Research exposure in UK paediatric training: how do we address the gaps-experience from the London REACH network.

Trainee-led Research Networks (TRNs) can mitigate against the lack of in-training academic opportunities by offering research experience, support and shared learning for paediatricians. The London Research, Evaluation and Audit for Child Health (REACH) Network, founded in 2021, has grown to involve a diverse group of 190 volunteer members at 28 London hospitals. Planning and delivery of a range of multisite projects bring not only many challenges but also a wealth of learning opportunities relating to research and quality improvement as well as leadership, management, education and fostering an accessible and equitable research culture. TRNs are an effective and valuable tool in improving the experience of trainees.

Maternal inflammatory and microbial drivers of low birthweight in low- and middle-income countries.

BACKGROUND: Low birthweight (LBW) is when an infant is born too soon or too small, and it affects one in seven infants in low- and middle-income countries. LBW has a significant impact on short-term morbidity and mortality, and it impairs long-term health and human capital. Antenatal microbial and inflammatory exposure may contribute to LBW. METHODS: Ovid-Medline, Embase and Cochrane databases were searched for English-language articles evaluating inflammatory, microbial or infective causes of LBW, small-for-gestational age, intra-uterine growth restriction or prematurity. Inclusion criteria were human studies including published data; conference abstracts and grey literature were excluded. A narrative synthesis of the literature was conducted. RESULTS: Local infections may drive the underlying causes of LBW: for example, vaginitis and placental infection are associated with a greater risk of prematurity. Distal infection and inflammatory pathways are also associated with LBW, with an association between periodontitis and preterm delivery and environmental enteric dysfunction and reduced intra-uterine growth. Systemic maternal infections such as malaria and HIV are associated with LBW, even when infants are exposed to HIV but not infected. This latter association may be driven by chronic inflammation, co-infections and socio-economic confounders. Antimicrobial prophylaxis against other bacteria in pregnancy has shown minimal impact in most trials, though positive effects on birthweight have been found in some settings with a high infectious disease burden. CONCLUSION: Maternal inflammatory and infective processes underlie LBW, and provide treatable pathways for interventions. However, an improved understanding of the mechanisms and pathways underlying LBW is needed, given the impact of LBW on life-course.

Research funding for newborn health and stillbirths, 2011-20: a systematic analysis of levels and trends.

BACKGROUND: Worldwide, an estimated 4·4 million newborn deaths and stillbirths occurred in 2020, and 98% of these deaths occurred in low-income and middle-income countries (LMICs). We aimed to analyse new research grants for newborns and stillbirth awarded by major funders in 2019-20, and all research funding allocated to LMIC-based institutions in 2011-20. METHODS: For this systematic analysis, we searched Dimensions, the world's largest research funding database, for grants relevant to neonatal and stillbirth research. Included grants were categorised by in-depth content analysis, with descriptive quantitative analyses by funder and recipient countries, research pipeline, topic, and year. FINDINGS: Globally, in 2019-20, major funders awarded a mean annual total of US$577·1 million per year for newborn and stillbirth research (mean total of 550 grants per year). $166·3 million (28·8%) of $577·1 million was directed to small and vulnerable newborn research, but only $8·4 million (1·5%) was directed to stillbirth research. The majority of funding, $537·0 million (93·0%), was allocated to organisations based in high-income countries. Between 2011 and 2020, LMIC-based recipients were named on 1985 grants from all funders worth $486·7 million, of which $73·1 million (15·0%) was allocated to small and vulnerable newborn research and $12·0 million (2·5%) was allocated to stillbirth research. Most LMIC funding supported preclinical or observational studies ($236·8 million [48·7%] of $486·7 million), with implementation research receiving only $13·9 million (2·9%). INTERPRETATION: Although investment in research related to neonatal health and stillbirths has increased between 2011 and 2020, there are marked disparities in distribution geographically, between major causes of mortality, and among research pipeline types. Stillbirth research received minimal funding in both high-income countries and LMICs, despite a similar number of deaths compared with neonates. Direct investment in LMIC-led research, especially for implementation research, could accelerate the slow global progress on stillbirth prevention and newborn survival. FUNDING: None. TRANSLATIONS: For the French, German and Spanish translations of the abstract see Supplementary Materials section.

Livelihood support for caregivers of children with developmental disabilities: findings from a scoping review and stakeholder survey.

PURPOSE: Poverty amongst families with a child with disability adversely impacts child and family quality of life. We aimed to identify existing approaches to livelihood support for caregivers of children with developmental disabilities in low- and middle-income countries. METHODS: This mixed-method study incorporated a scoping literature review and online stakeholder survey. We utilised the World Health Organization community-based rehabilitation (CBR) matrix as a guiding framework for knowledge synthesis and descriptively analysed the included articles and survey responses. RESULTS: We included 11 peer-reviewed publications, 6 grey literature articles, and 49 survey responses from stakeholders working in 22 countries. Identified programmes reported direct and indirect strategies for livelihood support targeting multiple elements of the CBR matrix; particularly skills development, access to social protection measures, and self-employment; frequently in collaboration with specialist partners, and as one component of a wider intervention. Self-help groups were also common. No publications examined effectiveness of livelihood support approaches in mitigating poverty, with most describing observational studies at small scale. CONCLUSION: Whilst stakeholders describe a variety of direct and indirect approaches to livelihood support for caregivers of children with disabilities, there is a lack of published literature on content, process, and impact to inform future programme development and delivery.

Disability and poverty are interlinked, but little is known on approaches to livelihood support for caregivers of children with developmental disabilities in low- and middle-income countries.Stakeholders report direct and indirect strategies for livelihood support targeting multiple livelihood elements; particularly skills development, access to social protection measures and self-employment; frequently in collaboration with specialist partners, and as one component of a wider intervention.Improved reporting of livelihood targeted activities inclusive of evaluation of feasibility, acceptability and impact would support wider implementation of effective livelihood programmes for caregivers of children with disability.

Sustainable care for children with cancer: a Lancet Oncology Commission.

We estimate that there will be 13·7 million new cases of childhood cancer globally between 2020 and 2050. At current levels of health system performance (including access and referral), 6·1 million (44·9%) of these children will be undiagnosed. Between 2020 and 2050, 11·1 million children will die from cancer if no additional investments are made to improve access to health-care services or childhood cancer treatment. Of this total, 9·3 million children (84·1%) will be in low-income and lower-middle-income countries. This burden could be vastly reduced with new funding to scale up cost-effective interventions. Simultaneous comprehensive scale-up of interventions could avert 6·2 million deaths in children with cancer in this period, more than half (56·1%) of the total number of deaths otherwise projected. Taking excess mortality risk into consideration, this reduction in the number of deaths is projected to produce a gain of 318 million life-years. In addition, the global lifetime productivity gains of US$2580 billion in 2020-50 would be four times greater than the cumulative treatment costs of $594 billion, producing a net benefit of $1986 billion on the global investment: a net return of $3 for every $1 invested. In sum, the burden of childhood cancer, which has been grossly underestimated in the past, can be effectively diminished to realise massive health and economic benefits and to avert millions of needless deaths.

Global public and philanthropic investment in childhood cancer research: systematic analysis of research funding, 2008-16.

Childhood cancers caused an estimated 75 000 deaths in children aged 0-14 years in 2018, of which 90% were in low-income and middle-income countries, and yet this group is missing from global health agendas. We examined global patterns in public and philanthropic funding for childhood cancer research-a proxy for global research activity-to address the critical gaps in knowledge. We used data from the Dimensions database to systematically search for and analyse 3414 grants from 115 funders across 35 countries between 2008 and 2016, organised by funding source, recipient, tumour type, research focus, and pipeline categories, to investigate trends over time. During this period, global funding for childhood cancer research was US$2 billion, of which $772 million (37·9%) was for general childhood cancer, $449 million (22·0%) was for leukaemias, and $330 million (16·2%) was for CNS tumours. $1·6 billion (77·7%) of funding was awarded from, and to, institutions based in the USA. Preclinical research received $1·2 billion (59·3%), and around $525 million (25·7%) included support for clinical trials, but only $113 million (5·5%) supported health-care delivery research. Overall, funding was inadequate and geographically inequitable, and new commitments to funding have declined since 2011.

Neonatal outcomes of waterbirth: a systematic review and meta-analysis.

INTRODUCTION: In 2015, 9% of babies born in the UK were delivered underwater. Waterbirth is increasing in popularity, despite uncertainty regarding its safety for neonates. This systematic review and meta-analysis appraises the existing evidence for neonatal outcomes following waterbirth. METHODS: A structured electronic database search was performed with no language restrictions. All comparative studies which reported neonatal outcomes following waterbirth, and that were published since 1995, were included. Quality appraisal was performed using a modified Critical Appraisal Skills Programme scoring system. The primary outcome was neonatal mortality. Data for each neonatal outcome were tabulated and analysed. Meta-analysis was performed for comparable studies which reported sufficient data. RESULTS: The majority of the 29 included studies were small, with limited follow-up and methodological flaws. They were mostly conducted in Europe and high-income countries. Reporting of data was heterogeneous. No significant difference in neonatal mortality, neonatal intensive care unit/special care baby unit admission rate, Apgar scores, umbilical cord gases or infection rates was found between babies delivered into water and on land. CONCLUSIONS: This systematic review and meta-analysis did not identify definitive evidence that waterbirth causes harm to neonates compared with land birth. However, there is currently insufficient evidence to conclude that there are no additional risks or benefits for neonates when comparing waterbirth and conventional delivery on land.

Health and disease in children born after assistive reproductive therapies (ART.

In vitro fertilisation (IVF) and other assisted reproductive therapies (ART) offer hope to subfertile couples worldwide. At least 5 million ART children have been born to date. Their health is an issue that is increasingly relevant: first, to those children and young adults themselves; second, to couples considering fertility treatment; and third, to the general population as ART has progressed from experimental treatment to routine practice. Many concerns about the potential risks to these children have been voiced with varying degrees of supportive evidence. This article summarises some key long-term data. Current evidence suggests that ART does increase risk of: higher order pregnancy (with its inherent pre- and perinatal risks); prematurity and low birth weight; congenital malformations in particular of the male urogenital system; imprinting disorders. Reassuringly, evidence points away from an increased overall cancer risk or differences in neurodevelopmental outcomes. Many unknowns remain, including future fertility and cardiovascular risks and risk of cerebral palsy.

Influence of PB2 host-range determinants on the intranuclear mobility of the influenza A virus polymerase.

Avian influenza A viruses often do not propagate efficiently in mammalian cells. The viral polymerase protein PB2 is important for this host restriction, with amino-acid polymorphisms at residue 627 and other positions acting as 'signatures' of avian- or human-adapted viruses. Restriction is hypothesized to result from differential interactions (either positive or inhibitory) with unidentified cellular factors. We applied fluorescence recovery after photobleaching (FRAP) to investigate the mobility of the viral polymerase in the cell nucleus using A/PR/8/34 and A/Turkey/England/50-92/91 as model strains. As expected, transcriptional activity of a polymerase with the avian PB2 protein was strongly dependent on the identity of residue 627 in human but not avian cells, and this correlated with significantly slower diffusion of the inactive polymerase in human but not avian nuclei. In contrast, the activity and mobility of the PR8 polymerase was affected much less by residue 627. Sequence comparison followed by mutagenic analyses identified residues at known host-range-specific positions 271, 588 and 701 as well as a novel determinant at position 636 as contributors to host-specific activity of both PR8 and Turkey PB2 proteins. Furthermore, the correlation between poor transcriptional activity and slow diffusional mobility was maintained. However, activity did not obligatorily correlate with predicted surface charge of the 627 domain. Overall, our data support the hypothesis of a host nuclear factor that interacts with the viral polymerase and modulates its activity. While we cannot distinguish between positive and inhibitory effects, the data have implications for how such factors might operate.

Repeated vaccination is required to optimize seroprotection against H1N1 in the immunocompromised host.

BACKGROUND: In 2009 the declaration by the World Health Organization of a global pandemic of influenza-H1N1 virus led to a vaccination campaign to ensure protection for immunocompromised patients. The goal of this study was to determine the efficacy of the 2009 H1N1 vaccine in patients with hematologic malignancies. DESIGN AND METHODS: We evaluated humoral and cellular immune responses to 2009 H1N1 vaccine in 97 adults with hematologic malignancies and compared these responses with those in 25 adult controls. Patients received two injections of vaccine 21 days apart and the controls received one dose. Antibody titers were measured using a hemagglutination-inhibition assay on days 0, 21 and 49 after injection of the first dose. Cellular immune responses to H1N1 were determined on days 0 and 49. RESULTS: By day 21 post-vaccination, protective antibody titers of 1:32 or more were seen in 100% of controls compared to 39% of patients with B-cell malignancies (P<0.001), 46% of allogeneic stem cell transplant recipients (P<0.001) and 85% of patients with chronic myeloid leukemia (P=0.086). After a second dose, seroprotection rates increased to 68%, (P=0.008), 73%, (P=0.031), and 95% (P=0.5) in patients with B-cell malignancies, after allogeneic stem cell transplantation and with chronic myeloid leukemia, respectively. On the other hand, T-cell responses to H1N1 vaccine were not significantly different between patients and controls. CONCLUSIONS: These data demonstrate the efficacy of H1N1 vaccine in most patients with hematologic malignancies and support the recommendation for the administration of two doses of vaccine in immunocompromised patients. These results may contribute towards the development of evidence-based guidelines for influenza vaccination in such patients in the future.

Humoral and cellular immunity to primary H1N1 infection in patients with hematologic malignancies following stem cell transplantation.

Limited data are available on immunologic responses to primary H1N1 infection in patients with hematologic malignancies. We present a prospective, case-surveillance study of such patients with real-time polymerase chain reaction (RT-PCR) confirmed H1N1-influenza who presented to our institution between September 2009 and January 2010. Ninety-two patients presented with influenza-like symptoms, and 13 had H1N1 infection confirmed by RT-PCR, including 4 allogeneic stem cell transplant recipients (1 with acute myelogenous leukemia, 1 with chronic lymphoblastic leukemia [CLL], 1 with non-Hodgkin lymphoma, and 1 with chronic myelogenous leukemia), 5 patients with multiple myeloma following autologous stem cell transplantation, 1 patient with multiple myeloma perimobilization, 2 patients with NHL post chemotherapy, and 1 patient with CLL. All 13 patients required hospitalization. Six (43%) were admitted to the intensive care unit (ICU), of whom 4 (67%) died. We evaluated B cell and T cell responses to H1N1 infection prospectively in these patients compared with those in 4 otherwise healthy controls. Within 12 weeks of diagnosis, only 6 of 11 patients developed seropositive antibody titers as measured by hemagglutination-inhibition or microneutralization assays, compared with 4 of 4 controls. H1N1-specific T cells were detected in only 2 of 8 evaluable patients compared with 4 of 4 controls. H1N1-specific T cells were functional, capable of producing interferon γ, tumor necrosis factor α, and CD107a mobilization. Furthermore, CD154 was up-regulated on CD4(+) T cells in 3 of 4 controls and 2 of 2 patients who had both B cell and T cell responses to H1N1. Post-H1N1 infection, 5 of 8 patients developed seasonal influenza-specific T cells, suggesting cross-reactivity induced by H1N1 infection. These data offer novel insights into humoral and cell-mediated immunologic responses to primary H1N1 infection.

Quantitative proteomics using SILAC coupled to LC-MS/MS reveals changes in the nucleolar proteome in influenza A virus-infected cells.

Influenza A virus (IAV) is a major human pathogen whose genotypic diversity results in unpredictable pandemics and epidemics. Interaction with the cell nucleus is essential to IAV infection, allowing recruitment of cellular components to facilitate virus replication. Viral proteins are also targeted to the nucleolus, a subnuclear structure involved in ribosomal biogenesis, RNA maturation, stress response, and control of cell growth, but the functional consequences of this are unclear. We took an unbiased approach to studying IAV-nucleolar interactions by using stable isotope labeling with amino acids in cell culture (SILAC) in conjunction with LC-MS/MS to quantify changes in the nucleolar proteome following infection with A/PR/8/34 (H1N1) and A/Udorn/72 (H3N2) strains of the virus. Only a minority of nucleolar proteins showed significant changes in abundance after infection; these alterations were mostly different between the two strains but could be validated by confocal microscopy of infected cells. Many of the affected proteins comprised functional groupings, including components of ribonuclease P, RNA polymerase I, the MLL1 histone methyltransferase complex, as well as nuclear paraspeckles and the RNA editing apparatus. This, as well as comparison with other viruses that cause changes in the nucleolar proteome, suggests that IAV targets specific nucleolar pathways.

Nuclear dynamics of influenza A virus ribonucleoproteins revealed by live-cell imaging studies.

The negative sense RNA genome of influenza A virus is transcribed and replicated in the nuclei of infected cells by the viral RNA polymerase. Only four viral polypeptides are required but multiple cellular components are potentially involved. We used fluorescence recovery after photobleaching (FRAP) to characterise the dynamics of GFP-tagged viral ribonucleoprotein (RNP) components in living cells. The nucleoprotein (NP) displayed very slow mobility that significantly increased on formation of transcriptionally active RNPs. Conversely, single or dimeric polymerase subunits showed fast nuclear dynamics that decreased upon formation of heterotrimers, suggesting increased interaction of the full polymerase complex with a relatively immobile cellular component(s). Treatment with inhibitors of cellular transcription indicated that in part, this reflected an interaction with cellular RNA polymerase II. Analysis of mutated influenza virus polymerase complexes further suggested that this was through an interaction between PB2 and RNA Pol II separate from PB2 cap-binding activity.