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1.  Prevalence of community-acquired bacteraemia in Guinea-Bissau: an observational study 
BMC Infectious Diseases  2014;14(1):3859.
Background
The burden of bloodstream infections is insufficiently studied in children in Africa and many healthcare facilities lack the capacity to identify invasive disease. Often studies have been limited to febrile patients or patients admitted to hospital.
Methods
Blood cultures and malaria diagnostics was performed on 372 consecutive children presenting with tachycardia and/or fever to a referral paediatric emergency department in Bissau, Guinea-Bissau. Bacterial species detection, antimicrobial susceptibility testing and molecular typing were performed. The capacity of clinical parameters to identify bacteraemia was evaluated.
Results
The prevalence of bloodstream infection was 12% (46/372) and in 46% (21/46) of the infections the child was non-febrile at presentation to the hospital. The predictive value for bacteraemia was poor for all assessed clinical parameters. Staphylococcus aureus accounted for 54% (26/48) of the isolates followed by non-typhoidal Salmonella, 10% (5/48), Streptococcus pneumoniae, 8% (4/48), and Salmonella Typhi, 6% (3/48). Among S. aureus there was a large diversity of spa types and 38% produced Pantone-Valentine leukocidin. Antibiotic resistance was low, however two out of three Klebsiella pneumoniae isolates produced extended-spectrum beta-lactamases. Malaria was laboratory confirmed in only 5% of the children but 64% (237/372) received a clinical malaria diagnosis.
Conclusions
Bacteraemia was common irrespective of the presence of fever among children presenting to the hospital. The high prevalence of Staphylococcus aureus may be due to contamination. There is an imminent need to improve microbiological diagnostic facilities and to identify algorithms that can identify children at risk of bloodstream infections in Africa.
doi:10.1186/s12879-014-0715-9
PMCID: PMC4297428  PMID: 25526763
Bacteraemia; Sub-Saharan Africa; Guinea-Bissau; Antibiotic resistance; Malaria; Paediatrics; Molecular epidemiology
2.  Plasmodium falciparum infection rates for some Anopheles spp. from Guinea-Bissau, West Africa 
F1000Research  2014;3:243.
Presence of Plasmodium falciparum circumsporozoite protein (CSP) was detected by enzyme linked immunosorbent assay (ELISA) in a sample of Anopheles gambiae s.s., A. melas and A. pharoensis collected in Guinea-Bissau during October and November 2009. The percentage of P. falciparum infected samples (10.2% overall; confidence interval (CI): 7.45-13.6%) was comparable to earlier studies from other sites in Guinea-Bissau (9.6-12.4%). The majority of the specimens collected were identified as A. gambiae which had an individual infection rate of 12.6 % (CI: 8.88-17.6) across collection sites. A small number of specimens of A. coluzzii, A. coluzzii x A. gambiae hybrids, A. melas and A. pharoensis were collected and had infection rates of 4.3% (CI:0.98-12.4), 4.1% (CI:0.35-14.5), 11.1% (CI:1.86-34.1) and 33.3% (CI:9.25-70.4) respectively. Despite being present in low numbers in indoor collections, the exophilic feeding behaviors of A. melas (N=18) and A. pharoensis (N=6) and high infection rates observed in this survey suggest falciparum-malaria transmission potential outside of the protection of bed nets.
doi:10.12688/f1000research.5485.2
PMCID: PMC4215749  PMID: 25383188
3.  Plasmodium falciparum infection rates for some Anopheles spp. from Guinea-Bissau, West Africa 
F1000Research  2014;3:243.
Presence of Plasmodium falciparum circumsporozoite protein (CSP) was detected by enzyme linked immunosorbent assay (ELISA) in a sample of Anopheles gambiae s.s., A. melas and A. pharoensis collected in Guinea-Bissau during October and November 2009. The percentage of P. falciparum infected samples (10.2% overall) was comparable to earlier studies from other sites in Guinea-Bissau (9.6-12.4%). The majority of the specimens collected were identified as A. gambiae which had an individual infection rate of 12.6 % across collection sites. A small number of specimens of A. coluzzii, A. coluzzii x A. gambiae hybrids, A. melas and A. pharoensis were collected and had infection rates of 4.3%, 4.1%, 11.1% and 33.3% respectively. Despite being present in low numbers in indoor collections, the exophilic feeding behaviors of A. melas (N=18) and A. pharoensis (N=6) and high infection rates observed in this survey suggest falciparum-malaria transmission potential outside of the protection of bed nets.
doi:10.12688/f1000research.5485.1
PMCID: PMC4215749  PMID: 25383188
4.  BCG coverage and barriers to BCG vaccination in Guinea-Bissau: an observational study 
BMC Public Health  2014;14(1):1037.
Background
BCG vaccination is recommended at birth in low-income countries, but vaccination is often delayed. Often 20-dose vials of BCG are not opened unless at least ten children are present for vaccination (“restricted vial-opening policy”). BCG coverage is usually reported as 12-month coverage, not disclosing the delay in vaccination. Several studies show that BCG at birth lowers neonatal mortality. We assessed BCG coverage at different ages and explored reasons for delay in BCG vaccination in rural Guinea-Bissau.
Methods
Bandim Health Project (BHP) runs a health and demographic surveillance system covering women and their children in 182 randomly selected village clusters in rural Guinea-Bissau. BCG coverage was assessed for children born in 2010, when the restricted vial-opening policy was universally implemented, and in 2012–2013, where BHP provided BCG to all children at monthly visits in selected intervention regions. Factors associated with delayed BCG vaccination were evaluated using logistic regression models. Coverage between intervention and control regions were evaluated in log-binomial regression models providing prevalence ratios.
Results
Among 3951 children born in 2010, vaccination status was assessed for 84%. BCG coverage by 1 week of age was 11%, 38% by 1 month, and 92% by 12 months. If BCG had been given at first contact with the health system, 1-week coverage would have been 35% and 1-month coverage 54%. When monthly visits were introduced in intervention regions, 1-month coverage was higher in intervention regions (88%) than in control regions (51%), the prevalence ratio being 1.74 (1.53-2.00). Several factors, including socioeconomic factors, were associated with delayed BCG vaccination in the 2010-birth cohort. When BCG was available at monthly visits these factors were no longer associated with delayed BCG vaccination, only region of residence was associated with delayed BCG vaccination.
Conclusion
BCG coverage during the first months of life is low in Guinea-Bissau. Providing BCG at monthly vaccination visits removes the risk factors associated with delayed BCG vaccination.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2458-14-1037) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2458-14-1037
PMCID: PMC4195857  PMID: 25282475
BCG; Coverage; Timeliness of vaccines; Implementation of the vaccination programme
5.  Interaction between neonatal vitamin A supplementation and timing of measles vaccination: A retrospective analysis of three randomized trials from Guinea-Bissau☆ 
Vaccine  2014;32(42):5468-5474.
Highlights
•Early measles vaccine and neonatal vitamin A supplementation may become policy in low-income countries.•Vaccines and vitamin A may interact.•In children who received early measles vaccine, neonatal vitamin A was associated with 5-fold higher overall mortality.•Implementation of both policies at the same time may lead to increased child mortality.•Co-packaging of child health interventions should be investigated for the effect on overall mortality.
Background
In Guinea-Bissau we conducted three trials of neonatal vitamin A supplementation (NVAS) from 2002 to 2008. None of the trials found a beneficial effect on mortality. From 2003 to 2007, an early measles vaccine (MV) trial was ongoing, randomizing children 1:2 to early MV at 4.5 months or no early MV, in addition to the usual MV at 9 months. We have previously found interactions between vitamin A and vaccines.
Objective
We investigated whether there were interactions between NVAS and early MV.
Design
We compared the mortality of NVAS and placebo recipients: first, from 4.5 to 8 months for children randomized to early MV or no early MV; and second, from 9 to 17 months in children who had received two MV or one MV. Mortality rates (MR) were compared in Cox models producing mortality rate ratios (MRR).
Results
A total of 5141 children were randomized to NVAS (N = 3015) or placebo (N = 2126) and were later randomized to early MV (N = 1700) or no early MV (N = 3441). Between 4.5 and 8 months, NVAS compared with placebo was associated with higher mortality in early MV recipients (MR = 30 versus MR = 0, p = 0.01), but not in children who did not receive early MV (p for interaction between NVAS and early MV = 0.03). From 9 to 17 months NVAS was not associated with mortality. Overall, from 4.5 to 17 months NVAS was associated with increased mortality in early MV recipients (Mortality rate ratio = 5.39 (95% confidence interval: 1.62, 17.99)).
Conclusions
These observations indicate that NVAS may interact with vaccines given several months later. This may have implications for the planning of future child intervention programs.
doi:10.1016/j.vaccine.2014.07.090
PMCID: PMC4180001  PMID: 25131735
Measles vaccine; Vitamin A; Children; Mortality; Low-income countries
6.  Malaria Transmission in Bissau, Guinea-Bissau between 1995 and 2012: Malaria Resurgence Did Not Negatively Affect Mortality 
PLoS ONE  2014;9(7):e101167.
Introduction
As Plasmodium falciparum prevalence decreases in many parts of Sub-Saharan Africa, so does immunity resulting in larger at risk populations and increased risk of malaria resurgence. In Bissau, malaria prevalence decreased from ∼50% to 3% between 1995 and 2003. The epidemiological characteristics of P. falciparum malaria within Bandim health and demographic surveillance site (population ∼100000) between 1995 and 2012 are described.
Methods and Findings
The population was determined by census. 3603 children aged <15 years that were enrolled in clinical trials at the Bandim health centre (1995–2012) were considered incident cases. The mean annual malaria incidence per thousand children in 1995–1997, 1999–2003, 2007, 2011, 2012 were as follows; age <5 years 22→29→4→9→3, age 5–9 years 15→28→4→33→12, age 10–14 years 9→15→1→45→19. There were 4 campaigns (2003–2010) to increase use of insecticide treated bed nets (ITN) amongst children <5 years. An efficacious high-dose chloroquine treatment regime was routinely used until artemisinin based combination therapy (ACT) was introduced in 2008. Long lasting insecticide treated bed nets (LLIN) were distributed in 2011. By 2012 there was 1 net per 2 people and 97% usage. All-cause mortality decreased from post-war peaks in 1999 until 2012 in all age groups and was not negatively affected by malaria resurgence.
Conclusion
The cause of decreasing malaria incidence (1995–2007) was probably multifactorial and coincident with the use of an efficacious high-dose chloroquine treatment regime. Decreasing malaria prevalence created a susceptible group of older children in which malaria resurged, highlighting the need to include all age groups in malaria interventions. ACT did not hinder malaria resurgence. Mass distribution of LLINs probably curtailed malaria epidemics. All-cause mortality was not negatively affected by malaria resurgence.
doi:10.1371/journal.pone.0101167
PMCID: PMC4077730  PMID: 24984039
7.  Measles Vaccination in the Presence or Absence of Maternal Measles Antibody: Impact on Child Survival 
In 2-dose trials, early measles vaccination at 4–6 months in presence of maternal measles antibody was associated with significantly better survival to age 5 years than vaccination in absence of measles antibody. Confounding factors did not explain the effect.
Background. Measles vaccine (MV) has a greater effect on child survival when administered in early infancy, when maternal antibody may still be present.
Methods. To test whether MV has a greater effect on overall survival if given in the presence of maternal measles antibody, we reanalyzed data from 2 previously published randomized trials of a 2-dose schedule with MV given at 4–6 months and at 9 months of age. In both trials antibody levels had been measured before early measles vaccination.
Results. In trial I (1993–1995), the mortality rate was 0.0 per 1000 person-years among children vaccinated with MV in the presence of maternal antibody and 32.3 per 1000 person-years without maternal antibody (mortality rate ratio [MRR], 0.0; 95% confidence interval [CI], 0–.52). In trial II (2003–2007), the mortality rate was 4.2 per 1000 person-years among children vaccinated in presence of maternal measles antibody and 14.5 per 1000 person-years without measles antibody (MRR, 0.29; 95% CI, .09–.91). Possible confounding factors did not explain the difference. In a combined analysis, children who had measles antibody detected when they received their first dose of MV at 4–6 months of age had lower mortality than children with no maternal antibody, the MRR being 0.22 (95% CI, .07–.64) between 4–6 months and 5 years.
Conclusions. Child mortality in low-income countries may be reduced by vaccinating against measles in the presence of maternal antibody, using a 2-dose schedule with the first dose at 4–6 months (earlier than currently recommended) and a booster dose at 9–12 months of age.
Clinical Trials Registration. NCT00168558.
doi:10.1093/cid/ciu354
PMCID: PMC4111916  PMID: 24829213
maternal measles antibodies; age of measles vaccination; nonspecific beneficial effects of measles vaccine; 2-dose measles vaccination
8.  Introducing the concept of a new pre-referral treatment for severely ill febrile children at community level: a sociological approach in Guinea-Bissau 
Malaria Journal  2014;13:50.
Background
Innovative strategies are needed to tackle childhood mortality in the rural tropics. Artesunate suppositories were developed to bring emergency treatment closer to severely ill children with malaria in rural areas where injectable treatment is not possible for several hours. Adding an antibacterial rectal drug would extend this strategy to treat non-malarial febrile illness as well. The objective of these studies was to assess acceptability of such a new pre-referral strategy by healthcare providers and likely uptake by the population.
Methods
Two qualitative studies were conducted between May and July 2009. Study 1 investigated the acceptability of introducing a combined antimalarial-antibacterial suppository by interviewing 27 representatives of the three administrative levels (central government, regional, local) of the health sector; Study 2 investigated treatment-seeking behaviour and acceptability of this intervention at community level by interviewing 74 mothers in 2 villages.
Results and Conclusions
Up to 92% of health representatives were in favour of introducing a new pre-referral strategy to tackle both malaria and non-malaria related severe illnesses in Guinea-Bissau, provided it was endorsed by international health authorities. The main obstacles to implementation were the very limited human and financial resources. In the two villages surveyed, 44% of the mothers associated severe illness with fever only, or fever plus one additional symptom. Mothers’ judgement of severity and ensuing decisions were not specific for serious illness, indicating that initial training to recognize signs of severe disease and treatment availability for non-severe, fever-associated symptoms will be required to prevent overuse of a new intervention designed as a pre-referral treatment for severely ill children. Level C health centres were the first resort in both villages (50% and 87% of respondents respectively). This information is encouraging for the implementation of a pre-referral treatment.
doi:10.1186/1475-2875-13-50
PMCID: PMC3922426  PMID: 24502695
Severe febrile illnesses; Malaria; Artesunate; Antibiotics; Rectal administration; Pre-referral treatment; Rural areas
9.  Chloroquine Is Grossly Under Dosed in Young Children with Malaria: Implications for Drug Resistance 
PLoS ONE  2014;9(1):e86801.
Background
Plasmodium falciparum malaria is treated with 25 mg/kg of chloroquine (CQ) irrespective of age. Theoretically, CQ should be dosed according to body surface area (BSA). The effect of dosing CQ according to BSA has not been determined but doubling the dose per kg doubled the efficacy of CQ in children aged <15 years infected with P. falciparum carrying CQ resistance causing genes typical for Africa. The study aim was to determine the effect of age on CQ concentrations.
Methods and Findings
Day 7 whole blood CQ concentrations were determined in 150 and 302 children treated with 25 and 50 mg/kg, respectively, in previously conducted clinical trials. CQ concentrations normalised for the dose taken in mg/kg of CQ decreased with decreasing age (p<0.001). CQ concentrations normalised for dose taken in mg/m2 were unaffected by age. The median CQ concentration in children aged <2 years taking 50 mg/kg and in children aged 10–14 years taking 25 mg/kg were 825 (95% confidence interval [CI] 662–988) and 758 (95% CI 640–876) nmol/l, respectively (p = 0.67). The median CQ concentration in children aged 10–14 taking 50 mg/kg and children aged 0–2 taking 25 mg/kg were 1521 and 549 nmol/l. Adverse events were not age/concentration dependent.
Conclusions
CQ is under-dosed in children and should ideally be dosed according to BSA. Children aged <2 years need approximately double the dose per kg to attain CQ concentrations found in children aged 10–14 years. Clinical trials assessing the efficacy of CQ in Africa are typically performed in children aged <5 years. Thus the efficacy of CQ is typically assessed in children in whom CQ is under dosed. Approximately 3 fold higher drug concentrations can probably be safely given to the youngest children. As CQ resistance is concentration dependent an alternative dosing of CQ may overcome resistance in Africa.
doi:10.1371/journal.pone.0086801
PMCID: PMC3900653  PMID: 24466245
10.  A Randomized Trial of a Standard Dose of Edmonston-Zagreb Measles Vaccine Given at 4.5 Months of Age: Effect on Total Hospital Admissions 
The Journal of Infectious Diseases  2014;209(11):1731-1738.
Observational studies and trials from low-income countries indicate that measles vaccine has beneficial nonspecific effects, protecting against non–measles-related mortality. It is not known whether measles vaccine protects against hospital admissions. Between 2003 and 2007, 6417 children who had received the third dose of diphtheria, tetanus, and pertussis vaccine were randomly assigned to receive measles vaccine at 4.5 months or no measles vaccine; all children were offered measles vaccine at 9 months of age. Using hospital admission data from the national pediatric ward in Bissau, Guinea-Bissau, we compared admission rates between enrollment and the 9-month vaccination in Cox models, providing admission hazard rate ratios (HRRs) for measles vaccine versus no measles vaccine. All analyses were conducted stratified by sex and reception of neonatal vitamin A supplementation (NVAS). Before enrollment the 2 groups had similar admission rates. Following enrollment, the measles vaccine group had an admission HRR of 0.70 (95% confidence interval [CI], .52–.95), with a ratio of 0.53 (95% CI, .32–.86) for girls and 0.86 (95% CI, .58–1.26) for boys. For children who had not received NVAS, the admission HRR was 0.53 (95% CI, .34–.84), with an effect of 0.30 (95% CI, .13–.70) for girls and 0.73 (95% CI, .42–1.28) for boys (P = .08, interaction test). The reduction in admissions was separately significant for measles infection (admission HRR, 0 [95% CI, 0–.24]) and respiratory infections (admission HRR, 0.37 [95% CI, .16–.89]). Early measles vaccine may have major benefits for infant morbidity patterns and healthcare costs.
Clinical trials registration
NCT00168558.
doi:10.1093/infdis/jit804
PMCID: PMC4017359  PMID: 24436454
Edmonston-Zagreb; hospital admissions; measles infection; measles vaccination; morbidity reduction; nonspecific effects of vaccine
11.  Trends and determinants of mortality in women of reproductive age in rural Guinea-Bissau, West Africa – a cohort study 
BMC Women's Health  2013;13:48.
Background
There are few studies reporting mortality of women of reproductive age (WRA) in developing countries. The trend and patterns of their mortality may be important for documenting the health status of the population in general.
Methods
We used a prospective open cohort of women aged 12 to 49 years living in the Bandim Health Project’s rural Health and Demographic Surveillance System (HDSS) in 5 regions of Guinea-Bissau from 1996 to 2007. Information on in- and out-migration and deaths were collected through the HDSS routine procedures. We assessed the trends in mortality and the associated determinants using Cox regression models.
Results
We followed 27,185 WRA for 141,693 person-years-at-risk (PYO) among whom 9,093 moved out and 1,006 died. Overall standardized mortality rate was 759 per 100,000 PYO. WRA mortality did not decline, but three periods could be distinguished: a stable mortality between 1996–2000 followed by 14% increase in mortality [Hazard rate ratio (HRR) = 1.14; 95% confidence interval (CI): 0.98-1.32; p = 0.08] between 2001–2003, and then in the last period from 2004–2007 a 25% decline (HRR = 0.75; 95% CI: 0.64-0.87; p < 0.001) in relation to the first period. Compared with the years 1990–1996 mortality increased in the first two periods until 2003; only in the last period did mortality reach the same level as in 1990–1996 (HRR = 0.96; 95% CI: 0.82-1.13; p = 0.62). The level of mortality differed between regions. In the adjusted analysis the eastern regions Bafata (HRR = 1.79; 95% CI: 1.38-2.32; p < 0.001) and Gabu (HRR = 1.70; 95% CI: 1.28-2.26; p < 0.001) had significantly higher mortality, but the hazard rate did not differ by ethnic group. As expected the rate increased with increasing age.
Conclusions
Over the twelve-year period mortality of WRA did not decline. A stable mortality in the beginning was followed by an increase and then a return to the previous levels. Further monitoring of mortality is needed to identify the risk factors for the striking regional differences. Advantage should be taken of the HDSS to monitor progress towards the MDGs and beyond.
doi:10.1186/1472-6874-13-48
PMCID: PMC4235026  PMID: 24304945
Women of reproductive age; Mortality; West Africa
12.  Characteristics of HIV-2 and HIV-1/HIV-2 Dually Seropositive Adults in West Africa Presenting for Care and Antiretroviral Therapy: The IeDEA-West Africa HIV-2 Cohort Study 
Ekouevi, Didier K. | Balestre, Eric | Coffie, Patrick A. | Minta, Daouda | Messou, Eugene | Sawadogo, Adrien | Minga, Albert | Sow, Papa Salif | Bissagnene, Emmanuel | Eholie, Serge P. | Gottlieb, Geoffrey S. | Dabis, François | Zannou, Djimon Marcel | Ahouada, Carin | Akakpo, Jocelyn | Ahomadegbé, Christelle | Bashi, Jules | Gougounon-Houéto, Alice | Azon-Kouanou, Angèle | Houngbé, Fabien | Koumakpaï, Sikiratou | Alihonou, Florence | d’Almeida, Marcelline | Hodonou, Irvine | Hounhoui, Ghislaine | Sagbo, Gracien | Tossa-Bagnan, Leïla | Adjide, Herman | Drabo, Joseph | Bognounou, René | Dienderé, Arnaud | Traore, Eliezer | Zoungrana, Lassane | Zerbo, Béatrice | Sawadogo, Adrien Bruno | Zoungrana, Jacques | Héma, Arsène | Soré, Ibrahim | Bado, Guillaume | Tapsoba, Achille | Yé, Diarra | Kouéta, Fla | Ouedraogo, Sylvie | Ouédraogo, Rasmata | Hiembo, William | Gansonré, Mady | Messou, Eugène | Gnokoro, Joachim Charles | Koné, Mamadou | Kouakou, Guillaume Martial | Bosse, Clarisse Amani | Brou, Kouakou | Assi, Achi Isidore | Chenal, Henri | Hawerlander, Denise | Soppi, Franck | Minga, Albert | Abo, Yao | Bomisso, Germain | Eholié, Serge Paul | Amego, Mensah Deborah Noelly | Andavi, Viviane | Diallo, Zelica | Ello, Frédéric | Tanon, Aristophane Koffi | Koule, Serge Olivier | Anzan, Koffi Charles | Guehi, Calixte | Aka, Edmond Addi | Issouf, Koffi Ladji | Kouakou, Jean-Claude | N’Gbeche, Marie-Sylvie | Touré, Pety | Avit-Edi, Divine | Kouakou, Kouadio | Moh, Magloire | Yao, Valérie Andoblé | Folquet, Madeleine Amorissani | Dainguy, Marie-Evelyne | Kouakou, Cyrille | Méa-Assande, Véronique Tanoh | Oka-Berete, Gladys | Zobo, Nathalie | Acquah, Patrick | Kokora, Marie-Berthe | Eboua, Tanoh François | Timité-Konan, Marguerite | Ahoussou, Lucrèce Diecket | Assouan, Julie Kebé | Sami, Mabéa Flora | Kouadio, Clémence | Renner, Lorna | Goka, Bamenla | Welbeck, Jennifer | Sackey, Adziri | Owiafe, Seth Ntiri | Wejse, Christian | Silva, Zacarias José Da | Paulo, Joao | Rodrigues, Amabelia | da Silva, David | Medina, Candida | Oliviera-Souto, Ines | Østergaard, Lars | Laursen, Alex | Sodemann, Morten | Aaby, Peter | Fomsgaard, Anders | Erikstrup, Christian | Eugen-Olsen, Jesper | Maïga, Moussa Y | Diakité, Fatoumata Fofana | Kalle, Abdoulaye | Katile, Drissa | Traore, Hamar Alassane | Minta, Daouda | Cissé, Tidiani | Dembelé, Mamadou | Doumbia, Mohammed | Fomba, Mahamadou | Kaya, Assétou Soukho | Traoré, Abdoulaye M | Traoré, Hamady | Toure, Amadou Abathina | Dicko, Fatoumata | Sylla, Mariam | Berthé, Alima | Traoré, Hadizatou Coulibaly | Koïta, Anta | Koné, Niaboula | N'Diaye, Clémentine | Coulibaly, Safiatou Touré | Traoré, Mamadou | Traoré, Naïchata | Charurat, Man | Ajayi, Samuel | Dapiap, Stephen | Otu,  | Igbinoba, Festus | Benson, Okwara | Adebamowo, Clément | James, Jesse | Obaseki,  | Osakede, Philip | Olasode, John | Sow, Papa Salif | Diop, Bernard | Manga, Noël Magloire | Tine, Judicael Malick | Signate Sy, Haby | Ba, Abou | Diagne, Aida | Dior, Hélène | Faye, Malick | Gueye, Ramatoulaye Diagne | Mbaye, Aminata Diack | Patassi, Akessiwe | Kotosso, Awèrou | Kariyare, Benjamin Goilibe | Gbadamassi, Gafarou | Komi, Agbo | Mensah-Zukong, Kankoé Edem | Pakpame, Pinuwe | Lawson-Evi, Annette Koko | Atakouma, Yawo | Takassi, Elom | Djeha, Améyo | Ephoévi-gah, Ayoko | Djibril, Sherifa El-Hadj | Dabis, François | Bissagnene, Emmanuel | Arrivé, Elise | Coffie, Patrick | Ekouevi, Didier | Jaquet, Antoine | Leroy, Valériane | Lewden, Charlotte | Sasco, Annie | Azani, Jean-Claude | Allou, Gérard | Balestre, Eric | Bohossou, Franck | Karcher, Sophie | Gonsan, Jules Mahan | Carrou, Jérôme Le | Lenaud, Séverin | Nchot, Célestin | Malateste, Karen | Yao, Amon Roseamonde | Siloué, Bertine | Clouet, Gwenaelle | Djetouan, Hugues | Doring, Alexandra | Kouakou, Adrienne | Rabourdin, Elodie | Rivenc, Jean | Anglaret, Xavier | Ba, Boubacar | Essanin, Jean Bosco | Ciaranello, Andrea | Datté, Sébastien | Desmonde, Sophie | Diby, Jean-Serge Elvis | Gottlieb, Geoffrey S. | Horo, Apollinaire Gninlgninrin | Kangah, Serge N'zoré | Malvy, Denis | Meless, David | Mounkaila-Harouna, Aida | Ndondoki, Camille | Shiboski, Caroline | Thiébaut, Rodolphe | PAC-CI,  | Abidjan,
PLoS ONE  2013;8(6):e66135.
Background
HIV-2 is endemic in West Africa. There is a lack of evidence-based guidelines on the diagnosis, management and antiretroviral therapy (ART) for HIV-2 or HIV-1/HIV-2 dual infections. Because of these issues, we designed a West African collaborative cohort for HIV-2 infection within the framework of the International epidemiological Databases to Evaluate AIDS (IeDEA).
Methods
We collected data on all HIV-2 and HIV-1/HIV-2 dually seropositive patients (both ARV-naive and starting ART) and followed-up in clinical centres in the IeDEA-WA network including a total of 13 clinics in five countries: Benin, Burkina-Faso Côte d’Ivoire, Mali, and Senegal, in the West Africa region.
Results
Data was merged for 1,754 patients (56% female), including 1,021 HIV-2 infected patients (551 on ART) and 733 dually seropositive for both HIV-1 and HIV 2 (463 on ART). At ART initiation, the median age of HIV-2 patients was 45.3 years, IQR: (38.3–51.7) and 42.4 years, IQR (37.0–47.3) for dually seropositive patients (p = 0.048). Overall, 16.7% of HIV-2 patients on ART had an advanced clinical stage (WHO IV or CDC-C). The median CD4 count at the ART initiation is 166 cells/mm3, IQR (83–247) among HIV-2 infected patients and 146 cells/mm3, IQR (55–249) among dually seropositive patients. Overall, in ART-treated patients, the CD4 count increased 126 cells/mm3 after 24 months on ART for HIV-2 patients and 169 cells/mm3 for dually seropositive patients. Of 551 HIV-2 patients on ART, 5.8% died and 10.2% were lost to follow-up during the median time on ART of 2.4 years, IQR (0.7–4.3).
Conclusions
This large multi-country study of HIV-2 and HIV-1/HIV-2 dual infection in West Africa suggests that routine clinical care is less than optimal and that management and treatment of HIV-2 could be further informed by ongoing studies and randomized clinical trials in this population.
doi:10.1371/journal.pone.0066135
PMCID: PMC3688850  PMID: 23824279
13.  An analysis of two island groups as potential sites for trials of transgenic mosquitoes for malaria control 
Evolutionary Applications  2013;6(4):706-720.
Considerable technological advances have been made towards the generation of genetically modified mosquitoes for vector control. In contrast, less progress has been made towards field evaluations of transformed mosquitoes which are critical for evaluating the success of, and hazards associated with, genetic modification. Oceanic islands have been highlighted as potentially the best locations for such trials. However, population genetic studies are necessary to verify isolation. Here, we used a panel of genetic markers to assess for evidence of genetic isolation of two oceanic island populations of the African malaria vector, Anopheles gambiae s.s. We found no evidence of isolation between the Bijagós archipelago and mainland Guinea-Bissau, despite separation by distances beyond the known dispersal capabilities of this taxon. Conversely, the Comoros Islands appear to be genetically isolated from the East African mainland, and thus represent a location worthy of further investigation for field trials. Based on assessments of gene flow within and between the Comoros islands, the island of Grande Comore was found to be genetically isolated from adjacent islands and also exhibited local population structure, indicating that it may be the most suitable site for trials with existing genetic modification technologies.
doi:10.1111/eva.12056
PMCID: PMC3684749  PMID: 23789035
Anopheles gambiae; Bijagós; Comoros; genetically modified mosquitoes; island population; isolation
14.  Breakdown in the Process of Incipient Speciation in Anopheles gambiae 
Genetics  2013;193(4):1221-1231.
Understanding genetic causes and effects of speciation in sympatric populations of sexually reproducing eukaryotes is challenging, controversial, and of practical importance for controlling rapidly evolving pests and pathogens. The major African malaria vector mosquito Anopheles gambiae sensu stricto (s.s.) is considered to contain two incipient species with strong reproductive isolation, hybrids between the M and S molecular forms being very rare. Following recent observations of higher proportions of hybrid forms at a few sites in West Africa, we conducted new surveys of 12 sites in four contiguous countries (The Gambia, Senegal, Guinea-Bissau, and Republic of Guinea). Identification and genotyping of 3499 A. gambiae s.s. revealed high frequencies of M/S hybrid forms at each site, ranging from 5 to 42%, and a large spectrum of inbreeding coefficient values from 0.11 to 0.76, spanning most of the range expected between the alternative extremes of panmixia and assortative mating. Year-round sampling over 2 years at one of the sites in The Gambia showed that M/S hybrid forms had similar relative frequencies throughout periods of marked seasonal variation in mosquito breeding and abundance. Genome-wide scans with an Affymetrix high-density single-nucleotide polymorphism (SNP) microarray enabled replicate comparisons of pools of different molecular forms, in three separate populations. These showed strong differentiation between M and S forms only in the pericentromeric region of the X chromosome that contains the molecular form-specific marker locus, with only a few other loci showing minor differences. In the X chromosome, the M/S hybrid forms were more differentiated from M than from S forms, supporting a hypothesis of asymmetric introgression and backcrossing.
doi:10.1534/genetics.112.148718
PMCID: PMC3606099  PMID: 23335339
Genomics; speciation; hybridization; introgression; mosquito
15.  Determinants of vitamin a deficiency in children between 6 months and 2 years of age in Guinea-Bissau 
BMC Public Health  2013;13:172.
Background
The World Health Organization (WHO) classifies Guinea-Bissau as having severe vitamin A deficiency (VAD). To date, no national survey has been conducted. We assessed vitamin A status among children in rural Guinea-Bissau to assess status and identify risk factors for VAD.
Methods
In a vitamin A supplementation trial in rural Guinea-Bissau, children aged 6 months to 2 years who were missing one or more vaccines were enrolled, vaccinated and randomized to vitamin A or placebo. Provided consent, a dried blood spot (DBS) sample was obtained from a subgroup of participants prior to supplementation. Vitamin A status and current infection was assessed by an ELISA measuring retinol-binding protein (RBP) and C-reactive protein (CRP). VAD was defined as RBP concentrations equivalent to plasma retinol <0.7 μmol/L; infection was defined as CRP >5 ml/L. In Poisson regression models providing prevalence ratios (PR), we investigated putative risk factors for VAD including sex, age, child factors, maternal factors, season (rainy: June-November; dry: December-May), geography, and use of health services.
Results
Based on DBS from 1102 children, the VAD prevalence was 65.7% (95% confidence interval 62.9-68.5), 11% higher than the WHO estimate of 54.7% (9.9-93.0). If children with infection were excluded, the prevalence was 60.2% (56.7-63.7). In the age group 9–11 months, there was no difference in prevalence of VAD among children who had received previous vaccines in a timely fashion and those who had not. Controlled for infection and other determinants of VAD, the prevalence of VAD was 1.64 (1.49-1.81) times higher in the rainy season compared to the dry, and varied up to 2-fold between ethnic groups and regions. Compared with having an inactivated vaccine as the most recent vaccine, having a live vaccine as the most recent vaccination was associated with lower prevalence of VAD (PR=0.84 (0.74-0.96)).
Conclusions
The prevalence of VAD was high in rural Guinea-Bissau. VAD varied significantly with season, ethnicity, region, and vaccination status.
Trial registration
Clinicaltrials.gov NCT00514891
doi:10.1186/1471-2458-13-172
PMCID: PMC3599523  PMID: 23442248
Vitamin A deficiency; Children; Guinea-Bissau; Risk factors; Retinol-binding protein
16.  Fecal Carriage of ESBL-Producing E. coli and K. pneumoniae in Children in Guinea-Bissau: A Hospital-Based Cross-Sectional Study 
PLoS ONE  2012;7(12):e51981.
Background
In recent years, the world has seen a surge in extended-spectrum β-lactamase (ESBL)-producing bacteria. However, data on the dissemination of ESBL-producing Enterobacteriaceae in the community from systematically enrolled study subjects in Africa remains limited. To determine the prevalence, phenotypic resistance patterns and genetic characteristics of ESBL-producing E. coli and K. pneumoniae in fecal carriage and to analyze associated risk factors in children attending a pediatric emergency department in Guinea-Bissau.
Methodology/Principal Findings
From June to September 2010, children <5 years of age with fever or tachycardia attending a pediatric emergency ward during the day was screened for ESBL carriage in feces. Socio-demographic and health seeking behavior data was collected. Antibiotic susceptibility was tested with VITEK2 and EUCAST disk diffusion method, molecular characterization of ESBL-encoding genes was performed with multiplex PCR and clonal relatedness was established by automated rep-PCR. Of 408 enrolled children 133 (32.6%) were ESBL carriers. In total, 83 E. coli and 91 K. pneumoniae ESBL-producing isolates were obtained. Nearly all isolates were multidrug-resistant. Co-resistance to ciprofloxacin, trimethoprim-sulfamethoxazole and aminoglycosides was common. Of the isolates, 38.5% were co-resistant to these classes plus extended-spectrum cephalosporins, which infers resistance to all easily available antibiotic agents for treatment of gram-negative sepsis in Guinea-Bissau. The predominant resistance-encoding gene subgroup was blaCTX-M-1 and epidemiologic typing showed that the bacterial ESBL population was highly diverse both for E. coli and K. pneumoniae. Bed sharing with another child <5 years of age was a risk factor for ESBL carriage, indicating crowding as a potential risk factor for transmission of ESBL-producing bacteria.
Conclusions/Significance
Prevalence of ESBL-producing bacteria in this population was high and clonally diverse. This is alarming considering the limited diagnostic and treatment possibilities in Guinea-Bissau and other resource-poor countries.
doi:10.1371/journal.pone.0051981
PMCID: PMC3527401  PMID: 23284838
17.  Asymmetric introgression between the M and S forms of the malaria vector, Anopheles gambiae, maintains divergence despite extensive hybridisation 
Molecular ecology  2011;20(23):4983-4994.
The suggestion that genetic divergence can arise and/or be maintained in the face of gene flow, has been contentious since first proposed. This controversy and a rarity of good examples has limited our understanding of this process. Partially reproductively isolated taxa have been highlighted as offering unique opportunities for identifying the mechanisms underlying divergence with gene flow. The African malaria vector, Anopheles gambiae s.s., is widely regarded as consisting of two sympatric forms, thought by many to represent incipient species, the M and S molecular forms. However, there has been much debate about the extent of reproductive isolation between M and S, with one view positing that divergence may have arisen and is being maintained in the presence of gene flow, and the other proposing a more advanced speciation process with little realised gene flow due to low hybrid fitness. These hypotheses have been difficult to address because hybrids are typically rare (<1%). Here, we assess samples from an area of high hybridisation and demonstrate that hybrids are fit and responsible for extensive introgression. Nonetheless, we show that strong divergent selection at a subset of loci combined with highly asymmetric introgression has enabled M and S to remain genetically differentiated despite extensive gene flow. We propose the extent of reproductive isolation between M and S varies across West Africa resulting in a “geographic mosaic of reproductive isolation”; a finding which adds further complexity to our understanding of divergence in this taxon and which has considerable implications for transgenic control strategies.
doi:10.1111/j.1365-294X.2011.05339.x
PMCID: PMC3222736  PMID: 22059383
Asymmetric introgression; sympatric speciation; malaria; ecological speciation; reproductive isolation
18.  Vaccination coverage and out-of-sequence vaccinations in rural Guinea-Bissau: an observational cohort study 
BMJ Open  2012;2(6):e001509.
Objective
The WHO aims for 90% coverage of the Expanded Program on Immunization (EPI), which in Guinea-Bissau included BCG vaccine at birth, three doses of diphtheria−tetanus−pertussis vaccine (DTP) and oral polio vaccine (OPV) at 6, 10 and 14 weeks and measles vaccine (MV) at 9 months when this study was conducted. The WHO assesses coverage by 12 months of age. The sequence of vaccines may have an effect on child mortality, but is not considered in official statistics or assessments of programme performance. We assessed vaccination coverage and frequency of out-of-sequence vaccinations by 12 and 24 months of age.
Design
Observational cohort study.
Setting and participants
The Bandim Health Project's (BHP) rural Health and Demographic Surveillance site covers 258 randomly selected villages in all regions of Guinea-Bissau. Villages are visited biannually and vaccination cards inspected to ascertain vaccination status. Between 2003 and 2009 vaccination status by 12 months of age was assessed for 5806 children aged 12–23 months; vaccination status by 24 months of age was assessed for 3792 children aged 24–35 months.
Outcome measures
Coverage of EPI vaccinations and frequency of out-of-sequence vaccinations.
Results
Half of 12-month-old children and 65% of 24-month-old children had completed all EPI vaccinations. Many children received vaccines out of sequence: by 12 months of age 54% of BCG-vaccinated children had received DTP with or before BCG and 28% of measles-vaccinated children had received DTP with or after MV. By 24 months of age the proportion of out-of-sequence vaccinations was 58% and 35%, respectively, for BCG and MV.
Conclusions
In rural Guinea-Bissau vaccination coverage by 12 months of age was low, but continued to increase beyond 12 months of age. More than half of all children received vaccinations out of sequence. This highlights the need to improve vaccination services.
doi:10.1136/bmjopen-2012-001509
PMCID: PMC3532986  PMID: 23166127
19.  Urban Cholera Transmission Hotspots and Their Implications for Reactive Vaccination: Evidence from Bissau City, Guinea Bissau 
Background
Use of cholera vaccines in response to epidemics (reactive vaccination) may provide an effective supplement to traditional control measures. In Haiti, reactive vaccination was considered but, until recently, rejected in part due to limited global supply of vaccine. Using Bissau City, Guinea-Bissau as a case study, we explore neighborhood-level transmission dynamics to understand if, with limited vaccine and likely delays, reactive vaccination can significantly change the course of a cholera epidemic.
Methods and Findings
We fit a spatially explicit meta-population model of cholera transmission within Bissau City to data from 7,551 suspected cholera cases from a 2008 epidemic. We estimated the effect reactive vaccination campaigns would have had on the epidemic under different levels of vaccine coverage and campaign start dates. We compared highly focused and diffuse strategies for distributing vaccine throughout the city. We found wide variation in the efficiency of cholera transmission both within and between areas of the city. “Hotspots”, where transmission was most efficient, appear to drive the epidemic. In particular one area, Bandim, was a necessary driver of the 2008 epidemic in Bissau City. If vaccine supply were limited but could have been distributed within the first 80 days of the epidemic, targeting vaccination at Bandim would have averted the most cases both within this area and throughout the city. Regardless of the distribution strategy used, timely distribution of vaccine in response to an ongoing cholera epidemic can prevent cases and save lives.
Conclusions
Reactive vaccination can be a useful tool for controlling cholera epidemics, especially in urban areas like Bissau City. Particular neighborhoods may be responsible for driving a city's cholera epidemic; timely and targeted reactive vaccination at such neighborhoods may be the most effective way to prevent cholera cases both within that neighborhood and throughout the city.
Author Summary
Cholera remains a major public health threat, causing 3–5 million cases and 100,000–120,000 deaths each year. In 2010, data on vaccine performance and the changing epidemiology of cholera prompted the WHO's Strategic Advisory Group to recommend that reactive vaccination be considered in specific areas. We built a spatially explicit stochastic model of cholera transmission and fit it to data from a 2008 epidemic in Bissau City, Guinea Bissau. Using this model we examined the potential effectiveness of reactive vaccination for controlling cholera transmission in Bissau City, comparing strategies for distributing limited vaccine. In simulations, early targeting of a single transmission “hotspot”, Bandim, was the most effective strategy, and led to the greatest reduction in cases both within Bandim and in areas where no vaccine was distributed. This finding has implications for cholera control in urban settings in general: public health officials will often know which areas of a city were hotspots of cholera transmission in the past or where conditions promote efficient transmission. When there is limited vaccine, our work suggests that targeting reactive vaccination at these areas will lead to the greatest reduction in cases both in these areas and elsewhere in the city.
doi:10.1371/journal.pntd.0001901
PMCID: PMC3493445  PMID: 23145204
20.  Testing the hypothesis that diphtheria–tetanus–pertussis vaccine has negative non-specific and sex-differential effects on child survival in high-mortality countries 
BMJ Open  2012;2(3):e000707.
Background
Measles vaccines (MV) have sex-differential effects on mortality not explained by protection against measles infection.
Objective
The authors examined whether whole-cell diphtheria–tetanus–pertussis (DTP) vaccine has sex-differential and non-specific effects.
Data sources and eligibility
Following previous reviews and a new search, the effect of DTP on mortality up to the next vaccination was assessed in all studies where DTP was given after BCG or DTP was given after MV and there was prospective follow-up after ascertainment of vaccination status.
Setting
High-mortality countries in Africa and Asia.
Methods
The initial observation of negative effect of DTP generated six hypotheses, which were examined in all available studies and two randomised trials reducing the time of exposure to DTP.
Main outcome
Consistency between studies.
Results
In the first study, DTP had negative effects on survival in contrast to the beneficial effects of BCG and MV. This pattern was repeated in the six other studies available. Second, the two ‘natural experiments’ found significantly higher mortality for DTP-vaccinated compared with DTP-unvaccinated children. Third, the female–male mortality ratio was increased after DTP in all nine studies; in contrast, the ratio was decreased after BCG and MV in all studies. Fourth, the increased female mortality associated with high-titre measles vaccine was found only among children who had received DTP after high-titre measles vaccine. Fifth, in six randomised trials of early MV, female but not male mortality was increased if DTP was likely to be given after MV. Sixth, the mortality rate declined markedly for girls but not for boys when DTP-vaccinated children received MV. The authors reduced exposure to DTP as most recent vaccination by administering a live vaccine (MV and BCG) shortly after DTP. Both trials reduced child mortality.
Conclusions
These observations are incompatible with DTP merely protecting against the targeted diseases. With herd immunity to whooping cough, DTP is associated with higher mortality for girls. Randomised studies of DTP are warranted to measure the true impact on survival.
Article summary
Article focus
MV has sex-differential non-specific effects for child survival. We examined whether DTP vaccine has negative effects for survival, particularly for girls.
We tested six hypotheses suggesting that DTP may have negative health consequences if found to be true.
Furthermore, we conducted two randomised trials reducing the time of exposure to DTP as most recent vaccination by providing a live vaccine shortly after DTP.
Key messages
All available studies suggest that the effect of DTP on child survival is opposite of the effects of BCG and MV. In the two natural experiments, DTP-vaccinated children had significantly higher mortality than DTP-unvaccinated children.
Among DTP-vaccinated children, girls have higher mortality than boys in all studies, whereas the tendency is the opposite for BCG- and measles-vaccinated children. DTP administered after MV in randomised trials of MV is associated with increased female but not male mortality.
Reducing time of exposure to DTP as the most recent vaccination with BCG or MV reduce child mortality.
Strengths and limitations of this study
Since the healthiest children are vaccinated first, one would expect DTP to be associated with a benefit. However, all the data suggest consistently that DTP is associated with a negative effect for girls.
A randomised trial of the effect of DTP on overall survival could not be conducted. There is a need to conduct such studies now.
doi:10.1136/bmjopen-2011-000707
PMCID: PMC3364456  PMID: 22619263
21.  The emergence and current performance of a health research system: lessons from Guinea Bissau 
Background
Little is known about how health research systems (HRS) in low-income countries emerge and evolve over time, and how this process relates to their performance. Understanding how HRSs emerge is important for the development of well functioning National Health Research Systems (NHRS). The aim of this study was to assess how the HRS in Guinea Bissau has emerged and evolved over time and how the present system functions.
Methods
We used a qualitative case-study methodology to explore the emergence and current performance of the HRS, using the NHRS framework. We reviewed documents and carried out 39 in-depth interviews, ranging from health research to policy and practice stakeholders. Using an iterative approach, we undertook a thematic analysis of the data.
Results
The research practices in Guinea Bissau led to the emergence of a HRS with both local and international links and strong dependencies on international partners and donors. The post-colonial, volatile and resource-dependent context, changes in donor policies, training of local researchers and nature of the research findings influenced how the HRS evolved. Research priorities have mostly been set by 'expatriate' researchers and focused on understanding and reducing child mortality. Research funding is almost exclusively provided by foreign donors and international agencies. The training of Guinean researchers started in the mid-nineties and has since reinforced the links with the health system, broadened the research agenda and enhanced local use of research. While some studies have made an important contribution to global health, the use of research within Guinea Bissau has been constrained by the weak and donor dependent health system, volatile government, top-down policies of international agencies, and the controversial nature of some of the research findings.
Conclusions
In Guinea Bissau a de facto 'system' of research has emerged through research practices and co-evolving national and international research and development dynamics. If the aim of research is to contribute to local decision making, it is essential to modulate the emerged system by setting national research priorities, aligning funding, building national research capacity and linking research to decision making processes. Donors and international agencies can contribute to this process by coordinating their efforts and aligning to national priorities.
doi:10.1186/1478-4505-10-5
PMCID: PMC3295730  PMID: 22321566
22.  Similar Efficacy and Tolerability of Double-Dose Chloroquine and Artemether-Lumefantrine for Treatment of Plasmodium falciparum Infection in Guinea-Bissau: A Randomized Trial 
The Journal of Infectious Diseases  2011;203(1):109-116.
Background. In 2008, Guinea-Bissau introduced artemether-lumefantrine for treatment of uncomplicated malaria. Previously, 3 times the standard dose of chloroquine, that was probably efficacious against Plasmodium falciparum with the resistance-associated chloroquine-resistance transporter (pfcrt) 76T allele, was routinely used. The present study compared the efficacy and tolerability of a double standard dose of chloroquine with the efficacy and tolerability of artemether-lumefantrine.
Methods. In a randomized open-label clinical trial, artemether-lumefantrine or chloroquine (50 mg/kg) were given as 6 divided doses over 3 days to children aged 6 months - 15 years who had uncomplicated P. falciparum monoinfection. Drug concentrations were measured on day 7. P. falciparum multidrug resistance gene N86Y and pfcrt K76T alleles were identified.
Results. The polymerase chain reaction–adjusted day 28 and 42 treatment efficacies were 162 (97%) of 168 and 155 (97%) of 161, respectively, for artemether-lumefantrine and 150 (95%) of 158 and 138 (94%) of 148, respectively, for chloroquine. When parasites with resistance-associated pfcrt 76T were treated, the day 28 efficacy of chloroquine was 87%. No severe drug-related adverse events were detected. Symptom resolution was similar with both treatments.
Conclusions. Both treatments achieved the World Health Organization–recommended efficacy for antimalarials that will be adopted as policy. High-dose chloroquine treatment regimes should be further evaluated with the aim of assessing chloroquine as a potential partner drug to artemisinin derivatives.
Clinical trials registration. NCT00426439
doi:10.1093/infdis/jiq001
PMCID: PMC3086436  PMID: 21148503
23.  The Effect of 50 000 IU Vitamin A with BCG Vaccine at Birth on Growth in the First Year of Life 
Journal of Tropical Medicine  2011;2011:570170.
Vitamin A supplements may interact with diphtheria-tetanus-pertussis (DTP) vaccine causing increased female mortality. In a randomised trial of neonatal vitamin A supplementation (VAS), we examined growth during the first year of life in 808 children, pursuing the hypothesis that a negative interaction between VAS and DTP in girls would be reflected in growth. Length and weight were measured at 6 weekly visits and WHO-growth-reference z-scores derived. Neonatal VAS had no effect on anthropometric measures at 12 months, but may interact sex differentially with routine vaccines. While BCG was the most recent vaccine, neonatal VAS benefitted growth (difference in weight-for-length z-score (dWFL: 0.31(95% CI: 0.03–0.59)). While DTP was the most recent vaccine, VAS tended to affect growth adversely in girls (dWFL = −0.21 (−0.48–0.06)). After measles vaccine (MV) there was no overall effect of neonatal VAS. The VAS effect differed significantly between the BCG and DTP windows (P = 0.03), and the difference was borderline significant between the DTP and MV windows for girls (P = 0.09).
doi:10.1155/2011/570170
PMCID: PMC3170791  PMID: 21912559
24.  The impact of different doses of vitamin A supplementation on male and female mortality. A randomised trial from Guinea-Bissau 
BMC Pediatrics  2011;11:77.
Background
Vitamin A supplementation (VAS) given to children between 6 months and 5 years of age is known to reduce mortality in low-income countries. We have previously observed that girls benefit more from a lower dose of VAS than the one recommended by WHO, the effect being strongest if diphtheria-tetanus-pertussis vaccine (DTP) was the most recent vaccination. We aimed to test these observations.
Methods
During national immunisations days in Guinea-Bissau, West Africa, combining oral polio vaccination and VAS, we randomised 8626 children between 6 months and 5 years of age to receive the dose of VAS recommended by WHO or half this dose. Mortality rate ratios (MRRs) were assessed after 6 and 12 month.
Results
The overall mortality rate among participants was lower than expected. There was no significant difference in mortality at 6 months and 12 months of follow up between the low dose VAS group and the recommended dose VAS group. The MRRs were 1.23 (0.60-2.54) after 6 months and 1.17 (0.73-1.87) after 12 months. This tendency was similar in boys and girls. The low dose was not associated with lower mortality in girls if the most recent vaccine was DTP (MRR = 0.60 (0.14-2.50) after 6 months).
Conclusion
Our sample size does not permit firm conclusions since mortality was lower than expected. We could not confirm a beneficial effect of a lower dose of VAS on mortality in girls.
Trial registration
The study was registered under clinicaltrials.gov, number NCT00168636
doi:10.1186/1471-2431-11-77
PMCID: PMC3175170  PMID: 21884606
25.  Vitamin A Supplementation at Birth Might Prime the Response to Subsequent Vitamin A Supplements in Girls. Three Year Follow-Up of a Randomized Trial 
PLoS ONE  2011;6(8):e23265.
Objectives
Within a randomised trial of neonatal vitamin A supplementation (VAS) in Guinea-Bissau, neonatal VAS did not affect overall infant mortality. We conducted a post-hoc analysis to test the hypothesis that neonatal VAS primes the response to subsequent vitamin A.
Methods
All trial children were offered VAS after follow-up ended at 1 year of age (FU-VAS). We compared mortality between 1 and 3 years of age according to initial randomization to neonatal VAS or placebo in Cox-regression models; we expected that children randomized to neonatal VAS compared with those randomized to placebo would have lower mortality after reception of FU-VAS.
Results
Of 4345 infants enrolled in the original trial, 3646 lived in the study area at 1 year of age and 2958 received FU-VAS. Between 1 and 3 years of age, 112 children died. After FU-VAS, neonatal VAS was associated with lower mortality than placebo: Mortality Rate Ratio (MRR) = 0.54 (95%CI: 0.31–0.94). The effect was more pronounced in girls (MRR = 0.37 (0.16–0.89)) than boys (MRR = 0.73 (0.35–1.51)). The beneficial effect of neonatal VAS may have been particularly strong for girls who received both VAS in a campaign and FU-VAS (MRR = 0.15 (0.03–0.67)). Among children who had not received FU-VAS, mortality in the second and third year of life did not differ according to reception of neonatal VAS or placebo. Hence, in the second and third year of life the effect of neonatal VAS versus placebo was different in girls who had or had not received FU-VAS (p for homogeneity = 0.01).
Conclusions
The present results suggest that neonatal VAS primes the response in girls such that they get a beneficial effect after a subsequent dose of VAS.
Trial Registration
Clinicaltrials.gov NCT00168597
doi:10.1371/journal.pone.0023265
PMCID: PMC3154934  PMID: 21853099

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