IMPORTANCE: Limited randomized clinical trial data exist on the safety of simultaneous administration of COVID-19 and influenza vaccines. OBJECTIVE: To compare the reactogenicity, safety, and changes in health-related quality of life (HRQOL) after simultaneous vs sequential receipt of messenger RNA (mRNA) COVID-19 vaccine and quadrivalent inactivated influenza vaccine (IIV4). DESIGN, SETTING, AND PARTICIPANTS: This randomized, placebo-controlled clinical trial was conducted between October 8, 2021, and June 14, 2023, at 3 US sites. Participants were nonpregnant persons aged 5 years or older with the intention of receiving both influenza and mRNA COVID-19 vaccines. INTERVENTIONS: Intramuscular administration in opposite arms of either IIV4 or saline placebo simultaneously with mRNA COVID-19 vaccine at visit 1. Those who received placebo at visit 1 received IIV4 and those who received IIV4 at visit 1 received placebo 1 to 2 weeks later at visit 2. MAIN OUTCOMES AND MEASURES: The primary composite reactogenicity outcome was the proportion of participants with fever, chills, myalgia, and/or arthralgia of moderate or greater severity within 7 days after vaccination visits 1 and/or 2, using a 10% noninferiority margin. Secondary outcomes were solicited reactogenicity events and unsolicited adverse events (AEs) for 7 days after each visit separately and HRQOL after visit 1, assessed by the EuroQol 5-Dimension 5-Level (EQ-5D-5L) Index. Serious AEs (SAEs) and AEs of special interest (AESIs) were assessed for 121 days. Outcomes were compared between groups. RESULTS: A total of 335 persons (mean [SD] age, 33.4 [15.1] years) were randomized (169 to the simultaneous group and 166 to the sequential group); 211 (63.0%) were female, and 255 (76.1%) received bivalent BNT162b2 mRNA COVID-19 vaccine. The proportion with the primary composite reactogenicity outcome in the simultaneous group (25.6% [n = 43]) was noninferior to the proportion in the sequential group (31.3% [n = 52]) (site-adjusted difference, -5.6 percentage points [pp]; 95% CI, -15.2 to 4.0 pp). Respective proportions in each group were similar after each visit separately (visit 1, 40 [23.8%] vs 47 [28.3%]; visit 2, 5 [3.0%] vs 9 [5.4%]). No significant group differences in participants with AEs (21 [12.4%] vs 16 [9.6%]), SAEs (1 [0.6%] vs 1 [0.6%]), and AESIs (19 [11.2%] vs 9 [5.4%]) were observed in the simultaneous vs sequential groups, respectively. Among participants with severe reactogenicity, the mean (SD) EQ-5D-5L Index score decreased from 0.92 (0.08) to 0.92 (0.09) prevaccination to 0.81 (0.09) to 0.82 (0.12) postvaccination. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial assessing simultaneous vs sequential administration of mRNA COVID-19 and IIV4 vaccines, reactogenicity was comparable in both groups. These findings support the option of simultaneous administration of these vaccines. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05028361.

INTRODUCTION: The current literature suggests that the frequency and complexity of public health emergencies are rising and this trend will likely continue. From 2000 to 2023, seven events have been declared as a Public Health Emergency of International Concern (PHEIC) by the World Health Organization (WHO). Organisational models such as the Incident Management System, Incident Response System and Incident Command System or country-specific models are essential in managing PHEIC.The review aims to achieve four key objectives. First, identify and describe the organisational models used in the South-East Asia Region (SEAR) nations defined by WHO as Bangladesh, Bhutan, India, Indonesia, Maldives, Myanmar, Nepal, Sri Lanka, Thailand, Timor-Leste and DPR Korea for managing PHEICs. Second, explore the indicators used to gauge the effectiveness of these models. Third, assess how these indicators impact the overall success of organisational models. Finally, the review will delve into the implementation aspects gaining a deeper understanding of how the organisational models are put into practice to manage PHEICs in the SEAR region. METHODS AND ANALYSIS: Following Preferred Reporting Items for Systematic review and Meta-Analysis Protocols guidelines, a qualitative evidence synthesis will be conducted. A defined search strategy will be employed to conduct a comprehensive literature search of the following academic databases: PubMed (MEDLINE), Excerpta Medica Database, Cochrane CENTRAL, Cumulative Index to Nursing and Allied Health Literature, WHO Library Database, US Centers for Disease Control and Prevention (CDC), CDC's Morbidity and Mortality Weekly Report and Web of Science; as well as non-academic databases including Google Scholar, Evidence Aid, Epistemonikos, Shodhganga and ResearchGate. This review will employ the SPIDER-D tool for searching qualitative studies. Two reviewers will check the quality of included studies and will be appraised using standard critical appraisal tools. In case of any difference between the two reviewers, a third reviewer will take the decision. ETHICS AND DISSEMINATION: No ethical approval is required. Results will be published in a peer-reviewed journal and disseminated through a workshop for stakeholders and policymakers. PROSPERO REGISTRATION NUMBER: CRD42023394418.

Acute encephalopathy syndrome (AES) is characterized by sudden onset of seizures and altered sensorium of infectious or non-infectious origin. Seasonal outbreaks of fatal hypoglycaemic AES in children, associated with eating fruit from the Sapindaceae family (e.g., ackee, litchi), have been reported globally [1,2]. Since 1995, AES outbreaks have been reported during the litchi-harvesting season from May–July in Muzaffarpur, the largest commercial litchi-producing district of Bihar, India [3]. An AES outbreak investigation in Muzaffarpur in 2014 linked known toxins hypoglycin A and α-methylene cyclopropyl glycine (MCPG) in litchi fruit to hypoglycaemic AES in children [3]. Following the 2014 outbreak, the Government of Bihar implemented community-based interventions to prevent hypoglycemia in children. They also strengthened the clinical management of hypoglycaemic seizures in public health facilities [4]. The number of AES cases and deaths declined from 2015–18, suggesting that the interventions were effective. However, in May–June 2019, AES cases increased. We conducted a descriptive epidemiological analysis of the AES cases. | | Methods | | We identified AES cases from established hospital-based surveillance in the two tertiary referral hospitals in Muzaffarpur. We defined a suspected AES case as seizures or altered sensorium in a child aged ≤15 years admitted from 1 May to 2nd July 2019. We excluded patients aged six months to 6 years who were admitted for fever and a single generalized convulsion of <15 minutes in duration and recovered consciousness within 60 minutes of seizure. We conducted a review of medical records and abstracted data using a structured tool for socio-demographics, clinical history, duration of hospitalization, treatment, and laboratory profile. We also assembled a prospective cohort of probable cases admitted to the hospital during the investigation. We defined a probable AES case as new-onset seizures or altered sensorium of <7 days duration in a child aged ≤15 years admitted t from 1 May to 2 July 2019. For the cohort of probable cases, we interviewed the caregivers using a structured clinical-epidemiological questionnaire for socio-demographics, anthropometry, illness characteristics, treatment-seeking behavior, meal assessment, exposure to litchi fruit, and exposure to health messages. For anthropometry, we calculated Z-scores using the World Health Organization 2006 standardized growth tables [5]. | | Results | | Of the 655 suspected and probable AES cases identified, the case fatality rate (CFR) was 21% (139 deaths). The median age was four years (interquartile range: 3 months–14 years), and 58% (378) were females. The first case was reported on 5 May 2019, cases peaked on 15 June, and the last case on 2 July (Figure 1). Among cases with available data, 75% (389/518) had blood glucose levels of <70 mg/dL upon hospital admission, and 75% (476/638) were residents of Muzaffarpur district. We identified cases from 15 (94%) of 16 blocks in the Muzaffarpur district and calculated a district incidence of 22 per 100,000 children ≤15 years old. | | The prospective cohort comprised 94 probable AES cases; CFR was 26%. Among probable cases, 63% (49/78) of caregivers were wage workers, and 34% (31/91) were of low socioeconomic status. Symptoms were reported in the early morning (3 am to 8 am) for 67% (62/93) of cases, and 97% (90/93) presented with seizures. Among probable cases with anthropometry data, 62% (43/69) were underweight (i.e., weight-for-age Z score <-2), 44% (25/57) stunted (i.e., height-for-age Z score <-2), and 43% (10/23) wasted (i.e., weight-for-height Z score <-2). Primary health facilities referred 46% (43/93) of probable cases to the two tertiary hospitals for admission. Among cases referred, only 30% (13/43) received hypoglycemia and seizure management at the primary health facility. | | Eating litchis in the 24 hours and seven days before illness onset was reported by 57% (54/94) and 87% (59/68) of caregivers, respectively. Skipping any meal and skipping the evening meal in the 24 hours before illness onset was reported by 55% (48/88) and 44% (28/63) of caregivers, respectively. Among probable cases, 45% (27/60) of caregivers reported Government Supplementary Nutrition (GSN) programme enrollment. Sixty percent (50/83) of caregivers said a visit by health workers in the week before illness. Still, only 8% (7/83) reported receiving messages on AES prevention and early treatment by health workers in the past month. | | Conclusions | | The 2019 AES outbreak in Muzaffarpur district, Bihar, occurred among young children with hypoglycemia upon hospital admission and had high associated mortality. Although the Government of Bihar implemented community and clinical measures to prevent AES cases after the 2014 outbreak, a large proportion of the AES cases did not benefit from the prevention measures based on our investigation [4]. New state and district health leadership, turnover of community and facility-level healthcare workers, lack of ongoing training and focused community outreach, and competing health priorities might have been factors responsible for the resurgence. To prevent future AES cases, we recommended prompt emergency management of hypoglycemia and seizures at primary health facilities before referral. We recommend enrollment of all eligible children to GSN and enhanced community health communications to reinforce the importance of an evening meal for children and limiting the eating of litchi fruit during the harvesting season from May to July

BACKGROUND: Point-of-care (POC) nucleic acid tests (NAT) have potential to diagnose acute HIV infection and monitor persons taking pre-exposure prophylaxis (PrEP) or antiretroviral treatment (ART). POC NATs have not yet been evaluated in the US. METHODS: From June 2018-March 2019, we conducted a cross-sectional evaluation of the SAMBA II POC NAT. PWH and persons testing for HIV were tested with the SAMBA II qualitative (Qual) whole blood (WB) test. From April-September 2019, the Qual test was used on persons who were ART-naïve, and SAMBA II semi-quantitative (Semi-Q) WB was used with ART-experienced PWH. Both were performed on unprocessed venipuncture (VP) and, when indicated by protocol, fingerstick (FS) WB and plasma. SAMBA results were compared to Abbott RealTime HIV-1 PCR results on plasma. We calculated sensitivity, specificity, and concordance between tests. RESULTS: SAMBA was used in 330 visits among 280 participants: 202 (61.2%) visits from PWH, and 128 (38.8%) from HIV-negative persons. Qual test sensitivity with ART-naïve participants was 91.4% (32/35, 95% CI: 77.6-97.0%) using VP WB and 100% (27/27, 95% CI: 87.5-100%) using FS WB. Specificity was 100% using both specimen types. Concordance between the gold standard and Semi-Q at 1000 copies/mL among PWH on ART was 97.7% (86/88, 95% CI: 92.1-99.4%) and 100% (30/30, 95% CI: 88.7-100%) using VP and FS WB, respectively. Conclusion: The SAMBA II POC NATs showed high sensitivity, specificity, and concordance with the gold-standard assay, indicating its potential use in diagnostics and monitoring. Future work will evaluate POC NAT implementation in the US.

BACKGROUND: Outbreaks of vaccine-derived poliovirus type 2 (VDPV2) continue to expand across Africa. We conducted a serological survey of polio antibodies in high-polio risk areas of Niger to assess risk of poliovirus outbreaks. METHODS: Children between 1 and 5 years of age were enrolled from structures randomly selected using satellite imaging enumeration in Diffa Province, Niger, in July 2019. After obtaining informed consent, dried blood spot cards were collected. Neutralizing antibodies against 3 poliovirus serotypes were detected using microneutralization assay at the Centers for Disease Control and Prevention. RESULTS: We obtained analyzable data from 309/322 (95.9%) enrolled children. Seroprevalence of polio antibodies was 290/309 (93.9%), 272/309 (88.0%), and 254/309 (82.2%) for serotypes 1, 2, and 3, respectively. For serotypes 1 and 2, the seroprevalence did not significantly change with age (P = .09 and P = .44, respectively); for serotype 3, it increased with age (from 65% in 1-2-year-olds to 91.1% in 4-5-year olds; P < .001). We did not identify any risk factors for type 2 seronegativity. CONCLUSIONS: With type 2 seroprevalence close to 90%, the risk of emergence of new cVDPV2 outbreaks in Niger is low; however, the risk of cVDPV2 importations from neighboring countries leading to local transmission persists. Niger should maintain its outbreak response readiness capacity and further strengthen its routine immunization.

BACKGROUND: Hepatitis C infection could be eliminated. Underdiagnosis and lack of treatment are the barriers to cure, especially for vulnerable populations (i.e. unable to pay for health care). METHODS: A multilevel intervention from September 2014 to September 2019 focused on the providers and organizations in 'the safety net' (providing health care to populations unable to pay), including: (i) public education, (ii) training for primary care providers (PCPs) and case managers, (iii) case management for high-risk populations, (iv) policy advice and (v) a registry (Registry) for 13 health centers contributing data. The project tracked the number of PCPs trained and, among Registry sites, the number of people screened, engaged in care (i.e. clinical follow-up after diagnosis), treated and/or cured. RESULTS: In Chicago, 215 prescribing PCPs and 56 other health professionals, 86% of whom work in the safety net, were trained to manage hepatitis C. Among Registry sites, there was a 137% increase in antibody screening and a 32% increase in current hepatitis C diagnoses. Engagement in care rose by 18%. CONCLUSIONS: Hepatitis C Community Alliance to Test and Treat (HepCCATT) successfully targeted safety net providers and organizations with a comprehensive care approach. While there were challenges, HepCCATT observed increased hepatitis C screening, diagnosis and engagement in care in the Chicago community.

A daily surveillance for disease detection and response at the Simhastha Kumbh Mela, in Ujjain, Madhya Pradesh, April-May 2016, was established. Existing weekly reporting of the Integrated Disease Surveillance Programme (IDSP) was modified to report 17 diseases or events from 22 public hospitals and three private hospitals in Ujjain. Water samples were also tested for fecal contamination in areas reporting diarrhea. We identified 56,600 ill persons (92% from government hospitals and 8% from private hospitals): 33% had fever, 28% acute respiratory infection, and 26% acute diarrheal diseases. There were 15 deaths (12 injury and 3 drowning). We detected two diarrhea outbreaks (Mahakaal Zone with 9 cases and Dutta Akhara Zone with 42 cases). Among 26 water samples, eight showed fecal contamination. This was a large implementation of daily disease surveillance in a religious mass gathering in India by IDSP. We recommended laboratory confirmation for diseases and similar daily surveillance in future mass gatherings in India.

Circulating vaccine-derived polioviruses (cVDPVs) can emerge in areas with low poliovirus immunity and cause outbreaks* of paralytic polio (1-5). Among the three types of wild poliovirus, type 2 was declared eradicated in 2015 (1,2). The use of trivalent oral poliovirus vaccine (tOPV; types 1, 2, and 3 Sabin strains) ceased in April 2016 via a 1-month-long, global synchronized switch to bivalent OPV (bOPV; types 1 and 3 Sabin strains) in immunization activities (1-4). Monovalent type 2 OPV (mOPV2; type 2 Sabin strain) is available for cVDPV type 2 (cVDPV2) outbreak response immunization (1-5). The number and geographic breadth of post-switch cVDPV2 outbreaks have exceeded forecasts that trended toward zero outbreaks 4 years after the switch and assumed rapid and effective control of any that occurred (4). New cVDPV2 outbreaks have been seeded by mOPV2 use, by both suboptimal mOPV2 coverage within response zones and recently mOPV2-vaccinated children or contacts traveling outside of response zones, where children born after the global switch are fully susceptible to poliovirus type 2 transmission (2-4). In addition, new emergences can develop by inadvertent exposure to Sabin OPV2-containing vaccine (i.e., residual response mOPV2 or tOPV) (4). This report updates the January 2018-June 2019 report with information on global cVDPV outbreaks during July 2019-February 2020 (as of March 25, 2020)(dagger) (2). Among 33 cVDPV outbreaks reported during July 2019-February 2020, 31 (94%) were cVDPV2; 18 (58%) of these followed new emergences. In mid-2020, the Global Polio Eradication Initiative (GPEI) plans to introduce a genetically stabilized, novel OPV type 2 (nOPV2) that has a lower risk for generating VDPV2 than does Sabin mOPV2; if nOPV2 is successful in limiting new VDPV2 emergences, GPEI foresees the replacement of Sabin mOPV2 with nOPV2 for cVDPV2 outbreak responses during 2021 (2,4,6).

While there have been no cases of type-2 wild poliovirus for over 20 years, transmission of type-2 vaccine-derived poliovirus (VDPV2) and associated paralytic cases in several continents represent a threat to eradication. The withdrawal of the type-2 component of oral poliovirus vaccine (OPV2) was implemented in April 2016 to stop VDPV2 emergence and secure eradication of all poliovirus type 2. Globally, children born after this date have limited immunity to prevent transmission. Using a statistical model, we estimate the emergence date and source of VDPV2s detected between May 2016 and November 2019. Outbreak response campaigns with monovalent OPV2 are the only available method to induce immunity to prevent transmission. Yet, our analysis shows that using monovalent OPV2 is generating more paralytic VDPV2 outbreaks with the potential for establishing endemic transmission. The novel OPV2 is urgently required, alongside a contingency strategy if this vaccine does not materialize or perform as anticipated.

Background: Sensitive surveillance for acute flaccid paralysis (AFP) allows for rapid detection of polio outbreaks and provides essential evidence to support certification of the eradication of polio. However, accurately assessing the sensitivity of surveillance systems can be difficult due to limitations in the reliability of available performance indicators, including the rate of detection of non-polio AFP and the proportion of adequate stool sample collection. Recent field reviews have found evidence of surveillance gaps despite indicators meeting expected targets. Methods: We propose two simple new approaches for AFP surveillance performance indicator analysis to supplement standard indicator analysis approaches commonly used by the Global Polio Eradication Initiative (GPEI): (1) using alternative groupings of low population districts in the country (spatial binning) and (2) flagging unusual patterns in surveillance data (surveillance flags analysis). Using GPEI data, we systematically compare AFP surveillance performance using standard indicator analysis and these new approaches. Results: Applying spatial binning highlights areas meeting surveillance indicator targets that do not when analyzing performance of low population districts. Applying the surveillance flags we find several countries with unusual data patterns, in particular age groups which are not well-covered by the surveillance system, and countries with implausible rates of adequate stool specimen collection. Conclusions: Analyzing alternate groupings of administrative units is a simple method to find areas where traditional AFP surveillance indicator targets are not reliably met. For areas where AFP surveillance indicator targets are met, systematic assessment of unusual patterns ('flags') can be a useful prompt for further investigation and field review.

The aim of the study is to determine the prevalence, outcomes, and survival (among live births [LB]), in pregnancies diagnosed with trisomy 13 (T13) and 18 (T18), by congenital anomaly register and region. Twenty-four population- and hospital-based birth defects surveillance registers from 18 countries, contributed data on T13 and T18 between 1974 and 2014 using a common data-reporting protocol. The mean total birth prevalence (i.e., LB, stillbirths, and elective termination of pregnancy for fetal anomalies [ETOPFA]) in the registers with ETOPFA (n = 15) for T13 was 1.68 (95% CI 1.3-2.06), and for T18 was 4.08 (95% CI 3.01-5.15), per 10,000 births. The prevalence varied among the various registers. The mean prevalence among LB in all registers for T13 was 0.55 (95%CI 0.38-0.72), and for T18 was 1.07 (95% CI 0.77-1.38), per 10,000 births. The median mortality in the first week of life was 48% for T13 and 42% for T18, across all registers, half of which occurred on the first day of life. Across 16 registers with complete 1-year follow-up, mortality in first year of life was 87% for T13 and 88% for T18. This study provides an international perspective on prevalence and mortality of T13 and T18. Overall outcomes and survival among LB were poor with about half of live born infants not surviving first week of life; nevertheless about 10% survived the first year of life. Prevalence and outcomes varied by country and termination policies. The study highlights the variation in screening, data collection, and reporting practices for these conditions.

Mumps, a vaccine-preventable disease, causes inflammation of salivary glands and may cause severe complications such as encephalitis, meningitis, deafness, and orchitis/oophoritis. In India, mumps vaccine is not included in the universal immunization program and during 2009-2014, 72 outbreaks with >1500 cases were reported. In August 2016, a suspected mumps outbreak was reported in Jaisalmer block, Rajasthan. We investigated to confirm the etiology, describe epidemiology, and recommend prevention and control measures. We defined a case as swelling in the parotid region in a Jaisalmer block resident between June 23 and September 10, 2016. We searched for cases in health facilities and house-to-house in affected villages and hamlets. We tested blood samples of cases for mumps IgM ELISA. We found 162 cases (60% males) with median age of 9.4 years (range: 7 month-38 years) and 65 (40%) were females. Symptoms included fever (70%) and bilateral swelling in neck (65%). None were vaccinated against mumps. Most (84%) cases were school-going children (3-16 years old). The overall attack rate was 2%. Village A, with two hamlets, had the highest attack rate (hamlet 1=13% and hamlet 2=12%). School A of village A, hamlet 1 which accommodated 200 children in two classrooms had an attack rate of 55%. Of 18 blood samples from cases, 11 tested positive for mumps IgM ELISA. This was a confirmed mumps outbreak in Jaisalmer bl0ock that disproportionately affected school-going children. We recommended continued surveillance, five-day absence from school, and vaccination. This article is protected by copyright. All rights reserved.

INTRODUCTION: Early diagnosis of HIV-1 infection and the prompt initiation of antiretroviral therapy are critical to achieving a reduction in the morbidity and mortality of infected infants. The SAMBA HIV-1 Qual Whole Blood Test was developed specifically for early infant diagnosis and prevention of mother-to-child transmission programs implemented at the point-of-care in resource-limited settings. METHODS: We have evaluated the performance of this test run on the SAMBA I semi-automated platform with fresh whole blood specimens collected from 202 adults and 745 infants in Kenya, Uganda, and Zimbabwe. Results were compared with those obtained with the Roche COBAS AmpliPrep/COBAS TaqMan (CAP/CTM) HIV-1 assay as performed with fresh whole blood or dried blood spots of the same subjects, and discrepancies were resolved with alternative assays. RESULTS: The performance of the SAMBA and CAP/CTM assays evaluated at five laboratories in the three countries was similar for both adult and infant samples. The clinical sensitivity, specificity, and positive and negative predictive values for the SAMBA test were 100%, 99.2%, 98.7%, and 100%, respectively, with adult samples, and 98.5%, 99.8%, 99.7%, and 98.8%, respectively, with infant samples. DISCUSSION: Our data suggest that the SAMBA HIV-1 Qual Whole Blood Test would be effective for early diagnosis of HIV-1 infection in infants at point-of care settings in sub-Saharan Africa.

Although access to antiretroviral therapy for HIV infection is increasing in resource-poor countries, viral load testing for monitoring of treatment efficacy remains limited, expensive, and confined to centralized laboratories. The SAMBA HIV-1 Semi-Q Test is a nucleic acid-based amplification assay developed for viral load monitoring performed on either the semi-automated SAMBA I system for laboratory use or the fully automated SAMBA II system for point-of care use. We have assessed the performance characteristics of the SAMBA HIV-1 Semi-Q Test on SAMBA I and SAMBA II systems according to the Common Technical Specifications of the European Community's 98/79 In Vitro Diagnostic Medical Devices Directive. The sensitivity, specificity, reproducibility, and viral subtype coverage of the test were similar on the SAMBA I and SAMBA II platforms. The clinical performance on the SAMBA I system was compared with the Roche CAP/CTM assay and evaluated in-house with 130 patient specimens from London as well as in the field with 390 specimens in Kenya and Zimbabwe. The overall concordance between the SAMBA and CAP/CTM assays was 98.1%. The clinical performance of the test on the SAMBA II platform in comparison with the Abbott HIV-1 RealTime Assay was evaluated in-house with 150 specimens from Ukraine, yielding a concordance of 98.0%. The results thus show that the SAMBA HIV-1 Semi-Q Test performs equivalently on SAMBA I and SAMBA II, and they suggest that the test is suitable for implementation at the point-of-care in resource-poor regions where viral load testing is desperately needed but often unavailable.

BACKGROUND: Outbreaks of unexplained illness frequently remain under-investigated. In India, outbreaks of an acute neurological illness with high mortality among children occur annually in Muzaffarpur, the country's largest litchi cultivation region. In 2014, we aimed to investigate the cause and risk factors for this illness. METHODS: In this hospital-based surveillance and nested age-matched case-control study, we did laboratory investigations to assess potential infectious and non-infectious causes of this acute neurological illness. Cases were children aged 15 years or younger who were admitted to two hospitals in Muzaffarpur with new-onset seizures or altered sensorium. Age-matched controls were residents of Muzaffarpur who were admitted to the same two hospitals for a non-neurologic illness within seven days of the date of admission of the case. Clinical specimens (blood, cerebrospinal fluid, and urine) and environmental specimens (litchis) were tested for evidence of infectious pathogens, pesticides, toxic metals, and other non-infectious causes, including presence of hypoglycin A or methylenecyclopropylglycine (MCPG), naturally-occurring fruit-based toxins that cause hypoglycaemia and metabolic derangement. Matched and unmatched (controlling for age) bivariate analyses were done and risk factors for illness were expressed as matched odds ratios and odds ratios (unmatched analyses). FINDINGS: Between May 26, and July 17, 2014, 390 patients meeting the case definition were admitted to the two referral hospitals in Muzaffarpur, of whom 122 (31%) died. On admission, 204 (62%) of 327 had blood glucose concentration of 70 mg/dL or less. 104 cases were compared with 104 age-matched hospital controls. Litchi consumption (matched odds ratio [mOR] 9.6 [95% CI 3.6 - 24]) and absence of an evening meal (2.2 [1.2-4.3]) in the 24 h preceding illness onset were associated with illness. The absence of an evening meal significantly modified the effect of eating litchis on illness (odds ratio [OR] 7.8 [95% CI 3.3-18.8], without evening meal; OR 3.6 [1.1-11.1] with an evening meal). Tests for infectious agents and pesticides were negative. Metabolites of hypoglycin A, MCPG, or both were detected in 48 [66%] of 73 urine specimens from case-patients and none from 15 controls; 72 (90%) of 80 case-patient specimens had abnormal plasma acylcarnitine profiles, consistent with severe disruption of fatty acid metabolism. In 36 litchi arils tested from Muzaffarpur, hypoglycin A concentrations ranged from 12.4 mug/g to 152.0 mug/g and MCPG ranged from 44.9 mug/g to 220.0 mug/g. INTERPRETATION: Our investigation suggests an outbreak of acute encephalopathy in Muzaffarpur associated with both hypoglycin A and MCPG toxicity. To prevent illness and reduce mortality in the region, we recommended minimising litchi consumption, ensuring receipt of an evening meal and implementing rapid glucose correction for suspected illness. A comprehensive investigative approach in Muzaffarpur led to timely public health recommendations, underscoring the importance of using systematic methods in other unexplained illness outbreaks. FUNDING: US Centers for Disease Control and Prevention.

Measles is a leading cause of child mortality, and reduction of child mortality is a key Millennium Development Goal. In 2014, the World Health Organization and the U.S. Centers for Disease Control and Prevention developed a measles programmatic risk assessment tool to support country measles elimination efforts. The tool was pilot tested in the State of Uttarakhand in August 2014 to assess its utility in India. The tool assessed measles risk for the 13 districts of Uttarakhand as a function of indicator scores in four categories: population immunity, surveillance quality, program delivery performance, and threat. The highest potential overall score was 100. Scores from each category were totaled to assign an overall risk score for each district. From this risk score, districts were categorized as low, medium, high, or very high risk. Of the 13 districts in Uttarakhand in 2014, the tool classified one district (Haridwar) as very high risk and three districts (Almora, Champawat, and Pauri Garhwal) as high risk. The measles risk in these four districts was largely due to low population immunity from high MCV1-MCV2 drop-out rates, low MCV1 and MCV2 coverage, and the lack of a supplementary immunization activity (SIA) within the past three years. This tool can be used to support measles elimination in India by identifying districts that might be at risk for measles outbreaks, and to guide risk mitigation efforts, including strengthening routine immunization services and implementing SIAs.

Outbreaks of an unexplained acute neurologic illness affecting young children and associated with high case-fatality rates have been reported in the Muzaffarpur district of Bihar state in India since 1995. The outbreaks generally peak in June and decline weeks later with the onset of monsoon rains. There have been multiple epidemiologic and laboratory investigations of this syndrome, leading to a wide spectrum of proposed causes for the illness, including infectious encephalitis and exposure to pesticides. An association between illness and litchi fruit has been postulated because Muzaffarpur is a litchi fruit-producing region. To better characterize clinical and epidemiologic features of the illness that might suggest its cause and how it can be prevented, the Indian National Centre for Disease Control (NCDC) and CDC investigated outbreaks in 2013 and 2014. Clinical and laboratory findings in 2013 suggested a noninflammatory encephalopathy, possibly caused by a toxin. A common laboratory finding was low blood glucose (<70 mg/dL) on admission, a finding associated with a poorer outcome; 44% of all cases were fatal. An ongoing 2014 investigation has found no evidence of any infectious etiology and supports the possibility that exposure to a toxin might be the cause. The outbreak period coincides with the month-long litchi harvesting season in Muzaffarpur. Although a specific etiology has not yet been determined, the 2014 investigation has identified the illness as a hypoglycemic encephalopathy and confirmed the importance of ongoing laboratory evaluation of environmental toxins to identify a potential causative agent, including markers for methylenecyclopropylglycine (MCPG), a compound found in litchi seeds known to cause hypoglycemia in animal studies. Current public health recommendations are focused on reducing mortality by urging affected families to seek prompt medical care, and ensuring rapid assessment and correction of hypoglycemia in ill children.

As polio eradication inches closer, the absence of poliovirus circulation in most of the world and imperfect vaccination coverage are resulting in immunity gaps and polio outbreaks affecting adults. Furthermore, imperfect, waning intestinal immunity among older children and adults permits reinfection and poliovirus shedding, prompting calls to extend the age range of vaccination campaigns even in the absence of cases in these age groups. The success of such a strategy depends on the contribution to poliovirus transmission by older ages, which has not previously been estimated. We fit a mathematical model of poliovirus transmission to time series data from two large outbreaks that affected adults (Tajikistan 2010, Republic of Congo 2010) using maximum-likelihood estimation based on iterated particle-filtering methods. In Tajikistan, the contribution of unvaccinated older children and adults to transmission was minimal despite a significant number of cases in these age groups [reproduction number, R = 0.46 (95% confidence interval, 0.42-0.52) for >5-y-olds compared to 2.18 (2.06-2.45) for 0- to 5-y-olds]. In contrast, in the Republic of Congo, the contribution of older children and adults was significant [R = 1.85 (1.83-4.00)], perhaps reflecting sanitary and socioeconomic variables favoring efficient virus transmission. In neither setting was there evidence for a significant role of imperfect intestinal immunity in the transmission of poliovirus. Bringing the immunization response to the Tajikistan outbreak forward by 2 wk would have prevented an additional 130 cases (21%), highlighting the importance of early outbreak detection and response.

In 2012, the World Health Assembly of the World Health Organization (WHO) declared completion of polio eradication a programmatic emergency. Polio cases are detected through surveillance of acute flaccid paralysis (AFP) cases and subsequent testing of stool specimens for polioviruses (PVs) at WHO-accredited laboratories within the Global Polio Laboratory Network (GPLN). AFP surveillance is supplemented by environmental surveillance, testing sewage samples from selected sites for PVs. Virologic surveillance, including genomic sequencing to identify isolates by genotype and measure divergence between isolates, guides Global Polio Eradication Initiative (GPEI) activities by confirming the presence of PV, tracking chains of PV transmission, and highlighting gaps in AFP surveillance quality. This report provides AFP surveillance quality indicators at national and subnational levels during 2012-2013 for countries that experienced PV cases during 2009-2013 in the WHO African Region (AFR) and Eastern Mediterranean Region (EMR), the remaining polio-endemic regions. It also summarizes the results of environmental surveillance and reviews indicators assessing the timeliness of reporting of PV isolation and of virus strain characterization globally. Regional-level performance indicators for timely reporting of PV isolation were met in five of six WHO regions in 2012 and 2013. Of 30 AFR and EMR countries that experienced cases of PV (wild poliovirus [WPV], circulating vaccine-derived poliovirus [cVDPV], or both) during 2009-2013, national performance indicator targets for AFP surveillance and collection of adequate specimens were met in 27 (90%) countries in 2012 and 22 (73%) in 2013. In 17 (57%) countries, ≥80% of the population lived in subnational areas meeting both AFP performance indicators in 2012, decreasing to 13 (43%) in 2013. To achieve polio eradication and certify interruption of PV transmission, intensive efforts to strengthen and maintain AFP surveillance are needed at subnational levels, including in field investigation and prompt collection of specimens, particularly in countries with current or recent active PV transmission.

BACKGROUND: Human noroviruses are among the most common enteropathogens globally, and are a leading cause of infant diarrhea in developing countries. However, data measuring the impact of norovirus at the community level are sparse. METHODS: We followed a birth cohort of children to estimate norovirus infection and diarrhea incidence in a Peruvian community. Stool samples from diarrheal episodes and randomly selected nondiarrheal samples were tested by polymerase chain reaction for norovirus genogroup and genotype. Excretion duration and rotavirus coinfection were evaluated in a subset of episodes. RESULTS: Two hundred twenty and 189 children were followed to 1 and 2 years of age, respectively. By 1 year, 80% (95% confidence interval [CI], 75%-85%) experienced at least 1 norovirus infection and by 2 years, 71% (95% CI, 65%-77%) had at least 1 episode of norovirus-associated diarrhea. Genogroup II (GII) infections were 3 times more frequent than genogroup 1 (GI) infections. Eighteen genotypes were found; GII genotype 4 accounted for 41%. Median excretion duration was 34.5 days for GII vs 8.5 days for GI infection (P = .0006). Repeat infections by the same genogroup were common, but repeat infections by the same genotype were rare. Mean length-for-age z score at 12 months was lower among children with prior norovirus infection compared to uninfected children (coefficient: -0.33 [95% CI, -.65 to -.01]; P = .04); the effect persisted at 24 months. CONCLUSIONS: Norovirus infection occurs early in life and children experience serial infections with multiple genotypes, suggesting genotype-specific immunity. An effective vaccine would have a substantial impact on morbidity, but may need to target multiple genotypes.

We explored the potential impact of human papillomavirus (HPV) testing on women's intentions to be screened for cervical cancer in a cohort of Canadian women. Participants aged 25-65 years from an ongoing trial were sent a questionnaire to assess women's intentions to be screened for cervical cancer with HPV testing instead of Pap smears and to be screened every 4 years or after 25 years of age. We created scales for attitudes about HPV testing, perceived behavioral control, and direct and indirect subjective norms. Demographic data and scales that were significantly different (p < 0.1) between women who intended to be screened with HPV and those who did not intend were included in a stepwise logistic regression model. Of the 2,016 invitations emailed, 1,538 were received, and 981 completed surveys for a response rate of 63% (981/1,538). Eighty-four percent of women (826/981) responded that they intended to attend for HPV-based cervical cancer screening, which decreased to 54.2% when the screening interval was extended, and decreased further to 51.4% when screening start was delayed to age of 25. Predictors of intentions to undergo screening were attitudes (odds ratio [OR]: 1.22; 95% confidence interval [CI]: 1.15, 1.30), indirect subjective norms (OR: 1.02; 95% CI: 1.01, 1.03) and perceived behavioral control (OR: 1.16; 95% CI: 1.10; 1.22). Intentions to be screened for cervical cancer with HPV testing decreased substantially when the screening interval was extended and screening started at age of 25. Use of primary HPV testing may optimize the screening paradigm, but programs should ensure robust planning and education to mitigate any negative impact on screening attendance rates.

Respondent Driven Sampling (RDS) is a novel variant of link tracing sampling that has primarily been used to estimate the characteristics of hard-to-reach groups, such as the HIV prevalence of drug users.1 ‘Seeds’ are selected by convenience from a population of interest (target population) and given coupons. Seeds then use these coupons to recruit other people, who themselves become recruiters. Recruits are given compensation, usually money, for taking part in the survey and also an incentive for recruiting others. This process continues in recruitment ‘waves’ until the survey is stopped. Estimation methods are then applied to account for the biased recruitment, for example, the presumed over-recruitment of people with more acquaintances, in an attempt to generate estimates for the underlying population. RDS has quickly become popular and relied on by major public health organisations, including the US Centers for Disease Control and Prevention and Family Health International, chiefly because it is often found to be an efficient method of recruitment in hard-to-reach groups, but also because of the availability of custom written software incorporating inference methods that are designed to generate estimates that are representative of the wider population of interest, despite the biased sampling. | As demonstrated by RDS's popularity,1 there was a clear need for new methods of data collection on hard-to-reach groups. However, RDS has not been without its critics. Its reliance on the target population for recruitment introduced ethicalw1 and sampling concerns.w2 If RDS estimates are overly biased or the variance is unacceptably high, then RDS will be little more than another method of convenience sampling. If these errors can be minimised however, then RDS has the potential to become a very useful survey methodology.

This study compares the immunogenicity and safety of a single dose of a new meningococcal A conjugate vaccine (PsA-TT, MenAfriVac, Serum Institute of India Ltd., Pune) against the meningococcal group A component of a licensed quadrivalent meningococcal polysaccharide vaccine (PsACWY, Mencevax ACWY((R)), GSK, Belgium) 28 days after vaccination in Indian children. This double-blind, randomized, controlled study included 340 Indian children aged 2-10 years enrolled from August to October 2007; 169 children received a dose of PsA-TT while 171 children received a dose of PsACWY. Intention-to-treat analysis showed that 95.2% of children in PsA-TT group had a ≥4-fold response in serum bactericidal titers (rSBA) 28 days post vaccination as compared to 78.2% in the PsACWY group. A significantly higher rSBA GMT (11,209, 95%CI 9708-12,942) was noted in the PsA-TT group when compared to PsACWY group (2838, 95%CI 2368-3401). Almost all children in both vaccine groups had a ≥4-fold response in group A-specific IgG concentration but the IgG GMC was significantly greater in the PsA-TT group (89.1mug/ml, 95%CI 75.5-105.0) when compared to the PsACWY group (15.3mug/ml, 95%CI 12.3-19.2). Local and systemic reactions during the 4 days after immunization were similar for both vaccine groups except for tenderness (30.2% in PsA-TT group vs 12.3% in PsACWY group). None of the adverse events or serious adverse events was related to the study vaccines. We conclude that MenAfriVac is well tolerated and significantly more immunogenic when compared to a licensed polysaccharide vaccine, in 2-to-10-year-old Indian children.

To better define areas of human Lyme disease risk, we compared US surveillance data with published data on the seroprevalence of Borrelia burgdorferi antibodies among domestic dogs. Canine seroprevalence >5% was a sensitive but nonspecific marker of human risk, whereas seroprevalence <1% was associated with minimal risk for human infection.

BACKGROUND: The World Health Organization European Region has a goal for rubella elimination and congenital rubella syndrome (CRS) prevention. Although all Member States recommend a rubella-containing vaccine in their national immunization programs, rubella and CRS continue to occur, and surveillance quality varies throughout the region. METHODS: To describe the status of regional rubella and CRS surveillance and assess progress toward elimination, we reviewed surveillance practices by surveying all 53 Member States and analyzed rubella and CRS surveillance data during 2005-2009. RESULTS: Overall, 41 (91%) of 45 responding Member States have nationwide rubella surveillance, and 39 (87%) have nationwide CRS surveillance. During 2005-2009, rubella cases reported in the region decreased by 94% from 206,359 cases to 11,623 cases. The greatest decrease (99%) was observed in newly independent states of the former Soviet Union. In the rest of the region, high rubella incidence was observed in Poland, Romania, Italy, and San Marino during 2005-2008 and in Poland, Bosnia and Herzegovina, and Austria in 2009. A total of 68 CRS cases were reported during 2005-2009. CONCLUSIONS: As the foundation to achieving and verifying rubella elimination, high-quality rubella and CRS surveillance needs to be implemented and sustained in all Member States.

BACKGROUND: Supplementary immunization activities (SIAs) using measles-containing vaccine (MCV) have had a substantial impact on reducing mortality associated with measles worldwide. METHODS: To assess impact of SIAs on measles incidence in the World Health Organization European Region and their role at the final stages of measles elimination efforts in Europe, we reviewed information on SIAs, measles surveillance, and routine vaccination coverage during 2000-2009. RESULTS: During 2000-2009, >57 million persons received MCV through SIAs in 16 countries. The Region primarily focused on catch-up campaigns with wider target age groups than in other regions and subsequently relied on routine vaccination rather than periodic follow-up SIAs for the second MCV dose. In addition, the concept of SIAs has been expanded from short-term (<30 days) mass campaigns implemented in other regions to incorporate vaccination efforts over longer periods and outbreak response vaccination. In 2009, 14 of 16 countries that conducted SIAs reported no measles cases or <1 case per 1,000,000 population, reflecting the post-SIA decrease in incidence. CONCLUSIONS: SIAs have made a substantial contribution to the success of measles elimination efforts and will likely remain an important strategy for interrupting measles virus transmission in the European Region, although specific approaches will vary by country.