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GBS is a leading cause of mortality in newborn babies in high- and low-income countries worldwide. Different strains of GBS are characterized by different degrees of virulence, where some are harmlessly carried by humans or animals and others are much more likely to cause disease. The genome sequences of almost 2,000 GBS samples isolated from both animals and humans in high- and low- income countries were analyzed using a pan-genome-wide association study approach. This allowed us to identify 279 genes which are associated with different lineages of GBS, characterized by a different virulence and preferred host. Additionally, we propose that the GBS now carried in humans may have first evolved in animals before expanding clonally once adapted to the human host. These findings are essential to help understand what is causing GBS disease and how the bacteria have evolved and are transmitted. Streptococcus agalactiae (group B streptococcus; GBS) is a colonizer of the gastrointestinal and urogenital tracts, and an opportunistic pathogen of infants and adults. The worldwide population of GBS is characterized by clonal complexes (CCs) with different invasive potentials. CC17, for example, is a hypervirulent lineage commonly associated with neonatal sepsis and meningitis, while CC1 is less invasive in neonates and more commonly causes invasive disease in adults with comorbidities. The genetic basis of GBS virulence and the extent to which different CCs have adapted to different host environments remain uncertain. We have therefore applied a pan-genome-wide association study (GWAS) approach to 1,988 GBS strains isolated from different hosts and countries. Our analysis identified 279 CC-specific genes associated with virulence, disease, metabolism, and regulation of cellular mechanisms that may explain the differential virulence potential of particular CCs. In CC17 and CC23, for example, we have identified genes encoding pilus, quorum-sensing proteins, and proteins for the uptake of ions and micronutrients which are absent in less invasive lineages. Moreover, in CC17, carriage and disease strains were distinguished by the allelic variants of 21 of these CC-specific genes. Together our data highlight the lineage-specific basis of GBS niche adaptation and virulence. IMPORTANCE GBS is a leading cause of mortality in newborn babies in high- and low-income countries worldwide. Different strains of GBS are characterized by different degrees of virulence, where some are harmlessly carried by humans or animals and others are much more likely to cause disease. The genome sequences of almost 2,000 GBS samples isolated from both animals and humans in high- and low- income countries were analyzed using a pan-genome-wide association study approach. This allowed us to identify 279 genes which are associated with different lineages of GBS, characterized by a different virulence and preferred host. Additionally, we propose that the GBS now carried in humans may have first evolved in animals before expanding clonally once adapted to the human host. These findings are essential to help understand what is causing GBS disease and how the bacteria have evolved and are transmitted.

To assess differences in cognition functions and gross brain structure in children seven years after an episode of severe acute malnutrition (SAM), compared with other Malawian children. Prospective longitudinal cohort assessing school grade achieved and results of five computer-based (CANTAB) tests, covering three cognitive domains. A subset underwent brain MRI scans which were reviewed using a standardized checklist of gross abnormalities and compared with a reference population of Malawian children. Blantyre, Malawi.ParticipantsChildren discharged from SAM treatment in 2006 and 2007 (n 320; median age 9·3 years) were compared with controls: siblings closest in age to the SAM survivors and age/sex-matched community children. SAM survivors were significantly more likely to be in a lower grade at school than controls (adjusted OR = 0·4; 95 % CI 0·3, 0·6; P < 0·0001) and had consistently poorer scores in all CANTAB cognitive tests. Adjusting for HIV and socio-economic status diminished statistically significant differences. There were no significant differences in odds of brain abnormalities and sinusitis between SAM survivors (n 49) and reference children (OR = 1·11; 95 % CI 0·61, 2·03; P = 0·73). Despite apparent preservation in gross brain structure, persistent impaired school achievement is likely to be detrimental to individual attainment and economic well-being. Understanding the multifactorial causes of lower school achievement is therefore needed to design interventions for SAM survivors to thrive in adulthood. The cognitive and potential economic implications of SAM need further emphasis to better advocate for SAM prevention and early treatment.

[...]the UN Charter reaffirms faith in fundamental human rights, in the dignity and worth of all human beings, in the equal rights of men and women and of nations, both large and small,11 while the SDGs prohibit any form of discrimination and seeks to ‘leave no one behind’.12 Hence, global health research and policies that violate EEDI principles are unlikely to reflect the legitimate aspirations of populations in LMICs. [...]some donor organisations only fund research projects if the principal investigator is from the country where the research is conducted. [...]tokenism and superficial diversity must be discouraged. [...]employees within the UN network should lead by example and not be allowed to co-author policy papers that violate EEDI principles in line with UN Charter and relevant mission statements of

Background Progress has been made in tackling malaria however there are still over 207 million cases worldwide, the majority in children. As survival rates improve, numbers of children with long-term neurodisabling sequelae are likely to increase. Most outcome studies in cerebral malaria (CM) have focused only on body function and structure and less on outcomes within the broader framework of the International Classification of Functioning and Disability (ICF). The aim of this study was to utilise qualitative methods to identify relevant clinical outcomes in CM to support formulation of a core outcome set relevant to CM and other acquired brain injuries for use in future clinical trials. Methods In depth interviews with parent/caregivers (CGs) of children with/without previous CM ( N  = 19), and in depth interviews with health professionals ( N  = 18) involved in their care were conducted in community and clinical settings in and around Blantyre, Malawi. Interviews were audio taped, transcribed, translated and a thematic content analysis was conducted. Themes were categorised and placed firstly in an iterative framework derived from the data but then within the ICF framework. Results Outcomes perceived as important to carers and professionals fulfilled each level of the ICF. These included impairment in body function and structure (contractures, impaired mobility, visual problems, seizures, cognitive function and feeding); activity and participation outcomes (learning, self-care, relationships in school, play and activities of daily living). Other issues emerging included the social and emotional implications of CM on the family, and balancing care of children with neurodisability with demands of daily life, financial pressures, and child protection. Themes of stigma and discrimination were described; these were perceived to negatively influence care, participation and integration of carer and child into the community. Conclusions Outcomes considered important for parents/caregivers and professionals working with children post CM cross all aspects of the ICF framework (impairment, functioning and participation). Outcomes emphasised by families and carers in cross-cultural settings must be given adequate attention when conducting clinical studies in these settings.

Malnutrition is highly prevalent in HIV-exposed perinatally uninfected infants (HEUs) increasing the risk of morbidity and mortality throughout the life course. We set out to compare the effect of postnatal exposure to maternal antiretroviral therapy (mART) in breastmilk versus infant Nevirapine prophylaxis (iNVP) on somatic growth of HEUs in the randomized PROMISE trial. We randomized 2431 mothers with HIV and their 2444 HEUs from six African countries and India 6-14 days after delivery to mART or iNVP for prevention of breastmilk HIV transmission. The mART regimen contained tenofovir/emtricitabine (99%) plus lopinavir/ritonavir. Infant growth parameters were compared at postnatal week 10, 26, 74 and 104 using World Health Organization (WHO) z-scores for length-for-age (LAZ), weight-for-age (WAZ), and head circumference-for-age (HCAZ). Week 26 LAZ was the primary endpoint measure. Student T-tests compared mean LAZ, WAZ, and HCAZ; estimated mean and 95% confidence interval (CI) are presented. In HEUs, growth effects from postnatal exposure to mART compared to iNVP were comparable for measures on length, weight and head circumference with no clinically relevant differences between the groups. Despite breastfeeding into the second year of life, length and weight were below reference population means at all ages in both arms. Further investment is needed to optimize postnatal growth of infants born to women with HIV.

High mortality burden from Acute Bacterial Meningitis (ABM) in resource-poor settings has been frequently blamed on delays in treatment seeking. We explored treatment-seeking pathways from household to primary health care and referral for ABM in Malawi. A cross-sectional qualitative study using narrative in-depth interviews, semi-structured interviews and focus group discussions. Adults and children with proven and probable acute bacterial meningitis and/or their carers; adults from urban and peri-urban communities; and primary health care workers (HCW). Queen Elizabeth Central Hospital (QECH), urban and peri-urban private and government primary health centres and communities in Blantyre District, Malawi. Whilst communities associated meningitis with a stiff neck, in practice responses focused on ability to recognise severe illness. Misdiagnosis of meningitis as malaria was common. Subsequent action by families depended on the extent to which normal social life was disrupted by the illness and depended on the age and social position of the sufferer. Seizures and convulsions were considered severe symptoms but were often thought to be malaria. Presumptive malaria treatment at home often delayed formal treatment seeking. Further delays in treatment seeking were caused by economic barriers and perceptions of inefficient or inadequate primary health services. Given the difficulties in diagnosis of meningitis where malaria is common, any intervention for ABM at primary level must focus on recognising severe illness, and encouraging action at the household, community and primary health levels. Overcoming barriers to recognition and social constraints at community level require broad community-based strategies and may provide a route to addressing poor clinical outcomes.

HIV-1 subtype B replication in the CNS can occur in CD4+ T cells or macrophages/microglia in adults. However, little is known about CNS infection in children or the ability of subtype C HIV-1 to evolve macrophage-tropic variants. In this study, we examined HIV-1 variants in ART-naïve children aged three years or younger to determine viral genotypes and phenotypes associated with HIV-1 subtype C pediatric CNS infection. We examined HIV-1 subtype C populations in blood and CSF of 43 Malawian children with neurodevelopmental delay or acute neurological symptoms. Using single genome amplification (SGA) and phylogenetic analysis of the full-length env gene, we defined four states: equilibrated virus in blood and CSF (n = 20, 47%), intermediate compartmentalization (n = 11, 25%), and two distinct types of compartmentalized CSF virus (n = 12, 28%). Older age and a higher CSF/blood viral load ratio were associated with compartmentalization, consistent with independent replication in the CNS. Cell tropism was assessed using pseudotyped reporter viruses to enter a cell line on which CD4 and CCR5 receptor expression can be differentially induced. In a subset of compartmentalized cases (n = 2, 17%), the CNS virus was able to infect cells with low CD4 surface expression, a hallmark of macrophage-tropic viruses, and intermediate compartmentalization early was associated with an intermediate CD4 entry phenotype. Transmission of multiple variants was observed for 5 children; in several cases, one variant was sequestered within the CNS, consistent with early stochastic colonization of the CNS by virus. Thus we hypothesize two pathways to compartmentalization: early stochastic sequestration in the CNS of one of multiple variants transmitted from mother to child, and emergence of compartmentalized variants later in infection, on average at age 13.5 months, and becoming fully apparent in the CSF by age 18 months. Overall, compartmentalized viral replication in the CNS occurred in half of children by year three.

Background We sought to identify perceptions of neurorehabilitation challenges for paediatric cerebral malaria (CM) survivors post-hospital discharge at Queen Elizabeth Central Hospital (QECH) in Blantyre, Malawi. Methods An exploratory approach was used to qualitatively investigate the perceived neurorehabilitation challenges for paediatric CM survivors. Data were collected through semi-structured in-depth interviews (IDIs) and focus group discussions (FGDs). Eighteen data-gathering sessions were conducted with 38 total participants, including 3 FGDs with 23 primary caregivers, 11 IDIs with healthcare workers at QECH, and 4 IDIs with community-based rehabilitation workers (CRWs). Results FGDs revealed that caregivers lack important knowledge about CM and fear recurrence of CM in their children. Post-CM children and families experience substantial stigma and sociocultural barriers to integrating into their community and accessing neurorehabilitative care. At a community-level, rehabilitation infrastructure, including trained staff, equipment, and programmes, is extremely limited. Rehabilitation services are inequitably accessible, and community-based rehabilitation remains largely unavailable. Conclusions There is an urgent need to establish further training of rehabilitation personnel at all levels and to build accessible rehabilitation infrastructure in Malawi for post-CM patients. Additional work is required to expand this study across multiple regions for a holistic understanding of neurorehabilitation needs.

Intestinal pathology in children with complicated severe acute malnutrition (SAM) persists despite standard management. Given the similarity with intestinal pathology in non-IgE mediated gastrointestinal food allergy and Crohn’s disease, we tested whether therapeutic feeds effective in treating these conditions may benefit children with complicated SAM. After initial clinical stabilisation, 95 children aged 6–23 months admitted at Queen Elizabeth Central Hospital, Blantyre, Malawi between January 1 st and December 31 st , 2016 were allocated randomly to either standard feeds, an elemental feed or a polymeric feed for 14 days. Change in faecal calprotectin as a marker of intestinal inflammation and the primary outcome was similar in each arm: elemental vs. standard 4.1 μg/mg stool/day (95% CI, −29.9, 38.15; P  = 0.81) and polymeric vs. standard 10 (−23.96, 43.91; P  = 0.56). Biomarkers of intestinal and systemic inflammation and mucosal integrity were highly abnormal in most children at baseline and abnormal values persisted in all three arms. The enteropathy in complicated SAM did not respond to either standard feeds or alternative therapeutic feeds administered for up to 14 days. A better understanding of the pathogenesis of the gut pathology in complicated SAM is an urgent priority to inform the development of improved therapeutic interventions.

Background Acute seizures are common in pediatric cerebral malaria (CM), but usual care with phenobarbital risks respiratory suppression. We undertook studies of enteral levetiracetam (eLVT) to evaluate pharmacokinetics (PK), safety and efficacy including an open-label, randomized controlled trial (RCT) comparing eLVT to phenobarbital. Methods Children 24–83 months old with CM were enrolled in an eLVT dose-finding study starting with standard dose (40 mg/kg load, then 30 mg/kg Q12 hours) titrated upward until seizure freedom was attained in 75% of subjects. The RCT that followed randomized children to eLVT vs. phenobarbital for acute seizures and compared the groups on minutes with seizures based upon continuous electroencephalogram. Due to safety concerns, midway through the study children allocated to phenobarbital received the drug only if they continued to have seizures (either clinically or electrographically) after benzodiazepine treatment. Secondary outcomes were treatment failure requiring cross over, coma duration and neurologic sequelae at discharge. PK and safety assessments were also undertaken. Results Among 30 comatose CM children, eLVT was rapidly absorbed and well-tolerated. eLVT clearance was lower in patients with higher admission serum creatinine (SCr), but overall PK parameters were similar to prior pediatric PK studies. Within 4 h of the first dose, 90% reached therapeutic levels (> 20 μg/mL) and all were above 6 μg/mL. 7/7 children achieved seizure freedom on the initial eLVT dose. Comparing 23 eLVT to 21 phenobarbital patients among whom 15/21 received phenobarbital, no differences were seen for minutes with seizure, seizure freedom, coma duration, neurologic sequelae or death, but eLVT was safer ( p  = 0.019). Phenobarbital was discontinued in 3/15 due to respiratory side effects. Conclusion Enteral LVT offers an affordable option for seizure control in pediatric CM and is safer than phenobarbital. Trial registration NCT01660672 . NCT01982812 .