: A matched case-control study was conducted at 16 hospitals in Sindh Province, Pakistan. Children <5years of age (eligible to receive PCV10) who presented with radiographic confirmed pneumonia and/or meningitis were enrolled as cases. PCR for Lyt A gene was conducted on blood (for radiographic pneumonia) and cerebrospinal fluid (for meningitis) samples to detect Sp. The proportion of IPD due to vaccine serotypes (including vaccine-related serogroups) was determined through serial multiplex PCR. For each case, at least five controls were enrolled from children hospitalized at the same institution, matched on age, district, and season. RESULTS: From 92 IPD cases enrolled during July 2013-March 2017, 24 cases (26.0%) were vaccine serotypes. Most case (87.5% of 24) and control (66.4% of 134) children had not received any PCV10 doses. Estimated effectiveness for PCV10 against vaccine type IPD was 72.7% (CI -7.2 to 92.6%) with at least one dose, 78.8% (CI -11.9 to 96.0%) for at least two doses and 81.9% (CI -55.7 to 97.9%) for all three doses of vaccine. INTERPRETATION: The VE point estimates for PCV10 were high and increased with increasing number of doses. However, VE estimates did not reach statistical significance, possibly due to low power. The findings indicate likely impact of vaccine in reducing burden of vaccine type IPD if vaccine uptake can be improved.

Leukocyte telomere length (LTL) is a heritable trait with two potential sources of heritability (h(2)): inherited variation in non-telomeric regions (e.g., SNPs that influence telomere maintenance) and variability in the lengths of telomeres in gametes that produce offspring zygotes (i.e., "direct" inheritance). Prior studies of LTL h(2) have not attempted to disentangle these two sources. Here, we use a novel approach for detecting the direct inheritance of telomeres by studying the association between identity-by-descent (IBD) sharing at chromosome ends and phenotypic similarity in LTL. We measured genome-wide SNPs and LTL for a sample of 5069 Bangladeshi adults with substantial relatedness. For each of the 6318 relative pairs identified, we used SNPs near the telomeres to estimate the number of chromosome ends shared IBD, a proxy for the number of telomeres shared IBD (Tshared). We then estimated the association between Tshared and the squared pairwise difference in LTL ((DeltaLTL)(2)) within various classes of relatives (siblings, avuncular, cousins, and distant), adjusting for overall genetic relatedness (varphi). The association between Tshared and (DeltaLTL)(2) was inverse among all relative pair types. In a meta-analysis including all relative pairs (varphi > 0.05), the association between Tshared and (DeltaLTL)(2) (P = 0.01) was stronger than the association between varphi and (DeltaLTL)(2) (P = 0.43). Our results provide strong evidence that telomere length (TL) in parental germ cells impacts TL in offspring cells and contributes to LTL h(2) despite telomere "reprogramming" during embryonic development. Applying our method to larger studies will enable robust estimation of LTL h(2) attributable to direct transmission of telomeres.

BACKGROUND: Leucocyte telomere length (TL) is a potential biomarker of ageing and risk for age-related disease. Leucocyte TL is heritable and shows substantial differences by race/ethnicity. Recent genome-wide association studies (GWAS) report ~10 loci harbouring SNPs associated with leucocyte TL, but these studies focus primarily on populations of European ancestry. OBJECTIVE: This study aims to enhance our understanding of genetic determinants of TL across populations. METHODS: We performed a GWAS of TL using data on 5075 Bangladeshi adults. We measured TL using one of two technologies (qPCR or a Luminex-based method) and used standardised variables as TL phenotypes. RESULTS: Our results replicate previously reported associations in the TERC and TERT regions (P=2.2x10(-8) and P=6.4x10(-6), respectively). We observed a novel association signal in the RTEL1 gene (intronic SNP rs2297439; P=2.82x10(-7)) that is independent of previously reported TL-associated SNPs in this region. The minor allele for rs2297439 is common in South Asian populations (>/=0.25) but at lower frequencies in other populations (eg, 0.07 in Northern Europeans). Among the eight other previously reported association signals, all were directionally consistent with our study, but only rs8105767 (ZNF208) was nominally significant (P=0.003). SNP-based heritability estimates were as high as 44% when analysing close relatives but much lower when analysing distant relatives only. CONCLUSIONS: In this first GWAS of TL in a South Asian population, we replicate some, but not all, of the loci reported in prior GWAS of individuals of European ancestry, and we identify a novel second association signal at the RTEL1 locus.

Brucellosis is a common livestock disease in the Middle East and North Africa, but remains poorly described in the region both genetically and epidemiologically. Traditionally found in goats and sheep, Brucella melitensis is increasingly recognized as infecting camels. Most studies of brucellosis in camels to date have focused on serological surveys, providing only limited understanding of the molecular epidemiology of circulating strains. We genotyped B. melitensis isolates from Omani camels using whole genome SNP assays and VNTRs to provide context for regional brucellosis cases. We identified a lineage of B. melitensis circulating in camels as well as in goats, sheep, and cattle in Oman. This lineage is genetically distinct from most genotypes from the Arabian Peninsula and from isolates from much of the rest of the Middle East. We then developed diagnostic assays that rapidly identify strains from this lineage. In analyses of genotypes from throughout the region, Omani isolates were genetically most closely related to strains from brucellosis cases in humans and livestock in North Africa. Our findings suggest an African origin for B. melitensis in Oman that has likely occurred through the trade of infected livestock. Moreover, African lineages of B. melitensis appear to be undersampled and consequently are underrepresented in genetic databases for Brucella. As we begin to more fully understand global genomic diversity of B. melitensis, finding and characterizing these unique but widespread lineages is essential. We predict that increased sampling of humans and livestock in Africa will reveal little known diversity in this important zoonotic pathogen.

BACKGROUND: Nigeria remains one of only three polio-endemic countries in the world. In 2016, after an absence of 2 years, wild poliovirus serotype 1 was again detected in North-Eastern Nigeria. To better guide programmatic action, we assessed the immunity status of infants and children in Borno and Yobe states, and evaluated the impact of recently introduced inactivated poliovirus vaccine (IPV) on antibody seroprevalence. METHODS AND FINDINGS: We conducted a facility-based study of seroprevalence to poliovirus serotypes 1, 2 and 3 among health-seeking patients in two sites each of Borno and Yobe States. Enrolment was conducted amongst children 6-9 and 36-47 months of age attending the paediatrics outpatient department of the selected hospitals in the two states between 11 January and 5 February 2016. Detailed demographic and immunization history of the child was taken and an assessment of the child's health and nutritional state was conducted via physical examination. Blood was collected to test for levels of neutralizing antibody titres against the three poliovirus serotypes. The seroprevalence in the two age groups, potential determinants of seropositivity and the impact of one dose of IPV on humoral immunity were assessed. A total of 583 subjects were enrolled and provided sufficient quantities of serum for testing. Among 6-9-month-old infants, the seroprevalence was 81% (74-87%), 86% (79-91%), and 72% (65-79%) in Borno State, and 75% (67-81%), 74% (66-81%) and 69% (61-76%) in Yobe States, for serotypes-1, 2 and 3, respectively. Among children aged 36-47 months, the seroprevalence was >90% in both states for all three serotypes, with the exception of type 3 seroprevalence in Borno [87% (80-91%)]. Median reciprocal anti-polio neutralizing antibody titers were consistently >900 for serotypes 1 and 2 across age groups and states; with lower estimates for serotype 3, particularly in Borno. IPV received in routine immunization was found to be a significant determinant of seropositivity and anti-polio neutralizing antibodies among 6-9-month-old infants for serotypes 1 and 3, but demonstrated a non-significant positive association for serotype 2. Children receiving IPV through SIAs demonstrated significantly higher anti-polio neutralizing antibodies for serotypes 1 and 3. CONCLUSIONS: The seroprevalence to poliovirus remains suboptimal in both Borno and Yobe States in Nigeria. The low seroprevalence facilitated the continued transmission of both wild serotype 1 and serotype 2 circulating vaccine-derived poliovirus detected in Borno State in 2016. Further efforts are necessary to improve the immunity status of these populations to ensure sufficient population immunity to interrupt transmission.

Recent manufacturing problems resulted in a shortage of the only U.S.-licensed yellow fever vaccine. This shortage is expected to lead to a complete depletion of yellow fever vaccine available for the immunization of U.S. travelers by mid-2017. CDC, the Food and Drug Administration (FDA), and Sanofi Pasteur are collaborating to ensure a continuous yellow fever vaccine supply in the United States. As part of this collaboration, Sanofi Pasteur submitted an expanded access investigational new drug (eIND) application to FDA in September 2016 to allow for the importation and use of an alternative yellow fever vaccine manufactured by Sanofi Pasteur France, with safety and efficacy comparable to the U.S.-licensed vaccine; the eIND was accepted by FDA in October 2016. The implementation of this eIND protocol included developing a systematic process for selecting a limited number of clinic sites to provide the vaccine. CDC and Sanofi Pasteur will continue to communicate with the public and other stakeholders, and CDC will provide a list of locations that will be administering the replacement vaccine at a later date.

INTRODUCTION: In September 2015, Nigeria was removed from the list of polio-endemic countries after more than 12months had passed since the detection of last wild poliovirus case in the country on 24 July 2014. We are presenting here a report of two polio seroprevalence surveys conducted in September 2013 and October 2014, respectively, in the Kano state of northern Nigeria. METHODS: Health facility based seroprevalence surveys were undertaken at Murtala Mohammad Specialist Hospital, Kano. Parents or guardians of children aged 6-9months, 36-47months, 5-9years and 10-14years in 2013 and 6-9months and 19-22months (corresponding to 6-9months range at the time of 2013 survey) in 2014 presenting to the outpatient department, were approached for participation, screened for eligibility and asked to provide informed consent. A questionnaire was administered and a blood sample collected for polio neutralization assay. RESULTS: Among subjects aged 6-9months in the 2013 survey, seroprevalence was 58% (95% confidence interval [CI] 51-66%) to poliovirus type 1, 42% (95% CI 34-50%) to poliovirus type 2, and 52% (95% CI 44-60%) to poliovirus type 3. Among children 36-47months and older, seroprevalence was 85% or higher for all three serotypes. In 2014, seroprevalence in 6-9month infants was 72% (95% CI 65-79%) for type 1, 59% (95% CI 52-66%) for type 2, and 65% (95% CI 57-72%) for type 3 and in 19-22months, 80% (95% CI 74-85%), 57% (49-63%) and 78% (71-83%) respectively. Seroprevalence was positively associated with history of increasing oral poliovirus vaccine doses. CONCLUSIONS: There was significant improvement in seroprevalence in 2014 over the 2013 levels indicating a positive impact of recent programmatic interventions. However the continued low seroprevalence in 6-9month age is a concern and calls for improved immunization efforts to sustain the polio-free Nigeria.

Emergency Operations Centers (EOCs) have been credited with driving the recent successes achieved in the Nigeria polio eradication program. EOC concept was also applied to the Ebola virus disease outbreak and is applicable to a range of other public health emergencies. This article outlines the structure and functionality of a typical EOC in addressing public health emergencies in low-resource settings. It ascribes the successful polio and Ebola responses in Nigeria to several factors including political commitment, population willingness to engage, accountability, and operational and strategic changes made by the effective use of an EOC and Incident Management System. In countries such as Nigeria where the central or federal government does not directly hold states accountable, the EOC provides a means to improve performance and use data to hold health workers accountable by using innovative technologies such as geographic position systems, dashboards, and scorecards.