Discrepancies in Management of Congenital Cytomegalovirus in Preterm Infants: An International Survey.

We performed an international survey regarding management of infants with congenital cytomegalovirus (cCMV) born at less than 32 weeks gestation or with birth weight under 1500 g. Replies from 51 level 3 neonatal intensive care units across 13 countries demonstrated striking discrepancies in screening practices, testing for cCMV, further investigations of confirmed cases, indications for initiation, and duration of treatment.

Delays in diagnosis and treatment initiation for congenital cytomegalovirus infection - Why we need universal screening.

Introduction: Congenital cytomegalovirus (cCMV) is the leading cause of neurodevelopmental and hearing impairment from in-utero infection. Late diagnosis results in limited treatment options and may compromise long-term outcome. Methods: A retrospective audit of infants with cCMV referred to a Tertiary Pediatric Infectious Diseases center from 2012-2021. Data collected included timing of diagnostics, treatment initiation and reasons for delays. Results: 90 infants with confirmed cCMV were included, 46/90 (51%) were symptomatic at birth. Most common reasons for diagnostics in asymptomatic infants were failed newborn hearing screening (17/44, 39%) and antenatal risk-factors (14/44, 32%). Median age at cCMV diagnosis was 3 (range 0-68) and 7 (0-515) days, with median referral age 10 (1-120) and 22 (2-760) days for symptomatic and asymptomatic infants respectively. There was a significant risk of delay in diagnosis (>21 days) for asymptomatic infants [RR 2.93 (1.15-7.45); p = 0.02]. Of asymptomatic infants who received treatment, 13/24 (54%) commenced it within 28 days of life, a significant delay in treatment compared to 30/36 (83%) symptomatic infants [RR 2.75 (1.18-6.43); p = 0.02]. The commonest reason for delayed treatment initiation was delayed first diagnostic test for both symptomatic 4/6 (67%) and asymptomatic infants 9/11 (82%). Conclusions: Delays in diagnosis and treatment for cCMV are unacceptably frequent and significantly higher in asymptomatic infants. Our study highlights the need for increased awareness among healthcare professionals, reconsideration of age-targets for Newborn Hearing Screening, and research that addresses the barriers to implementation of universal screening, which would ultimately facilitate prompt diagnosis and management of all infants with cCMV.

Early ART-initiation and longer ART duration reduces HIV-1 proviral DNA levels in children from the CHER trial.

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.

Direct and Ambient Light Pollution Alters Recruitment for a Diurnal Plant-Pollinator System.

Artificial light at night (ALAN) functions as a novel environmental stimulus that has the potential to disrupt interactions among species. Despite recent efforts to explain nocturnal pollinators' responses to this stimulus, the likelihood and associated mechanisms of attraction toward artificial light and potential consequences on fitness for diurnal pollinators are still largely unclear. Here, we took advantage of the obligate mutualism between yucca moths (Tegeticula maculata maculata) and yucca plants (Hesperoyucca whipplei) to understand how direct light exposure and skyglow can influence a pairwise plant-pollinator interaction. To surmise whether adult moths exhibit positive phototaxis, we deployed a set of field-placed light towers during the peak of yucca flowering and compared the number of moths caught in traps between dark-controlled and light-treated trials. Adult moth abundance was much higher when light was present, which suggests that ALAN may alter this diurnal moth's activity patterns to expand their temporal niche into the night. To evaluate ALAN effects on yucca fruit set and moth larva recruitment, we measured skyglow exposure above yucca plants and direct light intensity from a second set of light towers. Both larva and fruit recruitment increased with skyglow, and fruit set also increased with direct lighting, but the relationship was weaker. Contrarily, larva recruitment did not change when exposed to a gradient of direct light, which may instead reflect effects of ALAN on moth physiology, such as disrupted female oviposition, or misdirecting behaviors essential to oviposition activity. Our results suggest that ALAN can positively influence the fitness of both plants and moths in this tightly co-evolved mutualism, but the benefits to each species may depend on whether night lighting is direct or indirect. Whether such effects and mechanisms could relate to susceptibility to the presence of ALAN on this or other plant-pollinator relationships will remain an important focus of future research.

A Qualitative Study of the Views of Patients With Medically Unexplained Symptoms on The BodyMind Approach®: Employing Embodied Methods and Arts Practices for Self-Management.

The arts provide openings for symbolic expression by engaging the sensory experience in the body they become a source of insight through embodied cognition and emotion, enabling meaning-making, and acting as a catalyst for change. This synthesis of sensation and enactive, embodied expression through movement and the arts is capitalized on in The BodyMind Approach® (TBMA). It is integral to this biopsychosocial, innovative, unique intervention for people suffering medically unexplained symptoms (MUS) applied in primary healthcare. The relevance of embodiment and arts practices in TBMA are discussed in relation to the views of participants in the pursuit of self-management. If widely employed TBMA could have an enormous impact, reach, and significance for patients and global health services. This original pre-clinical trial of qualitative research reports on the perceptions of participant patients with generic MUS, a world-wide issue usually treated by either psychological therapy or physiotherapy. TBMA is not a therapy but a health education program founded upon the concept of an integration of psychological elements with physiological, bodily, and sensory experiences. Thematic analysis of qualitative data sets from open-ended questions in semi-structured interviews and a written questionnaire post intervention is presented. Five aspects which appear to be key to learning self-management were derived from analyzing the data: (1) body with mind connections; (2) importance of facilitation; (3) potential benefits; (4) preparedness for change; (5) self-acceptance/compassion. This article advances the discourse on the nature of self-management for MUS through changing the mind-set and the relationship participants have with their bodily symptom/s through employing embodied methods and arts practices, challenging current, and solely verbal, psychological conceptual frameworks. Rigor lies in the method of data analysis using cross verification of credibility between reported findings and scrutiny by stakeholders. We conclude that facilitated TBMA groups employing embodied methods and arts practices can act as a method for developing the self-management of MUS and improving wellbeing.

Comparison of Lymphocyte Subset Populations in Children From South Africa, US and Europe.

Background: Typically, African healthcare providers use immunological reference intervals adopted from Europe and the United States (US). This may be inappropriate in a setting with many differences including exposure to different environmental stimuli and pathogens. We compared immunological reference intervals for children from Europe and the US with South African children to explore whether healthy children living in settings with high rates of infectious diseases have different baseline immunological parameters. Methodology: Blood was taken from 381 HIV-uninfected children aged between 2 weeks and 13 years of age from a Child Wellness Clinic in an informal settlement in Cape Town to establish local hematological and lymphocyte reference intervals for South African children. Flow-cytometry quantified percentage and absolute counts of the B-cells, NK-cells, and T-cells including activated, naïve, and memory subsets. These parameters were compared to three separate studies of healthy children in Europe and the US. Results: Increased activated T-cells, and natural killer cells were seen in the younger age-groups. The main finding across all age-groups was that the ratio of naïve/memory CD4 and CD8 T-cells reached a 1:1 ratio around the first decade of life in healthy South African children, far earlier than in resource-rich countries, where it occurs around the fourth decade of life. Conclusions: This is the largest data set to date describing healthy children from an African environment. These data have been used to create local reference intervals for South African children. The dramatic decline in the naïve/memory ratio of both CD4 and CD8 T-cells alongside increased activation markers may indicate that South African children are exposed to a wider range of environmental pathogens in early life than in resource-rich countries. These marked differences illustrate that reference intervals should be relevant to the population they serve. The implications for the developing pediatric immune system requires further investigation.

Medically Unexplained Symptoms and Attachment Theory: The BodyMind Approach®.

This article discusses how The BodyMind Approach® (TBMA) addresses insecure attachment styles in medically unexplained symptoms (MUS). Insecure attachment styles are associated with adverse childhood experiences (ACEs) and MUS (Adshead and Guthrie, 2015) and affect sufferers' capacity to self-manage. The article goes on to make a new hypothesis to account for TBMA's effectiveness (Payne and Brooks, 2017), that is, it addresses insecure attachment styles, which may be present in some MUS sufferers, leading to their capacity to self-manage. Three insecure attachment styles (dismissive, pre-occupied and fearful) associated with MUS are discussed. TBMA is described and explanations provided of how TBMA has been specifically designed to support people's insecure attachment styles. Three key concepts to support insecure attachment styles involved in the content of TBMA are identified and debated: (a) emotional regulation; (b) safety; and (c) bodymindfulness. There is a rationale for the design of TBMA as opposed to psychological interventions for this population. The programme's structure, facilitation and content, takes account of the three insecure attachment styles above. Examples of how TBMA works with their specific characteristics are presented. TBMA has been tested and found to be effective during delivery in the United Kingdom National Health Service (NHS). Improved self-management has potential to reduce costs for the NHS and in General Practitioner time and resources.

Corrigendum: Different Strokes for Different Folks: The BodyMind Approach as a Learning Tool for Patients With Medically Unexplained Symptoms to Self-Manage.

[This corrects the article DOI: 10.3389/fpsyg.2018.02222.].

Naive B Cell Output in HIV-Infected and HIV-Uninfected Children.

In this study, we aimed to quantify KREC (kappa-deleting recombination excision circle) levels and naive B cell output in healthy HIV-uninfected children, compared with HIV-infected South African children, before and after starting ART (antiretroviral therapy). Samples were acquired from a Child Wellness Clinic (n = 288 HIV-uninfected South African children, 2 weeks-12 years) and the Children with HIV Early Antiretroviral Therapy (CHER) trial (n = 153 HIV-infected South African children, 7 weeks-8 years). Naive B cell output was estimated using a mathematical model combining KREC levels to reflect B cell emigration into the circulation, flow cytometry measures of naive unswitched B cells to quantify total body naive B cells, and their rates of proliferation using the intracellular marker Ki67. Naive B cell output increases from birth to 1 year, followed by a decline and plateau into late childhood. HIV-infected children on or off ART had higher naive B cell outputs than their uninfected counterparts (p = .01 and p = .04). This is the first study to present reference ranges for measurements of KRECs and naive B cell output in healthy and HIV-infected children. Comparison between HIV-uninfected healthy children and HIV-infected children suggests that HIV may increase naive B cell output. Further work is required to fully understand the mechanisms involved and clinical value of measuring naive B cell output in children.

Influence of external peer reviewer scores for funding applications on funding board decisions: a retrospective analysis of 1561 reviews.

OBJECTIVES: To evaluate the influence of external peer reviewer scores on the National Institute for Health Research (NIHR) research funding board decisions by the number of reviewers and type of reviewer expertise. DESIGN: Retrospective analysis of external peer review scores for shortlisted full applications for funding (280 funding applications, 1236 individual reviewers, 1561 review scores). SETTING: Four applied health research funding programmes of NIHR, UK. MAIN OUTCOME MEASURES: Board decision to fund or not fund research applications. RESULTS: The mean score of reviewers predicted funding decisions better than individual reviewer scores (area under the receiver operating characteristic (ROC) curve 0.75, 95% CI 0.69 to 0.81 compared with 0.62, CI 0.59 to 0.65). There was no substantial improvement in how accurately mean reviewer scores predicted funding decisions when the number of reviewers increased above 4 (area under ROC curve 0.75, CI 0.59 to 0.91 for four reviewers; 0.80, CI 0.67 to 0.92 for seven or more). Reviewers with differing expertise influenced the board's decision equally, including public and patient reviewers (area under ROC curves from 0.57, CI 0.47 to 0.66 for health economists to 0.64, CI 0.57 to 0.70 for subject-matter experts). The areas under the ROC curves were quite low when using reviewers' scores, confirming that boards do not rely solely on those scores alone to make their funding decisions, which are best predicted by the mean board score. CONCLUSIONS: Boards value scores that originate from a diverse pool of reviewers. On the basis of independent reviewer score alone, there is no detectable benefit of using more than four reviewer scores in terms of their influence on board decisions, so to improve efficiency, it may be possible to avoid using larger numbers of reviewers. The funding decision is best predicted by the board score.

Evaluation of stakeholder views on peer review of NIHR applications for funding: a qualitative study.

OBJECTIVES: Innovations resulting from research have both national and global impact, so selecting the most promising research studies to fund is crucial. Peer review of research funding applications is part of the selection process, and requires considerable resources. This study aimed to elicit stakeholder opinions about which factors contribute to and influence effective peer review of funding applications to the UK National Institute for Health Research (NIHR), and to identify possible minor improvements to current processes and any major changes or potential innovations to achieve a more efficient peer review process. DESIGN: Qualitative interviews with 30 stakeholders involved in the peer review process. PARTICIPANTS: Participants were drawn from three NIHR coordinating centres and represented four types of stakeholders: board members with responsibility for making funding decisions, applicants, external peer reviewers and NIHR staff. METHODS: All interviews were conducted by telephone apart from three that were face to face with NIHR staff. Data were analysed using a thematic template method. RESULTS: The responses from NIHR staff, board members and reviewers differed from those received from applicants. The first three groups focused on how well the process of peer review did or did not function. The applicants mentioned these points but in addition often reflected on how their personal application was assessed. Process improvements suggested included: developing a more proportionate review process; providing greater guidance, feedback, training, acknowledgement or incentives for peer reviewers; reducing the time commitment and amount of paperwork; and asking reviewers to comment on the importance, strengths and weaknesses of applications and flaws which are potentially 'fixable'. CONCLUSIONS: Overall, participants were supportive of the need for peer review in evaluating applications for research funding. This study revealed which parts of the process are working well and are valued, and barriers, difficulties and potential areas for improvement and development.

Different Strokes for Different Folks: The BodyMind Approach as a Learning Tool for Patients With Medically Unexplained Symptoms to Self-Manage.

Medically unexplained symptoms (MUS) are common and costly in both primary and secondary health care. It is gradually being acknowledged that there needs to be a variety of interventions for patients with MUS to meet the needs of different groups of patients with such chronic long-term symptoms. The proposed intervention described herewith is called The BodyMind Approach (TBMA) and promotes learning for self-management through establishing a dynamic and continuous process of emotional self-regulation. The problem is the mismatch between the patient's mind-set and profile and current interventions. This theoretical article, based on practice-based evidence, takes forward the idea that different approaches (other than cognitive behavioural therapy) are required for people with MUS. The mind-set and characteristics of patients with MUS are reflected upon to shape the rationale and design of this novel approach. Improving services for this population in primary care is crucial to prevent the iterative spiraling downward of frequent general practitioner (GP) visits, hospital appointments, and accident and emergency attendance (A&E), all of which are common for these patients. The approach derives from embodied psychotherapy (authentic movement in dance movement psychotherapy) and adult models of learning for self-management. It has been developed from research and practice-based evidence. In this article the problem of MUS in primary care is introduced and the importance of the reluctance of patients to accept a psychological/mental health referral in the first instance is drawn out. A description of the theoretical underpinnings and philosophy of the proposed alternative to current interventions is then presented related to the design, delivery, facilitation, and educational content of the program. The unique intervention is also described to give the reader a flavor.

Thymic Output and CD4 T-Cell Reconstitution in HIV-Infected Children on Early and Interrupted Antiretroviral Treatment: Evidence from the Children with HIV Early Antiretroviral Therapy Trial.

OBJECTIVES: Early treatment of HIV-infected children and adults is important for optimal immune reconstitution. Infants' immune systems are more plastic and dynamic than older children's or adults', and deserve particular attention. This study aimed to understand the response of the HIV-infected infant immune system to early antiretroviral therapy (ART) and planned ART interruption and restart. METHODS: Data from HIV-infected children enrolled the CHER trial, starting ART aged between 6 and 12 weeks, were used to explore the effect of ART on immune reconstitution. We used linear and non-linear regression and mixed-effects models to describe children's CD4 trajectories and to identify predictors of CD4 count during early and interrupted ART. RESULTS: Early treatment arrested the decline in CD4 count but did not fully restore it to the levels observed in HIV-uninfected children. Treatment interruption at 40 or 96 weeks resulted in a rapid decline in CD4 T-cells, which on retreatment returned to levels observed before interruption. Naïve CD4 T-cell count was an important determinant of overall CD4 levels. A strong correlation was observed between thymic output and the stable CD4 count both before and after treatment interruption. CONCLUSION: Early identification and treatment of HIV-infected infants is important to stabilize CD4 counts at the highest levels possible. Once stabilized, children's CD4 counts appear resilient, with good potential for recovery following treatment interruption. The naïve T-cell pool and thymic production of naive cells are key determinants of children's CD4 levels.

Transferring research from a university to the United Kingdom National Health Service: the implications for impact.

The aim of this article is to inform readers of the author's reflections on the experience of transferring university-based research into the commercial sector, and of the processes and strategies employed when preparing for impact in so doing. Concepts for the transfer are illustrated by the author's reflection on aspects that arose during the birthing and subsequent start-up of a university spin-off, Pathways2Wellbeing, a form of reflection-on-action. This is the vehicle for the adaption required to transfer research into the delivery of a specialised clinic in the United Kingdom National Health Service for people with medically unexplained, persistent, bodily symptoms such as fibromyalgia, chronic fatigue and chronic pain. It is hoped that the article will provide readers with an insight into how knowledge transfer can take place through engagement with stakeholders to create an exchange of knowledges to result in impact on health service policy for service users, despite the challenges, and the enablers that facilitated this process. The reflections on the process of knowledge transfer and the implications for impact are underpinned by relevant theory.

Through the Kinesthetic Lens: Observation of Social Attunement in Autism Spectrum Disorders.

This paper will present a movement-informed perspective to social attunement in Autism Spectrum Disorders (ASD). BACKGROUND: Dance movement therapy (DMT) is a psychotherapeutic intervention that is used with participants with ASD in various settings. Regular clinical outcome monitoring in an outpatient setting in the Netherlands had shown positive effects on social attunement capacities in young people with ASD. However, a systematic study of the development of social attunement movement behaviors of participants with ASD throughout a DMT intervention was not yet available. METHODS: A series of individual cases of DMT with young people with ASD (mean age 12.2 years.) were analyzed for changes in interpersonal movement behaviors employing video-based retrospective observation. RESULTS: The findings were summarized in an observation scale for interpersonal movement behaviors. This scale was then tested for its applicability for the monitoring of social attunement behaviors throughout therapy. DISCUSSION: A movement-informed perspective may be helpful to inventory changes in social attunement behaviors in participants with ASD. The relevance of a movement-informed perspective for the concept of social attunement in ASD will be discussed.

RAD51 Is a Selective DNA Repair Target to Radiosensitize Glioma Stem Cells.

Patients with glioblastoma die from local relapse despite surgery and high-dose radiotherapy. Resistance to radiotherapy is thought to be due to efficient DNA double-strand break (DSB) repair in stem-like cells able to survive DNA damage and repopulate the tumor. We used clinical samples and patient-derived glioblastoma stem cells (GSCs) to confirm that the DSB repair protein RAD51 is highly expressed in GSCs, which are reliant on RAD51-dependent DSB repair after radiation. RAD51 expression and RAD51 foci numbers fall when these cells move toward astrocytic differentiation. In GSCs, the small-molecule RAD51 inhibitors RI-1 and B02 prevent RAD51 focus formation, reduce DNA DSB repair, and cause significant radiosensitization. We further demonstrate that treatment with these agents combined with radiation promotes loss of stem cells defined by SOX2 expression. This indicates that RAD51-dependent repair represents an effective and specific target in GSCs.

Observed full blood count and lymphocyte subset values in a cohort of clinically healthy South African children from a semi-informal settlement in Cape Town.

BACKGROUND: The paediatric full blood count and lymphocyte subset reference intervals used by the National Health Laboratory Service (NHLS), South Africa (SA), are taken from two international reference interval publications. Differences in reference intervals suggest that international data sets may not be appropriate for use in SA. OBJECTIVE: To study immunohaematological values of a group of clinically healthy children from an informal settlement in Cape Town, SA, to assess whether international paediatric reference intervals used by the NHLS are appropriate. METHODS: A cross-sectional study of 207 female and 174 male HIV-uninfected children living in an informal settlement in Cape Town was performed. Full blood counts, automated differential counts and lymphocyte subset analysis were done using internationally accepted technologies. Data were categorised by age and reference intervals compiled using medians and 95% confidence intervals (CIs). Gender comparisons were calculated by non-parametric tests. RESULTS: Although median and 95% CI values differed slightly, physiological trends for red cell, platelet, white blood cell differential and lymphocyte subsets were similar to international reference intervals currently in use at the NHLS. Benign ethnic neutropenia was not a significant finding, and gender-specific intervals were not necessary until 12 years of age. Lower overall median values for haemoglobin and haematocrit, and higher median values for mean cell volume and red cell distribution width, were noted. Assessment of haemoglobin, red cell distribution width and calculated Mentzer ratios suggested underlying iron deficiency in 14.2% of participants. CONCLUSION: Paediatric immunohaematological reference intervals observed in this study are similar to, and support continued use of, international paediatric reference intervals. Underlying iron and related nutritional deficiencies may be contributing to lower haemoglobin levels noted in local children. A larger nationwide study, including all ethnic groups, is recommended.

Diversity of group A rotavirus on a UK pig farm.

Group A rotaviruses (GARV) are a significant cause of enteritis in young pigs. The aim of this study was to extend our understanding of the molecular epidemiology of porcine GARV in the UK by investigating the genetic diversity of GARV on a conventional farrow-to-finish farm. Faecal samples were obtained from six batches of pigs in 2009 and 8 batches in 2010, when the pigs were 2, 3 (time point omitted in 2009), 4, 5, 6 and 8 weeks of age. Presence of rotavirus was detected by reverse transcriptase-polymerase chain reaction (RT-PCR) in 89% and 80% of samples from 2009 and 2010, respectively. A combination of multiplex PCRs and sequencing identified four VP7 genotypes (G2, G3, G4 and G5) and three VP4 genotypes (P[6], P[7] and P[32]) present in almost every combination over the 2 years. The predominant genotype combination was G5P[32] in 2009 and G4P[32] in 2010. Conservation among the P[32] sequences between 2009 and 2010 suggests that reassortment may have led to the different genotype combinations. There were significant changes in the predominant VP7 genotype prior to weaning at 4 weeks, and post weaning when pigs were moved to a different building. Phylogenetic analysis indicated that introduction of new viruses onto the farm was limited. Taken together, these findings suggest that genetically diverse GARV strains persist within the farm environment.

Reactivity of routine HIV antibody tests in children who initiated antiretroviral therapy in early infancy as part of the Children with HIV Early Antiretroviral Therapy (CHER) trial: a retrospective analysis.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: Wellcome Trust, Medical Research Council, and National Institutes of Health.

Incidence of pneumococcal and varicella disease in HIV-infected children and adolescents in the United Kingdom and Ireland, 1996-2011.

BACKGROUND: To define the burden of hospitalization due to 2 vaccine-preventable infections, invasive pneumococcal disease (IPD) and varicella zoster (VZ), among HIV-infected children in the UK and Ireland. METHODS: Analysis of hospitalizations of HIV-infected children <18 years receiving pediatric care and reported to the Collaborative HIV Paediatric Study (CHIPS) between 1996 and 2011. RESULTS: Admissions for IPD and VZ combined accounted for ~5% of all hospital admissions for HIV-infected children each year. When compared with background rates for healthy children, the admission rate ratio for HIV-infected children on combination antiretroviral therapy (cART) was 16.7, 14.8 and 126.7 for IPD, varicella and herpes zoster, respectively, and 156.7, 86.1 and 470, respectively, for HIV-infected children not on cART. Those admitted with IPD or VZ were more likely to have Centers for Disease Control stage B/C at presentation with HIV than those without such admissions (36.8% for IPD, 29.7% for VZ and 22.1% for no IPD or VZ, P = 0.006), and were more likely to subsequently commence cART (94.7%, 91.3% and 80.2% respectively, P = 0.004). CONCLUSIONS: There is a clear increased risk of admission with IPD or VZ in HIV-infected compared with uninfected children, magnified in those who have not yet commenced cART. It is anticipated that the introduction of new guidelines will result in improved vaccine uptake and thereby reduce the burden of IPD and VZ disease. Subsequent evaluation will assess the impact of these guidelines.