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Preterm birth is a major cause of neonatal mortality and morbidity worldwide. Bacterial infection and the subsequent inflammatory response are recognised as an important cause of preterm birth. It is hypothesised that these organisms ascend the cervical canal, colonise placental tissues, cause chorioamnionitis and in severe cases infect amniotic fluid and the foetus. However, the presence of bacteria within the intrauterine cavity does not always precede chorioamnionitis or preterm birth. Whereas previous studies observing the types of bacteria present have been limited in size and the specificity of a few predetermined organisms, in this study we characterised bacteria found in placental tissues from a cohort of 1391 women in rural Malawi using 16S ribosomal RNA gene sequencing. We found that specific bacteria found concurrently on placental tissues associate with chorioamnionitis and delivery of a smaller newborn. Severe chorioamnionitis was associated with a distinct difference in community members, a higher bacterial load and lower species richness. Furthermore, Sneathia sanguinengens and Peptostreptococcus anaerobius found in both matched participant vaginal and placental samples were associated with a lower newborn length-for-age Z-score. This is the largest study to date to examine the placental microbiome and its impact of birth outcomes. Our results provide data on the role of the vaginal microbiome as a source of placental infection as well as the possibility of therapeutic interventions against targeted organisms during pregnancy.

The pathway to a thriving newborn begins before conception and continues in utero with a healthy placenta and the right balance of nutrients and growth factors that are timed and sequenced alongside hormonal suppression of labour until a mature infant is ready for birth. Optimal nutrition that includes adequate quantities of quality protein, energy, essential fats, and an extensive range of vitamins and minerals not only supports fetal growth but could also prevent preterm birth by supporting the immune system and alleviating oxidative stress. Infection, illness, undernourishment, and harmful environmental exposures can alter this trajectory leading to an infant who is too small due to either poor growth during pregnancy or preterm birth. Systemic inflammation suppresses fetal growth by interfering with growth hormone and its regulation of insulin-like growth factors. Evidence supports the prevention and treatment of several maternal infections during pregnancy to improve newborn health. However, microbes, such as Ureaplasma species, which are able to ascend the cervix and cause membrane rupture and chorioamnionitis, require new strategies for detection and treatment. The surge in fetal cortisol late in pregnancy is essential to parturition at the right time, but acute or chronically high maternal cortisol levels caused by psychological or physical stress could also trigger labour onset prematurely. In every pathway to the small vulnerable newborn, there is a possibility to modify the course of pregnancy by supporting improved nutrition, protection against infection, holistic maternal wellness, and healthy environments.

Escherichia coli is a leading cause of invasive bacterial infections in humans. Capsule polysaccharide has an important role in bacterial pathogenesis, and the K1 capsule has been firmly established as one of the most potent capsule types in E. coli through its association with severe infections. However, little is known about its distribution, evolution and functions across the E. coli phylogeny, which is fundamental to elucidating its role in the expansion of successful lineages. Using systematic surveys of invasive E. coli isolates, we show that the K1- cps locus is present in a quarter of bloodstream infection isolates and has emerged in at least four different extraintestinal pathogenic E. coli (ExPEC) phylogroups independently in the last 500 years. Phenotypic assessment demonstrates that K1 capsule synthesis enhances E. coli survival in human serum independent of genetic background, and that therapeutic targeting of the K1 capsule re-sensitizes E. coli from distinct genetic backgrounds to human serum. Our study highlights that assessing the evolutionary and functional properties of bacterial virulence factors at population levels is important to better monitor and predict the emergence of virulent clones, and to also inform therapies and preventive medicine to effectively control bacterial infections whilst significantly lowering antibiotic usage. Little is known about the distribution, evolution and functions of the K1 capsule at a population level, despite the important role in the pathogenesis of E. coli ; authors explore this through the utilisation of over 5,000 clinical isolates in population genomics studies and statistical modelling.

Early antiretroviral therapy (ART) and virological suppression can affect evolving antibody responses to HIV infection. We aimed to assess frequency and predictors of seronegativity in infants starting early ART. We compared HIV antibody results between two of three treatment groups of the Children with HIV Early Antiretroviral Therapy (CHER) trial, done from July, 2005, until July, 2011, in which infants with HIV infection aged 5·7–12·0 weeks with a percentage of CD4-positive T lymphocytes of at least 25% were randomly assigned to immediate ART for 96 weeks (ART-96W) or deferred ART until clinical or immunological progression (ART-Def). We measured antibody from all available stored samples for ART-96W and ART-Def at trial week 84 using three assays: fourth-generation enzyme immunoassay HIV antigen–antibody combination, HIV-1 and HIV-2 rapid antibody test, and quantitative anti-gp120 IgG ELISA. We also assessed odds of seropositivity with respect to age of ART initiation and cumulative viral load. The CHER trial was registered with ClinicalTrials.gov, number NCT00102960. The median age of the infants from when samples were taken (184 samples from 268 infants) was 92 weeks (IQR 90·6–93·4). More specimens from the ART-96W group were seronegative than from the ART-Def group by enzyme immunoassay (ART-96W 49 [46%] of 107 vs ART-Def eight [11%] of 75; p<0·0001) and rapid antibody test (54 [53%] of 101 vs eight [11%] of 74; p<0·0001). Median anti-gp120 IgG concentration was lower in the ART-96W group (230 μg/μL [IQR 133–13 129]) than in the ART-Def group (6870 μg/μL [1706–53 645]; p<0·0001). If ART was started between 12 and 24 weeks of age, odds of seropositivity were increased 13·7 times (95% CI 3·1–60·2; p=0·001) compared with starting it between 0 and 12 weeks. All children starting ART aged older than 24 weeks were seropositive. Cumulative viral load to week 84 correlated with anti-gp120 IgG concentrations (coefficient 0·54; p<0·0001) and increased odds of seropositivity (odds ratio 1·59 [95% CI 1·1–2·3]) adjusted for ART initiation age. About half of children starting ART before 12 weeks of age were HIV seronegative by almost 2 years of age. HIV antibody tests cannot be used to reconfirm HIV diagnosis in children starting early ART. Long-term effects of seronegativity need further study. Clear guidelines are needed for retesting alongside improved diagnostic tests. Wellcome Trust, Medical Research Council, and National Institutes of Health.

A discordant immune response (DIR) is a failure to satisfactorily increase CD4 counts on ART despite successful virological control. Literature on the clinical effects of DIR has not been systematically evaluated. We aimed to summarise the risk of mortality, AIDS and serious non-AIDS events associated with DIR with a systematic review. The protocol is registered with the Centre for Review Dissemination, University of York (registration number CRD42014010821). Included studies investigated the effect of DIR on mortality, AIDS, or serious non-AIDS events in cohort studies or cohorts contained in arms of randomised controlled trials for adults aged 16 years or older. DIR was classified as a suboptimal CD4 count (as defined by the study) despite virological suppression following at least 6 months of ART. We systematically searched PubMed, Embase, and the Cochrane Library to December 2015. Risk of bias was assessed using the Cochrane tool for assessing risk of bias in cohort studies. Two authors applied inclusion criteria and one author extracted data. Risk ratios were calculated for each clinical outcome reported. Of 20 studies that met the inclusion criteria, 14 different definitions of DIR were used. Risk ratios for mortality in patients with and without DIR ranged between 1.00 (95% CI 0.26 to 3.92) and 4.29 (95% CI 1.96 to 9.38) with the majority of studies reporting a 2 to 3 fold increase in risk. DIR is associated with a marked increase in mortality in most studies but definitions vary widely. We propose a standardised definition to aid the development of management options for DIR.

One-third of people with HIV in sub-Saharan Africa start antiretroviral therapy (ART) with advanced disease. We investigated associations between immune biomarkers and mortality in participants with advanced HIV randomised to cotrimoxazole or enhanced antimicrobial prophylaxis in the Reduction of Early Mortality in HIV-Infected Adults and Children Starting Antiretroviral Therapy (REALITY) trial (ISRCTN43622374). Biomarkers were assayed using ELISA and Luminex. Associations between baseline values and all-cause 24-week mortality were analysed using Cox models, and for cause-specific mortality used Fine & Gray models, including prophylaxis randomisation, viral load, CD4, WHO stage, age, BMI, and site as covariates; and weighted according to inverse probability of selection into the substudy. Higher baseline CRP, IFN-γ, IL-6 and IP-10 were associated with higher all-cause mortality; and higher IL-23, IL-2 and RANTES with lower all-cause mortality. Associations varied by cause of death: tuberculosis-associated mortality was most strongly associated with higher CRP and sST2, and cryptococcosis-associated mortality with higher IL-4 and lower IL-8. Changes in I-FABP ( p  = 0.002), faecal alpha-1 antitrypsin ( p  = 0.01) and faecal myeloperoxidase ( p  = 0.005) between baseline and 4 weeks post-ART were greater in those receiving enhanced versus cotrimoxazole prophylaxis. Our findings highlight how the immune milieu shapes outcomes following ART initiation, and how adjunctive antimicrobials can modulate the gut environment in advanced HIV. In this study, by analysing immune biomarkers in a cohort of people with advanced HIV, the authors show that elevated levels of some biomarkers at baseline were associated with either increased (CRP, IFN-ƴ, IL-6 and IP-10) or decreased (IL-23, IL-2 and RANTES) likelihood of all-cause mortality.

There are currently limited data regarding paediatric Behçet’s disease (BD), particularly in the UK. We describe the clinical spectrum, treatment and outcome of BD, and explore the relative sensitivities of the criteria for the diagnosis of BD in a UK paediatric cohort. Single retrospective case note review of children with a clinical diagnosis of BD presenting between 1987 and 2012. Demographics, clinical features, treatment and outcomes were recorded. The sensitivities of the International Study Group (ISG) and International Criteria for BD (ICBD) criteria were explored. BD disease activity was calculated using the Behçet’s Disease Activity Index (BDAI). Forty-six patients (22 male) were identified. Median age of onset was 4.87 (0.04–15.71) years; median time to diagnosis was 3.74 (0.25–13.48) years. Clinical features were recurrent oral ulceration (97.8 %), recurrent genital ulceration (73.9 %), gastrointestinal (58.7 %), musculoskeletal (47.83 %), cutaneous (23.9 %) involvement and uveitis (2 %). Recurrent genital ulceration was more common in female patients ( P  = 0.044). Thirty-seven patients (80.4 %) fulfilled the ICBD criteria; only 12 patients (26.1 %) fulfilled the ISG criteria. BDAI score at diagnosis was 7/20 (0–10/20) and significantly decreased to 5/20 (0–9/20) ( P  < 0.0001) at latest follow-up. The commonest systemic treatment was colchicine (76.1 %); anti-TNFα treatment was reserved for severe cases (15.5 %). Paediatric BD in the UK may present very early in life, sometimes with a family history, and with a low incidence of ocular involvement. Diagnostic delay is common. The majority of our patients required systemic therapy; anti-TNFα was reserved for severe cases and has largely superseded the use of thalidomide.

Background Reduction of the reservoir of latent HIV-infected cells might increase the possibility of long-term remission in individuals living with HIV. We investigated factors associated with HIV-1 proviral DNA levels in children receiving different antiretroviral therapy (ART) strategies in the children with HIV early antiretroviral therapy (CHER) trial. Methods Infants with HIV  <  12 weeks old with CD4%  ≥  25% were randomized in the CHER trial to early limited ART for 40 or 96 weeks (ART-40 W, ART-96 W), or deferred ART (ART-Def). For ART-Def infants or following ART interruption in ART-40 W/ART-96 W, ART was started/re-started for clinical progression or CD4%  <  25%. In 229 participants, HIV-1 proviral DNA was quantified by PCR from stored peripheral blood mononuclear cells from children who had received  ≥  24 weeks ART and two consecutive undetectable HIV-1 RNA 12–24 weeks apart. HIV-1 proviral DNA was compared between ART-Def and ART-96 W at week 96, and in all arms at week 248. Factors associated with HIV-1 proviral DNA levels were evaluated using linear regression. Findings Longer duration of ART was significantly associated with lower HIV-1 proviral DNA at both 96 (p  =  0.0003) and 248 weeks (p  =  0.0011). Higher total CD8 count at ART initiation was associated with lower HIV-1 proviral DNA at both 96 (p  =  0.0225) and 248 weeks (p  =  0.0398). Week 248 HIV-1 proviral DNA was significantly higher in those with positive HIV-1 serology at week 84 than those with negative serology (p  =  0.0042). Intepretation Longer ART duration is key to HIV-1 proviral DNA reduction. Further understanding is needed of the effects of “immune-attenuation” through early HIV-1 exposure. Funding Wellcome Trust, National Institutes of Health, Medical Research Council.

Monogenic autoinflammatory diseases (AID) are a rapidly expanding group of genetically diverse but phenotypically overlapping systemic inflammatory disorders associated with dysregulated innate immunity. They cause significant morbidity, mortality and economic burden. Here, we aimed to develop and evaluate the clinical impact of a NGS targeted gene panel, the \"Vasculitis and Inflammation Panel\" (VIP) for AID and vasculitis. The Agilent SureDesign tool was used to design 2 versions of VIP; VIP1 targeting 113 genes, and a later version, VIP2, targeting 166 genes. Captured and indexed libraries (QXT Target Enrichment System) prepared for 72 patients were sequenced as a multiplex of 16 samples on an Illumina MiSeq sequencer in 150bp paired-end mode. The cohort comprised 22 positive control DNA samples from patients with previously validated mutations in a variety of the genes; and 50 prospective samples from patients with suspected AID in whom previous Sanger based genetic screening had been non-diagnostic. VIP was sensitive and specific at detecting all the different types of known mutations in 22 positive controls, including gene deletion, small INDELS, and somatic mosaicism with allele fraction as low as 3%. Six/50 patients (12%) with unclassified AID had at least one class 5 (clearly pathogenic) variant; and 11/50 (22%) had at least one likely pathogenic variant (class 4). Overall, testing with VIP resulted in a firm or strongly suspected molecular diagnosis in 16/50 patients (32%). The high diagnostic yield and accuracy of this comprehensive targeted gene panel validate the use of broad NGS-based testing for patients with suspected AID.

ObjectiveNeonatal encephalopathy (NE) is the third leading cause of child mortality. Preclinical studies suggest infection and inflammation can sensitise or precondition the newborn brain to injury. This study examined perinatal risks factor for NE in Uganda.DesignUnmatched case–control study.SettingMulago National Referral Hospital, Kampala, Uganda.Methods210 term infants with NE and 409 unaffected term infants as controls were recruited over 13 months. Data were collected on preconception, antepartum and intrapartum exposures. Blood culture, species-specific bacterial real-time PCR, C reactive protein and placental histology for chorioamnionitis and funisitis identified maternal and early newborn infection and inflammation. Multivariable logistic regression examined associations with NE.ResultsNeonatal bacteraemia (adjusted OR (aOR) 8.67 (95% CI 1.51 to 49.74), n=315) and histological funisitis (aOR 11.80 (95% CI 2.19 to 63.45), n=162) but not chorioamnionitis (aOR 3.20 (95% CI 0.66 to 15.52), n=162) were independent risk factors for NE. Among encephalopathic infants, neonatal case fatality was not significantly higher when exposed to early neonatal bacteraemia (OR 1.65 (95% CI 0.62 to 4.39), n=208). Intrapartum antibiotic use did not improve neonatal survival (p=0.826). After regression analysis, other identified perinatal risk factors (n=619) included hypertension in pregnancy (aOR 3.77), male infant (aOR 2.51), non-cephalic presentation (aOR 5.74), lack of fetal monitoring (aOR 2.75), augmentation (aOR 2.23), obstructed labour (aOR 3.8) and an acute intrapartum event (aOR 8.74).ConclusionsPerinatal infection and inflammation are independent risk factors for NE in this low-resource setting, supporting a role in the aetiological pathway of term brain injury. Intrapartum antibiotic administration did not mitigate against adverse outcomes. The importance of intrapartum risk factors in this sub-Saharan African setting is highlighted.