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Michel Kabamba Nzaji,1 Anselme Manyong Kapit,1 Kristen B Stolka,2 Shanice Fezeu Meyou,2 Charlie K Kasendue,3 Melissa Dahlke,4 Robert T Perry,4 Reena H Doshi,4 Brooke Noel Aksnes,4 Richard R Luce,3 Stephane Hans Bateyi Mustafa,5 Crispin Kazadi Mwina-Ngoie,5 Cikomola Mwana Wa Bene Aimé,5 Pia DM MacDonald,1,6 Claire J Standley7,8 1Social, Statistical, & Environmental Sciences, RTI International, Kinshasa, Democratic Republic of the Congo; 2Social, Statistical, & Environmental Sciences, RTI International, Research Triangle Park, NC, United States America; 3Division of Global Health Protection (DGHP), U.S. Centers for Disease Control and Prevention (CDC), Kinshasa, Democratic Republic of the Congo; 4Global Immunization Division (GID), U.S. Centers for Disease Control and Prevention (CDC), Atlanta, GA, United States America; 5Expanded Programme on Immunization (EPI), Ministry of Public Health & Hygiene, Kinshasa, Democratic Republic of the Congo; 6Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, United States America; 7Center for Global Health Science and Security, Georgetown University, Washington, DC, United States America; 8Heidelberg Institute of Global Health, University of Heidelberg, Heidelberg, GermanyCorrespondence: Michel Kabamba Nzaji, RTI International, Social, Statistical, & Environmental Sciences, Kinshasa, Democratic Republic of the Congo, Tel +243978467432, Email michelnzaji@yahoo.frBackground: Low levels of COVID-19 vaccination coverage in many countries prompted the use of rapid assessments to characterize barriers to vaccination and identify corrective measures. The World Health Organization recommended the use of intra-action reviews (IARs) to identify best practices, gaps, and lessons learned to make real-time improvements to the COVID-19 vaccination response.Objective: The Democratic Republic of the Congo (DRC) implemented a national IAR in July 2021 that was poorly attended by the provincial health level, where vaccination activities are planned and implemented. To bridge this gap, we proposed sub-national IARs focused on COVID-19 vaccine program implementation at the provincial level.Methods: Using the WHO methodology, we organized a four-day provincial IAR workshop and invited national, provincial and health zone Ministry of Health (MoH) representatives and private and non-governmental organizations involved in the provincial COVID-19 vaccination response. Participants were divided into six groups based on their expertise, affiliation, and role within the health system to assess and identify lessons learned, challenges and the solutions within each of the six technical areas: (1) coordination, planning and monitoring; (2) service delivery; (3) risk communication and community engagement; (4) adverse effects following immunization (AEFI); (5) logistics; (6) and data management, monitoring and evaluation.Results: The first provincial COVID-19 IAR was conducted in Goma, North Kivu, from January 19– 22, 2022. A total of 56 participants came from provincial and health zone offices, and non-governmental organizations. Through work group discussions, they identified best practices, challenges, and lessons learned, and made recommendations to improve implementation of vaccination activities and reach coverage targets. Activities were proposed to operationalize recommendations and address challenges to improve the provincial response.Conclusion: This provincial IAR was a useful tool for reviewing progress and areas of improvement, while evaluating aspects of the COVID-19 vaccine rollout. It provided a means to share information with vaccination partners on areas of intervention, tailored to the local context.Keywords: COVID-19, intra-action review, COVID-19 vaccination, public health preparedness and response, Democratic Republic of Congo, public health emergency management

Discusses measles-vaccination activities in Cambodia during the period between 1999 and 2002. Routine and supplementary vaccination; Options for future measles-control efforts in postconflict situations; Measles incidence statistics.

OBJECTIVE: We investigated whether vitamin A supplementation would decrease mortality and morbidity rates in children infected with the human immunodeficiency virus (HIV). METHODS: We conducted a randomized, double-blind, placebo-controlled clinical trial at Mulago Hospital, a large hospital that serves the urban and semiurban populations of Kampala, Uganda. One hundred eighty-one HIV-infected children were enrolled at 6 mo and randomized to receive vitamin A supplementation, 60 mg retinol equivalent, or placebo every 3 mo from ages 15 to 36 mo. Morbidity was assessed through a 7-d morbidity history every 3 mo, and vital events were measured. Children received daily trimethoprim-sulfamethoxazole prophylactic therapy. RESULTS: After age 15 mo, children were followed for a median of 17.8 mo (interquartile range = 11.1 to 21.0 mo). The trial was stopped when there was a new policy to implement a program of mass supplementation of vitamin A in the country. Mortality rates among 87 children in the vitamin A group and 94 children in the control group were 20.6% and 32.9%, respectively, yielding a relative risk of 0.54 (95% confidence interval, 0.30 to 0.98; P = 0.044) after adjusting for baseline weight-for-height Z score. Children who received vitamin A had lower modified point prevalences of persistent cough (odds ratio, 0.47; 95% confidence interval, 0.23 to 0.96; P = 0.038) and chronic diarrhea (odds ratio, 0.48; 95% confidence interval, 0.19 to 1.18; P = 0.11) and a shorter duration of ear discharge (P = 0.03). Vitamin A supplementation had no significant effect on modified point prevalences of fever, ear discharge, bloody stools, or hospitalizations. CONCLUSIONS: Vitamin A supplementation decreases mortality rate in HIV-infected children and should be considered in the care for these children in developing countries. [ABSTRACT FROM AUTHOR]

Measles is a highly contagious disease and remains a major cause of child mortality worldwide. While measles vaccine is highly effective, high levels of population immunity are needed to prevent outbreaks. Simple but accurate tools are needed to estimate the profile of population measles immunity by age to identify and fill immunity gaps caused by low levels of vaccination coverage. The measles immunity profile estimates and visualizes the percentage of each birth cohort immune or susceptible to measles based on measles vaccination coverage. Several tools that employed this approach have been developed in the past, including informal unpublished versions. However, these tools used varying assumptions and produced inconsistent results. We updated the measles population immunity profile methodology to standardize and better document the assumptions and methods; provide timely estimates of measles population immunity; and facilitate prompt actions to close immunity gaps and prevent outbreaks. We recommend assuming that the second dose of the measles-containing vaccine (MCV2) and doses given during supplementary immunization activities (SIAs) first reach children who have been previously vaccinated against measles, so that previously unvaccinated children are reached only when the coverage of MCV2 or SIA is higher than the coverage achieved by all previous measles vaccination opportunities. This updated method provides a conservative estimate of immunization program impact to assess measles outbreak risk and to facilitate early planning of timely preventive SIAs to close population immunity gaps.

Measles or rubella elimination is verified when endemic transmission of the corresponding virus has been absent for over 36 months in a defined area, in the presence of a well-performing surveillance system. This report updates the progress by 47 countries in the WHO African Region towards the goal of attaining verification of measles and rubella elimination in at least 80% of the countries of the region by 2030. We reviewed the WHO-UNICEF vaccination coverage estimates for the first and second doses of measles- and measles-rubella-containing vaccines, as well as the available coverage data for measles supplementary immunization activities, during 2022-2023. We also reviewed the measles-surveillance performance and analyzed the epidemiological trends of measles and rubella as reported in the case-based surveillance database. The WHO-UNICEF estimates of first measles vaccine dose (MCV1) and second measles vaccine dose (MCV2) coverage for the African Region for 2022 were 69% and 45%, respectively. Rubella-containing vaccines have been introduced in the routine immunization program in 32 of 47 (68%) countries as of the end of 2022, with no introductions during 2023. In 2022 and 2023, a total of 144,767,764 children were vaccinated in the region with measles or MR vaccines in 24 countries through 32 mass vaccination campaigns. The administrative coverage target of 95% was reached in only 15 (49%) of the 32 vaccination campaigns. In 2023, a total of 125,957 suspected cases of measles were reported through the case-based surveillance system, and 73,625 cases (58%) were confirmed to be measles, either by laboratory testing, by epidemiological linkage, or based on clinical compatibility. A total of 4805 confirmed rubella cases were reported, though this total represents substantial under-ascertainment. The regional incidence of measles was 60.3 cases per million population. Twenty-six countries (55%) met the targets for the two principal surveillance system performance-monitoring indicators. No country in the region has attained the verification of measles or rubella elimination as of the end of 2023. Addressing systemic problems with routine immunization and using tailored approaches to reach unvaccinated children can contribute to progress towards measles and rubella elimination. In addition, periodic and timely high-quality preventive SIAs remain a critical programmatic strategy to reach unvaccinated children.

Objectives: To determine whether a nurse practitioner and physician assistant (NP/PA)-led rapid staffing. Model in the cardiac surgical intensive care unit (ICU) can optimize resource utilization without compromising safety or increasing hospital length of stay (LoS)., Design: Retrospective observational cohort study comparing before-and-after implementation of an NP/PA-led rapid recovery pathway., Setting: A large tertiary referral academic cardiac surgery ICU., Participants: There were 116 patients in the prerapid recovery cohort and 153 in the postimplementation rapid recovery phase., Interventions: Low-risk cardiac surgery patients were selected for postoperative care by an NP/PA-led ICU staffing model., Measurements and Main Results: Mean hospital LoS in the prerapid recovery cohort was 5.7 days compared to 5.2 days in the rapid recovery pathway cohort ( P  = .02). Thirty-day hospital readmission in the prerapid recovery pathway cohort was 7.8% compared with 2.0% in the rapid recovery cohort ( P  = .04). The ICU readmission rate for prerapid recovery cohort was 4.3%, while the rapid recovery percentage was 2.0% ( P  = .30)., Conclusions: Overall, implementation of an NP/PA-led postcardiac surgical ICU team ( rapid recovery pathway ) was associated with similar ICU LoS, hospital LoS, ICU readmission rates, 30-day readmission rates, and no significant signal of increased adverse events or safety concerns., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Worldwide, measles remains a major cause of disease and death; the highest incidence is in the World Health Organization African Region (AFR). In 2011, the 46 AFR member states established a goal of regional measles elimination by 2020; this report describes progress during 2017-2021. Regional coverage with a first dose of measles-containing vaccine (MCV) decreased from 70% in 2017 to 68% in 2021, and the number of countries with ≥95% coverage decreased from six (13%) to two (4%). The number of countries providing a second MCV dose increased from 27 (57%) to 38 (81%), and second-dose coverage increased from 25% to 41%. Approximately 341 million persons were vaccinated in supplementary immunization activities, and an estimated 4.5 million deaths were averted by vaccination. However, the number of countries meeting measles surveillance performance indicators declined from 26 (62%) to nine (22%). Measles incidence increased from 69.2 per 1 million population in 2017 to 81.9 in 2021. The number of estimated annual measles cases and deaths increased 22% and 8%, respectively. By December 2021, no country in AFR had received verification of measles elimination. To achieve a renewed regional goal of measles elimination in at least 80% of countries by 2030, intensified efforts are needed to recover and surpass levels of surveillance performance and coverage with 2 MCV doses achieved before the COVID-19 pandemic., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

The US Centers for Disease Control and Prevention (CDC) supports international partners in introducing vaccines, including those against SARS-CoV-2 virus. CDC contributes to the development of global technical tools, guidance, and policy for COVID-19 vaccination and has established its COVID-19 International Vaccine Implementation and Evaluation (CIVIE) program. CIVIE supports ministries of health and their partner organizations in developing or strengthening their national capacities for the planning, implementation, and evaluation of COVID-19 vaccination programs. CIVIE's 7 priority areas for country-specific technical assistance are vaccine policy development, program planning, vaccine confidence and demand, data management and use, workforce development, vaccine safety, and evaluation. We discuss CDC's work on global COVID-19 vaccine implementation, including priorities, challenges, opportunities, and applicable lessons learned from prior experiences with Ebola, influenza, and meningococcal serogroup A conjugate vaccine introductions.

Global emergence of the COVID-19 pandemic in 2020 curtailed vaccine-preventable disease (VPD) surveillance activities, but little is known about which surveillance components were most affected. In May 2021, we surveyed 214 STOP (originally Stop Transmission of Polio) Program consultants to determine how VPD surveillance activities were affected by the COVID-19 pandemic throughout 2020, primarily in low- and middle-income countries, where program consultants are deployed. Our report highlights the responses from 154 (96%) of the 160 consultants deployed to the World Health Organization African Region, which comprises 75% (160/214) of all STOP Program consultants deployed globally in early 2021. Most survey respondents observed that VPD surveillance activities were somewhat or severely affected by the COVID-19 pandemic in 2020. Reprioritization of surveillance staff and changes in health-seeking behaviors were factors commonly perceived to decrease VPD surveillance activities. Our findings suggest the need for strategies to restore VPD surveillance to prepandemic levels.

Background: Long-lasting insecticidal nets (LLINs) and indoor residual spraying (IRS) are the main malaria vector control measures deployed in Kenya. Widespread pyrethroid resistance among the primary vectors in Western Kenya has necessitated the re-introduction of IRS using an organophosphate insecticide, pirimiphos-methyl (Actellic® 300CS), as a pyrethroid resistance management strategy. Evaluation of the effectiveness of the combined use of non-pyrethroid IRS and LLINs has yielded varied results. We aimed to evaluate the effect of non-pyrethroid IRS and LLINs on malaria indicators in a high malaria transmission area., Methods: We reviewed records and tallied monthly aggregate of outpatient department (OPD) attendance, suspected malaria cases, those tested for malaria and those testing positive for malaria at two health facilities, one from Nyatike, an intervention sub-county, and one from Suba, a comparison sub-county, both located in Western Kenya, from February 1, 2016, through March 31, 2018. The first round of IRS was conducted in February-March 2017 in Nyatike sub-county and the second round one year later in both Nyatike and Suba sub-counties. The mass distribution of LLINs has been conducted in both locations. We performed descriptive analysis and estimated the effect of the interventions and temporal changes of malaria indicators using Poisson regression for a period before and after the first round of IRS., Results: A higher reduction in the intervention area in total OPD, the proportion of OPD visits due to suspected malaria, testing positivity rate and annual malaria incidences were observed except for the total OPD visits among the under 5 children (59% decrease observed in the comparison area vs 33% decrease in the intervention area, net change -27%, P <0.001). The percentage decline in annual malaria incidence observed in the intervention area was more than twice the observed percentage decline in the comparison area across all the age groups. A marked decline in the monthly testing positivity rate (TPR) was noticed in the intervention area, while no major changes were observed in the comparison area. The monthly TPR reduced from 46% in February 2016 to 11% in February 2018, representing a 76% absolute decrease in TPR among all ages (RR = 0.24, 95% CI 0.12-0.46). In the comparison area, TPR was 16% in both February 2016 and February 2018 (RR = 1.0, 95% CI 0.52-2.09). A month-by-month comparison revealed lower TPR in Year 2 compared to Year 1 in the intervention area for most of the one year after the introduction of the IRS., Conclusions: Our findings demonstrated a reduced malaria burden among populations protected by both non-pyrethroid IRS and LLINs implying a possible additional benefit afforded by the combined intervention in the malaria-endemic zone., Competing Interests: The authors have declared that no competing interests exist.

Background: Cognitive processing speed is important for performing everyday activities in persons with mild cognitive impairment (MCI). However, its role in daily function has not been examined while simultaneously accounting for contributions of Alzheimer's disease (AD) risk biomarkers. We examine the relationships of processing speed and genetic and neuroimaging biomarkers to composites of daily function, mobility, and driving., Method: We used baseline data from 103 participants on the MCI/mild dementia spectrum from the Applying Programs to Preserve Skills trial. Linear regression models examined relationships of processing speed, structural magnetic resonance imaging (MRI), and genetic risk alleles for AD to composites of performance-based instrumental activities of daily living (IADLs), community mobility, and on-road driving evaluations., Results: In multivariable models, processing speed and the brain MRI neurodegeneration biomarker Spatial Pattern of Abnormality for Recognition of Early Alzheimer's disease (SPARE-AD) were significantly associated with functional and mobility composite performance. Better processing speed and younger age were associated with on-road driving ratings. Genetic risk markers, left hippocampal atrophy, and white matter lesion volumes were not significant correlates of these abilities. Processing speed had a strong positive association with IADL function (p < .001), mobility (p < .001), and driving (p = .002)., Conclusions: Cognitive processing speed is strongly and consistently associated with critical daily functions in persons with MCI in models including genetic and neuroimaging biomarkers of AD risk. SPARE-AD scores also significantly correlate with IADL performance and mobility. Results highlight the central role of processing speed in everyday task performance among persons with MCI/mild dementia., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Indoor residual spraying (IRS) of insecticides is a major vector control strategy for malaria prevention. We evaluated the impact of a single round of IRS with the organophosphate, pirimiphos-methyl (Actellic 300CS), on entomological and parasitological parameters of malaria in Migori County, western Kenya in 2017, in an area where primary vectors are resistant to pyrethroids but susceptible to the IRS compound. Entomological monitoring was conducted by indoor CDC light trap, pyrethrum spray catches (PSC) and human landing collection (HLC) before and after IRS. The residual effect of the insecticide was assessed monthly by exposing susceptible An. gambiae s.s. Kisumu strain to sprayed surfaces in cone assays and measuring mortality at 24 hours. Malaria case burden data were extracted from laboratory records of four health facilities within the sprayed area and two adjacent unsprayed areas. IRS was associated with reductions in An. funestus numbers in the intervention areas compared to non-intervention areas by 88% with light traps (risk ratio [RR] 0.12, 95% CI 0.07-0.21, p < 0.001) and 93% with PSC collections (RR = 0.07, 0.03-0.17, p < 0.001). The corresponding reductions in the numbers of An. arabiensis collected by PSC were 69% in the intervention compared to the non-intervention areas (RR = 0.31, 0.14-0.68, p = 0.006), but there was no significant difference with light traps (RR = 0.45, 0.21-0.96, p = 0.05). Before IRS, An. funestus accounted for over 80% of Anopheles mosquitoes collected by light trap and PSC in all sites. After IRS, An. arabiensis accounted for 86% of Anopheles collected by PSC and 66% by CDC light trap in the sprayed sites while the proportion in non-intervention sites remained unchanged. No sporozoite infections were detected in intervention areas after IRS and biting rates by An. funestus were reduced to near zero. Anopheles funestus and An. arabiensis were fully susceptible to pirimiphos-methyl and resistant to pyrethroids. The residual effect of Actellic 300CS lasted ten months on mud and concrete walls. Malaria case counts among febrile patients within IRS areas was lower post- compared to pre-IRS by 44%, 65% and 47% in Rongo, Uriri and Nyatike health facilities respectively. A single application of IRS with Actellic 300CS in Migori County provided ten months protection and resulted in the near elimination of the primary malaria vector An. funestus and a corresponding reduction of malaria case count among out-patients. The impact was less on An. arabiensis, most likely due to their exophilic nature.

Objective: Worldwide, the highest frequencies of APOL1-associated kidney variants are found in indigenous West Africans among whom small vessel disease (SVD) ischemic stroke is the most common stroke phenotype. The objective of this study was to investigate the association and effect sizes of 23 selected SNPs in 14 genes of relevance, including the APOL1 G1 variants, with the occurrence of SVD ischemic stroke among indigenous West African participants in the Stroke Investigative Research and Education Network (SIREN) Study., Materials and Methods: Cases were consecutively recruited consenting adults (aged 18 years or older) with neuroimaging-confirmed first clinical stroke. Stroke-free controls were ascertained using a locally validated version of the Questionnaire for Verifying Stroke-Free Status (QVSFS). Logistic regression models adjusting for known vascular risk factors were fitted to assess the associations of the 23 SNPs in rigorously phenotyped cases (N = 154) of SVD ischemic stroke and stroke-free (N = 483) controls., Results: Apolipoprotein L1 (APOL1) rs73885319 (OR = 1.52; CI: 1.09-2.13, P-value = .013), rs2383207 in CDKN2A/CDKN2B (OR = 3.08; CI: 1.15-8.26, P -value = .026) and rs2107595 (OR = 1.70; CI: 1.12-2.60, P-value = .014) and rs28688791 (OR = 1.52; CI: 1.03-2.26, P-value = .036) in HDAC9 gene were associated with SVD stroke at 0.05 significance level. Polymorphisms in other genes did not show significant associations., Conclusion: This is the first report of a specific association of APOL1 with a stroke subtype. Further research is needed to confirm these initial findings and deepen understanding of the genetics of stroke in people of African ancestry with possible implications for other ancestries as all humans originated from Africa., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Inherited genetic variations offer a possible explanation for the observed peculiarities of stroke in sub - Saharan African populations. Interleukin-6 polymorphisms have been previously associated with ischemic stroke in some non-African populations., Aim: Herein we investigated, for the first time, the association of genetic polymorphisms of IL-6, CDKN2A- CDKN2B and other genes with ischemic stroke among indigenous West African participants in the Stroke Investigative Research and Education Network (SIREN) Study., Methods: Twenty-three previously identified single nucleotide polymorphisms (SNPs) in 14 genes of relevance to the neurobiology of ischemic stroke were investigated. Logistic regression models adjusting for known cardiovascular disease risk factors were constructed to assess the associations of the 23 SNPs in rigorously phenotyped cases (N=429) of ischemic stroke (Men=198; Women=231) and stroke- free (N=483) controls (Men=236; Women=247)., Results: Interleukin-6 (IL6) rs1800796 (C minor allele; frequency: West Africans=8.6%) was significantly associated with ischemic stroke in men (OR=2.006, 95% CI=[1.065, 3.777], p=0.031) with hypertension in the model but not in women. In addition, rs2383207 in CDKN2A/CDKN2B (minor allele A with frequency: West Africans=1.7%) was also associated with ischemic stroke in men (OR=2.550, 95% CI=[1.027, 6.331], p=0.044) with primary covariates in the model, but not in women. Polymorphisms in other genes did not show significant association with ischemic stroke., Conclusion: Polymorphisms rs1800796 in IL6 gene and rs2383207 in CDKN2A/CDKN2B gene have significant associations with ischemic stroke in indigenous West African men. CDKN2A/CDKN2B SNP rs2383207 is independently associated with ischemic stroke in indigenous West African men. Further research should focus on the contributions of inflammatory genes and other genetic polymorphisms, as well as the influence of sex on the neurobiology of stroke in people of African ancestry., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Trimethylamine-N-oxide (TMAO), an atherogenic metabolite species, has emerged as a possible new risk factor for cardiovascular disease. Animal studies have shown that circulating TMAO levels are regulated by genetic and environmental factors. However, large-scale human studies have failed to replicate the observed genetic associations, and epigenetic factors such as DNA methylation have never been examined in relation to TMAO levels., Methods and Results: We used data from the family-based Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) to investigate the heritable determinants of plasma TMAO in humans. TMAO was not associated with other plasma markers of cardiovascular disease, e.g. lipids or inflammatory cytokines. We first estimated TMAO heritability at 27%, indicating a moderate genetic influence. We used 1000 Genomes imputed data (n=626) to estimate genome-wide associations with TMAO levels, adjusting for age, sex, family relationships, and study site. The genome-wide study yielded one significant hit at the genome-wide level, located in an intergenic region on chromosome 4. We subsequently quantified epigenome-wide DNA methylation using the Illumina Infinium array on CD4+ T-cells. We tested for association of methylation loci with circulating TMAO (n=847), adjusting for age, sex, family relationships, and study site as the genome-wide study plus principal components capturing CD4+ T-cell purity. Upon adjusting for multiple testing, none of the epigenetic findings were statistically significant., Conclusions: Our findings contribute to the growing body of evidence suggesting that neither genetic nor epigenetic factors play a critical role in establishing circulating TMAO levels in humans., Competing Interests: Competing interests: The authors declare that they have no competing interests

All six World Health Organization (WHO) regions have now set goals for measles elimination by or before 2020. To prioritize measles elimination efforts and use available resources efficiently, there is a need to identify at-risk areas that are offtrack from meeting performance targets and require strengthening of programmatic efforts. This article describes the development of a WHO measles programmatic risk assessment tool to be used for monitoring, guiding, and sustaining measles elimination efforts at the subnational level. We outline the tool development process; the tool specifications and requirements for data inputs; the framework of risk categories, indicators, and scoring; and the risk category assignment. Overall risk was assessed as a function of indicator scores that fall into four main categories: population immunity, surveillance quality, program performance, and threat assessment. On the basis of the overall score, the tool assigns each district a risk of either low, medium, high, or very high. The cut-off criteria for the risk assignment categories were based on the distribution of scores from all possible combinations of individual indicator cutoffs. The results may be used for advocacy to communicate risk to policymakers, mobilize resources for corrective actions, manage population immunity, and prioritize programmatic activities. Ongoing evaluation of indicators will be needed to evaluate programmatic performance and plan risk mitigation activities effectively. The availability of a comprehensive tool that can identify at-risk districts will enhance efforts to prioritize resources and implement strategies for achieving the Global Vaccine Action Plan goals for measles elimination., (© 2015 Society for Risk Analysis.)

Objectives/background: Sequence variants in HPV16 confer differences in oncogenic potential; however, to date there have not been any HPV sequence studies performed in Nepal. The objective of this study was to characterize HPV16 viral genome sequences from Nepal compared to a reference sequence in order to determine their lineages. Additionally, we sought to determine if five High-grade Squamous Intraepithelial Lesion (HSIL) subjects were genetically distinct from the non-HSIL subjects., Methods: DNA was isolated from exfoliated cervical cells from 17 individuals in Nepal who were previously identified to be HPV16-positive. A custom HPV16 Ion Ampliseq panel of multiplexed degenerate primers was designed that generated 47 overlapping amplicons and covered 99% of the viral genome for all known HPV16 variant lineages. All sequence data were processed through a custom quality control and analysis pipeline of sequence comparisons and phylogenetic analysis., Results: There were high similarities across the genomes, with two major indels observed in the non-coding region between E5 and L2. Compared to the PAVE reference HPV16 genome, there were up to 9, 4, 38, 27, 8, 7, 52, and 32 nucleotide variants in the E6, E7, E1, E2, E4, E5, L2, and L1 genes in the Nepalese samples, respectively. Based on sequence variation, HPV16 from Nepal falls across the A, C, and D lineages in this study. We found no evidence of genetic distinctness between HSIL and non-HSIL subjects., Conclusions: The evolutionary and pathological characteristics of the representative HPV16 genomes from Nepal seem similar to results from other parts of the world and provide the basis for further studies., Competing Interests: of Conflicts of Interest. None, (Copyright © 2016 Elsevier B.V. All rights reserved.)

Population immunity depends on the dynamic levels of immunization coverage that countries achieve over time and any transmission of viruses that occur within the population that induce immunity. In the context of developing a dynamic transmission model for measles and rubella to support analyses of future immunization policy options, we assessed the model inputs required to reproduce past behavior and to provide some confidence about model performance at the national level. We reviewed the data available from the World Health Organization (WHO) and existing measles and rubella literature for evidence of historical reported routine and supplemental immunization activities and reported cases and outbreaks. We constructed model input profiles for 180 WHO member states and three other areas to support disease transmission model development and calibration. The profiles demonstrate the significant variability in immunization strategies used historically by regions and member states and the epidemiological implications of these historical choices. The profiles provide a historical perspective on measles and rubella immunization globally at the national level, and they may help immunization program managers identify existing immunity and/or knowledge gaps., (© 2015 Society for Risk Analysis.)

Importance: DNA methylation may play an important role in schizophrenia (SZ), either directly as a mechanism of pathogenesis or as a biomarker of risk., Objective: To scan genome-wide DNA methylation data to identify differentially methylated CpGs between SZ cases and controls., Design, Setting, and Participants: Epigenome-wide association study begun in 2008 using DNA methylation levels of 456 513 CpG loci measured on the Infinium HumanMethylation450 array (Illumina) in a consortium of case-control studies for initial discovery and in an independent replication set. Primary analyses used general linear regression, adjusting for age, sex, race/ethnicity, smoking, batch, and cell type heterogeneity. The discovery set contained 689 SZ cases and 645 controls (n = 1334), from 3 multisite consortia: the Consortium on the Genetics of Endophenotypes in Schizophrenia, the Project among African-Americans To Explore Risks for Schizophrenia, and the Multiplex Multigenerational Family Study of Schizophrenia. The replication set contained 247 SZ cases and 250 controls (n = 497) from the Genomic Psychiatry Cohort., Main Outcomes and Measures: Identification of differentially methylated positions across the genome in SZ cases compared with controls., Results: Of the 689 case participants in the discovery set, 477 (69%) were men and 258 (37%) were non-African American; of the 645 controls, 273 (42%) were men and 419 (65%) were non-African American. In our replication set, cases/controls were 76% male and 100% non-African American. We identified SZ-associated methylation differences at 923 CpGs in the discovery set (false discovery rate, <0.2). Of these, 625 showed changes in the same direction including 172 with P < .05 in the replication set. Some replicated differentially methylated positions are located in a top-ranked SZ region from genome-wide association study analyses., Conclusions and Relevance: This analysis identified 172 replicated new associations with SZ after careful correction for cell type heterogeneity and other potential confounders. The overlap with previous genome-wide association study data can provide potential insights into the functional relevance of genetic signals for SZ.

In 2013, the 66th session of the Regional Committee of the World Health Organization (WHO) South-East Asia Region (SEAR) established a goal to eliminate measles and to control rubella and congenital rubella syndrome (CRS) in SEAR by 2020. Current recommended measles elimination strategies in the region include 1) achieving and maintaining ≥95% coverage with 2 doses of measles-containing vaccine (MCV) in every district, delivered through the routine immunization program or through supplementary immunization activities (SIAs); 2) developing and sustaining a sensitive and timely measles case-based surveillance system that meets minimum recommended performance indicators; 3) developing and maintaining an accredited measles laboratory network; and 4) achieving timely identification, investigation, and response to measles outbreaks. In 2013, Nepal, one of the 11 SEAR member states, adopted a goal for national measles elimination by 2019. This report updates a previous report and summarizes progress toward measles elimination in Nepal during 2007-2014. During 2007-2014, estimated coverage with the first MCV dose (MCV1) increased from 81% to 88%. Approximately 3.9 and 9.7 million children were vaccinated in SIAs conducted in 2008 and 2014, respectively. Reported suspected measles incidence declined by 13% during 2007-2014, from 54 to 47 cases per 1 million population. However, in 2014, 81% of districts did not meet the measles case-based surveillance performance indicator target of ≥2 discarded non-measles cases per 100,000 population per year. To achieve and maintain measles elimination, additional measures are needed to strengthen routine immunization services to increase coverage with MCV1 and a recently introduced second dose of MCV (MCV2) to ≥95% in all districts, and to enhance sensitivity of measles case-based surveillance by adopting a more sensitive case definition, expanding case-based surveillance sites nationwide, and ensuring timely transport of specimens to the accredited national laboratory.

In 2000, the United Nations General Assembly adopted the Millennium Development Goals (MDG), with MDG4 being a two-thirds reduction in child mortality by 2015, and with measles vaccination coverage being one of the three indicators of progress toward this goal.* In 2010, the World Health Assembly established three milestones for measles control by 2015: 1) increase routine coverage with the first dose of measles-containing vaccine (MCV1) for children aged 1 year to ≥90% nationally and ≥80% in every district; 2) reduce global annual measles incidence to fewer than five cases per million population; and 3) reduce global measles mortality by 95% from the 2000 estimate (1).† In 2012, the World Health Assembly endorsed the Global Vaccine Action Plan§ with the objective to eliminate measles in four World Health Organization (WHO) regions by 2015. WHO member states in all six WHO regions have adopted measles elimination goals. This report updates the 2000–2013 report (2) and describes progress toward global control and regional measles elimination during 2000–2014. During this period, annual reported measles incidence declined 73% worldwide, from 146 to 40 cases per million population, and annual estimated measles deaths declined 79%, from 546,800 to 114,900. However, progress toward the 2015 milestones and elimination goals has slowed markedly since 2010. To resume progress toward milestones and goals for measles elimination, a review of current strategies and challenges to improving program performance is needed, and countries and their partners need to raise the visibility of measles elimination, address barriers to measles vaccination, and make substantial and sustained additional investments in strengthening health systems.

Fenofibrate lowers triglycerides (TG) and raises high density lipoprotein cholesterol (HDLc) in dyslipidemic individuals. Several studies have shown genetic variability in lipid responses to fenofibrate treatment. It is, however, not known whether epigenetic patterns are also correlated with the changes in lipids due to fenofibrate treatment. The present study was therefore undertaken to examine the changes in DNA methylation among the participants of Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study. A total of 443 individuals were studied for epigenome-wide changes in DNA methylation, assessed using the Illumina Infinium HumanMethylation450 array, before and after a 3-week daily treatment with 160 mg of fenofibrate. The association between the change in DNA methylation and changes in TG, HDLc, and low-density lipoprotein cholesterol (LDLc) were assessed using linear mixed models adjusted for age, sex, baseline lipids, and study center as fixed effects and family as a random effect. Changes in DNA methylation were not significantly associated with changes in TG, HDLc, or LDLc after 3 weeks of fenofibrate for any CpG. CpG changes in genes known to be involved in fenofibrate response, e.g., PPAR-α, APOA1, LPL, APOA5, APOC3, CETP, and APOB, also did not show evidence of association. In conclusion, changes in lipids in response to 3-week treatment with fenofibrate were not associated with changes in DNA methylation. Studies of longer duration may be required to detect treatment-induced changes in methylation.

Introduction: Despite accelerated measles control efforts, a massive measles resurgence occurred in the Democratic Republic of the Congo (DRC) starting in mid-2010, prompting an investigation into likely causes., Methods: We conducted a descriptive epidemiological analysis using measles immunization and surveillance data to understand the causes of the measles resurgence and to develop recommendations for elimination efforts in DRC., Results: During 2004-2012, performance indicator targets for case-based surveillance and routine measles vaccination were not met. Estimated coverage with the routine first dose of measles-containing vaccine (MCV1) increased from 57% to 73%. Phased supplementary immunization activities (SIAs) were conducted starting in 2002, in some cases with sub-optimal coverage (≤95%). In 2010, SIAs in five of 11 provinces were not implemented as planned, resulting in a prolonged interval between SIAs, and a missed birth cohort in one province. During July 1, 2010-December 30, 2012, high measles attack rates (>100 cases per 100,000 population) occurred in provinces that had estimated MCV1 coverage lower than the national estimate and did not implement planned 2010 SIAs. The majority of confirmed case-patients were aged <10 years (87%) and unvaccinated or with unknown vaccination status (75%). Surveillance detected two genotype B3 and one genotype B2 measles virus strains that were previously identified in the region., Conclusion: The resurgence was likely caused by an accumulation of unvaccinated, measles-susceptible children due to low MCV1 coverage and suboptimal SIA implementation. To achieve the regional goal of measles elimination by 2020, efforts are needed in DRC to improve case-based surveillance and increase two-dose measles vaccination coverage through routine services and SIAs.

Background: Memory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal declarative memory in a community setting., Methods: We conducted genome-wide association studies for paragraph or word list delayed recall in 19 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, comprising 29,076 dementia- and stroke-free individuals of European descent, aged ≥45 years. Replication of suggestive associations (p < 5 × 10(-6)) was sought in 10,617 participants of European descent, 3811 African-Americans, and 1561 young adults., Results: rs4420638, near APOE, was associated with poorer delayed recall performance in discovery (p = 5.57 × 10(-10)) and replication cohorts (p = 5.65 × 10(-8)). This association was stronger for paragraph than word list delayed recall and in the oldest persons. Two associations with specific tests, in subsets of the total sample, reached genome-wide significance in combined analyses of discovery and replication (rs11074779 [HS3ST4], p = 3.11 × 10(-8), and rs6813517 [SPOCK3], p = 2.58 × 10(-8)) near genes involved in immune response. A genetic score combining 58 independent suggestive memory risk variants was associated with increasing Alzheimer disease pathology in 725 autopsy samples. Association of memory risk loci with gene expression in 138 human hippocampus samples showed cis-associations with WDR48 and CLDN5, both related to ubiquitin metabolism., Conclusions: This largest study to date exploring the genetics of memory function in ~40,000 older individuals revealed genome-wide associations and suggested an involvement of immune and ubiquitin pathways., (Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Carotid intima-media thickness (cIMT) is a subclinical measure of atherosclerosis with mounting evidence that higher cIMT confers an increased risk of cardiovascular disease. The ryanodine receptor 3 gene (RYR3) has previously been linked to increased cIMT; however, the causal variants have not yet been localized. Therefore, we sequenced 339,480 bp encompassing 104 exons and 2 kb flanking region of the RYR3 gene in 96 HIV-positive white men from the extremes of the distribution of common cIMT from the Fat Redistribution and Metabolic Changes in HIV infection study (FRAM). We identified 2710 confirmed variants (2414 single-nucleotide polymorphisms (SNPs) and 296 insertion/deletions (indels)), with a mean count of 736 SNPs (ranging from 528 to 1032) and 170 indels (ranging from 128 to 214) distributed in each individual. There were 39 variants in the exons and 15 of these were non-synonymous, of which with only 4 were common variants and the remaining 11 were rare variants, one was a novel SNP. We confirmed that the common variant rs2229116 was significantly associated with cIMT in this design (P<7.9 × 10(-9)), and observed seven other significantly associated SNPs (P<10(-8)). These variants including the private non-synonymous SNPs need to be followed up in a larger sample size and also tested with clinical atherosclerotic outcomes.

In 2012, the World Health Assembly endorsed the Global Vaccine Action Plan with the objective to eliminate measles in four World Health Organization (WHO) regions by 2015. Member states of all six WHO regions have adopted measles elimination goals. In 2010, the World Health Assembly established three milestones for 2015: 1) increase routine coverage with the first dose of measles-containing vaccine (MCV1) for children aged 1 year to ≥90% nationally and ≥80% in every district; 2) reduce global annual measles incidence to <5 cases per million; and 3) reduce global measles mortality by 95% from the 2000 estimate. This report updates the 2000-2012 report and describes progress toward global control and regional measles elimination during 2000-2013. During this period, annual reported measles incidence declined 72% worldwide, from 146 to 40 per million population, and annual estimated measles deaths declined 75%, from 544,200 to 145,700. Four of six WHO regions have established regional verification commissions (RVCs); in the European (EUR) and Western Pacific regions (WPR), 19 member states successfully documented the absence of endemic measles. Resuming progress toward 2015 milestones and elimination goals will require countries and their partners to raise the visibility of measles elimination, address barriers to measles vaccination, and make substantial and sustained additional investments in strengthening health systems.

Gene copy number variation (CNV) of the CC Chemokine ligand 3-Like-1 (CCL3L1) gene located on chromosome 17q12 has been associated with many diseases, including viral infections and autoimmune diseases. High sequence homology between CCL3L1 and three other related genes within the same cluster, CCL3, CCL3L2, and CCL3L3, make it difficult to determine the copy number of each gene as well as distinguishing variants within each gene versus between genes. We identified a total of 50SNPs, 31 known and 19 novel SNPs, in a subset of West Africa Reference (Yoruba individuals from Ibadan, Nigeria (YRI)) samples from HapMap. One of these previously unidentified variations is a non-synonymous change while several other unreported variations are located near potential regulatory sites. The variations identified in these immune-related genes from this study will shed light in the understanding of both structural and nucleotide polymorphisms that can be used in association studies of diseases in populations., (Copyright © 2014 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

Background: Updated estimates of measles case fatality rates (CFR) are critical for monitoring progress towards measles elimination goals. India accounted for 36% of total measles deaths occurred globally in 2011. We conducted a retrospective cohort study to estimate measles CFR and identify the risk factors for measles death in Bihar-one of the north Indian states historically known for its low vaccination coverage., Methods: We systematically selected 16 of the 31 laboratory-confirmed measles outbreaks occurring in Bihar during 1 October 2011 to 30 April 2012. All households of the villages/urban localities affected by these outbreaks were visited to identify measles cases and deaths. We calculated CFR and used multivariate analysis to identify risk factors for measles death., Results: The survey found 3670 measles cases and 28 deaths (CFR: 0.78, 95% confidence interval: 0.47-1.30). CFR was higher among under-five children (1.22%) and children belonging to scheduled castes/tribes (SC/ST, 1.72%). On multivariate analysis, independent risk factors associated with measles death were age <5 years, SC/ST status and non-administration of vitamin A during illness. Outbreaks with longer interval between the occurrence of first case and notification of the outbreak also had a higher rate of deaths., Conclusions: Measles CFR in Bihar was low. To further reduce case fatality, health authorities need to ensure that SC/ST are targeted by the immunization programme and that outbreak investigations target for vitamin A treatment of cases in high risk groups such as SC/ST and young children and ensure regular visits by health-workers in affected villages to administer vitamin A to new cases.

In 2010, the World Health Assembly established three milestones toward global measles eradication to be reached by 2015: 1) increase routine coverage with the first dose of measles-containing vaccine (MCV1) for children aged 1 year to ≥90% nationally and ≥80% in every district, 2) reduce and maintain annual measles incidence at <5 cases per million, and 3) reduce measles mortality by 95% from the 2000 estimate. After the adoption by member states of the South-East Asia Region (SEAR) of the goal of measles elimination by 2020, elimination goals have been set by member states of all six World Health Organization (WHO) regions, and reaching measles elimination in four WHO regions by 2015 is an objective of the Global Vaccine Action Plan (GVAP). This report updates the previous report for 2000-2011 and describes progress toward global control and regional elimination of measles during 2000-2012. During this period, increases in routine MCV coverage, plus supplementary immunization activities (SIAs) reaching 145 million children in 2012, led to a 77% decrease worldwide in reported measles annual incidence, from 146 to 33 per million population, and a 78% decline in estimated annual measles deaths, from 562,400 to 122,000. Compared with a scenario of no vaccination, an estimated 13.8 million deaths were prevented by measles vaccination during 2000-2012. Achieving the 2015 targets and elimination goals will require countries and their partners to raise the visibility of measles elimination and make substantial and sustained additional investments in strengthening health systems.

Background: Herpes virus infections can cause cognitive impairment during and after acute encephalitis. Although chronic, latent/persistent infection is considered to be relatively benign, some studies have documented cognitive impairment in exposed persons that is untraceable to encephalitis. These studies were conducted among schizophrenia (SZ) patients or older community dwellers, among whom it is difficult to control for the effects of co-morbid illness and medications. To determine whether the associations can be generalized to other groups, we examined a large sample of younger control individuals, SZ patients and their non-psychotic relatives (n=1852). Method Using multivariate models, cognitive performance was evaluated in relation to exposures to herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2) and cytomegalovirus (CMV), controlling for familial and diagnostic status and sociodemographic variables, including occupation and educational status. Composite cognitive measures were derived from nine cognitive domains using principal components of heritability (PCH). Exposure was indexed by antibodies to viral antigens., Results: PCH1, the most heritable component of cognitive performance, declines with exposure to CMV or HSV-1 regardless of case/relative/control group status (p = 1.09 × 10-5 and 0.01 respectively), with stronger association with exposure to multiple herpes viruses (β = -0.25, p = 7.28 × 10-10). There were no significant interactions between exposure and group status., Conclusions: Latent/persistent herpes virus infections can be associated with cognitive impairments regardless of other health status.

Background: Genome-wide association studies (GWAS) implicate single nucleotide polymorphisms (SNPs) on chromosome 6p21.3-22.1, the human leukocyte antigen (HLA) region, as common risk factors for schizophrenia (SZ). Other studies implicate viral and protozoan exposure. Our study tests chromosome 6p SNPs for effects on SZ risk with and without exposure., Method: GWAS-significant SNPs and ancestry-informative marker SNPs were analyzed among African American patients with SZ (n = 604) and controls (n = 404). Exposure to herpes simplex virus, type 1 (HSV-1), cytomegalovirus (CMV), and Toxoplasma gondii (TOX) was assayed using specific antibody assays., Results: Five SNPs were nominally associated with SZ, adjusted for population admixture (P < .05, uncorrected for multiple comparisons). These SNPs were next analyzed in relation to infectious exposure. Multivariate analysis indicated significant association between rs3130297 genotype and HSV-1 exposure; the associated allele was different from the SZ risk allele., Conclusions: We propose a model for the genesis of SZ incorporating genomic variation in the HLA region and neurotropic viral exposure for testing in additional, independent African American samples.

Objective: Fenofibrate, a peroxisome proliferator-activated receptor-α (PPARα) agonist, reduces triglyceride (TG) concentrations by 25-60%. Given significant interindividual variations in the TG response, we investigated the association of PPARA rare variants with treatment response in the Genetics of Lipid-Lowering Drugs and Diet Network study., Methods: We calculated the change in the TG concentration (ΔTG) among 861 GOLDN participants treated with fenofibrate (160 mg/day) for 3 weeks. From the distribution of ΔTG adjusted for age and sex, the 150 highest and 150 lowest fenofibrate responders were selected from the tails of the distribution for PPARA resequencing. The resequencing strategy was based on VariantSEQr technology for the amplification of exons and regulatory regions., Results: We identified 73 variants with an average minor allele frequency of 4.8% (range: 0.2-16%). We tested the association of rare variants located in a coding or a regulatory region (minor allele frequency<1%, 13 variants) with treatment response group by an indicator variable (presence/absence of ≥1 rare variant) using general linear mixed models to allow for adjustment for family relationship. After adjusting for baseline, fasting TG concentration carrying at least one rare variant was associated with a low fenofibrate response (odds ratio=6.46; 95% confidence interval: 1.4-30.8). Carrier status was also associated with a relative change in the total cholesterol concentration (P=0.02), but not high-density lipoprotein or low-density lipoprotein concentration., Conclusion: Rare, potentially functional variants in PPARA may play a role in the TG response to fenofibrate, but future experimental studies will be necessary to replicate the findings and confirm functional effects.

When susceptibility to diseases is caused by cis-effects of multiple alleles at adjacent polymorphic sites, it may be difficult to assess with confidence the genetic phase and identify individuals carrying the risk haplotype. Experimental assessment of genetic phase is still challenging and most population studies use statistical approaches to infer haplotypes given the observed genotypes. While these statistical approaches are powerful and have been proven very useful in large scale genetic population studies, they may be prone to errors in studies with small sample size, especially in the presence of compound heterozygotes. Here, we describe a simple and novel approach using the popular PCR-RFLP based strategy to assess the genetic phase in compound heterozygotes. We apply this method to two extensively studied SNPs in two clustered immune-related genes: The -308 (G > A) and the +252 (A > G) SNPs of the tumor necrosis factor (TNF) alpha and the lymphotoxin alpha (LTA) genes, respectively. Using this method, we successfully determined the genetic phase of these two SNPs in known compound heterozygous individuals and in every sample tested. We show that the A allele of TNF -308 is carried on the same chromosome as the LTA +252(G) allele.

Background: Measles caused mortality in >164,000 children in 2008, with most deaths occurring during outbreaks. Nonetheless, the impact and desirability of conducting measles outbreak response immunization (ORI) in middle- and low-income countries has been controversial. World Health Organization guidelines published in 1999 recommended against ORI in such settings, although recently these guidelines have been reversed for countries with measles mortality reduction goals., Methods: We searched literature published during 1995-2009 for papers reporting on measles outbreaks. Papers identified were reviewed by 2 reviewers to select those that mentioned ORI. World Bank classification of country income was used to identify reports of outbreaks in middle- and low-income countries., Results: We identified a total of 485 articles, of which 461 (95%) were available. Thirty-eight of these papers reported on a total of 38 outbreaks in which ORI was used. ORI had a clear impact in 16 (42%) of these outbreaks. In the remaining outbreaks, we were unable to independently assess the impact of ORI., Conclusions: These findings generally support ORI in middle- and low-income countries. However, the decision to conduct ORI and the nature and extent of the vaccination response need to be made on a case-by-case basis., (Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2011. All rights reserved.)

Background: In 2009, the first national long-lasting insecticide-treated net (LLIN) distribution campaign in Senegal resulted in the distribution of 2.2 million LLINs in two phases to children aged 6-59 months. Door-to-door teams visited all households to administer vitamin A and mebendazole, and to give a coupon to redeem later for an LLIN., Methods: A nationwide community-based two-stage cluster survey was conducted, with clusters selected within regions by probability proportional to size sampling, followed by GPS-assisted mapping, simple random selection of households in each cluster, and administration of a questionnaire using personal digital assistants (PDAs). The questionnaire followed the Malaria Indicator Survey format, with rosters of household members and bed nets, and questions on campaign participation., Results: There were 3,280 households in 112 clusters representing 33,993 people. Most (92.1%) guardians of eligible children had heard about the campaign, the primary sources being health workers (33.7%), neighbours (26.2%), and radio (22.0%). Of eligible children, 82.4% received mebendazole, 83.8% received vitamin A, and 75.4% received LLINs. Almost all (91.4%) LLINs received during the campaign remained in the household; of those not remaining, 74.4% had been given away and none were reported sold. At least one insecticide-treated net (ITN) was present in 82.3% of all households, 89.2% of households with a child < 5 years and 57.5% of households without a child < 5 years. Just over half (52.4%) of ITNs had been received during the campaign. Considering possible indicators of universal coverage, 39.8% of households owned at least one ITN per two people, 21.6% owned at least one ITN per sleeping space and 34.7% of the general population slept under an ITN the night before the survey. In addition, 45.6% of children < 5 years, and 49.2% of pregnant women had slept under an ITN., Conclusions: The nationwide integrated LLIN distribution campaign allowed household ITN ownership of one or more ITNs to surpass the RBM target of 80% set for 2010, though additional distribution strategies are needed to reach populations missed by the targeted campaign and to reach the universal coverage targets of one ITN per sleeping space and 80% of the population using an ITN.

Rationale: Left ventricular (LV) mass and related phenotypes are heritable, important predictors of cardiovascular disease, particularly in hypertensive individuals., Objective: Identify genetic predictors of echocardiographic phenotypes in hypertensive families., Methods and Results: A multistage genome-wide association study (GWAS) was conducted in hypertensive-ascertained black families (HyperGEN, stage I; GENOA, stage II); findings were replicated in HyperGEN white families (stage III). Echocardiograms were collected using a common protocol, and participants were genotyped with the Affymetrix Genome-Wide Human SNP 6.0 Array. The following were analyzed using mixed models adjusted for ancestry: in stages I and II, 1258 and 989 blacks, respectively; and in stage III, 1316 whites. Phenotypes included LV mass, LV internal dimension (LVID), wall thicknesses (posterior [PWT] and intraventricular septum [IVST]), and relative wall thickness (RWT). In stage I, 5 single nucleotide polymorphisms (SNPs) had P≤10(-6). In stage II, 1 SNP (rs1436109; NCAM1 intron 1) replicated with the same phenotype (PWT, P=0.025) in addition to RWT (P=0.032). In stage III, rs1436109 was associated with RWT (P=5.47×10(-4)) and LVID (P=1.86×10(-4)). Fisher combined probability value for all stages was RWT=3.80×10(-9), PWT=3.12×10(-7), IVST=8.69×10(-7), LV mass=2.52×10(-3), and LVID=4.80×10(-4)., Conclusions: This GWAS conducted in hypertensive families identified a variant in NCAM1 associated with LV wall thickness and RWT. NCAM is upregulated during the remodeling period of hypertrophy to heart failure in Dahl salt-sensitive rats. Our initial screening in hypertensive blacks may have provided the context for this novel locus.

We conducted a measles outbreak investigation in Dar es Salaam, Tanzania. Surveillance data were analyzed; a susceptibility profile developed, and case-control study conducted. The age distribution of cases peaked among those <2, 5-7, and > or =18 years, corresponding to the age distribution of susceptibles. Risk factors included being unvaccinated (aOR=5.7, p<0.01) or having received one dose of vaccine compared to two (aOR=2.4, p=0.01), being younger, and having a less-educated caretaker. Vaccine effectiveness was 88% (one dose) and 96% (two doses). Results highlight the importance of receiving one dose of measles vaccine, and the added benefit of two doses., (Published by Elsevier Ltd.)

We assessed the impact of a measles outbreak response vaccination campaign (ORV) in Dar es Salaam, Tanzania. Age-specific incidence rates were calculated before and after the ORV. Incidence rate ratios for the two time periods were compared and used to estimate expected cases and deaths prevented by ORV. The ratio of measles incidence rates in the age groups targeted and not targeted by ORV decreased from 5.8 prior to ORV to 1.8 (p<0.0001) after; 506 measles cases and 18 measles deaths were likely averted. These results support the need for revised recommendations concerning ORV in general settings in Africa.

While many studies have sought a window into the genetics of schizophrenia, few have focused on African-American families. An exception is the Project among African-Americans to Explore Risks for Schizophrenia (PAARTNERS), which seeks to identify novel and known risk variation for schizophrenia by genetic analyses of African-American families. We report a linkage study of diagnostic status in 217 African-American families using the Illumina Linkage Panel. Due to assumed incomplete and time-dependent penetrance, we performed linkage analysis using two different treatments of diagnosis: (1) treating both affected and unaffected individuals as informative for linkage (using the program SIBPAL) and (2) treating only affected individuals as informative (using the program MERLIN). We also explore three definitions of affected status: narrowly defined schizophrenia; one broadened to include schizoaffective disorder; and another including all diagnoses indicating psychosis. Several regions show a decrease in the evidence for linkage as the definition broadens 8q22.1 (rs911, 99.26 cM; SIBPAL p-value [p] goes from 0.006 to 0.02), 16q24.3 (rs1006547, 130.48 cM; p from 0.00095 to 0.0085), and 20q13.2 (rs1022689, 81.73 cM; p from 0.00015 to 0.032). One region shows a substantial increase in evidence for linkage, 11p15.2 (rs722317, 24.27 cM; p from 0.0022 to 0.0000003); MERLIN results support the significance of the SIBPAL results (p=0.00001). Our linkage results overlap two broad, previously-reported linkage regions: 8p23.3-p12 found in studies sampling largely families of European ancestry; and 11p11.2-q22.3 reported by a study of African-American families. These results should prove quite useful for uncovering loci affecting risk for schizophrenia.

We performed linkage analysis for age at onset (AAO) in the total Alzheimer's disease (AD) NIMH sample (N = 437 families). Families were subset as late-onset (320 families, AAO > or = 65) and early/mixed (117 families, at least 1 member with 50 < AAO < 65). Treating AAO as a censored trait, we obtained the gender and APOE adjusted residuals in a parametric survival model and analyzed the residuals as the quantitative trait (QT) in variance-component linkage analysis. For comparison, AAO-age at exam (AAE) was analyzed as the QT adjusting for affection status, gender, and APOE. Heritabilities for residual and AAO-AAE outcomes were 66.3% and 74.0%, respectively for the total sample, 56.0% and 57.0% in the late-onset sample, and 33.0% for both models in the early/mixed sample. The residual model yielded the largest peaks on chromosome 1 with LOD = 2.0 at 190 cM in the total set, LOD = 1.7 at 116 cM on chromosome 3 in the early/mixed subset, and LOD = 1.4 at 71 and 86 cM, respectively, on chromosome 6 in the late-onset subset. For the AAO-AAE outcome model the largest peaks were identified on chromosome 1 at 137 cM (LOD = 2.8) and chromosome 6 at 69 cM (LOD = 2.3) and 86 cM (LOD = 2.2) all in the late-onset subset. Additional peaks with LOD > or = 1 were identified on chromosomes 1, 2, 3, 6, 8, 9, 10, and 12 for the total sample and each subset. Results replicate previous findings, but identify additional suggestive peaks indicating the genetics of AAO in AD is complex with many chromosomal regions potentially containing modifying genes., (2008 Wiley-Liss, Inc.)

Brain-derived neurotrophic factor (BDNF)/tyrosine receptor kinase (TRK) signaling pathway activates a wide range of downstream intracellular cascades, regulating neuronal development and plasticity, long-term potentiation, and apoptosis. The NTRK family encodes the receptors TRKA, TRKB, and TRKC, to which the neurotrophins, nerve growth factor (NGF), BDNF and neurotrophin-3 (NT-3) bind, respectively, with high affinity. Signaling through these receptors appears to be compromised in Alzheimer's disease (AD). This study is the most comprehensive investigation of genetic variants of NTRK2, and the first to show significant association between NTRK2 with AD. Fourteen single nucleotide polymorphisms (SNPs), located in 8 of 18 linkage disequilibrium (LD) blocks, were genotyped in 203 families with at least two AD affected siblings with mean age of onset (MAO) of 70.9 +/- 7.4 years and one unaffected sibling from the NIMH-ADGJ dataset. Family based association testing found no single SNP association, however, significant associations were found for two and three locus haplotypes (P = 0.012, P = 0.009, respectively) containing SNPs rsl624327, rsl443445, and rs378645. These SNPs are located in areas of the gene containing sequences that could be involved in alternative splicing and/or regulation of NTRK2. Our results suggest that NTRK2 may be a genetic susceptibility gene contributing to AD pathology., (Copyright 2007 Wiley-Liss, Inc.)

From a normal human brain phage display library screen we identified the gamma (A)-globin chain of fetal hemoglobin (Hb F) as a protein that bound strongly to A beta1-42. We showed the oxidized form of adult Hb (metHb A) binds with greater affinity to A beta1-42 than metHb F. MetHb is more toxic than oxyhemoglobin because it loses its heme group more readily. Free Hb and heme readily damage vascular endothelial cells similar to Alzheimer's disease (AD) vascular pathology. The XmnI polymorphism (C-->T) at -158 of the gamma (G)-globin promoter region can contribute to increased Hb F expression. Using family-based association testing, we found a significant protective association of this polymorphism in the NIMH sibling dataset (n=489) in families, with at least two affected and one unaffected sibling (p=0.006), with an age of onset >50 years (p=0.010) and >65 years (p=0.013), and families not homozygous for the APOE4 allele (p=0.041). We hypothesize that Hb F may be less toxic than adult Hb in its interaction with A beta and may protect against the development of AD.

The objective of this research was to develop a procedure to identify candidate genes under linkage peaks confirmed in a follow-up of candidate regions of interests (CRIs) identified in our original genome scan in the NIMH Alzheimer's diseases (AD) Initiative families (Blacker et al. [1]). There were six CRIs identified that met the threshold of multipoint lod score (MLS) of >or= 2.0 from the original scan. The most significant peak (MLS = 7.7) was at 19q13, which was attributed to APOE. The remaining CRIs with 'suggestive' evidence for linkage were identified at 9q22, 6q27, 14q22, 11q25, and 3p26. We have followed up and narrowed the 9q22 CRI signal using simple tandem repeat (STR) markers (Perry et al. [2]). In this confirmatory project, we have followed up the 6q27, 14q22, 11q25, and 3p26 CRIs with a total of 24 additional flanking STRs, reducing the mean interval marker distance (MID) in each CRI, and substantially increase in the information content (IC). The linkage signals at 6q27, 14q22 and 11q25 remain 'suggestive', indicating that these CRIs are promising and worthy of detailed fine mapping and assessment of candidate genes associated with AD. We have developed a bioinformatics approach for identifying candidate genes in these confirmed regions based on the Gene Ontology terms that are annotated and enriched among the systematic meta-analyzed genes, confirmed by at least three case-control samples, and cataloged in the "AlzGene database" as potential Alzheimer disease susceptibility genes (http://www.alzgene.org).

Genes involved in cellular mechanisms to repair oxidative damage are strong candidates as etiologic factors for Alzheimer's disease (AD). One important enzyme involved in this mechanism is superoxide dismutase 2 (SOD2). The gene for this enzyme lies within a single haplotype block at 6q25.3, a region showing evidence for linkage to AD in a genome scan. We genotyped four single nucleotide polymorphisms (SNPs) in SOD2 in families of the National Institute of Mental Health-AD Genetics Initiative (ADGI): rs2758346 in the 5' untranslated region (UTR), rs4880 in exon 2, rs2855116 in intron 3 and rs5746136 in the 3'UTR. Under a dominant model, family-based association tests showed significant evidence for association of AD with the first three loci in a candidate gene set of families with individuals having age of onset of at least 50 years and two affected and one unaffected sibling, and in a late-onset subset of families (families with all affected individuals having age of onset of at least 65 years) from the full ADGI sample. The alleles transmitted more frequently to cases than expected under the null hypothesis were T, C, G, and G. Global tests of the transmission of haplotypes indicate that the first two loci have the most consistent association with risk of AD. Because of the high linkage disequilibrium in this small (14 kb) gene, and the presence of 100 SNPs in this gene, 26 of which may have functional significance, additional genotyping and sequencing are needed to identify the functionally relevant SNP. We discuss the importance of our findings and the relevance of SOD2 to AD risk.

Other than the APOE peak at 19q13, the 9q22 region was identified in our original genomic scan as the candidate region with the highest multipoint lod score (MLS) in the subset of late onset Alzheimer's Disease (AD) families (MLS = 2.9 at 101 cM) from the NIMH Genetics Initiative sample. We have now genotyped an additional 12 short tandem repeats (STR) in this region. Multipoint analysis shows the region remains significant with an increase in the peak MLS from 2.9 to 3.8 at 95 cM near marker D9S1815, and the 1 LOD interval narrows from 21.5 to 11 cM. HLOD scores also provide evidence for significant linkage (4.5 with an alpha = 31%) with a further narrowing of the region to 6.6 cM (92.2-98.8 cM). Single nucleotide polymorphisms (SNPs) in the Ubiquilin1 gene (UBQLN1), located at 83.3 cM, have been reported to be significantly associated to AD, accounting for a substantial portion of the original linkage signal [Bertram et al., 2005]. Our analyses of the higher resolution genotype data generated here provide further support for the existence of a least one additional locus on chromosome 9q22. In an effort to pinpoint this putative AD susceptibility gene, we have begun to analyze SNPs in other candidate genes in and around this narrowed region to test for additional associations to AD., ((c) 2007 Wiley-Liss, Inc.)

The chromosome 10q region has recently received a great deal of attention in late-onset Alzheimer's disease (LOAD), given the growing evidence of linkage to LOAD, or to A-beta levels, reported by several groups. In a recent paper we reported evidence of linkage in this region in our subset of the NIMH AD genetics initiative pedigrees, approaching genome-wide significance (non-parametric LOD score = 3.27), when only families with maternal disease origin were analyzed [Bassett et al. (2002); Am J Med Genet 114:679-686]. We have now extended this work, using an independent subset of NIMH AD pedigrees from the University of Alabama at Birmingham (UAB), and show further evidence of linkage using parent-of-origin information. As in our Hopkins sample, maternal but not paternal pedigrees show significantly increased linkage in the chromosome 10q region compared to the unstratified sample. Combining data from our previous fine-mapping work on this region and five new markers genotyped in all pedigrees results in a non-parametric LOD score of 3.73 in the same region, a value that reaches genome wide significance for linkage, with an empirical P value = 0.003. These results support our earlier findings and narrow the region of interest. In combination with findings from other groups, these results provide further evidence that this chromosome 10 region harbors a gene implicated in LOAD, and our use of parent-of-origin information has been useful in further narrowing the region of interest., ((c) 2006 Wiley-Liss, Inc.)