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Abstract Background Accurate measurement of anti-malarial drug concentrations in therapeutic efficacy studies is essential to distinguish between inadequate drug exposure and anti-malarial drug resistance, and to inform optimal anti-malarial dosing in key target population groups. Methods A sensitive and selective LC–MS/MS method was developed and validated for the simultaneous determination of amodiaquine and its active metabolite, desethylamodiaquine, and used to describe their pharmacokinetic parameters in Ghanaian patients with uncomplicated falciparum malaria treated with the fixed-dose combination, artesunate-amodiaquine. Results The day-28 genotype-adjusted adequate clinical and parasitological response rate in 308 patients studied was > 97% by both intention-to-treat and per-protocol analysis. After excluding 64 patients with quantifiable amodiaquine concentrations pre-treatment and 17 with too few quantifiable concentrations, the pharmacokinetic analysis included 227 patients (9 infants, 127 aged 1–4 years, 91 aged ≥ 5 years). Increased median day-3 amodiaquine concentrations were associated with a lower risk of treatment failure [HR 0.87 (95% CI 0.78–0.98), p = 0.021]. Amodiaquine exposure (median AUC0-∞) was significantly higher in infants (4201 ng h/mL) and children aged 1–5 years (1994 ng h/mL) compared to older children and adults (875 ng h/mL, p = 0.001), even though infants received a lower mg/kg amodiaquine dose (median 25.3 versus 33.8 mg/kg in older patients). Desethylamodiaquine AUC0-∞ was not significantly associated with age. No significant safety concerns were identified. Conclusions Efficacy of artesunate-amodiaquine at currently recommended dosage regimens was high across all age groups. Reassuringly, amodiaquine and desethylamodiaquine exposure was not reduced in underweight-for-age young children or those with high parasitaemia, two of the most vulnerable target populations. A larger pharmacokinetic study with close monitoring of safety, including full blood counts and liver function tests, is needed to confirm the higher amodiaquine exposure in infants, understand any safety implications and assess whether dose optimization in this vulnerable, understudied population is needed.

MalariaGEN is a data-sharing network that enables groups around the world to work together on the genomic epidemiology of malaria. Here we describe a new release of curated genome variation data on 7,000 Plasmodium falciparum samples from MalariaGEN partner studies in 28 malaria-endemic countries. High-quality genotype calls on 3 million single nucleotide polymorphisms (SNPs) and short indels were produced using a standardised analysis pipeline. Copy number variants associated with drug resistance and structural variants that cause failure of rapid diagnostic tests were also analysed. Almost all samples showed genetic evidence of resistance to at least one antimalarial drug, and some samples from Southeast Asia carried markers of resistance to six commonly-used drugs. Genes expressed during the mosquito stage of the parasite life-cycle are prominent among loci that show strong geographic differentiation. By continuing to enlarge this open data resource we aim to facilitate research into the evolutionary processes affecting malaria control and to accelerate development of the surveillance toolkit required for malaria elimination.

BackgroundIn low- and middle-income countries (LMICs), the continuum of care (CoC) for maternal, newborn, and child health (MNCH) is not always complete. This study aimed to evaluate the effectiveness of an integrated package of CoC interventions on the CoC completion, morbidity, and mortality outcomes of woman-child pairs in Ghana.Methods and findingsThis cluster-randomized controlled trial (ISRCTN: 90618993) was conducted at 3 Health and Demographic Surveillance System (HDSS) sites in Ghana. The primary outcome was CoC completion by a woman-child pair, defined as receiving antenatal care (ANC) 4 times or more, delivery assistance from a skilled birth attendant (SBA), and postnatal care (PNC) 3 times or more. Other outcomes were the morbidity and mortality of women and children. Women received a package of interventions and routine services at health facilities (October 2014 to December 2015). The package comprised providing a CoC card for women, CoC orientation for health workers, and offering women with 24-hour stay at a health facility or a home visit within 48 hours after delivery. In the control arm, women received routine services only. Eligibility criteria were as follows: women who gave birth or had a stillbirth from September 1, 2012 to September 30, 2014 (before the trial period), from October 1, 2014 to December 31, 2015 (during the trial period), or from January 1, 2016 to December 31, 2016 (after the trial period). Health service and morbidity outcomes were assessed before and during the trial periods through face-to-face interviews. Mortality was assessed using demographic surveillance data for the 3 periods above. Mixed-effects logistic regression models were used to evaluate the effectiveness as difference in differences (DiD). For health service and morbidity outcomes, 2,970 woman-child pairs were assessed: 1,480 from the baseline survey and 1,490 from the follow-up survey. Additionally, 33,819 cases were assessed for perinatal mortality, 33,322 for neonatal mortality, and 39,205 for maternal mortality. The intervention arm had higher proportions of completed CoC (410/870 [47.1%]) than the control arm (246/620 [39.7%]; adjusted odds ratio [AOR] for DiD = 1.77; 95% confidence interval [CI]: 1.08 to 2.92; p = 0.024). Maternal complications that required hospitalization during pregnancy were lower in the intervention (95/870 [10.9%]) than in the control arm (83/620 [13.4%]) (AOR for DiD = 0.49; 95% CI: 0.29 to 0.83; p = 0.008). Maternal mortality was 8/6,163 live births (intervention arm) and 4/4,068 live births during the trial period (AOR for DiD = 1.60; 95% CI: 0.40 to 6.34; p = 0.507) and 1/4,626 (intervention arm) and 9/3,937 (control arm) after the trial period (AOR for DiD = 0.11; 95% CI: 0.11 to 1.00; p = 0.050). Perinatal and neonatal mortality was not significantly reduced. As this study was conducted in a real-world setting, possible limitations included differences in the type and scale of health facilities and the size of subdistricts, contamination for intervention effectiveness due to the geographic proximity of the arms, and insufficient number of cases for the mortality assessment.ConclusionsThis study found that an integrated package of CoC interventions increased CoC completion and decreased maternal complications requiring hospitalization during pregnancy and maternal mortality after the trial period. It did not find evidence of reduced perinatal and neonatal mortality.Trial registrationThe study protocol was registered in the International Standard Randomised Controlled Trial Number Registry (90618993).

Background: The World Health Organization recommends use of a single yellow fever (YF) vaccine dose for life and fractional doses in outbreaks when there are limited vaccine stocks. In endemic regions, this vaccine is given as part of routine infant immunization programs around 9 months of age. There is a need to better understand immune responses when vaccinating infants particularly in contexts where the child may be malnourished. Methods: Data from 393 Malian and Ghanaian infants who concomitantly received measles and YF vaccines at 9 to 11 months of age were retrospectively analyzed. Response to YF vaccine was examined for association with nutritional status at time of vaccination, sex, age, pre-vaccination titers and season of vaccination. Results: Neutralizing antibodies following vaccination were unaffected by season of vaccination, sex, pre-vaccination titers or nutritional status, though there was a trend to higher titers in males and children with higher height for age z-scores. Seroconversion rates differed significantly between countries (63.5 in Ghana vs. 91.0% in Mali). Conclusion: Longitudinal, prospective studies are needed to optimize the use of YF vaccine in infants in endemic settings. There may be a need for booster vaccinations and to compare various vaccine preparations to optimize the use of available vaccines.

Abstract Background Skilled birth delivery has increased up to nearly 74% in Ghana, but its quality has been questioned over the years. As understanding women’s satisfaction could be important to improving service quality, this study aimed to determine what factors were associated with women’s overall satisfaction with delivery services quantitatively and qualitatively in rural Ghanaian health facilities. Results This cross-sectional, mixed methods study used an explanatory sequential design across three Ghana Health Service research areas in 2013. Participants were women who had delivered in the preceding 2 years. Two-stage random sampling was used to recruit women for the quantitative survey. Relationships between women’s socio-demographic characteristics and their overall satisfaction with health facility delivery services were examined using univariate and multiple logistic regression analyses. For qualitative analyses, women who completed the quantitative survey were purposively selected to participate in focus group discussions. Data from the focus group discussions were analyzed based on predefined and emerging themes. Overall, 1130 women were included in the quantitative analyses and 136 women participated in 15 focus group discussions. Women’s mean age was 29 years. Nearly all women (94%) were satisfied with the overall services received during delivery. Women with middle level/junior high school education [adjusted odds ratio (AOR) = 0.50, 95% confidence interval (CI) = (0.26–0.98)] were less likely to be satisfied with overall delivery services compared to women with no education. Qualitatively, women were not satisfied with the unconventional demands, negative attitude, and unavailability of healthcare workers, as well as the long wait time. Conclusions Although most women were satisfied with the overall service they received during delivery, they were not satisfied with specific aspects of the health services; therefore, higher quality service delivery is necessary to improve women’s satisfaction. Additional sensitivity training and a reduction in work hours may also improve the experience of clients.

MalariaGEN is a data-sharing network that enables groups around the world to work together on the genomic epidemiology of malaria. Here we describe a new release of curated genome variation data on 7,000 Plasmodium falciparum samples from MalariaGEN partner studies in 28 malaria-endemic countries. High-quality genotype calls on 3 million single nucleotide polymorphisms (SNPs) and short indels were produced using a standardised analysis pipeline. Copy number variants associated with drug resistance and structural variants that cause failure of rapid diagnostic tests were also analysed. Almost all samples showed genetic evidence of resistance to at least one antimalarial drug, and some samples from Southeast Asia carried markers of resistance to six commonly-used drugs. Genes expressed during the mosquito stage of the parasite life-cycle are prominent among loci that show strong geographic differentiation. By continuing to enlarge this open data resource we aim to facilitate research into the evolutionary processes affecting malaria control and to accelerate development of the surveillance toolkit required for malaria elimination.

Background: The umbilical cord is a major route of infection among newborns. In Ghana, infections among neonates accounts for majority of under-five deaths. This study sought to investigate what mothers apply to the umbilical cord of their newborns and what motivates them to put such applications on the cord. Methods: This was a descriptive cross-sectional study of neonatal cord care practices among mothers and caregivers in the Nkwanta South District of the Volta region of Ghana. Quantitative and qualitative methods were used. Results: Majority of the mothers/caregivers used substances that have not been recommended for umbilical cord dressing (64.3%). Factors such as level of education [χ2=8.2, p=0.02], place of delivery [χ2 = 40.1, p

An amendment to this paper has been published and can be accessed via the original article.

Background: The benefits of integrated control of malaria, schistosomiasis, and soil-transmitted helminth infections have not been fully explored in Ghanaian schoolchildren. Objective: To assess the impact of co-administered artemether-lumefantrine plus albendazole, and artemether-lumefantrine plus albendazole plus praziquantel compared to albendazole plus praziquantel on anaemia, sustained attention, and recall in schoolchildren. Design: This three-arm, open-label intervention study was carried out in Ghana among class three schoolchildren. Artemether-lumefantrine and albendazole were co-administered to 131 schoolchildren in Study Arm 1; artemether-lumefantrine, albendazole, and praziquantel to 90 children in Study Arm 2 versus albendazole and praziquantel to 127 children in Control Arm 3. Medicines were administered to all children at least 30 min after a meal. A HemoCue® photometer was used to measure haemoglobin (Hb), while the code transmission test (CTT), adapted from the Test of Everyday Attention for Children (TEA-Ch), was used to measure sustained attention and recall before-and-after interventions in June 2011 and June 2012. Results: We observed significant malaria parasite prevalence reductions of 62.8 and 59.2% in Study Arm 1 from 24.2 to 9.0%, p0.05). Meanwhile, anaemia prevalence reduced significantly (p

BackgroundMeasles vaccine (MV) administered as the last vaccine after the third dose of diphtheria-tetanus-pertussis (DTP) may be associated with better child survival unrelated to prevention of measles infection. Other studies have shown that MV administered after DTP was more beneficial and was associated with lower mortality compared with DTP administered after MV or DTP administered simultaneously with MV. We compared the difference in mortality between measles vaccinated after DTP3 and measles-unvaccinated children in Navrongo, Ghana.MethodsThis was a follow-up study involving annual cohort of children aged 9–23 months from 1996 to 2012. We assessed survival in relation to the measles vaccination status within the first 12 months from interview date and until 5 years of age using Cox proportional hazards models.ResultsIn all, 38,333 children were included in the study. The proportion of children vaccinated with MV-after-DTP3 increased from 45% in 1996 to 95% in 2012. The adjusted hazard ratio (HR) for measles unvaccinated compared with MV-after-DTP3 vaccinated children was 1.38 (1.15–1.66) in the first 12 months after assessment of vaccination status and 1.22 (1.05–1.41) with follow-up to 5 years of age. The national immunization days campaigns with oral polio vaccine or MV might have reduced the effect of being MV-after-DTP3 vaccinated vs MV-unvaccinated. For 12 months of follow-up, the HR before a campaign for MV-unvaccinated children was 1.63 (1.23–2.17) compared to those who received MV-after-DTP3. After the campaign, the HR reduced to 1.23 (0.97–1.54). Stratifying the analysis by sex, measles-unvaccinated boys had a HR of 1.69 (1.33–2.61) compared to measles-unvaccinated girls who had a HR 1.06 (0.79–1.40) during 1-year follow-up. In 1989, only 7% of children in the area had received MV-after-DTP3; the increase in MV-after-DTP3 coverage from 1989 to 2012 may have lowered mortality rate among children aged 9 months to 3 years by 24%.ConclusionThough an observational study, our findings suggest that measles vaccination, administered in the recommended sequence, is associated with improved child survival and may have contributed importantly to the mortality decline toward the achievement of Millennium Development Goal 4.

Serum bactericidal antibody titres that correlate with protection against invasive meningococcal disease have been characterised. However, titres that are associated with protection against acquisition of pharyngeal carriage of Neisseria meningitidis are not known.Sera were obtained from the members of a household in seven countries of the African meningitis belt in which a pharyngeal carrier of N. meningitidis had been identified during a cross-sectional survey. Serum bactericidal antibody titres at baseline were compared between individuals in the household of the carrier who became a carrier of a meningococcus of the same genogroup during six months of subsequent follow-up and household members who did not become a carrier of a meningococcus of this genogroup during this period.Serum bacterial antibody titres were significantly higher in carriers of a serogroup W or Y meningococcus at the time of recruitment than in those who were not a carrier of N. meningitidis of the same genogroup. Serum bactericidal antibody titres to a strain of N. meningitis of the same genogroup as the index cases were no different in individuals who acquired carriage with a meningococcus of the same genogroup as the index case than in those who did not become a carrier during six months of follow-up.Serum bacterial antibody titres to N. meningitidis of genogroup W or Y in the range of those acquired by natural exposure to meningococci of these genogroups, or with cross-reactive bacteria, are not associated with protection against acquisition of carriage with meningococci of either of these genogroups.

Background: Improving maternal health is a global challenge. In Ghana, maternal morbidity and mortality rates remain high, particularly in rural areas. Antenatal care (ANC) attendance is known to improve maternal health. However, few studies have updated current knowledge regarding determinants of ANC attendance. Objective: This study examined factors associated with ANC attendance in predominantly rural Ghana. Methods: We conducted a cross-sectional study at three sites (i.e. Navrongo, Kintampo, and Dodowa) in Ghana between August and September 2013. We selected 1500 women who had delivered within the two years preceding the survey (500 from each site) using two-stage random sampling. Data concerning 1497 women’s sociodemographic characteristics and antenatal care attendance were collected and analyzed, and factors associated with attending ANC at least four times were identified using logistic regression analysis. Results: Of the 1497 participants, 86% reported attending ANC at least four times, which was positively associated with possession of national health insurance (AOR 1.64, 95% CI: 1.14–2.38) and having a partner with a high educational level (AOR 1.64, 95% CI: 1.02–2.64) and negatively associated with being single (AOR 0.39, 95% CI: 0.22–0.69) and cohabiting (AOR 0.57, 95% CI: 0.34–0.97). In site-specific analyses, factors associated with ANC attendance included marital status in Navrongo; marital status, possession of national health insurance, partners’ educational level, and wealth in Kintampo; and preferred pregnancy timing in Dodowa. In the youngest, least educated, and poorest women and women whose partners were uneducated, those with health insurance were more likely to report at least four ANC attendances relative to those who did not have insurance. Conclusions: Ghanaian women with low socioeconomic status were less likely to report at least four ANC attendances during pregnancy if they did not possess health insurance. The national health insurance scheme should include a higher number of deprived women in predominantly rural communities.

Background: Malaria continues to be a major cause of infectious disease mortality in tropical regions. However, deaths from malaria are most often not individually documented, and as a result overall understanding of malaria epidemiology is inadequate. INDEPTH Network members maintain population surveillance in Health and Demographic Surveillance System sites across Africa and Asia, in which individual deaths are followed up with verbal autopsies. Objective: To present patterns of malaria mortality determined by verbal autopsy from INDEPTH sites across Africa and Asia, comparing these findings with other relevant information on malaria in the same regions. Design: From a database covering 111,910 deaths over 12,204,043 person-years in 22 sites, in which verbal autopsy data were handled according to the WHO 2012 standard and processed using the InterVA-4 model, over 6,000 deaths were attributed to malaria. The overall period covered was 1992–2012, but two-thirds of the observations related to 2006–2012. These deaths were analysed by site, time period, age group and sex to investigate epidemiological differences in malaria mortality. Results: Rates of malaria mortality varied by 1:10,000 across the sites, with generally low rates in Asia (one site recording no malaria deaths over 0.5 million person-years) and some of the highest rates in West Africa (Nouna, Burkina Faso: 2.47 per 1,000 person-years). Childhood malaria mortality rates were strongly correlated with Malaria Atlas Project estimates of Plasmodium falciparum parasite rates for the same locations. Adult malaria mortality rates, while lower than corresponding childhood rates, were strongly correlated with childhood rates at the site level. Conclusions: The wide variations observed in malaria mortality, which were nevertheless consistent with various other estimates, suggest that population-based registration of deaths using verbal autopsy is a useful approach to understanding the details of malaria epidemiology.

Background: Childhood mortality, particularly in the first 5 years of life, is a major global concern and the target of Millennium Development Goal 4. Although the majority of childhood deaths occur in Africa and Asia, these are also the regions where such deaths are least likely to be registered. The INDEPTH Network works to alleviate this problem by collating detailed individual data from defined Health and Demographic Surveillance sites. By registering deaths and carrying out verbal autopsies to determine cause of death across many such sites, using standardised methods, the Network seeks to generate population-based mortality statistics that are not otherwise available. Objective: To present a description of cause-specific mortality rates and fractions over the first 15 years of life as documented by INDEPTH Network sites in sub-Saharan Africa and south-east Asia. Design: All childhood deaths at INDEPTH sites are routinely registered and followed up with verbal autopsy (VA) interviews. For this study, VA archives were transformed into the WHO 2012 VA standard format and processed using the InterVA-4 model to assign cause of death. Routine surveillance data also provided person-time denominators for mortality rates. Cause-specific mortality rates and cause-specific mortality fractions are presented according to WHO 2012 VA cause groups for neonatal, infant, 1–4 year and 5–14 year age groups. Results: A total of 28,751 childhood deaths were documented during 4,387,824 person-years over 18 sites. Infant mortality ranged from 11 to 78 per 1,000 live births, with under-5 mortality from 15 to 152 per 1,000 live births. Sites in Vietnam and Kenya accounted for the lowest and highest mortality rates reported. Conclusions: Many children continue to die from relatively preventable causes, particularly in areas with high rates of malaria and HIV/AIDS. Neonatal mortality persists at relatively high, and perhaps sometimes under-documented, rates. External causes of death are a significant childhood problem in some settings.

Objective: Verbal autopsy (VA) is a systematic approach for determining causes of death (CoD) in populations without routine medical certification. It has mainly been used in research contexts and involved relatively lengthy interviews. Our objective here is to describe the process used to shorten, simplify, and standardise the VA process to make it feasible for application on a larger scale such as in routine civil registration and vital statistics (CRVS) systems. Methods: A literature review of existing VA instruments was undertaken. The World Health Organization (WHO) then facilitated an international consultation process to review experiences with existing VA instruments, including those from WHO, the Demographic Evaluation of Populations and their Health in Developing Countries (INDEPTH) Network, InterVA, and the Population Health Metrics Research Consortium (PHMRC). In an expert meeting, consideration was given to formulating a workable VA CoD list [with mapping to the International Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) CoD] and to the viability and utility of existing VA interview questions, with a view to undertaking systematic simplification. Findings: A revised VA CoD list was compiled enabling mapping of all ICD-10 CoD onto 62 VA cause categories, chosen on the grounds of public health significance as well as potential for ascertainment from VA. A set of 221 indicators for inclusion in the revised VA instrument was developed on the basis of accumulated experience, with appropriate skip patterns for various population sub-groups. The duration of a VA interview was reduced by about 40% with this new approach. Conclusions: The revised VA instrument resulting from this consultation process is presented here as a means of making it available for widespread use and evaluation. It is envisaged that this will be used in conjunction with automated models for assigning CoD from VA data, rather than involving physicians.

BACKGROUND:Maternal and neonatal mortality indicators remain high in Ghana and other sub-Saharan African countries. Both maternal and neonatal health outcomes improve when skilled personnel provide delivery services within health facilities. Determinants of delivery location are crucial to promoting health facility deliveries, but little research has been done on this issue in Ghana. This study explored factors influencing delivery location in predominantly rural communities in Ghana. METHODS:Data were collected from 1,500 women aged 15-49 years with live or stillbirths that occurred between January 2011 and April 2013. This was done within the three sites operating Health and Demographic Surveillance Systems, i.e., the Dodowa (Greater Accra Region), Kintampo (Brong Ahafo Region), and Navrongo (Upper-East Region) Health Research Centers in Ghana. Multivariable logistic regression was used to identify the determinants of delivery location, controlling for covariates that were statistically significant in univariable regression models. RESULTS:Of 1,497 women included in the analysis, 75.6% of them selected health facilities as their delivery location. After adjusting for confounders, the following factors were associated with health facility delivery across all three sites: healthcare provider's influence on deciding health facility delivery, (AOR = 13.47; 95% CI 5.96-30.48), place of residence (AOR = 4.49; 95% CI 1.14-17.68), possession of a valid health insurance card (AOR = 1.90; 95% CI 1.29-2.81), and socio-economic status measured by wealth quintiles (AOR = 2.83; 95% CI 1.43-5.60). CONCLUSION:In addition to known factors such as place of residence, socio-economic status, and possession of valid health insurance, this study identified one more factor associated with health facility delivery: healthcare provider's influence. Ensuring care provider's counseling of clients could improve the uptake of health facility delivery in rural communities in Ghana.

This paper contributes evidence documenting the continued decline in all-cause mortality and changes in the cause of death distribution over time in four developing country populations in Africa and Asia. We present levels and trends in age-specific mortality (all-cause and cause-specific) from four demographic surveillance sites: Agincourt (South Africa), Navrongo (Ghana) in Africa; Filabavi (Vietnam), Matlab (Bangladesh) in Asia. We model mortality using discrete time event history analysis. This study illustrates how data from INDEPTH Network centers can provide a comparative, longitudinal examination of mortality patterns and the epidemiological transition. Health care systems need to be reconfigured to deal simultaneously with continuing challenges of communicable disease and increasing incidence of non-communicable diseases that require long-term care. In populations with endemic HIV, long-term care of HIV patients on ART will add to the chronic care needs of the community.

[This corrects the article DOI: 10.1371/journal.pone.0147928.].

The pattern of epidemic meningococcal disease in the African meningitis belt may be influenced by the background level of population immunity but this has been measured infrequently. A standardised enzyme-linked immunosorbent assay (ELISA) for measuring meningococcal serogroup A IgG antibodies was established at five centres within the meningitis belt. Antibody concentrations were then measured in 3930 individuals stratified by age and residence from six countries. Seroprevalence by age was used in a catalytic model to determine the force of infection. Meningococcal serogroup A IgG antibody concentrations were high in each country but showed heterogeneity across the meningitis belt. The geometric mean concentration (GMC) was highest in Ghana (9.09 μg/mL [95% CI 8.29, 9.97]) and lowest in Ethiopia (1.43 μg/mL [95% CI 1.31, 1.57]) on the margins of the belt. The force of infection was lowest in Ethiopia (λ = 0.028). Variables associated with a concentration above the putative protective level of 2 μg/mL were age, urban residence and a history of recent vaccination with a meningococcal vaccine. Prior to vaccination with the serogroup A meningococcal conjugate vaccine, meningococcal serogroup A IgG antibody concentrations were high across the African meningitis belt and yet the region remained susceptible to epidemics.

Background: Verbal autopsy (VA) is the only available approach for determining the cause of many deaths, where routine certification is not in place. Therefore, it is important to use standards and methods for VA that maximise efficiency, consistency and comparability. The World Health Organization (WHO) has led the development of the 2012 WHO VA instrument as a new standard, intended both as a research tool and for routine registration of deaths. Objective: A new public-domain probabilistic model for interpreting VA data, InterVA-4, is described, which builds on previous versions and is aligned with the 2012 WHO VA instrument. Design: The new model has been designed to use the VA input indicators defined in the 2012 WHO VA instrument and to deliver causes of death compatible with the International Classification of Diseases version 10 (ICD-10) categorised into 62 groups as defined in the 2012 WHO VA instrument. In addition, known shortcomings of previous InterVA models have been addressed in this revision, as well as integrating other work on maternal and perinatal deaths. Results: The InterVA-4 model is presented here to facilitate its widespread use and to enable further field evaluation to take place. Results from a demonstration dataset from Agincourt, South Africa, show continuity of interpretation between InterVA-3 and InterVA-4, as well as differences reflecting specific issues addressed in the design and development of InterVA-4. Conclusions: InterVA-4 is made freely available as a new standard model for interpreting VA data into causes of death. It can be used for determining cause of death both in research settings and for routine registration. Further validation opportunities will be explored. These developments in cause of death registration are likely to substantially increase the global coverage of cause-specific mortality data.

Background: Globally, ageing impacts all countries, with a majority of older persons residing in lower- and middle-income countries now and into the future. An understanding of the health and well-being of these ageing populations is important for policy and planning; however, research on ageing and adult health that informs policy predominantly comes from higher-income countries. A collaboration between the WHO Study on global AGEing and adult health (SAGE) and International Network for the Demographic Evaluation of Populations and Their Health in developing countries (INDEPTH), with support from the US National Institute on Aging (NIA) and the Swedish Council for Working Life and Social Research (FAS), has resulted in valuable health, disability and well-being information through a first wave of data collection in 2006–2007 from field sites in South Africa, Tanzania, Kenya, Ghana, Viet Nam, Bangladesh, Indonesia and India. Objective: To provide an overview of the demographic and health characteristics of participating countries, describe the research collaboration and introduce the first dataset and outputs. Methods: Data from two SAGE survey modules implemented in eight Health and Demographic Surveillance Systems (HDSS) were merged with core HDSS data to produce a summary dataset for the site-specific and cross-site analyses described in this supplement. Each participating HDSS site used standardised training materials and survey instruments. Face-to-face interviews were conducted. Ethical clearance was obtained from WHO and the local ethical authority for each participating HDSS site. Results: People aged 50 years and over in the eight participating countries represent over 15% of the current global older population, and is projected to reach 23% by 2030. The Asian HDSS sites have a larger proportion of burden of disease from non-communicable diseases and injuries relative to their African counterparts. A pooled sample of over 46,000 persons aged 50 and over from these eight HDSS sites was produced. The SAGE modules resulted in self-reported health, health status, functioning (from the WHO Disability Assessment Scale (WHODAS-II)) and well-being (from the WHO Quality of Life instrument (WHOQoL) variables). The HDSS databases contributed age, sex, marital status, education, socio-economic status and household size variables. Conclusion: The INDEPTH WHO–SAGE collaboration demonstrates the value and future possibilities for this type of research in informing policy and planning for a number of countries. This INDEPTH WHO–SAGE dataset will be placed in the public domain together with this open-access supplement and will be available through the GHA website (www.globalhealthaction.net) and other repositories. An improved dataset is being developed containing supplementary HDSS variables and vignette-adjusted health variables. This living collaboration is now preparing for a next wave of data collection.

Background: Declining rates of fertility and mortality are driving demographic transition in all regions of the world, leading to global population ageing and consequently changing patterns of global morbidity and mortality. Understanding sex-related health differences, recognising groups at risk of poor health and identifying determinants of poor health are therefore very important for both improving health trajectories and planning for the health needs of ageing populations. Objectives: To determine the extent to which demographic and socio-economic factors impact upon measures of health in older populations in Africa and Asia; to examine sex differences in health and further explain how these differences can be attributed to demographic and socio-economic determinants. Methods : A total of 46,269 individuals aged 50 years and over in eight Health and Demographic Surveillance System (HDSS) sites within the INDEPTH Network were studied during 2006–2007 using an abbreviated version of the WHO Study on global AGEing and adult health (SAGE) Wave I instrument. The survey data were then linked to longitudinal HDSS background information. A health score was calculated based on self-reported health derived from eight health domains. Multivariable regression and post-regression decomposition provide ways of measuring and explaining the health score gap between men and women. Results: Older men have better self-reported health than older women. Differences in household socio-economic levels, age, education levels, marital status and living arrangements explained from about 82% and 71% of the gaps in health score observed between men and women in South Africa and Kenya, respectively, to almost nothing in Bangladesh. Different health domains contributed differently to the overall health scores for men and women in each country. Conclusion: This study confirmed the existence of sex differences in self-reported health in low- and middle-income countries even after adjustments for differences in demographic and socio-economic factors. A decomposition analysis suggested that sex differences in health differed across the HDSS sites, with the greatest level of inequality found in Bangladesh. The analysis showed considerable variation in how differences in socio-demographic and economic characteristics explained the gaps in self-reported health observed between older men and women in African and Asian settings. The overall health score was a robust indicator of health, with two domains, pain and sleep/energy, contributing consistently across the HDSS sites. Further studies are warranted to understand other significant individual and contextual determinants to which these sex differences in health can be attributed. This will lay a foundation for a more evidence-based approach to resource allocation, and to developing health promotion programmes for older men and women in these settings.

Background: Ghana is experiencing significant increases in its ageing population, yet research on the health and quality of life of older people is limited. Lack of data on the health and well-being of older people in the country makes it difficult to monitor trends in the health status of adults and the impact of social policies on their health and welfare. Research on ageing is urgently required to provide essential data for policy formulation and programme implementation. Objective: To describe the health status and identify factors associated with self-rated health (SRH) among older adults in a rural community in northern Ghana. Methods: The data come from a survey on Adult Health and Ageing in the Kassena-Nankana District involving 4,584 people aged 50 and over. Survey participants answered questions pertaining to their health status, including self-rated overall health, perceptions of well-being and quality of life, and self-reported assessment of functioning on a range of different health domains. Socio-demographic information such as age, sex, marital status and education were obtained from a demographic surveillance database. Results: The majority of older people rated their health status as good, with the oldest old reporting poorer health. Multivariate regression analysis showed that functional ability and sex are significant factors in SRH status. Adults with higher levels of functional limitations were much more likely to rate their health as being poorer compared with those having lower disabilities. Household wealth was significantly associated with SRH, with wealthier adults more likely to rate their health as good. Conclusion: The depreciation in health and daily functioning with increasing age is likely to increase people's demand for health care and other services as they grow older. There is a need for regular monitoring of the health status of older people to provide public health agencies with the data they need to assess, protect and promote the health and well-being of older people.

Background: Under-five mortality is a major public health problem and one of the health indicators of health care in sub-Saharan Africa. In order to address inefficient health systems, there is a need to identify the spatial distribution of under-five mortality, especially areas of high mortality clustering. This study aimed to explore spatial and temporal clustering in under-five mortality in the Kassena-Nankana District of the Upper East region. Methods: We used data from the Navrongo Health and Demographic Surveillance System in the Kassena- Nankana District of northern Ghana, which had an average population of 140,000 of which about 18,400 were under five years of age. We analysed under-five mortality in 49 villages during the period 1997–2006. We calculated total under-five mortality rates and investigated their geographical distributions. A spatial scan statistic was used to test for clustering of the mortality in both space and time. Results: Under-five mortality has been declining during the period. However, the data show a persistently higher than average clustering of mortality over the period among villages mainly in the north-eastern parts of the district. Conclusion: There is a higher than average under-five mortality clustering in the villages in the north-east of the district and this may suggest a relatively poor health care system despite the many health interventions that took place over time in the district, including the Community Health and Family Planning Project, whose impact may not have been felt in these parts of the district between 1995 and 2004.

BackgroundSlow progress has been made in achieving the Millennium Development Goals 4 and 5 in Ghana. Ensuring continuum of care (at least four antenatal visits; skilled birth attendance; postnatal care within 48 hours, at two weeks, and six weeks) for mother and newborn is crucial in helping Ghana achieve these goals and beyond. This study examined the levels and factors associated with continuum of care (CoC) completion among Ghanaian women aged 15-49.MethodsA retrospective cross-sectional survey was conducted among women who experienced live births between January 2011 and April 2013 in three regions of Ghana. In a two-stage random sampling method, 1,500 women with infants were selected and interviewed about maternal and newborn service usage in line with CoC. Multiple logistic regression models were used to assess factors associated with CoC completion.ResultsOnly 8.0% had CoC completion; the greatest gap and contributor to the low CoC was detected between delivery and postnatal care within 48 hours postpartum. About 95% of women had a minimum of four antenatal visits and postnatal care at six weeks postpartum. A total of 75% had skilled assisted delivery and 25% received postnatal care within 48 hours. Factors associated with CoC completion at 95% CI were geographical location (OR = 0.35, CI 0.13-0.39), marital status (OR = 0.45; CI 0.22-0.95), education (OR = 2.71; CI 1.11-6.57), transportation (OR = 1.97; CI 1.07-3.62), and beliefs about childhood illnesses (OR = 0.34; CI0.21-0.61).ConclusionThe continuum of care completion rate is low in the study site. Efforts should focus on increasing postnatal care within 48 hours and overcoming the known obstacles to increasing the continuum of care completion rate.

Sulphadoxine-Pyrimethamine (SP) is still the only recommended antimalarial for use in intermittent preventive treatment of malaria during pregnancy (IPTp) in some malaria endemic countries including Ghana. SP has the potential to cause acute haemolysis in G6PD deficient people resulting in significant haemoglobin (Hb) drop but there is limited data on post SP-IPTp Hb drop. This study determined the difference, if any in proportions of women with significant acute haemoglobin drop between G6PD normal, partial deficient and full deficient women after SP-IPTp.Prospectively, 1518 pregnant women who received SP for IPTp as part of their normal antenatal care were enrolled. Their G6PD status were determined at enrollment followed by assessments on days 3, 7,14 and 28 to document any adverse effects and changes in post-IPTp haemoglobin (Hb) levels. The three groups were comparable at baseline except for their mean Hb (10.3 g/dL for G6PD normal, 10.8 g/dL for G6PD partial deficient and 10.8 g/dL for G6PD full defect women).The prevalence of G6PD full defect was 2.3% and 17.0% for G6PD partial defect. There was no difference in the proportions with fractional Hb drop ≥ 20% as compared to their baseline value post SP-IPTp among the 3 groups on days 3, 7, 14. The G6PD full defect group had the highest median fractional drop at day 7. There was a weak negative correlation between G6PD activity and fractional Hb drop. There was no statistical difference between the three groups in the proportions of those who started the study with Hb ≥ 8g/dl whose Hb level subsequently fell below 8g/dl post-SP IPTp. No study participant required transfusion or hospitalization for severe anaemia.There was no significant difference between G6PD normal and deficient women in proportions with significant acute haemoglobin drop post SP-IPTp and lower G6PD enzyme activity was not strongly associated with significant acute drug-induced haemoglobin drop post SP-IPTp but a larger study is required to confirm consistency of findings.

Continuum of care has the potential to improve maternal, newborn, and child health (MNCH) by ensuring care for mothers and children. Continuum of care in MNCH is widely accepted as comprising sequential time (from pre-pregnancy to motherhood and childhood) and space dimensions (from community-family care to clinical care). However, it is unclear which linkages of care could have a greater effect on MNCH outcomes. The objective of the present study is to assess the effectiveness of different continuum of care linkages for reducing neonatal, perinatal, and maternal mortality in low- and middle-income countries.We searched for randomized and quasi-randomized controlled trials that addressed two or more linkages of continuum of care and attempted to increase mothers' uptake of antenatal care, skilled birth attendance, and postnatal care. The outcome variables were neonatal, perinatal, and maternal mortality.Out of the 7,142 retrieved articles, we selected 19 as eligible for the final analysis. Of these studies, 13 used packages of intervention that linked antenatal care, skilled birth attendance, and postnatal care. One study each used packages that linked antenatal care and skilled birth attendance or skilled birth attendance and postnatal care. Four studies used an intervention package that linked antenatal care and postnatal care. Among the packages that linked antenatal care, skilled birth attendance, and postnatal care, a significant reduction was observed in combined neonatal, perinatal, and maternal mortality risks (RR 0.83; 95% CI 0.77 to 0.89, I2 79%). Furthermore, this linkage reduced combined neonatal, perinatal, and maternal mortality when integrating the continuum of care space dimension (RR 0.85; 95% CI 0.77 to 0.93, I2 81%).Our review suggests that continuous uptake of antenatal care, skilled birth attendance, and postnatal care is necessary to improve MNCH outcomes in low- and middle-income countries. The review was conclusive for the reduction of neonatal and perinatal deaths. Although maternal deaths were not significantly reduced, composite measures of all mortality were. Thus, the evidence is sufficient to scale up this intervention package for the improvement of MNCH outcomes.

Reducing neonatal mortality is a major public health priority in sub-Saharan Africa. Numerous studies have examined the determinants of neonatal mortality, but few have explored neonatal danger signs which potentially cause morbidity. This study assessed danger signs observed in neonates at birth, determined the correlations of multiple danger signs and complications between neonates and their mothers, and identified factors associated with neonatal danger signs.A cross-sectional study was conducted in three sites across Ghana between July and September in 2013. Using two-stage random sampling, we recruited 1,500 pairs of neonates and their mothers who had given birth within the preceding two years. We collected data on their socio-demographic characteristics, utilization of maternal and neonatal health services, and experiences with neonatal danger signs and maternal complications. We calculated the correlations of multiple danger signs and complications between neonates and their mothers, and performed multiple logistic regression analysis to identify factors associated with neonatal danger signs.More than 25% of the neonates were born with danger signs. At-birth danger signs in neonates were correlated with maternal delivery complications (r = 0.20, p < 0.001), and neonatal complications within the first six weeks of life (r = 0.19, p < 0.001). However, only 29.1% of neonates with danger signs received postnatal care in the first two days, and 52.4% at two weeks of life. In addition to maternal complications during delivery, maternal age less than 20 years, maternal education level lower than secondary school, and fewer than four antenatal care visits significantly predicted neonatal danger signs.Over a quarter of neonates are born with danger signs. Maternal factors can be used to predict neonatal health condition at birth. Management of maternal health and close medical attention to high-risk neonates are crucial to reduce neonatal morbidity in Ghana.

While many Ghanaian adolescents encounter sexual and reproductive health problems, their usage of services remains low. A social learning intervention, incorporating environment, motivation, education, and self-efficacy to change behaviour, was implemented in a low-income district of northern Ghana to increase adolescent services usage. This study aimed to assess the impact of this intervention on usage of sexual and reproductive health services by young people.Twenty-six communities were randomly allocated to (i) an intervention consisting of school-based curriculum, out-of-school outreach, community mobilisation, and health-worker training in youth-friendly health services, or (ii) comparison consisting of community mobilisation and youth-friendly health services training only. Outcome measures were usage of sexually-transmitted infections (STIs) management, HIV counselling and testing, antenatal care or perinatal services in the past year and reported service satisfaction. Data was collected, at baseline and three years after, from a cohort of 2,664 adolescents aged 15-17 at baseline.Exposure was associated with over twice the odds of using STI services (AOR 2.47; 95%CI 1.78-3.42), 89% greater odds of using perinatal services (AOR 1.89; 95%CI 1.37-2.60) and 56% greater odds of using antenatal services (AOR 1.56; 95%CI 1.10-2.20) among participants in intervention versus comparison communities, after adjustment for baseline differences.The addition of targeted school-based and outreach activities increased service usage by young people more than community mobilisation and training providers in youth-friendly services provision alone.

BACKGROUND:The efficacy of intermittent preventive treatment for malaria with sulfadoxine-pyrimethamine (IPTp-SP) in pregnancy is threatened in parts of Africa by the emergence and spread of resistance to SP. Intermittent screening with a rapid diagnostic test (RDT) and treatment of positive women (ISTp) is an alternative approach. METHODS AND FINDINGS:An open, individually randomized, non-inferiority trial of IPTp-SP versus ISTp was conducted in 5,354 primi- or secundigravidae in four West African countries with a low prevalence of resistance to SP (The Gambia, Mali, Burkina Faso and Ghana). Women in the IPTp-SP group received SP on two or three occasions whilst women in the ISTp group were screened two or three times with a RDT and treated if positive for malaria with artemether-lumefantrine (AL). ISTp-AL was non-inferior to IPTp-SP in preventing low birth weight (LBW), anemia and placental malaria, the primary trial endpoints. The prevalence of LBW was 15.1% and 15.6% in the IPTp-SP and ISTp-AL groups respectively (OR = 1.03 [95% CI: 0.88, 1.22]). The mean hemoglobin concentration at the last clinic attendance before delivery was 10.97g/dL and 10.94g/dL in the IPTp-SP and ISTp-AL groups respectively (mean difference: -0.03 g/dL [95% CI: -0.13, +0.06]). Active malaria infection of the placenta was found in 24.5% and in 24.2% of women in the IPTp-SP and ISTp-AL groups respectively (OR = 0.95 [95% CI 0.81, 1.12]). More women in the ISTp-AL than in the IPTp-SP group presented with malaria parasitemia between routine antenatal clinics (310 vs 182 episodes, rate difference: 49.4 per 1,000 pregnancies [95% CI 30.5, 68.3], but the number of hospital admissions for malaria was similar in the two groups. CONCLUSIONS:Despite low levels of resistance to SP in the study areas, ISTp-AL performed as well as IPTp-SP. In the absence of an effective alternative medication to SP for IPTp, ISTp-AL is a potential alternative to IPTp in areas where SP resistance is high. It may also have a role in areas where malaria transmission is low and for the prevention of malaria in HIV positive women receiving cotrimoxazole prophylaxis in whom SP is contraindicated. TRIAL REGISTRATION:ClinicalTrials.gov NCT01084213 Pan African Clinical trials Registry PACT201202000272122.

The genetic diversity of 134 serogroup X Neisseria meningitis isolates from Africa, Europe, and North America was analyzed by multilocus sequence typing and pulsed-field gel electrophoresis. Although most European and American isolates were highly diverse, one clonal grouping was identified in sporadic disease and carrier strains isolated over the last 2 decades in the United Kingdom, the Netherlands, Germany, and the United States. In contrast to the diversity in the European and American isolates, most carrier and disease isolates recovered during the last 30 years in countries in the African meningitis belt belonged to a second clonal grouping. During the last decade, these bacteria have caused meningitis outbreaks in Niger and Ghana. These results support the development of a comprehensive conjugate vaccine that would include serogroup X polysaccharide.

Neisseria meningitidis is a major cause of bacterial meningitis and a considerable health problem in the 25 countries of the ‘African Meningitis Belt’ that extends from Senegal in West Africa to Ethiopia in the East. Approximately 80% of cases of meningococcal meningitis in Africa have been caused by strains belonging to capsular serogroup A. After the introduction of a serogroup A conjugate polysaccharide vaccine, MenAfriVac™, that began in December 2010, the incidence of meningitis due to serogroup A has markedly declined in this region. Currently, serogroup W of N. meningitidis accounts for the majority of cases. Vaccines based on sub-capsular antigens, such as Generalized Modules for Membrane Antigens (GMMA), are under investigation for use in Africa. To analyse the antigenic properties of a serogroup W wave of colonisation and disease, we investigated the molecular diversity of the protein vaccine antigens PorA, Neisserial Adhesin A (NadA), Neisserial heparin-binding antigen (NHBA) and factor H binding protein (fHbp) of 31 invasive and carriage serogroup W isolates collected as part of a longitudinal study from Ghana and Burkina Faso between 2003 and 2009. We found that the isolates all expressed fHbp variant 2 ID 22 or 23, differing from each other by only one amino acid, and a single PorA subtype of P1.5,2. Of the isolates, 49% had a functional nhbA gene and 100% had the nadA allele 3, which contained the insertion sequence IS1301 in five isolates. Of the W isolates tested, 41% had high fHbp expression when compared with a reference serogroup B strain, known to be a high expresser of fHbp variant 2. Our results indicate that in this collection of serogroup W isolates, there is limited antigenic diversification over time of vaccine candidate outer membrane proteins (OMP), thus making them promising candidates for inclusion in a protein-based vaccine against meningococcal meningitis for Africa.

ABSTRACT In the African “meningitis belt,” outbreaks of meningococcal meningitis occur in cycles, representing a model for the role of host-pathogen interactions in epidemic processes. The periodicity of the epidemics is not well understood, nor is it currently possible to predict them. In our longitudinal colonization and disease surveys, we have observed waves of clonal replacement with the same serogroup, suggesting that immunity to noncapsular antigens plays a significant role in natural herd immunity. Here, through comparative genomic analysis of 100 meningococcal isolates, we provide a high-resolution view of the evolutionary changes that occurred during clonal replacement of a hypervirulent meningococcal clone (ST-7) by a descendant clone (ST-2859). We show that the majority of genetic changes are due to homologous recombination of laterally acquired DNA, with more than 20% of these events involving acquisition of DNA from other species. Signals of adaptation to evade herd immunity were indicated by genomic hot spots of recombination. Most striking is the high frequency of changes involving the pgl locus, which determines the glycosylation patterns of major protein antigens. High-frequency changes were also observed for genes involved in the regulation of pilus expression and the synthesis of Maf3 adhesins, highlighting the importance of these surface features in host-pathogen interaction and immune evasion. IMPORTANCE While established meningococcal capsule polysaccharide vaccines are protective through the induction of anticapsular antibodies, findings of our longitudinal studies in the African meningitis belt have indicated that immunity to noncapsular antigens plays a significant role in natural herd immunity. Our results show that meningococci evade herd immunity through the rapid homologous replacement of just a few key genomic loci that affect noncapsular cell surface components. Identification of recombination hot spots thus represents an eminent approach to gain insight into targets of protective natural immune responses. Moreover, our results highlight the role of the dynamics of the protein glycosylation repertoire in immune evasion by Neisseria meningitidis. These results have major implications for the design of next-generation protein-based subunit vaccines.

To describe the variation in household crowding and social mixing patterns in the African meningitis belt and to assess any association with self-reported recent respiratory symptoms.In 2010, the African Meningococcal Carriage Consortium (MenAfriCar) conducted cross-sectional surveys in urban and rural areas of seven countries. The number of household members, rooms per household, attendance at social gatherings and meeting places were recorded. Associations with self-reported recent respiratory symptoms were analysed by univariate and multivariate regression models.The geometric mean people per room ranged from 1.9 to 2.8 between Ghana and Ethiopia respectively. Attendance at different types of social gatherings was variable by country, ranging from 0.5 to 1.5 per week. Those who attended 3 or more different types of social gatherings a week (frequent mixers) were more likely to be older, male (OR 1.27, p

ObjectiveTo estimate the direct and indirect costs of meningitis to households in the Kassena-Nankana District of Ghana.MethodsA Cost of illness (COI) survey was conducted between 2010 and 2011. The COI was computed from a retrospective review of 80 meningitis cases answers to questions about direct medical costs, direct non-medical costs incurred and productivity losses due to recent meningitis incident.ResultsThe average direct and indirect costs of treating meningitis in the district was GH¢152.55 (US$101.7) per household. This is equivalent to about two months minimum wage earned by Ghanaians in unskilled paid jobs in 2009. Households lost 29 days of work per meningitis case and thus those in minimum wage paid jobs lost a monthly minimum wage of GH¢76.85 (US$51.23) due to the illness. Patients who were insured spent an average of GH¢38.5 (US$25.67) in direct medical costs whiles the uninsured patients spent as much as GH¢177.9 (US$118.6) per case. Patients with sequelae incurred additional costs of GH¢22.63 (US$15.08) per case. The least poor were more exposed to meningitis than the poorest.ConclusionMeningitis is a debilitating but preventable disease that affects people living in the Sahel and in poorer conditions. The cost of meningitis treatment may further lead to impoverishment for these households. Widespread mass vaccination will save households' an equivalent of GH¢175.18 (US$117) and impairment due to meningitis.

OBJECTIVE:Detection of meningococcal carriers is key to understanding the epidemiology of Neisseria meningitidis, yet no gold standard has been established. Here, we directly compare two methods for collecting pharyngeal swabs to identify meningococcal carriers. METHODS:We conducted cross-sectional surveys of schoolchildren at multiple sites in Africa to compare swabbing the posterior pharynx behind the uvula (U) to swabbing the posterior pharynx behind the uvula plus one tonsil (T). Swabs were cultured immediately and analyzed using molecular methods. RESULTS:One thousand and six paired swab samples collected from schoolchildren in four countries were analyzed. Prevalence of meningococcal carriage was 6.9% (95% CI: 5.4-8.6%) based on the results from both swabs, but the observed prevalence was lower based on one swab type alone. Prevalence based on the T swab or the U swab alone was similar (5.2% (95% CI: 3.8-6.7%) versus 4.9% (95% CI: 3.6-6.4%) respectively (p=0.6)). The concordance between the two methods was 96.3% and the kappa was 0.61 (95% CI: 0.50-0.73), indicating good agreement. CONCLUSIONS:These two commonly used methods for collecting pharyngeal swabs provide consistent estimates of the prevalence of carriage, but both methods misclassified carriers to some degree, leading to underestimates of the prevalence.

BACKGROUND: Antenatal care (ANC) is a key strategy to improve maternal and infant health. However, survey data from sub-Saharan Africa indicate that women often only initiate ANC after the first trimester and do not achieve the recommended number of ANC visits. Drawing on qualitative data, this article comparatively explores the factors that influence ANC attendance across four sub-Saharan African sites in three countries (Ghana, Kenya and Malawi) with varying levels of ANC attendance. METHODS: Data were collected as part of a programme of qualitative research investigating the social and cultural context of malaria in pregnancy. A range of methods was employed interviews, focus groups with diverse respondents and observations in local communities and health facilities. RESULTS: Across the sites, women attended ANC at least once. However, their descriptions of ANC were often vague. General ideas about pregnancy care - checking the foetus' position or monitoring its progress - motivated women to attend ANC; as did, especially in Kenya, obtaining the ANC card to avoid reprimands from health workers. Women's timing of ANC initiation was influenced by reproductive concerns and pregnancy uncertainties, particularly during the first trimester, and how ANC services responded to this uncertainty; age, parity and the associated implications for pregnancy disclosure; interactions with healthcare workers, particularly messages about timing of ANC; and the cost of ANC, including charges levied for ANC procedures - in spite of policies of free ANC - combined with ideas about the compulsory nature of follow-up appointments. CONCLUSION: In these socially and culturally diverse sites, the findings suggest that 'supply' side factors have an important influence on ANC attendance: the design of ANC and particularly how ANC deals with the needs and concerns of women during the first trimester has implications for timing of initiation.

OBJECTIVES: To determine the neonatal mortality rate in the Kassena-Nankana District (KND) of northern Ghana, and to identify the leading causes and timing of neonatal deaths. METHODS: The KND falls within the Navrongo Health Research Centre's Health and Demographic Surveillance System (HDSS), which uses trained field workers to gather and update health and demographic information from community members every four months. We utilized HDSS data from 2003-2009 to examine patterns of neonatal mortality. RESULTS: A total of 17,751 live births between January 2003 and December 2009 were recorded, including 424 neonatal deaths 64.8%(275) of neonatal deaths occurred in the first week of life. The overall neonatal mortality rate was 24 per 1000 live births (95%CI 22 to 26) and early neonatal mortality rate was 16 per 1000 live births (95% CI 14 to 17). Neonatal mortality rates decreased over the period from 26 per 1000 live births in 2003 to 19 per 1000 live births in 2009. In all, 32%(137) of the neonatal deaths were from infections, 21%(88) from birth injury and asphyxia and 18%(76) from prematurity, making these three the leading causes of neonatal deaths in the area. Birth injury and asphyxia (31%) and prematurity (26%) were the leading causes of early neonatal deaths, while infection accounted for 59% of late neonatal deaths. Nearly 46% of all neonatal deaths occurred during the first three postnatal days. In multivariate analysis, multiple births, gestational age

Haemoglobin S (HbS) and C (HbC) are variants of the HBB gene which both protect against malaria. It is not clear, however, how these two alleles have evolved in the West African countries where they co-exist at high frequencies. Here we use haplotypic signatures of selection to investigate the evolutionary history of the malaria-protective alleles HbS and HbC in the Kassena-Nankana District (KND) of Ghana.The haplotypic structure of HbS and HbC alleles was investigated, by genotyping 56 SNPs around the HBB locus. We found that, in the KND population, both alleles reside on extended haplotypes (approximately 1.5 Mb for HbS and 650 Kb for HbC) that are significantly less diverse than those of the ancestral HbA allele. The extended haplotypes span a recombination hotspot that is known to exist in this region of the genomeOur findings show strong support for recent positive selection of both the HbS and HbC alleles and provide insights into how these two alleles have both evolved in the population of northern Ghana.

BACKGROUND: Combining meningococcal vaccination with routine immunization in infancy may reduce the burden of meningococcal meningitis, especially in the meningitis belt of Africa. We have evaluated the immunogenicity, persistence of immune response, immune memory and safety of an investigational DTPw-HBV/Hib-MenAC conjugate vaccine given to infants in Northern Ghana. METHODS AND FINDINGS: In this phase II, double blind, randomized, controlled study, 280 infants were primed with DTPw-HBV/Hib-MenAC or DTPw-HBV/Hib vaccines at 6, 10 and 14 weeks of age. At 12 months of age, children in each group received a challenge dose of serogroup A+C polysaccharides. Antibody responses were assessed pre, and one month-post dose 3 of the priming schedule and pre and 1 month after administration of the challenge dose. One month post-dose 3, 87.8% and 88.2% of subjects in the study group had bactericidal meningococcal serogroup A (SBA-MenA) and meningococcal serogroup C (SBA-MenC) antibody titres > or = 1:8 respectively. Seroprotection/seropositivity rates to the 5 antigens administered in the routine EPI schedule were non-inferior in children in the study group compared to those in the control group. The percentages of subjects in the study group with persisting SBA-MenA titres > or = 1:8 or SBA-MenC titres > or = 1:8 at the age of 12 months prior to challenge were significantly higher than in control group (47.7% vs 25.7% and 56.4% vs 5.1% respectively). The administration of 10 microg of serogroup A polysaccharide increased the SBA-MenA GMT by 14.0-fold in the DTPW-HBV/HibMenAC-group compared to a 3.8 fold increase in the control-group. Corresponding fold-increases in SBA-MenC titres following challenge with 10 microg of group C polysaccharide were 18.8 and 1.9 respectively. Reactogenicity following primary vaccination or the administration of the challenge dose was similar in both groups, except for swelling (Grade 3) after primary vaccination which was more frequent in children in the vaccine than in the control group (23.7%; 95%CI [19.6-28.1] of doses vs 14.1%; 95% CI [10.9-17.8] of doses). Fifty-nine SAEs (including 8 deaths), none of them related to vaccination, were reported during the entire study. CONCLUSIONS: Three dose primary vaccination with DTPw-HBV/Hib-MenAC was non-inferior to DTPw-HBV/Hib for the 5 common antigens used in the routine EPI schedule and induced bactericidal antibodies against Neisseria meningitidis of serogroups A and C in the majority of infants. Serogroup A and C bactericidal antibody levels had fallen below titres associated with protection in nearly half of the infants by the age of 12 months confirming that a booster dose is required at about that age. An enhanced memory response was shown after polysaccharide challenge. This vaccine could provide protection against 7 important childhood diseases (including meningococcal A and C) and be of particular value in countries of the African meningitis belt. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN35754083.

The Kassena-Nankana District of northern Ghana lies in the African "meningitis belt" where epidemics of meningococcal meningitis have been reoccurring every eight to 12 years for the last 100 years. The dynamics of meningococcal colonisation and disease are incompletely understood, and hence we embarked on a long-term study to determine how levels of colonisation with different bacterial serogroups change over time, and how the patterns of disease relate to such changes.Between February 1998 and November 2005, pharyngeal carriage of Neisseria meningitidis in the Kassena-Nankana District was studied by twice-yearly colonisation surveys. Meningococcal disease was monitored throughout the eight-year study period, and patient isolates were compared to the colonisation isolates. The overall meningococcal colonisation rate of the study population was 6.0%. All culture-confirmed patient isolates and the majority of carriage isolates were associated with three sequential waves of colonisation with encapsulated (A ST5, X ST751, and A ST7) meningococci. Compared to industrialised countries, the colonising meningococcal population was less constant in genotype composition over time and was genetically less diverse during the peaks of the colonisation waves, and a smaller proportion of the isolates was nonserogroupable. We observed a broad age range in the healthy carriers, resembling that of meningitis patients during large disease epidemics.The observed lack of a temporally stable and genetically diverse resident pharyngeal flora of meningococci might contribute to the susceptibility to meningococcal disease epidemics of residents in the African meningitis belt. Because capsular conjugate vaccines are known to impact meningococcal carriage, effects on herd immunity and potential serogroup replacement should be monitored following the introduction of such vaccines.

Neisseria meningitidis is a major cause of bacterial meningitis and a considerable health problem in the 25 countries of the ‘African Meningitis Belt’ that extends from Senegal in West Africa to Ethiopia in the East. Approximately 80% of cases of meningococcal meningitis in Africa have been caused by strains belonging to capsular serogroup A. After the introduction of a serogroup A conjugate polysaccharide vaccine, MenAfriVac ™, that began in December 2010, the incidence of meningitis due to serogroup A has markedly declined in this region. Currently, serogroup W of N. meningitidis accounts for the majority of cases. Vaccines based on sub-capsular antigens, such as Generalized Modules for Membrane Antigens (GMMA), are under investigation for use in Africa. To analyse the antigenic properties of a serogroup W wave of colonisation and disease, we investigated the molecular diversity of the protein vaccine antigens PorA, Neisserial Adhesin A (NadA), Neisserial heparin-binding antigen (NHBA) and factor H binding protein (fHbp) of 31 invasive and carriage serogroup W isolates collected as part of a longitudinal study from Ghana and Burkina Faso between 2003 and 2009. We found that the isolates all expressed fHbp variant 2 ID 22 or 23, differing from each other by only one amino acid, and a single PorA subtype of P1.5,2. Of the isolates, 49% had a functional nhbA gene and 100% had the nadA allele 3, which contained the insertion sequence IS1301 in five isolates. Of the W isolates tested, 41% had high fHbp expression when compared with a reference serogroup B strain, known to be a high expresser of fHbp variant 2. Our results indicate that in this collection of serogroup W isolates, there is limited antigenic diversification over time of vaccine candidate outer membrane proteins (OMP), thus making them promising candidates for inclusion in a protein-based vaccine against meningococcal meningitis for Africa.