Impact of Intrapartum Azithromycin on the Carriage and Antibiotic Resistance of Escherichia coli and Klebsiella pneumoniae in Mothers and their Newborns: a sub-study of a Randomized Double-Blind Trial Conducted in The Gambia and Burkina Faso.

BACKGROUND: Limited data exists on effects of intrapartum azithromycin on prevalence of carriage and antibiotic resistance of Enterobacterales. METHODS: We conducted a randomized trial in Gambia and Burkina Faso where women received intrapartum azithromycin (2g) or placebo. We determined impact of treatment on prevalence of carriage and antibiotic resistance of Escherichia coli and Klebsiella pneumoniae by analysing rectal swabs (RS), nasopharyngeal swabs (NPS), breast milk and recto-vaginal swabs (RVS). Bacteria were isolated microbiologically; antibiotic susceptibility was confirmed with an E-test. Prevalence ratios (PR) with 95% confidence intervals (CI's) were used for comparison between arms. RESULTS: In infants, E. coli carriage in RS was lower in the intervention than placebo arm at days 6 (63.0% vs. 75.2%, PR, 0.84; CI, 0.75-0.95) and 28 (52.7% vs. 70.4%, 0.75; 0.64-0.87) post-intervention. Prevalence of azithromycin-resistant E. coli was higher in the azithromycin arm at days 6 (13.4% vs. 3.6%, 3.75; 1.83-7.69) and 28 (16.4% vs. 9.6%, 1.71; 1.05-2.79). For K. pneumoniae, carriage in RS was higher in the intervention than placebo arm at days 6 (49.6% vs. 37.2%, 1.33; 1.08-1.64) and 28 (53.6% vs. 32.9%, 1.63; 1.31-2.03). Prevalence of azithromycin-resistant K. pneumoniae was higher in the azithromycin arm at day 28 (7.3% vs. 2.1%, 3.49; 1.30-9.37). No differences were observed for other sample types. CONCLUSION: Intrapartum azithromycin decreased E. coli carriage but increased both K. pneumoniae carriage and azithromycin resistance in both bacteria. These data need to be considered together with efficacy results to balance the potential short- and long-term impact of the intervention. CLINICAL TRIALS REGISTRATION: www.clinicaltrials.gov: NCT03199547.

Genomic approach to determine sources of neonatal Staphylococcus aureus infection from carriage in the Gambia.

Staphylococcus aureus is a major cause of neonatal infections in various anatomical sites, resulting in high morbidity and mortality in The Gambia. These clinical infections are often preceded by nasal carriage of S. aureus, a known risk factor. To determine whether potential sources of newborn S. aureus infections were from carriage, and to characterize S. aureus present in different anatomical sites (blood, ear, eye, umbilical cord, skin, pus, oropharynx, breast milk and vagina), we performed whole-genome sequencing of 172 isolates from clinical sites as well as from healthy and unhealthy carriage. A random selection of mothers (n = 90) and newborns (n = 42) participating in a clinical trial and testing positive for S. aureus were considered for this study. Sequence data were analyzed to determine S. aureus multilocus sequence types and selected antimicrobial and virulence gene profiles. Our findings revealed that in The Gambia, ST15 is the dominant sequence type associated with both carriage and clinical infection. In addition, S. aureus isolates causing clinical infection among neonates were genetically similar to those colonizing their oropharynx, and the different anatomical sites were not found to be uniquely colonized by S. aureus of a single genomic profile. Furthermore, while S. aureus associated with clinical infection had similar antimicrobial resistance gene profiles to carriage isolates, only hemolysin and adhesive factor virulence genes were significantly higher among clinical isolates. In conclusion, this study confirmed S. aureus oropharyngeal colonization among neonates as a potential source of clinical infection in The Gambia. Hence, interventions aiming to reduce neonatal clinical infections in The Gambia should consider decreasing oropharyngeal S. aureus carriage.Trial registration The trial was registered at ClinicalTrials.gov NCT03199547.

Evans syndrome caused by a deleterious mutation affecting the adaptor protein SASH3.

Increasing evidence suggests multilineage cytopenias (also known as Evans syndrome) may be caused by inborn errors of immunity (IEI) with immune dysregulation. We studied a patient with autoimmune haemolytic anaemia and immune thrombocytopenia and identified a germline mutation in SASH3 (c.862C>T;p.Arg288Ter), indicating a recently identified IEI. Immunohistochemistry performed after clinically indicated splenectomy revealed severe hypoplasia/absence of germinal centres. The autoimmune phenotype was associated with an increased CD21low T-bet+ CD11c+ subset along with decreased regulatory T cells, impaired T-cell proliferation and T-cell exhaustion. The younger brother carries the same SASH3 mutation and shares immunophenotypic features but is currently clinical asymptomatic, indicating heterogeneity of SASH3 deficiency.

Effect of Intrapartum Azithromycin vs Placebo on Neonatal Sepsis and Death: A Randomized Clinical Trial.

Importance: Neonatal sepsis is a leading cause of neonatal mortality. New interventions are needed to decrease neonatal sepsis and mortality in regions with highest burden. Objective: To evaluate the efficacy of intrapartum azithromycin to reduce neonatal sepsis or mortality, as well as neonatal and maternal infections. Design, Setting, and Participants: This double-blind, placebo-controlled, randomized clinical trial enrolled and followed up birthing parents and their infants at 10 health facilities in The Gambia and Burkina Faso, West Africa, between October 2017 and May 2021. Interventions: Participants were assigned at random to receive oral azithromycin (2 g) or placebo (ratio 1:1) during labor. Main Outcomes and Measures: The primary outcome was a composite of neonatal sepsis or mortality, with the former defined based on microbiologic or clinical criteria. Secondary outcomes were neonatal infections (skin, umbilical, eye and ear infections), malaria, and fever; postpartum infections (puerperal sepsis, mastitis), fever, and malaria; and use of antibiotics during 4-week follow-up. Results: The trial randomized 11 983 persons in labor (median age, 29.9 years). Overall, 225 newborns (1.9% of 11 783 live births) met the primary end point. The incidence of neonatal mortality or sepsis was similar in the azithromycin and placebo groups (2.0% [115/5889] vs 1.9% [110/5894]; risk difference [RD], 0.09 [95% CI, -0.39 to 0.57]), as was the incidence of neonatal mortality (0.8% vs 0.8%; RD, 0.04 [95% CI, -0.27 to 0.35]) and neonatal sepsis (1.3% vs 1.3%; RD, 0.02 [95% CI, -0.38 to 0.43]). Newborns in the azithromycin group compared with the placebo group had lower incidence of skin infections (0.8% vs 1.7%; RD, -0.90 [95% CI, -1.30 to -0.49]) and need for antibiotics (6.2% vs 7.8%; RD, -1.58 [95% CI, -2.49 to -0.67]). Postpartum parents in the azithromycin group had lower incidence of mastitis (0.3% vs 0.5%; RD, -0.24 [95% CI, -0.47 to -0.01]) and puerperal fever (0.1% vs 0.3%; RD, -0.19 [95% CI, -0.36 to -0.01]). Conclusions and Relevance: Azithromycin administered orally during labor did not reduce neonatal sepsis or mortality. These results do not support routine introduction of oral intrapartum azithromycin for this purpose. Trial Registration: ClinicalTrials.gov Identifier: NCT03199547.

Impact of intra-partum azithromycin on carriage of group A streptococcus in the Gambia: a posthoc analysis of a double-blind randomized placebo-controlled trial.

BACKGROUND: Group A Streptococcus (GAS) is a major human pathogen and an important cause of maternal and neonatal sepsis. Asymptomatic bacterial colonization is considered a necessary step towards sepsis. Intra-partum azithromycin may reduce GAS carriage. METHODS: A posthoc analysis of a double-blind, placebo-controlled randomized-trial was performed to determine the impact of 2 g oral dose of intra-partum azithromycin on maternal and neonatal GAS carriage and antibiotic resistance. Following screening, 829 mothers were randomized who delivered 843 babies. GAS was determined by obtaining samples from the maternal and newborn nasopharynx, maternal vaginal tract and breastmilk. Whole Genome Sequencing (WGS) of GAS isolates was performed using the Illumina Miseq platform. RESULTS: GAS carriage was lower in the nasopharynx of both mothers and babies and breast milk among participants in the azithromycin arm. No differences in GAS carriage were found between groups in the vaginal tract. The occurrence of azithromycin-resistant GAS was similar in both arms, except for a higher prevalence in the vaginal tract among women in the azithromycin arm. WGS revealed all macrolide-resistant vaginal tract isolates from the azithromycin arm were Streptococcus dysgalactiae subspecies equisimilis expressing Lancefield group A carbohydrate (SDSE(A)) harbouring macrolide resistant genes msr(D) and mef(A). Ten of the 45 GAS isolates (22.2%) were SDSE(A). CONCLUSIONS: Oral intra-partum azithromycin reduced GAS carriage among Gambian mothers and neonates however carriage in the maternal vaginal tract was not affected by the intervention due to azithromycin resistant SDSE(A). SDSE(A) resistance must be closely monitored to fully assess the public health impact of intrapartum azithromycin on GAS. Trial registration ClinicalTrials.gov Identifier NCT01800942.

Persistent and Emerging Pneumococcal Carriage Serotypes in a Rural Gambian Community After 10 Years of Pneumococcal Conjugate Vaccine Pressure.

BACKGROUND: The continuing impact of pneumococcal conjugate vaccines (PCVs) in regions with high pneumococcal transmission is threatened by the persistence of vaccine serotypes (VTs) and the emergence of nonvaccine serotypes (NVTs). METHODS: In 2016, we conducted a cross-sectional carriage survey (CSS5) in a community where PCV7 was first introduced in 2006 during a cluster-randomized trial conducted before nationwide introduction of PCV7 (2009) and PCV13 (2011). We estimated prevalence of PCV13 VT and NVT by age and compared these with earlier surveys before (CSS0), during (CSS1-3), and after the trial but before PCV13 (CSS4). Genomic analysis was conducted for the nontypeable pneumococci. RESULTS: Prevalence of PCV13 VT carriage decreased during the 10 years between CSS0 and CSS5 across all age groups (67.6% to 13.5%, P < .001; 59.8% to 14.4%, P < .001; 43.1% to 17.9%, P < .001; and 24.0% to 5.1%, P < .001, in <2, 2-4, 5-14, and ≥15 years, respectively). However, there was no difference between CSS4 and CSS5 in children ≥2 years and adults (children <2 years, no data). The prevalence of PCV13 NVT increased between CSS0 and CSS5 for children <2 years but decreased in older children and adults. In CSS5, serotypes 3, 6A, and 19F were the most common VT and nontypeable isolates were the most common NVT. Among nontypeable isolates, 73.0% lost the ability to express a capsule. Of these, 70.8% were from a VT background. CONCLUSIONS: The decrease in PCV13 VT that has occurred since the introduction of PCV13 appears to have plateaued. Significant carriage of these serotypes remains in all age groups.

Intense and Mild First Epidemic Wave of Coronavirus Disease, The Gambia.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is evolving differently in Africa than in other regions. Africa has lower SARS-CoV-2 transmission rates and milder clinical manifestations. Detailed SARS-CoV-2 epidemiologic data are needed in Africa. We used publicly available data to calculate SARS-CoV-2 infections per 1,000 persons in The Gambia. We evaluated transmission rates among 1,366 employees of the Medical Research Council Unit The Gambia (MRCG), where systematic surveillance of symptomatic cases and contact tracing were implemented. By September 30, 2020, The Gambia had identified 3,579 SARS-CoV-2 cases, including 115 deaths; 67% of cases were identified in August. Among infections, MRCG staff accounted for 191 cases; all were asymptomatic or mild. The cumulative incidence rate among nonclinical MRCG staff was 124 infections/1,000 persons, which is >80-fold higher than estimates of diagnosed cases among the population. Systematic surveillance and seroepidemiologic surveys are needed to clarify the extent of SARS-CoV-2 transmission in Africa.

Impact of Intrapartum Oral Azithromycin on the Acquired Macrolide Resistome of Infants' Nasopharynx: A Randomized Controlled Trial.

In a post hoc analysis of samples from an intrapartum azithromycin randomized clinical trial, we found that children whose mothers had been treated with the drug had higher prevalence of macrolide-resistance genes msr(A) and ermC at 28 days but not at 12 months. The 2 genes were positively associated in the nasopharynx. CLINICAL TRIALS REGISTRATION: NCT1800942.

Harnessing the PRECISE network as a platform to strengthen global capacity for maternal and child health research in sub-Saharan Africa.

It is widely acknowledged across the global health sector that research programmes need to be designed and implemented in a way that maximise opportunities for strengthening local capacity. This paper examines how the United Kingdom Research and Innovation (UKRI) Grand Challenges Research Fund (GCRF) funded PRECISE (PREgnancy Care Integrating translational Science, Everywhere) Network has been established as a platform to strengthen global capacity for research focused on the improvement of maternal, fetal and newborn health in sub-Saharan Africa.Best practice principles outlined in an ESSENCE on Health Research report have been considered in relation to the PRECISE Network capacity-building activities described in this paper. These activities are described at the individual, programmatic and institutional levels, and successes, challenges and recommendations for future work are outlined.The paper concludes that the PRECISE leadership have an opportunity to review and refresh activity plans for capacity building at this stage in the project to build on achievements to date.

The PRECISE (PREgnancy Care Integrating translational Science, Everywhere) database: open-access data collection in maternal and newborn health.

In less-resourced settings, adverse pregnancy outcome rates are unacceptably high. To effect improvement, we need accurate epidemiological data about rates of death and morbidity, as well as social determinants of health and processes of care, and from each country (or region) to contextualise strategies. The PRECISE database is a unique core infrastructure of a generic, unified data collection platform. It is built on previous work in data harmonisation, outcome and data field standardisation, open-access software (District Health Information System 2 and the Baobab Laboratory Information Management System), and clinical research networks. The database contains globally-recommended indicators included in Health Management Information System recording and reporting forms. It comprises key outcomes (maternal and perinatal death), life-saving interventions (Human Immunodeficiency Virus testing, blood pressure measurement, iron therapy, uterotonic use after delivery, postpartum maternal assessment within 48 h of birth, and newborn resuscitation, immediate skin-to-skin contact, and immediate drying), and an additional 17 core administrative variables for the mother and babies. In addition, the database has a suite of additional modules for 'deep phenotyping' based on established tools. These include social determinants of health (including socioeconomic status, nutrition and the environment), maternal co-morbidities, mental health, violence against women and health systems. The database has the potential to enable future high-quality epidemiological research integrated with clinical care and discovery bioscience.

The PRECISE (PREgnancy Care Integrating translational Science, Everywhere) Network's first protocol: deep phenotyping in three sub-Saharan African countries.

BACKGROUND: The PRECISE (PREgnancy Care Integrating translational Science, Everywhere) Network is a new and broadly-based group of research scientists and health advocates based in the UK, Africa and North America. METHODS: This paper describes the protocol that underpins the clinical research activity of the Network, so that the investigators, and broader global health community, can have access to 'deep phenotyping' (social determinants of health, demographic and clinical parameters, placental biology and agnostic discovery biology) of women as they advance through pregnancy to the end of the puerperium, whether those pregnancies have normal outcomes or are complicated by one/more of the placental disorders of pregnancy (pregnancy hypertension, fetal growth restriction and stillbirth). Our clinical sites are in The Gambia (Farafenni), Kenya (Kilifi County), and Mozambique (Maputo Province). In each country, 50 non-pregnant women of reproductive age will be recruited each month for 1 year, to provide a final national sample size of 600; these women will provide culturally-, ethnically-, seasonally- and spatially-relevant control data with which to compare women with normal and complicated pregnancies. Between the three countries we will recruit ≈10,000 unselected pregnant women over 2 years. An estimated 1500 women will experience one/more placental complications over the same epoch. Importantly, as we will have accurate gestational age dating using the TraCer device, we will be able to discriminate between fetal growth restriction and preterm birth. Recruitment and follow-up will be primarily facility-based and will include women booking for antenatal care, subsequent visits in the third trimester, at time-of-disease, when relevant, during/immediately after birth and 6 weeks after birth. CONCLUSIONS: To accelerate progress towards the women's and children's health-relevant Sustainable Development Goals, we need to understand how a variety of social, chronic disease, biomarker and pregnancy-specific determinants health interact to result in either a resilient or a compromised pregnancy for either mother or fetus/newborn, or both. This protocol has been designed to create such a depth of understanding. We are seeking funding to maintain the cohort to better understand the implications of pregnancy complications for both maternal and child health.

Persistence of Nasopharyngeal Pneumococcal Vaccine Serotypes and Increase of Nonvaccine Serotypes Among Vaccinated Infants and Their Mothers 5 Years After Introduction of Pneumococcal Conjugate Vaccine 13 in The Gambia.

BACKGROUND: The widespread use of pneumococcal conjugate vaccine (PCV) has brought about a dramatic decrease in pneumococci of vaccine serotypes (VTs) but nonvaccine serotypes (NVTs) have emerged. METHODS: We conducted a cross-sectional survey (CSS) among infants who received 3 doses of 13-valent PCV (PCV13) and their mothers 5 years (CSS3) after PCV13 introduction. Nasopharyngeal swab samples were collected and cultured for isolation of Streptococcus pneumoniae. Whole-genome sequencing of the nontypeable strains was performed. Data were compared with those from 2 previous surveys conducted before PCV13 introduction (CSS1) and 1 year later (CSS2). RESULTS: Among infants, VT carriage decreased from 33.3% (113/339) in CSS1 to 11.4% (40/351) in CSS3 (P = .001) while NVTs increased from 53.1% (180/339) in CSS1 to 74.4% (261/351) in CSS3 (P < .001). Among mothers, there was a significant decrease in VTs between CSS2 8.4% (29/347) and CSS3 5.6% (19/342) (P = .006). NVTs increased from 16.6% (55/331) in CSS1 to 32.2% (110/342) in CSS3 (P < .001). In CSS3, the most prevalent VTs were 7F in infants and 3 in mothers, and the most prevalent NVTs were serogroup 16 and nontypeables, respectively. Genomic analysis showed that VTs were more likely than NVTs to lose their ability to express the capsule. CONCLUSIONS: Five years after PCV13 introduction, we show both direct (infants) and indirect effects (mothers) of the vaccine, while NVT replacement has occurred in both groups. Ongoing circulation of VTs warrants further study of their relevance in any consideration of a reduced dose schedule.

Community-acquired Invasive Bacterial Disease in Urban Gambia, 2005-2015: A Hospital-based Surveillance.

BACKGROUND: Invasive bacterial diseases cause significant disease and death in sub-Saharan Africa. Several are vaccine preventable, although the impact of new vaccines and vaccine policies on disease patterns in these communities is poorly understood owing to limited surveillance data. METHODS: We conducted a hospital-based surveillance of invasive bacterial diseases in The Gambia where blood and cerebrospinal fluid (CSF) samples of hospitalized participants were processed. Three surveillance periods were defined in relation to the introduction of pneumococcal conjugate vaccines (PCVs), before (2005- 2009), during (2010-2011) and after (2012-2015) PCV introduction. We determined the prevalences of commonly isolated bacteria and compared them between the different surveillance periods. RESULTS: A total of 14 715 blood and 1103 CSF samples were collected over 11 years; overall, 1045 clinically significant organisms were isolated from 957 patients (972 organisms [6.6%] from blood and 73 [6.6%] from CSF). The most common blood culture isolates were Streptococcus pneumoniae (24.9%), Staphylococcus aureus (22.0%), Escherichia coli (10.9%), and nontyphoidal Salmonella (10.0%). Between the pre-PCV and post-PCV eras, the prevalence of S. pneumoniae bacteremia dropped across all age groups (from 32.4% to 16.5%; odds ratio, 0.41; 95% confidence interval, .29-.58) while S. aureus increased in prevalence, becoming the most prevalent bacteria (from 16.9% to 27.2%; 1.75; 1.26-2.44). Overall, S. pneumoniae (53.4%), Neisseria meningitidis (13.7%), and Haemophilus influenzae (12.3%) were the predominant isolates from CSF. Antimicrobial resistance to common antibiotics was low. CONCLUSIONS: Our findings demonstrate that surveillance data on the predominant pathogens associated with invasive disease is necessary to inform vaccine priorities and appropriate management of patients.

Ethical Considerations for Movement Mapping to Identify Disease Transmission Hotspots.

Traditional public health methods for detecting infectious disease transmission, such as contact tracing and molecular epidemiology, are time-consuming and costly. Information and communication technologies, such as global positioning systems, smartphones, and mobile phones, offer opportunities for novel approaches to identifying transmission hotspots. However, mapping the movements of potentially infected persons comes with ethical challenges. During an interdisciplinary meeting of researchers, ethicists, data security specialists, information and communication technology experts, epidemiologists, microbiologists, and others, we arrived at suggestions to mitigate the ethical concerns of movement mapping. These suggestions include a template Data Protection Impact Assessment that follows European Union General Data Protection Regulations.

Genomic investigation of Staphylococcus aureus recovered from Gambian women and newborns following an oral dose of intra-partum azithromycin.

BACKGROUND: Oral azithromycin given during labour reduces carriage of bacteria responsible for neonatal sepsis, including Staphylococcus aureus. However, there is concern that this may promote drug resistance. OBJECTIVES: Here, we combine genomic and epidemiological data on S. aureus isolated from mothers and babies in a randomized intra-partum azithromycin trial (PregnAnZI) to describe bacterial population dynamics and resistance mechanisms. METHODS: Participants from both arms of the trial, who carried S. aureus in day 3 and day 28 samples post-intervention, were included. Sixty-six S. aureus isolates (from 7 mothers and 10 babies) underwent comparative genome analyses and the data were then combined with epidemiological data. Trial registration (main trial): ClinicalTrials.gov Identifier NCT01800942. RESULTS: Seven S. aureus STs were identified, with ST5 dominant (n = 40, 61.0%), followed by ST15 (n = 11, 17.0%). ST5 predominated in the placebo arm (73.0% versus 49.0%, P = 0.039) and ST15 in the azithromycin arm (27.0% versus 6.0%, P = 0.022). In azithromycin-resistant isolates, msr(A) was the main macrolide resistance gene (n = 36, 80%). Ten study participants, from both trial arms, acquired azithromycin-resistant S. aureus after initially harbouring a susceptible isolate. In nine (90%) of these cases, the acquired clone was an msr(A)-containing ST5 S. aureus. Long-read sequencing demonstrated that in ST5, msr(A) was found on an MDR plasmid. CONCLUSIONS: Our data reveal in this Gambian population the presence of a dominant clone of S. aureus harbouring plasmid-encoded azithromycin resistance, which was acquired by participants in both arms of the study. Understanding these resistance dynamics is crucial to defining the public health drug resistance impacts of azithromycin prophylaxis given during labour in Africa.

Clinical, genetic and neuropathological characterization of spinocerebellar ataxia type 37.

The autosomal dominant spinocerebellar ataxias (SCAs) consist of a highly heterogeneous group of rare movement disorders characterized by progressive cerebellar ataxia variably associated with ophthalmoplegia, pyramidal and extrapyramidal signs, dementia, pigmentary retinopathy, seizures, lower motor neuron signs, or peripheral neuropathy. Over 41 different SCA subtypes have been described evidencing the high clinical and genetic heterogeneity. We previously reported a novel spinocerebellar ataxia type subtype, SCA37, linked to an 11-Mb genomic region on 1p32, in a large Spanish ataxia pedigree characterized by ataxia and a pure cerebellar syndrome distinctively presenting with early-altered vertical eye movements. Here we demonstrate the segregation of an unstable intronic ATTTC pentanucleotide repeat mutation within the 1p32 5' non-coding regulatory region of the gene encoding the reelin adaptor protein DAB1, implicated in neuronal migration, as the causative genetic defect of the disease in four Spanish SCA37 families. We describe the clinical-genetic correlation and the first SCA37 neuropathological findings caused by dysregulation of cerebellar DAB1 expression. Post-mortem neuropathology of two patients with SCA37 revealed severe loss of Purkinje cells with abundant astrogliosis, empty baskets, occasional axonal spheroids, and hypertrophic fibres by phosphorylated neurofilament immunostaining in the cerebellar cortex. The remaining cerebellar Purkinje neurons showed loss of calbindin immunoreactivity, aberrant dendrite arborization, nuclear pathology including lobulation, irregularity, and hyperchromatism, and multiple ubiquitinated perisomatic granules immunostained for DAB1. A subpopulation of Purkinje cells was found ectopically mispositioned within the cerebellar cortex. No significant neuropathological alterations were identified in other brain regions in agreement with a pure cerebellar syndrome. Importantly, we found that the ATTTC repeat mutation dysregulated DAB1 expression and induced an RNA switch resulting in the upregulation of reelin-DAB1 and PI3K/AKT signalling in the SCA37 cerebellum. This study reveals the unstable ATTTC repeat mutation within the DAB1 gene as the underlying genetic cause and provides evidence of reelin-DAB1 signalling dysregulation in the spinocerebellar ataxia type 37.

Long-term Impact of Oral Azithromycin Taken by Gambian Women During Labor on Prevalence and Antibiotic Susceptibility of Streptococcus pneumoniae and Staphylococcus aureus in Their Infants: Follow-up of a Randomized Clinical Trial.

Background: Oral azithromycin given to women in labor decreases maternal and neonatal bacterial carriage but increases azithromycin-resistant bacteria during at least 4 weeks following the intervention. We assessed the prevalence of bacterial carriage and azithromycin resistance 12 months after treatment among study infants. Methods: Nasopharyngeal swabs (NPSs) were collected between November 2014 and May 2015 from children aged 11-13 months whose mothers had received azithromycin or placebo during labor. Streptococcus pneumoniae and Staphylococcus aureus were isolated using conventional microbiological methods. Antibiotic susceptibility was determined by disk diffusion and confirmed by Etest or VITEK-2. Results: NPSs were collected from 461 children. The prevalence of S. pneumoniae and S. aureus was similar between children from the azithromycin and placebo arms (85.0% vs 82.1%; odds ratio [OR], 1.23 [95% confidence interval {CI}, .73-2.08] for S. pneumoniae and 21.7% vs 21.3%; OR, 1.02 [95% CI, .64-1.64] for S. aureus). Prevalence of azithromycin-resistant S. pneumoniae was similar in both arms (1.8% vs 0.9% in children from the azithromycin and placebo arms, respectively; OR, 2.10 [95% CI, .30-23.38]); resistance to other antibiotics was also similar between arms. For S. aureus, there was no difference in azithromycin resistance between children in the azithromycin (3.1%) and placebo (2.6%) arms (OR, 1.22 [95% CI, .35-4.47]) or resistance to any other antibiotics. Conclusions: The higher prevalence of S. aureus azithromycin resistance observed among women treated during labor and their babies 4 weeks after treatment had waned 12 months after delivery. Azithromycin intervention did not induce other antibiotic resistance to S. pneumoniae or S. aureus. Clinical Trials Registration: NCT01800942.

Vaccine wastage in The Gambia: a prospective observational study.

BACKGROUND: Vaccination is a cost-effective and life-saving intervention. Recently several new, but more expensive vaccines have become part of immunization programmes in low and middle income countries (LMIC). Monitoring vaccine wastage helps to improve vaccine forecasting and minimise wastage. As the costs of vaccination increases better vaccine management is essential. Many LMIC however do not consistently monitor vaccine wastage. METHODS: We conducted two surveys in health facilities in rural and urban Gambia; 1) a prospective six months survey in two regions to estimate vaccine wastage rates and type of wastage for each of the vaccines administered by the Expanded programme on Immunization (EPI) and 2) a nationwide cross sectional survey of health workers from randomly selected facilities to assess knowledge, attitude and practice on vaccine waste management. We used WHO recommended forms and standard questionnaires. Wastage rates were compared to EPI targets. RESULTS: Wastage rates for the lyophilised vaccines BCG, Measles and Yellow Fever ranged from 18.5-79.0%, 0-30.9% and 0-55.0% respectively, mainly through unused doses at the end of an immunization session. Wastage from the liquid vaccines multi-dose/ single dose vials were minimal, with peaks due to expiry or breakage of the vaccine diluent. We interviewed 80 health workers and observed good knowledge. Batching children for BCG was uncommon (19%) whereas most health workers (73.4%) will open a vial as needed. CONCLUSION: National projected wastage targets were met for the multi-dose/single dose vials, but for lyophilised vaccines, the target was only met in the largest major health facility.

Short-term increase in prevalence of nasopharyngeal carriage of macrolide-resistant Staphylococcus aureus following mass drug administration with azithromycin for trachoma control.

BACKGROUND: Mass drug administration (MDA) with azithromycin is a corner-stone of trachoma control however it may drive the emergence of antimicrobial resistance. In a cluster-randomized trial (Clinical trial gov NCT00792922), we compared the reduction in the prevalence of active trachoma in communities that received three annual rounds of MDA to that in communities that received a single treatment round. We used the framework of this trial to carry out an opportunistic study to investigate if the increased rounds of treatment resulted in increased prevalence of nasopharyngeal carriage of macrolide-resistant Staphylococcus aureus. Three cross-sectional surveys were conducted in two villages receiving three annual rounds of MDA (3 × treatment arm). Surveys were conducted immediately before the third round of MDA (CSS-1) and at one (CSS-2) and six (CSS-3) months after MDA. The final survey also included six villages that had received only one round of MDA 30 months previously (1 × treatment arm). RESULTS: In the 3 × treatment arm, a short-term increase in prevalence of S. aureus carriage was seen following MDA from 24.6% at CSS-1 to 38.6% at CSS-2 (p < 0.001). Prevalence fell to 8.8% at CSS-3 (p < 0.001). A transient increase was also seen in prevalence of carriage of azithromycin resistant (AzmR) strains from 8.9% at CSS-1 to 34.1% (p < 0.001) in CSS-2 and down to 7.3% (p = 0.417) in CSS-3. A similar trend was observed for prevalence of carriage of macrolide-inducible-clindamycin resistant (iMLSB) strains. In CSS-3, prevalence of carriage of resistant strains was higher in the 3 × treatment arm than in the 1 × treatment (AzmR 7.3% vs. 1.6%, p = 0.010; iMLSB 5.8% vs. 0.8%, p < 0.001). Macrolide resistance was attributed to the presence of msr and erm genes. CONCLUSIONS: Three annual rounds of MDA with azithromycin were associated with a short-term increase in both the prevalence of nasopharyngeal carriage of S. aureus and prevalence of carriage of AzmR and iMLSB S. aureus. TRIAL REGISTRATION: This study was ancillary to the Partnership for the Rapid Elimination of Trachoma, ClinicalTrials.gov NCT00792922 , registration date November 17, 2008.