Safety and immunogenicity of BK-SE36/CpG malaria vaccine in healthy Burkinabe adults and children: a phase 1b randomised, controlled, double-blinded, age de-escalation trial.

Background: BK-SE36/CpG is a recombinant blood-stage malaria vaccine candidate based on the N-terminal Plasmodium falciparum serine repeat antigen5 (SE36), adsorbed to aluminium hydroxide gel and reconstituted, prior to administration, with synthetic oligodeoxynucleotides bearing CpG motifs. In healthy Japanese adult males, BK-SE36/CpG was well tolerated. This study assessed its safety and immunogenicity in healthy malaria-exposed African adults and children. Methods: A double-blind, randomised, controlled, age de-escalating clinical trial was conducted in an urban area of Ouagadougou, Burkina Faso. Healthy participants (n=135) aged 21-45 years (Cohort 1), 5-10 years (Cohort 2) and 12-24 months (Cohort 3) were randomised to receive three vaccine doses (Day 0, 28 and 112) of BK-SE36/CpG or rabies vaccine by intramuscular injection. Results: One hundred thirty-four of 135 (99.2%) subjects received all three scheduled vaccine doses. Vaccinations were well tolerated with no related Grade 3 (severe) adverse events (AEs). Pain/limitation of limb movement, headache in adults and fever in younger children (all mild to moderate in intensity) were the most frequently observed local and systemic AEs. Eighty-three of BK-SE36/CpG (91%) recipients and 37 of control subjects (84%) had Grade 1/2 events within 28 days post vaccination. Events considered by the investigator to be vaccine related were experienced by 38% and 14% of subjects in BK-SE36/CpG and control arms, respectively. Throughout the trial, six Grade 3 events (in 4 subjects), not related to vaccination, were recorded in the BK-SE36/CpG arm: 5 events (in 3 subjects) within 28 days of vaccination. All serious adverse events (SAEs) (n=5) were due to severe malaria (52-226 days post vaccination) and not related to vaccination. In all cohorts, BK-SE36/CpG arm had higher antibody titres after Dose 3 than after Dose 2. Younger cohorts had stronger immune responses (12-24-month-old > 5-10 years-old > 21-45 years-old). Sera predominantly reacted to peptides that lie in intrinsically unstructured regions of SE36. In the control arm, there were no marked fold changes in antibody titres and participants' sera reacted poorly to all peptides spanning SE36. Conclusion: BK-SE36/CpG was well-tolerated and immunogenic. These results pave the way for further proof-of-concept studies to demonstrate vaccine efficacy. Clinical trial registration: https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=1921, PACTR201701001921166.

Modelling the effect of a mass radio campaign on child mortality using facility utilisation data and the Lives Saved Tool (LiST): findings from a cluster randomised trial in Burkina Faso.

BACKGROUND: A cluster randomised trial (CRT) in Burkina Faso was the first to demonstrate that a radio campaign increased health-seeking behaviours, specifically antenatal care attendance, health facility deliveries and primary care consultations for children under 5 years. METHODS: Under-five consultation data by diagnosis was obtained from primary health facilities in trial clusters, from January 2011 to December 2014. Interrupted time-series analyses were conducted to assess the intervention effect by time period on under-five consultations for separate diagnosis categories that were targeted by the media campaign. The Lives Saved Tool was used to estimate the number of under-five lives saved and the per cent reduction in child mortality that might have resulted from increased health service utilisation. Scenarios were generated to estimate the effect of the intervention in the CRT study areas, as well as a national scale-up in Burkina Faso and future scale-up scenarios for national media campaigns in five African countries from 2018 to 2020. RESULTS: Consultations for malaria symptoms increased by 56% in the first year (95% CI 30% to 88%; p<0.001) of the campaign, 37% in the second year (95% CI 12% to 69%; p=0.003) and 35% in the third year (95% CI 9% to 67%; p=0.006) relative to the increase in the control arm. Consultations for lower respiratory infections increased by 39% in the first year of the campaign (95% CI 22% to 58%; p<0.001), 25% in the second (95% CI 5% to 49%; p=0.010) and 11% in the third year (95% CI -20% to 54%; p=0.525). Diarrhoea consultations increased by 73% in the first year (95% CI 42% to 110%; p<0.001), 60% in the second (95% CI 12% to 129%; p=0.010) and 107% in the third year (95% CI 43% to 200%; p<0.001). Consultations for other diagnoses that were not targeted by the radio campaign did not differ between intervention and control arms. The estimated reduction in under-five mortality attributable to the radio intervention was 9.7% in the first year (uncertainty range: 5.1%-15.1%), 5.7% in the second year and 5.5% in the third year. The estimated number of under-five lives saved in the intervention zones during the trial was 2967 (range: 1110-5741). If scaled up nationally, the estimated reduction in under-five mortality would have been similar (9.2% in year 1, 5.6% in year 2 and 5.5% in year 3), equating to 14 888 under-five lives saved (range: 4832-30 432). The estimated number of lives that could be saved by implementing national media campaigns in other low-income settings ranged from 7205 in Burundi to 21 443 in Mozambique. CONCLUSION: Evidence from a CRT shows that a child health radio campaign increased under-five consultations at primary health centres for malaria, pneumonia and diarrhoea (the leading causes of postneonatal child mortality in Burkina Faso) and resulted in an estimated 7.1% average reduction in under-five mortality per year. These findings suggest important reductions in under-five mortality can be achieved by mass media alone, particularly when conducted at national scale.

Cost-effectiveness and economies of scale of a mass radio campaign to promote household life-saving practices in Burkina Faso.

INTRODUCTION: Child health promotion through mass media has not been rigorously evaluated for cost-effectiveness in low-income and middle-income countries. We assessed the cost-effectiveness of a mass radio campaign on health-seeking behaviours for child survival within a trial in Burkina Faso and at national scale. METHODS: We collected provider cost data prospectively alongside a 35-month cluster randomised trial in rural Burkina Faso in 2012-2015. Out-of-pocket costs of care-seeking were estimated through a household survey. We modelled intervention effects on child survival based on increased care-seeking and estimated the intervention's incremental cost-effectiveness ratio (ICER) in terms of the cost per disability-adjusted life year (DALY) averted versus current practice. Model uncertainty was gauged using one-way and probabilistic sensitivity analyses. We projected the ICER of national-scale implementation in five sub-Saharan countries with differing media structures. All costs are in 2015 USD. RESULTS: The provider cost of the campaign was $7 749 128 ($9 146 101 including household costs). The campaign broadcast radio spots 74 480 times and 4610 2-hour shows through seven local radio stations, reaching approximately 2.4 million people including 620 000 direct beneficiaries (pregnant women and children under five). It resulted in an average estimated 24% increase in care-seeking for children under five and a 7% reduction in child mortality per year. The ICER was estimated at $94 ($111 including household costs (95% CI -38 to 320)). The projected provider cost per DALY averted of a national level campaign in Burkina Faso, Burundi, Malawi, Mozambique and Niger in 2018-2020, varied between $7 in Malawi to $27 in Burundi. CONCLUSION: This study suggests that mass-media campaigns can be very cost-effective in improving child survival in areas with high media penetration and can potentially benefit from considerable economies of scale. TRIAL REGISTRATION NUMBER: NCT01517230; Results.

Effect of a mass radio campaign on family behaviours and child survival in Burkina Faso: a repeated cross-sectional, cluster-randomised trial.

BACKGROUND: Media campaigns can potentially reach a large audience at relatively low cost but, to our knowledge, no randomised controlled trials have assessed their effect on a health outcome in a low-income country. We aimed to assess the effect of a radio campaign addressing family behaviours on all-cause post-neonatal under-5 child mortality in rural Burkina Faso. METHODS: In this repeated cross-sectional, cluster randomised trial, clusters (distinct geographical areas in rural Burkina Faso with at least 40 000 inhabitants) were selected by Development Media International based on their high radio listenership (>60% of women listening to the radio in the past week) and minimum distances between radio stations to exclude population-level contamination. Clusters were randomly allocated to receive the intervention (a comprehensive radio campaign) or control group (no radio media campaign). Household surveys were performed at baseline (from December, 2011, to February, 2012), midline (in November, 2013, and after 20 months of campaigning), and endline (from November, 2014, to March, 2015, after 32 months of campaigning). Primary analyses were done on an intention-to-treat basis, based on cluster-level summaries and adjusted for imbalances between groups at baseline. The primary outcome was all-cause post-neonatal under-5 child mortality. The trial was designed to detect a 20% reduction in the primary outcome with a power of 80%. Routine data from health facilities were also analysed for evidence of changes in use and these data had high statistical power. The indicators measured were new antenatal care attendances, facility deliveries, and under-5 consultations. This trial is registered with ClinicalTrial.gov, number NCT01517230. FINDINGS: The intervention ran from March, 2012, to January, 2015. 14 clusters were selected and randomly assigned to the intervention group (n=7) or the control group (n=7). The average number of villages included per cluster was 34 in the control group and 29 in the intervention group. 2269 (82%) of 2784 women in the intervention group reported recognising the campaign's radio spots at endline. Post-neonatal under-5 child mortality decreased from 93·3 to 58·5 per 1000 livebirths in the control group and from 125·1 to 85·1 per 1000 livebirths in the intervention group. There was no evidence of an intervention effect (risk ratio 1·00, 95% CI 0·82-1·22; p>0·999). In the first year of the intervention, under-5 consultations increased from 68 681 to 83 022 in the control group and from 79 852 to 111 758 in the intervention group. The intervention effect using interrupted time-series analysis was 35% (95% CI 20-51; p<0·0001). New antenatal care attendances decreased from 13 129 to 12 997 in the control group and increased from 19 658 to 20 202 in the intervention group in the first year (intervention effect 6%, 95% CI 2-10; p=0·004). Deliveries in health facilities decreased from 10 598 to 10 533 in the control group and increased from 12 155 to 12 902 in the intervention group in the first year (intervention effect 7%, 95% CI 2-11; p=0·004). INTERPRETATION: A comprehensive radio campaign had no detectable effect on child mortality. Substantial decreases in child mortality were observed in both groups over the intervention period, reducing our ability to detect an effect. This, nevertheless, represents the first randomised controlled trial to show that mass media alone can change health-seeking behaviours. FUNDING: Wellcome Trust and Planet Wheeler Foundation.

Phacoemulsification compared with phacotrabeculectomy surgery: a within-person observational cohort study.

AIM: To compare reduction in intraocular pressure (IOP) and gain in visual acuity (VA) following phacotrabeculectomy (PT) and phacoemulsification(phaco) in Tanzanian patients with primary open angle glaucoma(POAG). SETTING: CCBRT Hospital, Dar es Salaam, Tanzania. DESIGN: Within-person observational cohort study. METHODS: Within each patient, one eye had PT and the other phaco. Patients were followed for up to 5-1/2 years, and IOP and VA in each eye were assessed. For a small group of patients, two additional postoperative time points were compared. RESULTS: 52 patients (34 male) with a mean age of 70 years (SD 8 years) were enrolled in the study. For those with 250 days or more follow-up, both operations resulted in lower IOPs and improved VA (p<0.001). The average drop in IOP was 50% (95%CI 45% to 55%) for PT and 41% (95% CI 36% to 46%) for phaco. Mean IOP was lower in the PT group 12.9 mm Hg vs 16.8 mm Hg (p=0.004). Extended follow-up in nine patients showed a rise in IOP of 1.8 mm Hg for PT and 4.2 mm Hg for phaco eyes between first (mean, 337 days) and second (mean 1482 days) follow-up (p=0.18). CONCLUSION: In this small study in African patients, PT resulted in lower IOPs than phacoemulsification alone but the difference between the procedures was relatively small. Phacoemulsification alone was effective in reducing IOP and improving VA for several years in this population. Given the relative simplicity of phacoemulsification, it is a therapeutic option worthy of consideration in some settings.

Incidence and determinants of hysterectomy in a low-income setting in Gujarat, India.

Hysterectomy is a leading reason for use of health insurance amongst low-income women in India, but there are limited population-level data available to inform policy. This paper reports on the findings of a mixed-methods study to estimate incidence and identify predictors of hysterectomy in a low-income setting in Gujarat, India. The estimated incidence of hysterectomy, 20.7/1000 woman- years (95% CI: 14.0, 30.8), was considerably higher than reported from other countries, at a relatively low mean age of 36 years. There was strong evidence that among women of reproductive age, those with lower income and at least two children underwent hysterectomy at higher rates. Nearly two-thirds of women undergoing hysterectomy utilized private hospitals, while the remainder used government or other non-profit facilities. Qualitative research suggested that weak sexual and reproductive health services, a widespread perception that the post-reproductive uterus is dispensable and lack of knowledge of side effects have resulted in the normalization of hysterectomy. Hysterectomy appears to be promoted as a first or second-line treatment for menstrual and gynaecological disorders that are actually amenable to less invasive procedures. Most women sought at least two medical opinions prior to hysterectomy, but both public and private providers lacked equipment, skills and motivation to offer alternatives. Profit and training benefits also appeared to play a role in some providers' behaviour. Although women with insecure employment underwent the procedure knowing the financial and physical implications of undergoing a major surgery, the future health and work security afforded by hysterectomy appeared to them to outweigh risks. Findings suggest that sterilization may be associated with an increased risk of hysterectomy, potentially through biological or attitudinal links. Health policy interventions require improved access to sexual and reproductive health services and health education, along with surveillance and medical audits to promote high-quality choices for women through the life cycle.

Is Beta Radiation Better than 5 Flurouracil as an Adjunct for Trabeculectomy Surgery When Combined with Cataract Surgery? A Randomised Controlled Trial.

INTRODUCTION: In an African setting surgery is generally accepted as the treatment of first choice for glaucoma. A problem with trabeculectomy surgery for the glaucomas is the frequent co-existence and exacerbation of cataract. We report a randomized controlled trial to compare the use of beta radiation with 5FU in combined cataract and glaucoma surgery. PARTICIPANTS AND METHODS: Consenting adults aged >40 years with glaucoma, an IOP>21mmHG and cataract were enrolled and randomised to receive either 1000cG ß radiation application or sub-conjunctival 5fluorouracil (5FU) at the time of combined trabeculectomy and phaco-emulsification with lens implant surgery. RESULTS: 385 individuals were eligible for inclusion of whom 301 consented to inclusion in the study (one eye per patient). 150 were randomised to the 5FU arm and 151 received ß radiation. In the 12 months following surgery there were 40 failures (IOP>21mmHg) in the 5FU arm and 34 failures in the beta arm. The hazard ratio for the beta radiation arm compared to the 5FU arm, adjusted for IOP at baseline, was 0.83 (95% c.i. 0.54 to 1.28; P = 0.40). The improvement from mean presenting visual acuities of 0.91 and 0.86 logMAR to 0.62 and 0.54 in the 5FU and beta arms respectively was comparable between groups (P = 0.4 adjusting for baseline VA). Incidence of complications did not differ between the two groups. DISCUSSION: This study highlights several important issues in the quest for a therapeutic strategy for the glaucomas in an African context. Firstly, there is no evidence of an important difference between the use of 5FU and beta radiation as an anti-metabolite in phacotrabeculectomy. Secondly phacotrabeculectomy is a successful operation that improves visual acuity as well as controlling IOP in a majority of patients. Although the success of trabeculectomy in lowering IOP is reduced when combined with phacoemulsification compared with trabeculectomy alone, this finding has to be set against the possible need for subsequent cataract surgery following trabeculectomy alone, which represents a second trip and expense for the patient and results in 10-61% failure of the trabeculectomy at one year post-cataract surgery. TRIAL REGISTRATION: ISRCTN Registry ISRCTN36436933.

Setting health research priorities using the CHNRI method: VI. Quantitative properties of human collective opinion.

INTRODUCTION: Crowdsourcing has become an increasingly important tool to address many problems - from government elections in democracies, stock market prices, to modern online tools such as TripAdvisor or Internet Movie Database (IMDB). The CHNRI method (the acronym for the Child Health and Nutrition Research Initiative) for setting health research priorities has crowdsourcing as the major component, which it uses to generate, assess and prioritize between many competing health research ideas. METHODS: We conducted a series of analyses using data from a group of 91 scorers to explore the quantitative properties of their collective opinion. We were interested in the stability of their collective opinion as the sample size increases from 15 to 90. From a pool of 91 scorers who took part in a previous CHNRI exercise, we used sampling with replacement to generate multiple random samples of different size. First, for each sample generated, we identified the top 20 ranked research ideas, among 205 that were proposed and scored, and calculated the concordance with the ranking generated by the 91 original scorers. Second, we used rank correlation coefficients to compare the ranks assigned to all 205 proposed research ideas when samples of different size are used. We also analysed the original pool of 91 scorers to to look for evidence of scoring variations based on scorers' characteristics. RESULTS: The sample sizes investigated ranged from 15 to 90. The concordance for the top 20 scored research ideas increased with sample sizes up to about 55 experts. At this point, the median level of concordance stabilized at 15/20 top ranked questions (75%), with the interquartile range also generally stable (14-16). There was little further increase in overlap when the sample size increased from 55 to 90. When analysing the ranking of all 205 ideas, the rank correlation coefficient increased as the sample size increased, with a median correlation of 0.95 reached at the sample size of 45 experts (median of the rank correlation coefficient = 0.95; IQR 0.94-0.96). CONCLUSIONS: Our analyses suggest that the collective opinion of an expert group on a large number of research ideas, expressed through categorical variables (Yes/No/Not Sure/Don't know), stabilises relatively quickly in terms of identifying the ideas that have most support. In the exercise we found a high degree of reproducibility of the identified research priorities was achieved with as few as 45-55 experts.

Small-for-Gestational-Age Births are Associated with Maternal Relationship Status: A Population-Wide Analysis.

Objectives To examine the association between maternal relationship status during pregnancy and infant birth outcomes. Methods Observational study of the National Longitudinal Survey of Youth 1979, a nationally representative sample of 12,686 men and women between the ages of 14 and 21. We used data from surveys of women reporting childbirth between 1979 and 2004. Relationship status was defined as relationship with an opposite-sex partner in the child's birth year. Relationship stability was defined as the consistency in relationship status in the 1 year before, of, and after the child's birth. Childbirth outcome included small-for-gestational age (SGA) infant. We applied random effects logistic regression models to assess the association between relationship status and stability and childbirth outcome-adjusting for maternal race, infant sex, history of miscarriage, employment, maternal age, multiparity, cohort-entry year, household poverty status, and tobacco use. Results The study included 4439 women with 8348 live births. In fully adjusted models, term SGA infants were more commonly born to partnered women (AOR 1.81; 95 % CI 1.20-2.73) and unmarried women (AOR 1.82; CI 1.34-2.47; LRT p value 0.0001), compared to married women. SGA infants were also more commonly born in unstable relationships (AOR 1.72; 95 % CI 1.14-2.63; LRT p value 0.01) compared to stable relationships. Conclusions for Practice Maternal relationship status and stability during pregnancy is independently associated with risk of SGA infant birth.

Behavior Change After 20 Months of a Radio Campaign Addressing Key Lifesaving Family Behaviors for Child Survival: Midline Results From a Cluster Randomized Trial in Rural Burkina Faso.

BACKGROUND: In Burkina Faso, a comprehensive 35-month radio campaign addressed key, multiple family behaviors for improving under-5 child survival and was evaluated using a repeated cross-sectional, cluster randomized design. The primary outcome of the trial was postneonatal under-5 child mortality. This paper reports on behavior change achieved at midline. METHOD: Fourteen community radio stations in 14 geographic areas were selected based on their high listenership. Seven areas were randomly allocated to receive the intervention while the other 7 areas served as controls. The campaign was launched in March 2012. Cross-sectional surveys of about 5,000 mothers of under-5 children, living in villages close to the radio stations, were conducted at baseline (from December 2011 to February 2012) and at midline (in November 2013), after 20 months of campaigning. Statistical analyses were based on cluster-level summaries using a difference-in-difference (DiD) approach and adjusted for imbalances between arms at baseline. In addition, routine health facility data were analyzed for evidence of changes in health facility utilization. RESULTS: At midline, 75% of women in the intervention arm reported recognizing radio spots from the campaign. There was some evidence of the campaign having positive effects on care seeking for diarrhea (adjusted DiD, 17.5 percentage points; 95% confidence interval [CI], 2.5 to 32.5; P= .03), antibiotic treatment for fast/difficult breathing (adjusted DiD, 29.6 percentage points; 95% CI, 3.5 to 55.7; P= .03), and saving money during pregnancy (adjusted DiD, 12.8 percentage points; 95% CI, 1.4 to 24.2; P= .03). For other target behaviors, there was little or no evidence of an impact of the campaign after adjustment for baseline imbalances and confounding factors. There was weak evidence of a positive correlation between the intensity of broadcasting of messages and reported changes in target behaviors. Routine health facility data were consistent with a greater increase in the intervention arm than in the control arm in all-cause under-5 consultations (33% versus 17%, respectively), but the difference was not statistically significant (P= .40). CONCLUSION: The radio campaign reached a high proportion of the primary target population, but the evidence for an impact on key child survival-related behaviors at midline was mixed.

Effect of provision of daily zinc and iron with several micronutrients on growth and morbidity among young children in Pakistan: a cluster-randomised trial.

BACKGROUND: Powders containing iron and other micronutrients are recommended as a strategy to prevent nutritional anaemia and other micronutrient deficiencies in children. We assessed the effects of provision of two micronutrient powder formulations, with or without zinc, to children in Pakistan. METHODS: We did a cluster randomised trial in urban and rural sites in Sindh, Pakistan. A baseline survey identified 256 clusters, which were randomly assigned (within urban and rural strata, by computer-generated random numbers) to one of three groups: non-supplemented control (group A), micronutrient powder without zinc (group B), or micronutrient powder with 10 mg zinc (group C). Children in the clusters aged 6 months were eligible for inclusion in the study. Powders were to be given daily between 6 and 18 months of age; follow-up was to age 2 years. Micronutrient powder sachets for groups B and C were identical except for colour; investigators and field and supervisory staff were masked to composition of the micronutrient powders until trial completion. Parents knew whether their child was receiving supplementation, but did not know whether the powder contained zinc. Primary outcomes were growth, episodes of diarrhoea, acute lower respiratory tract infection, fever, and incidence of admission to hospital. This trial is registered with ClinicalTrials.gov, number NCT00705445. RESULTS: The trial was done between Nov 1, 2008, and Dec 31, 2011. 947 children were enrolled in group A clusters, 910 in group B clusters, and 889 in group C clusters. Micronutrient powder administration was associated with lower risk of iron-deficiency anaemia at 18 months compared with the control group (odds ratio [OR] for micronutrient powder without zinc=0·20, 95% CI 0·11-0·36; OR for micronutrient powder with zinc=0·25, 95% CI 0·14-0·44). Compared with the control group, children in the group receiving micronutrient powder without zinc gained an extra 0·31 cm (95% CI 0·03-0·59) between 6 and 18 months of age and children receiving micronutrient powder with zinc an extra 0·56 cm (0·29-0·84). We recorded strong evidence of an increased proportion of days with diarrhoea (p=0·001) and increased incidence of bloody diarrhoea (p=0·003) between 6 and 18 months in the two micronutrient powder groups, and reported chest indrawing (p=0·03). Incidence of febrile episodes or admission to hospital for diarrhoea, respiratory problems, or febrile episodes did not differ between the three groups. INTERPRETATION: Use of micronutrient powders reduces iron-deficiency anaemia in young children. However, the excess burden of diarrhoea and respiratory morbidities associated with micronutrient powder use and the very small effect on growth recorded suggest that a careful assessment of risks and benefits must be done in populations with malnourished children and high diarrhoea burdens. FUNDING: Bill & Melinda Gates Foundation.

Using causal diagrams to guide analysis in missing data problems.

Estimating causal effects from incomplete data requires additional and inherently untestable assumptions regarding the mechanism giving rise to the missing data. We show that using causal diagrams to represent these additional assumptions both complements and clarifies some of the central issues in missing data theory, such as Rubin's classification of missingness mechanisms (as missing completely at random (MCAR), missing at random (MAR) or missing not at random (MNAR)) and the circumstances in which causal effects can be estimated without bias by analysing only the subjects with complete data. In doing so, we formally extend the back-door criterion of Pearl and others for use in incomplete data examples. These ideas are illustrated with an example drawn from an occupational cohort study of the effect of cosmic radiation on skin cancer incidence.

Mathematical models in the evaluation of health programmes.

Modelling is valuable in the planning and evaluation of interventions, especially when a controlled trial is ethically or logistically impossible. Models are often used to calculate the expected course of events in the absence of more formal assessments. They are also used to derive estimates of rare or future events from recorded intermediate points. When developing models, decisions are needed about the appropriate level of complexity to be represented and about model structure and assumptions. The degree of rigor in model development and assessment can vary greatly, and there is a danger that existing beliefs inappropriately influence judgments about model assumptions and results.

Folic acid to reduce neonatal mortality from neural tube disorders.

BACKGROUND: Neural tube defects (NTDs) remain an important, preventable cause of mortality and morbidity. High-income countries have reported large reductions in NTDs associated with folic acid supplementation or fortification. The burden of NTDs in low-income countries and the effectiveness of folic acid fortification/supplementation are unclear. OBJECTIVE: To review the evidence for, and estimate the effect of, folic acid fortification/supplementation on neonatal mortality due to NTDs, especially in low-income countries. METHODS: We conducted systematic reviews, abstracted data meeting inclusion criteria and evaluated evidence quality using adapted Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology. Where appropriate, meta-analyses were performed. RESULTS: Meta-analysis of three randomized controlled trials (RCTs) of folic acid supplementation for women with a previous pregnancy with NTD indicates a 70% [95% confidence interval (CI): 35-86] reduction in recurrence (secondary prevention). For NTD primary prevention through folic acid supplementation, combining one RCT with three cohort studies which adjusted for confounding, suggested a reduction of 62% (95% CI: 49-71). A meta-analysis of eight population-based observational studies examining folic acid food fortification gave an estimated reduction in NTD incidence of 46% (95% CI: 37-54). In low-income countries an estimated 29% of neonatal deaths related to visible congenital abnormalities are attributed to NTD. Assuming that fortification reduces the incidence of NTDs, but does not alter severity or case-fatality rates, we estimate that folic acid fortification could prevent 13% of neonatal deaths currently attributed to congenital abnormalities in low-income countries. DISCUSSION: Scale-up of periconceptional supplementation programmes is challenging. Our final effect estimate was therefore based on folic acid fortification data. If folic acid food fortification achieved 100% population coverage the number of NTDs in low-income countries could be approximately halved. CONCLUSION: The evidence supports both folic acid supplementation and fortification as effective in reducing neonatal mortality from NTDs.

Safety and immunogenicity of the malaria vaccine candidate MSP3 long synthetic peptide in 12-24 months-old Burkinabe children.

BACKGROUND: A Phase Ia trial in European volunteers of the candidate vaccine merozoite surface protein 3 (MSP3), a Plasmodium falciparum blood stage membrane, showed that it induces biologically active antibodies able to achieve parasite killing in vitro, while a phase Ib trial in semi-immune adult volunteers in Burkina Faso confirmed that the vaccine was safe. The aim of this study was to assess the safety and immunogenicity of this vaccine candidate in children aged 12-24 months living in malaria endemic area of Burkina Faso. METHODS: The study was a double-blind, randomized, controlled, dose escalation phase Ib trial, designed to assess the safety, reactogenicity and immunogenicity of three doses of either 15 or 30 microg of MSP3-LSP adsorbed on aluminum hydroxide in 45 children 12 to 24 months of age randomized into three equal groups. Each group received 3 vaccine doses (on days 0, 28 and 56) of either 15 microg of MSP3-LSP, 30 microg of MSP3-LSP or of the Engerix B hepatitis B vaccine. Children were visited at home daily for the 6 days following each vaccination to solicit symptoms which might be related to vaccination. Serious adverse events occurring during the study period (1 year) were recorded. Antibody responses to MSP3-LSP were measured on days 0, 28, 56 and 84. RESULTS: All 45 enrolled children received three MSP3 vaccine doses. No serious adverse events were reported. Most of the adverse events reported were mild to moderate in severity. The only reported local symptoms with grade 3 severity were swelling and induration, with an apparently dose related response. All grade 3 adverse events resolved without any sequelae. Both MSP3 doses regimens were able to elicit high levels of anti-MSP3 specific IgG1 and IgG3 antibodies in the volunteers with very little or no increase in IgG2, IgG4 and IgM classes: i.e. vaccination induced predominantly the isotypes involved in the monocyte-dependent mechanism of P. falciparum parasite-killing. CONCLUSION: Our results support the promise of MSP3-LSP as a malaria vaccine candidate, both in terms of tolerability and of immunogenicity. Further assessment of the efficacy of this vaccine is recommended. TRIAL REGISTRATION: ClinicalTrials.gov NCT00452088.

Risk factors for sporadic Creutzfeldt-Jakob disease.

OBJECTIVE: Although surgical transmission of Creutzfeldt-Jakob disease (CJD) has been demonstrated, these iatrogenic cases account for only a small proportion of all CJD cases. The majority are sporadic CJD (sCJD) cases of unknown cause. This study investigated whether some cases classified as sCJD might have an unrecognized iatrogenic basis through surgical or other medical procedures METHODS: This study compared medical risk factors from 431 sCJD cases referred 1998 to 2006 with 454 population control subjects. Possible geographic and temporal links between neurological and gynecological operations in 857 sCJD cases referred from 1990 to 2006 were investigated RESULTS: A reported history of ever having undergone surgery was associated with increased risk for sCJD (odds ratio, 2.0; 95% confidence interval, 1.3-2.1; p = 0.003). Increased risk was not associated with surgical categories chosen a priori but was confined to the residual category "other surgery," in which the increase in risk appeared most marked for three subcategories: skin stitches, nose/throat operations, and removal of growths/cysts/moles. No convincing evidence was found of links (same hospital, within 2 years) between cases undergoing neurosurgery or gynecological surgery INTERPRETATION: It is unlikely that a high proportion of UK sCJD cases are the result of transmission during surgery, but we cannot exclude the possibility that such transmission occurs occasionally. A study based on accurate surgical histories obtained from medical records is required to determine whether the increased risk associated with reported surgical history reflects a causal association or recall bias.

Effect of beta radiation on success of glaucoma drainage surgery in South Africa: randomised controlled trial.

OBJECTIVE: To evaluate whether beta radiation may offer a practical method of improving surgical success for glaucoma drainage surgery in South Africa. DESIGN: Double blind, randomised controlled trial. SETTING: Three public hospitals in South Africa. PARTICIPANTS: 450 black Africans with primary glaucoma. INTERVENTIONS: Trabeculectomy with 1000 cGy beta radiation or standard trabeculectomy without beta radiation (placebo). MAIN OUTCOME MEASURES: Primary outcome measure was surgical failure within 12 months (intraocular pressure > 21 mm Hg while receiving no treatment for ocular hypotension). Secondary outcomes were visual acuity, surgical reintervention for cataract, and intraoperative and postoperative complications. RESULTS: 320 people were recruited. beta radiation was given to 164; 20 (6%) were not seen again after surgery. One year after surgery the estimated risk of surgical failure was 30% (95% confidence interval 22% to 38%) in the placebo arm compared with 5% (2% to 10%) in the radiation arm. The radiation group experienced a higher incidence of operable cataract (18 participants) than the placebo group (five participants; P = 0.01). At two years the estimated risks with placebo and beta radiation were, respectively, 2.8% (0.9% to 8.3%) and 16.7% (10.0% to 27.3%). CONCLUSION: beta radiation substantially reduced the risk of surgical failure after glaucoma surgery. Some evidence was, however, found of an increased risk for cataract surgery (a known complication of trabeculectomy) in the beta radiation arm during the two years after surgery. TRIAL REGISTRATION: ISRCTN62430622 [controlled-trials.com].

Neonatal measles immunity in rural Kenya: the influence of HIV and placental malaria infections on placental transfer of antibodies and levels of antibody in maternal and cord serum samples.

INTRODUCTION: Young infants are protected from measles infection by maternal measles antibodies. The level of these antibodies at birth depends on the level of antibodies in the mother and the extent of placental transfer. We investigated predictors of levels of measles antibodies in newborns in rural Kenya. METHODS: A total of 747 paired maternal-cord serum samples (91 from human immunodeficiency virus [HIV]-infected and 656 from HIV-uninfected mothers) were tested for measles immunoglobulin G antibodies. Placental malaria infection was determined by biopsy. Data on pregnancy history, gestational age, and anthropometric and socioeconomic status were collected. RESULTS: Infants born to HIV-infected mothers were more likely (odds ratio, 4.6 [95% confidence interval {CI}, 2.2-9.7]) to be seronegative and had 35.1% (95% CI, 9.8%-53.2%) lower levels of measles antibodies than did those born to HIV-uninfected mothers. Preterm delivery, early maternal age, and ethnic group were also associated with reduced levels of measles antibodies. There was little evidence that placental malaria infection was associated with levels of measles antibodies in newborns. CONCLUSION: Our results suggest that maternal HIV infection may reduce levels of measles antibodies in newborns. Low levels of measles antibodies at birth render children susceptible to measles infection at an early age. This is of concern in sub-Saharan African countries, where not only is the prevalence of HIV high, but measles is the cause of much morbidity and mortality.

Analysis of the geographical distribution of sporadic Creutzfeldt-Jakob disease in France between 1992 and 1998.

BACKGROUND: Creutzfeldt-Jakob disease (CJD) is a rare fatal dementia caused by a transmissible agent. However, the mechanism leading to the disease is unknown in the majority of cases. The presence of geographically clustered cases might indicate a common environmental exposure to the transmissible agent, or case-to-case transmission of the agent. This study sought evidence of clustering of cases of sporadic CJD in France. METHODS: A total of 402 individuals who died from definite or probable sporadic CJD in France between 1992 and 1998 were analysed. The geographical distribution of cases was analysed using three different clustering methods. An analysis of the distribution of the distances between pairs was performed to look for evidence of clustering. Then, two methods of cluster detection were used to identify the locations of clusters. RESULTS: Each of our analyses found some evidence of clustering, though the extent of that clustering differed between approaches. The strongest evidence, statistically, related to three cases living in a small rural area in South-West France (P = 0.001). Two of the three cases lived in the same area throughout life. They had also both undergone surgery on several occasions. Little information is available on the third case. CONCLUSION: Some sporadic CJD cases in France may be aetiologically linked. There was strong evidence that three cases in South-West France formed a cluster but the precise mechanism underlying this cluster of cases remains unclear. The potentially long incubation period of the disease makes the identification of links between such cases difficult.