Grant Ref Research Articles

Childhood socioeconomic position and sex-specific trajectories of metabolic traits across early life: prospective cohort study

Socioeconomic inequalities in cardiovascular disease risk begin early in life and are more pronounced in females than males later in life. Causal atherogenic traits explaining this are not well understood. We explored sex-specific associations between childhood socioeconomic position (SEP) and molecular measures of systemic metabolism across early life. Data were from the Avon Longitudinal Study of Parents and Children (ALSPAC), a population-based birth cohort in southwest England. Pregnant women with an expected delivery date between 1991 and 1992 were invited to participate. Maternal education was the primary indicator of SEP. Concentrations of 148 metabolic traits from targeted metabolomics (nuclear magnetic resonance spectroscopy) from research clinics at ages 7, 15, 18 and 25years were analysed. The sex-specific slope index of inequality (SII) in trajectories of metabolic traits was estimated using multilevel models. Total number of participants included was 6537 (12,543 repeated measures). Lower maternal education was associated with more adverse levels of several atherogenic lipids and key metabolic traits among females at age 7years, but not males. For instance, SII for very small very-low-density lipoprotein (VLDL) concentrations was 0.16SD (95% CI: 0.01, 0.30) among females and-0.02SD (95% CI:-0.16, 0.13) among males. Between 7and 25years, inequalities widened among females and emerged among males particularly for VLDL particle concentrations, apolipoprotein-B concentrations, and inflammatory glycoprotein acetyls. For instance, at 25years, SII for very small VLDL concentrations was 0.36SD (95% CI: 0.20, 0.52) and 0.22SD (95% CI: 0.04, 0.40) among females and males respectively. Prevention of socioeconomic inequalities in cardiovascular disease risk requires a life course approach beginning at the earliest opportunity, especially among females. The UK Medical Research Council and Wellcome (grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. A comprehensive list of grants funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf). KON is supported by a Health Research Board (HRB) of Ireland Investigator Led Award (ILP-PHR-2022-008). JB, GDS and KT work in a unit funded by the UK MRC (MC_UU_00011/1 and MC UU 00011/3) and the University of Bristol. OR is supported by a UKRI Future Leaders Fellowship (MR/S03532X/1). These funding sources had no role in the design and conduct of this study. This publication is the work of the authors and KON will serve as guarantor for the contents of this paper.

Eleven key measures for monitoring general practice clinical activity during COVID-19: A retrospective cohort study using 48 million adults' primary care records in England through OpenSAFELY.

The COVID-19 pandemic has had a significant impact on delivery of NHS care. We have developed the OpenSAFELY Service Restoration Observatory (SRO) to develop key measures of primary care activity and describe the trends in these measures throughout the COVID-19 pandemic. With the approval of NHS England, we developed an open source software framework for data management and analysis to describe trends and variation in clinical activity across primary care electronic health record (EHR) data on 48 million adults.We developed SNOMED-CT codelists for key measures of primary care clinical activity such as blood pressure monitoring and asthma reviews, selected by an expert clinical advisory group and conducted a population cohort-based study to describe trends and variation in these measures January 2019-December 2021, and pragmatically classified their level of recovery one year into the pandemic using the percentage change in the median practice level rate. We produced 11 measures reflective of clinical activity in general practice. A substantial drop in activity was observed in all measures at the outset of the COVID-19 pandemic. By April 2021, the median rate had recovered to within 15% of the median rate in April 2019 in six measures. The remaining measures showed a sustained drop, ranging from a 18.5% reduction in medication reviews to a 42.0% reduction in blood pressure monitoring. Three measures continued to show a sustained drop by December 2021. The COVID-19 pandemic was associated with a substantial change in primary care activity across the measures we developed, with recovery in most measures. We delivered an open source software framework to describe trends and variation in clinical activity across an unprecedented scale of primary care data. We will continue to expand the set of key measures to be routinely monitored using our publicly available NHS OpenSAFELY SRO dashboards with near real-time data. This research used data assets made available as part of the Data and Connectivity National Core Study, led by Health Data Research UK in partnership with the Office for National Statistics and funded by UK Research and Innovation (grant ref MC_PC_20058).The OpenSAFELY Platform is supported by grants from the Wellcome Trust (222097/Z/20/Z); MRC (MR/V015757/1, MC_PC-20059, MR/W016729/1); NIHR (NIHR135559, COV-LT2-0073), and Health Data Research UK (HDRUK2021.000, 2021.0157).

Come Together, Right Now? An Empirical Study of Collaborations in the Music Industry

Artist collaborations in music have been on the rise, and they tend to produce commercially and critically successful songs. We seek to uncover the effect of these collaborative projects on career trajectories and identify the factors that lift an artist’s profile in the short and long term. We develop a theory of collaboration based on the transfer of capital between the collaborating artists that facilitates spillovers across time. To validate the theory, we use weekly radio plays of individual songs across 25 European countries between the years 2011 to 2018, together with a multiattribute Spotify data set of songs and Hofstede’s cultural dimensions in relation to artist origins. We create pairs of similar artists who released a collaboration and a solo song in the same week and measure the impact of collaborations based on the difference-in-differences methodology. We find that releasing a collaboration song, in comparison with a solo song, increases the number of plays of an artist in the future by +4.6%. This lift can be broken down into +9.6% for the current song and +7.7% for subsequently released songs, whereas past songs are unaffected. The effect is moderated by the difference in economic, social, and cultural capitals and is significantly larger when one’s partner has higher economic and social capital or is highly dissimilar along the cultural dimension. Our theoretical and empirical exploration of such strategic alliances uncovers several underlying mechanisms at play in the success of these pairings and can serve as the basis for future work targeted at prescriptive contributions. This paper was accepted by David Simchi-Levi, operations management. Funding: The research was supported by the Spanish Ministry of Science and Innovation (Ministerio de Ciencia e Innovación) [Grant Ref. PID2020-116135GB-I00/AEI/10.13039/501100011033]. Supplemental Material: The online appendix and data are available at https://doi.org/10.1287/mnsc.2023.4743 .

Antibody levels following vaccination against SARS-CoV-2: associations with post-vaccination infection and risk factors in two UK longitudinal studies.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody levels can be used to assess humoral immune responses following SARS-CoV-2 infection or vaccination, and may predict risk of future infection. Higher levels of SARS-CoV-2 anti-Spike antibodies are known to be associated with increased protection against future SARS-CoV-2 infection. However, variation in antibody levels and risk factors for lower antibody levels following each round of SARS-CoV-2 vaccination have not been explored across a wide range of socio-demographic, SARS-CoV-2 infection and vaccination, and health factors within population-based cohorts. Samples were collected from 9361 individuals from TwinsUK and ALSPAC UK population-based longitudinal studies and tested for SARS-CoV-2 antibodies. Cross-sectional sampling was undertaken jointly in April-May 2021 (TwinsUK, N=4256; ALSPAC, N=4622), and in TwinsUK only in November 2021-January 2022 (N=3575). Variation in antibody levels after first, second, and third SARS-CoV-2 vaccination with health, socio-demographic, SARS-CoV-2 infection, and SARS-CoV-2 vaccination variables were analysed. Using multivariable logistic regression models, we tested associations between antibody levels following vaccination and: (1) SARS-CoV-2 infection following vaccination(s); (2) health, socio-demographic, SARS-CoV-2 infection, and SARS-CoV-2 vaccination variables. Within TwinsUK, single-vaccinated individuals with the lowest 20% of anti-Spike antibody levels at initial testing had threefold greater odds of SARS-CoV-2 infection over the next 6-9 months (OR = 2.9, 95% CI: 1.4, 6.0), compared to the top 20%. In TwinsUK and ALSPAC, individuals identified as at increased risk of COVID-19 complication through the UK 'Shielded Patient List' had consistently greater odds (two- to fourfold) of having antibody levels in the lowest 10%. Third vaccination increased absolute antibody levels for almost all individuals, and reduced relative disparities compared with earlier vaccinations. These findings quantify the association between antibody level and risk of subsequent infection, and support a policy of triple vaccination for the generation of protective antibodies. Antibody testing was funded by UK Health Security Agency. The National Core Studies program is funded by COVID-19 Longitudinal Health and Wellbeing - National Core Study (LHW-NCS) HMT/UKRI/MRC ([MC_PC_20030] and [MC_PC_20059]). Related funding was also provided by the NIHR 606 (CONVALESCENCE grant [COV-LT-0009]). TwinsUK is funded by the Wellcome Trust, Medical Research Council, Versus Arthritis, European Union Horizon 2020, Chronic Disease Research Foundation (CDRF), Zoe Ltd and the National Institute for Health Research (NIHR) Clinical Research Network (CRN) and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust in partnership with King's College London. The UK Medical Research Council and Wellcome (Grant ref: [217065/Z/19/Z]) and the University of Bristol provide core support for ALSPAC.

High Dose Methotrexate Does Not Reduce the Risk of CNS Relapse in Children and Young Adults with Acute Lymphoblastic Leukaemia and Lymphoblastic Lymphoma. Results of the Randomised Phase III Study UKALL 2011

Introduction UKALL 2011 randomised children and young adults (up to 25) with Acute Lymphoblastic Leukaemia (ALL) or Lymphoblastic Lymphoma (LBL). The aims were to reduce induction toxicity (R1: Short [14 days] vs Standard [28 days] dexamethasone), CNS relapse risk (R2IM: HD MTX (HDM) vs standard interim maintenance (SIM)) and maintenance morbidity (R2pulses: Vincristine (VCR)/dexamethasone pulses or not). R1 results were presented at ASH 2017 and did not show a reduction in toxicity with short dexamethasone. Results of R2IM and R2pulses are reported here. Patients and Methods Patients were stratified by NCI risk, cytogenetics and end of induction MRD to receive Regimens A (NCI standard risk, MRD low risk), B (NCI high risk, MRD low risk) or C (Cytogenetic poor risk or MRD intermediate risk regardless of NCI risk). MRD high risk (end of consolidation MRD >0.5%, n=14) were not eligible for randomisation and received off protocol therapy. R2 was a factorial randomisation stratified by factors including NCI and MRD risk groups and resulted in 4 arms: HDM with pulses, HDM without pulses, standard interim maintenance (SIM) with pulses (standard of care) and SIM without pulses. SIM was for 2 months with oral mercaptopurine/MTX, monthly pulses and single IT MTX in Regimens A and B, and 5 doses of escalating IV MTX (Capizzi) + VCR + 2 doses of Pegylated asparaginase in Regimen C. HDM was given at a dose of 5g/m2 x 4 doses 2 weeks apart, low dose 6-MP and 2 doses of Pegylated asparaginase (Regimen C only). The primary endpoint for R2IM was the CNS relapse rate (CNSR) and for R2pulses was the bone marrow relapse rate (BMR) in ALL only; non-inferiority, 5% margin at 5 years. Event Free Survival (EFS) was considered a primary endpoint for both. Results Of the 2750 patients registered on trial between April 2012 and December 2018, 1902 were randomised to R1 (closed April 2017) and 1570 to R2. Median age 5 years (IQR: 3-11), 83% B-ALL, 12% T-ALL, 1% B-LBL and 4% T-ABL, 43% NCI high risk. Median follow-up for R1 is 76 months and R1 or R2 is 72 months. Overall, we found no difference in CNSR (HR: 0.99 (0.65-1.51), p=0.97, 5-year rates: 5.6% and 5.6%), or any other endpoints for R2IM. However, there was an interaction between the R1 and R2IM randomisations (p=0.006 for EFS) with inferior outcomes for patients treated with short dexamethasone followed by HDM, particularly in those who did not receive pulses (Figure 1). Limiting analyses to patients treated with standard dexamethasone (N=995, including those that received it after closure of R1) there was a significant reduction in BMR rate with HDM (HR 0.62 (95% CI: 0.40 - 0.95) p = 0.029) and a trend for improvements in EFS and OS (HRs: 0.75 (95%CI: 0.53 - 1.04), p=0.087 and 0.61 (0.37 - 1.03), p=0.067) but no difference in CNSR. In subgroup analyses there were no significant interactions, but the effect appeared stronger for B-lineage, NCI high risk and MRD low risk patients (Figure 2). Overall, the BMR for R2pulses was non-inferior (+2.1% increase BMR at 5 years for ALL patients (95% CI: -1.4% to 4.7%), HR 1.22 (95%CI: 0.89 - 1.67). Considering all four R2 treatment arms in standard dexamethasone only, standard IM without pulses has a lower EFS, whilst there is no appreciable benefit of pulses in HDM treated patients; 5-year EFS difference: -2.8% (95% CI: -7.4% to 4.4%) and BMR (ALL): +0.4% (-6.7% to 4.3%). Conclusions HDM does not improve CNSR within a UKALL treatment backbone, but pre-specified analyses suggest it may improve BMR for some sub-groups of B-lineage patients when given following standard dexamethasone induction. Although the 'no pulses' arm was non-inferior overall for BMR, further sub-group and toxicity analyses are to be performed and will presented at the meeting. Acknowledgements Children with Cancer, Blood Cancer (grant ref 09042) and Cancer Research UK funded the trial. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Abortion decision-making process trajectories and determinants in low- and middle-income countries: A mixed-methods systematic review and meta-analysis.

SummaryBackgroundAbout 45.1% of all induced abortions are unsafe and 97% of these occur in low- and middle-income countries (LMICs). Women's abortion decisions may be complex and are influenced by various factors. We aimed to delineate women's abortion decision-making trajectories and their determinants in LMICs.MethodsWe searched Medline, EMBASE, PsychInfo, Global Health, Web of Science, Scopus, IBSS, CINAHL, WHO Global Index Medicus, the Cochrane Library, WHO website, ProQuest, and Google Scholar for primary studies and reports published between January 1, 2000, and February 16, 2021 (updated on June 06, 2022), on induced abortion decision-making trajectories and/or their determinants in LMICs. We excluded studies on spontaneous abortion. Two independent reviewers extracted and assessed quality of each paper. We used “best fit” framework synthesis to synthesise abortion decision-making trajectories and thematic synthesis to synthesise their determinants. We analysed quantitative findings using random effects model. The study protocol is registered with PROSPERO number CRD42021224719.FindingsOf the 6960 articles identified, we included 79 in the systematic review and 14 in the meta-analysis. We identified nine abortion decision-making trajectories: pregnancy awareness, self-reflection, initial abortion decision, disclosure and seeking support, negotiations, final decision, access and information, abortion procedure, and post-abortion experience and care. Determinants of trajectories included three major themes of autonomy in decision-making, access and choice. A meta-analysis of data from 7737 women showed that the proportion of the overall women's involvement in abortion decision-making was 0.86 (95% CI:0.73–0.95, I2 = 99.5%) and overall partner involvement was 0.48 (95% CI:0.29–0.68, I2 = 99.6%).InterpretationPolicies and strategies should address women's perceptions of safe abortion socially, legally, and economically, and where appropriate, involvement of male partners in abortion decision-making processes to facilitate safe abortion. Clinical heterogeneity, in which various studies defined “the final decision-maker” differentially, was a limitation of our study.FundingNuffield Department of Population Health DPhil Scholarship for PL, University of Oxford, and the Medical Research Council Career Development Award for MN (Grant Ref: MR/P022030/1).

Prioritization of THose aWaiting hip and knee ArthroplastY(PATHWAY): protocol for development of a stakeholder led clinical prioritization tool.

The extended wait that most patients are now experiencing for hip and knee arthroplasty has raised questions about whether reliance on waiting time as the primary driver for prioritization is ethical, and if other additional factors should be included in determining surgical priority. Our Prioritization of THose aWaiting hip and knee ArthroplastY (PATHWAY) project will explore which perioperative factors are important to consider when prioritizing those on the waiting list for hip and knee arthroplasty, and how these factors should be weighted. The final product will include a weighted benefit score that can be used to aid in surgical prioritization for those awaiting elective primary hip and knee arthroplasty. There will be two linked work packages focusing on opinion from key stakeholders (patients and surgeons). First, an online modified Delphi process to determine a consensus set of factors that should be involved in patient prioritization. This will be performed using standard Delphi methodology consisting of multiple rounds where following initial individual rating there is feedback, discussion, and further recommendations undertaken towards eventual consensus. The second stage will then consist of a Discrete Choice Experiment (DCE) to allow for priority setting of the factors derived from the Delphi through elicitation of weighted benefit scores. The DCE consists of several choice tasks designed to elicit stakeholder preference regarding included attributes (factors). The study is co-funded by the University of Aberdeen Knowledge Exchange Commission (Ref CF10693-29) and a Chief Scientist Office (CSO) Scotland Clinical Research Fellowship which runs from 08/2021 to 08/2024 (Grant ref: CAF/21/06). Approval from the University of Aberdeen Institute of Applied Health Sciences School Ethics Review Board was granted 22/03/2022 - Reference number SERB/2021/12/2210. The PATHWAY project provides the first attempt to use patient and surgeon opinions to develop a unified approach to prioritization for those awaiting hip and knee arthroplasty. Development of such a tool will provide more equitable access to arthroplasty services, as well as providing a framework for developing similar approaches in other areas of healthcare delivery.Cite this article: Bone Jt Open2022;3(10):753-758.

Pre-clinical evaluation of antiviral activity of nitazoxanide against SARS-CoV-2.

SummaryBackgroundTo address the emergence of SARS-CoV-2, multiple clinical trials in humans were rapidly started, including those involving an oral treatment by nitazoxanide, despite no or limited pre-clinical evidence of antiviral efficacy.MethodsIn this work, we present a complete pre-clinical evaluation of the antiviral activity of nitazoxanide against SARS-CoV-2.FindingsFirst, we confirmed the in vitro efficacy of nitazoxanide and tizoxanide (its active metabolite) against SARS-CoV-2. Then, we demonstrated nitazoxanide activity in a reconstructed bronchial human airway epithelium model. In a SARS-CoV-2 virus challenge model in hamsters, oral and intranasal treatment with nitazoxanide failed to impair viral replication in commonly affected organs. We hypothesized that this could be due to insufficient diffusion of the drug into organs of interest. Indeed, our pharmacokinetic study confirmed that concentrations of tizoxanide in organs of interest were always below the in vitro EC50.InterpretationThese preclinical results suggest, if directly applicable to humans, that the standard formulation and dosage of nitazoxanide is not effective in providing antiviral therapy for Covid-19.FundingThis work was supported by the Fondation de France “call FLASH COVID-19”, project TAMAC, by “Institut national de la santé et de la recherche médicale” through the REACTing (REsearch and ACTion targeting emerging infectious diseases), by REACTING/ANRS MIE under the agreement No. 21180 (‘Activité des molécules antivirales dans le modèle hamster’), by European Virus Archive Global (EVA 213 GLOBAL) funded by the European Union's Horizon 2020 research and innovation program under grant agreement No. 871029 and DNDi under support by the Wellcome Trust Grant ref: 222489/Z/21/Z through the COVID-19 Therapeutics Accelerator”.

May the brief physical activity assessment tool accurately measure physical activity in patients with resistant hypertension?

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): FEDER Funds through the Operational Competitiveness Factors Program—COMPETE National Funds through the Portuguese Foundation for Science and Technology (FCT) “PTDC/DTP-DES/1725/2014”. SL is a PhD fellow supported by the FCT (Grant Ref: SFRH/BD/129454/2017). Introduction Resistant hypertension is a major health problem due to the increased risk of cardiovascular events and mortality. Physical activity and exercise reduces blood pressure in resistant hypertension and is associated with lower cardiovascular risk and mortality. It is presently recommended that physical activity assessment should be a priority in all visits to health settings Purpose This study aims to determine if the Brief Physical Activity Assessment Tool (BPAAT), a 2-question tool to assess physical activity, is a valid instrument to detect inactive patients with resistant hypertension. Methods Sixty patients with a diagnosis of resistant hypertension were recruited. Outcome measures included clinical data, blood pressure and daily physical activity. Physical activity was objectively measured over a 7-day period with an accelerometer and subjectively assessed (self-assessment) by the BPAAT. The association between the BPAAT and accelerometry, according to the BPAAT scoring categories, was assessed bythe percentage of agreement, Cohen’s Kappa and sensitivity and specificity. Results Patients (33 were male) had a mean age of 59.4 ± 9.1years, were on average overweight (BMI 29.5 ± 4.5 kg/m2) and on an average of 4.5 ± 0.7 antihypertensive medications. Forty-two patients (70%) were classified as insufficiently active by the BPAAT compared to the 38 (63.3%) insufficiently active patients identified by the accelerometry data. Regarding the questionnaire’s specificity and sensitivity, the BPAAT correctly identified 32 [84.2 (73.1 – 95.3) %] of the 38 ‘insufficiently active’ patients and 12 [54.5 (34.3 – 74.7) %] of the 22 ‘sufficiently active’ patients identified by accelerometry. The agreement between BPAAT and accelerometry to identify sufficiently/insufficiently active patients, according to the BPAAT’s cut-off values was fair to moderate (Kappa = 0.403 (0.162 – 0.674), with a percentage of agreement of 73.3%. Conclusion The BPAAT, a 2-question tool to assess physical activity, seems to be a valid and fast solution to identify insufficiently active adults with resistant hypertension during routine clinical visits.

Association of medically assisted reproduction with offspring cord blood DNA methylation across cohorts.

STUDY QUESTIONIs cord blood DNA methylation associated with having been conceived by medically assisted reproduction?SUMMARY ANSWERThis study does not provide strong evidence of an association of conception by medically assisted reproduction with variation in infant blood cell DNA methylation.WHAT IS KNOWN ALREADYMedically assisted reproduction consists of procedures used to help infertile/subfertile couples conceive, including ART. Due to its importance in gene regulation during early development programming, DNA methylation and its perturbations associated with medically assisted reproduction could reveal new insights into the biological effects of assisted reproductive technologies and potential adverse offspring outcomes.STUDY DESIGN, SIZE, DURATIONWe investigated the association of DNA methylation and medically assisted reproduction using a case–control study design (N = 205 medically assisted reproduction cases and N = 2439 naturally conceived controls in discovery cohorts; N = 149 ART cases and N = 58 non-ART controls in replication cohort).PARTICIPANTS/MATERIALS, SETTINGS, METHODSWe assessed the association between medically assisted reproduction and DNA methylation at birth in cord blood (205 medically assisted conceptions and 2439 naturally conceived controls) at >450 000 CpG sites across the genome in two sub-samples of the UK Avon Longitudinal Study of Parents and Children (ALSPAC) and two sub-samples of the Norwegian Mother, Father and Child Cohort Study (MoBa) by meta-analysis. We explored replication of findings in the Australian Clinical review of the Health of adults conceived following Assisted Reproductive Technologies (CHART) study (N = 149 ART conceptions and N = 58 controls).MAIN RESULTS AND THE ROLE OF CHANCEThe ALSPAC and MoBa meta-analysis revealed evidence of association between conception by medically assisted reproduction and DNA methylation (false-discovery-rate-corrected P-value < 0.05) at five CpG sites which are annotated to two genes (percentage difference in methylation per CpG, cg24051276: Beta = 0.23 (95% CI 0.15,0.31); cg00012522: Beta = 0.47 (95% CI 0.31, 0.63); cg17855264: Beta = 0.31 (95% CI 0.20, 0.43); cg17132421: Beta = 0.30 (95% CI 0.18, 0.42); cg18529845: Beta = 0.41 (95% CI 0.25, 0.57)). Methylation at three of these sites has been previously linked to cancer, aging, HIV infection and neurological diseases. None of these associations replicated in the CHART cohort. There was evidence of a functional role of medically assisted reproduction-induced hypermethylation at CpG sites located within regulatory regions as shown by putative transcription factor binding and chromatin remodelling.LIMITATIONS, REASONS FOR CAUTIONSWhile insufficient power is likely, heterogeneity in types of medically assisted reproduction procedures and between populations may also contribute. Larger studies might identify replicable variation in DNA methylation at birth due to medically assisted reproduction.WIDER IMPLICATIONS OF THE FINDINGSNewborns conceived with medically assisted procedures present with divergent DNA methylation in cord blood white cells. If these associations are true and causal, they might have long-term consequences for offspring health.STUDY FUNDING/COMPETING INTERESTS(S)This study has been supported by the US National Institute of Health (R01 DK10324), the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007-2013)/ERC Grant agreement no. 669545, European Union’s Horizon 2020 research and innovation programme under Grant agreement no. 733206 (LifeCycle) and the NIHR Biomedical Centre at the University Hospitals Bristol NHS Foundation Trust and the University of Bristol. The UK Medical Research Council and Wellcome (Grant ref: 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. Methylation data in the ALSPAC cohort were generated as part of the UK BBSRC funded (BB/I025751/1 and BB/I025263/1) Accessible Resource for Integrated Epigenomic Studies (ARIES, http://www.ariesepigenomics.org.uk). D.C., J.J., C.L.R. D.A.L and H.R.E. work in a Unit that is supported by the University of Bristol and the UK Medical Research Council (Grant nos. MC_UU_00011/1, MC_UU_00011/5 and MC_UU_00011/6). B.N. is supported by an NHMRC (Australia) Investigator Grant (1173314). ALSPAC GWAS data were generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. The Norwegian Mother, Father and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research, NIH/NIEHS (Contract no. N01-ES-75558), NIH/NINDS (Grant nos. (i) UO1 NS 047537-01 and (ii) UO1 NS 047537-06A1). For this work, MoBa 1 and 2 were supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01-ES-49019) and the Norwegian Research Council/BIOBANK (Grant no. 221097). This work was partly supported by the Research Council of Norway through its Centres of Excellence funding scheme, Project no. 262700.D.A.L. has received support from national and international government and charity funders, as well as from Roche Diagnostics and Medtronic for research unrelated to this study. The other authors declare no conflicts of interest.TRIAL REGISTRATION NUMBERN/A.

How Prepared Were Households for COVID-19? Implications for Young Children in 45 Low- and Middle-Income Countries

Background: COVID-19 and governments&rsquo; attempts to contain the pandemic are having many negative impacts on young children&rsquo;s health and development, including confining them and their families to their homes. However, little is known about levels of household preparedness for protecting young children from the direct and indirect effects of the pandemic in low- and middle-income countries&rsquo; (LMICs). Methods: Using data from nationally-representative household surveys (Demographic and Health Surveys, Multiple Indicator Cluster Surveys) in 45 LMICs since 2016, we estimated the percentages of young children living in households prepared for the pandemic and associated socioeconomic disparities. Preparedness was defined on the basis of space for quarantine, adequacy of toilet facilities and hand hygiene, mass media exposure, and phone ownership. The assessment was made at the country and aggregate levels. The final data set included 681,682 children under age five. Findings: Of all young children in the sample, only 19&middot;6% (95% CI, 16&middot;8%-22&middot;4%) lived in households prepared for COVID-19, ranging from 0&middot;6% in Ethiopia (95% CI, 0&middot;3-0&middot;9%) in 2016 to 70&middot;9% (95% CI, 68&middot;4-73&middot;4%) in Tunisia in 2018. In close to 90% of countries (40), fewer than 50% of young children lived in prepared households and fewer than 10% in 23 countries. Young children in rural areas or in the poorest households were less likely to live in prepared households than their counterparts, with an average gap of 11&middot;2 (95% CI, 9&middot;2-13&middot;3) and 34&middot;3 (95% CI, 26&middot;9-41&middot;7) percentage points, respectively. In 28 countries, fewer than 1% of young children in the poorest wealth quintiles lived in households prepared for the COVID-19, mostly concentrated in sub-Saharan Africa. Interpretation: A large portion of young children in 45 LMICs were not protected from COVID-19 in their homes and were at risk of worsening health and development. Global and national investments are urgently needed to improve housing conditions needed to prevent spread of COVID and other communicable diseases. Funding Statement: UKRI Collective Fund Award (Grant Ref: ES/T003936/1) to the University of Oxford, &ldquo;UKRI GCRF Harnessing the power of global data to support young children's learning and development: Analyses, dissemination and implementation&rdquo; Declaration of Interests: The authors declare no competing interests.

B Cell Receptor Repertoire Kinetics after SARS-CoV-2 Infection and Vaccination

B cells play a central role in the immune response to both SARS-CoV-2 infection and vaccination, but the development of the B cell receptor (BCR) repertoire in both contexts has not been defined nor compared. We analysed serial samples from 171 SARS-CoV-2-infected individuals with a range of disease severities together with 63 vaccine recipients, and found marked differences in the global BCR repertoire after natural infection compared to vaccination. Following infection, the proportion of BCRs bearing IgG1/3 and IgA1 isotypes increased, somatic hypermutation (SHM) was markedly decreased and, in patients with severe disease, expansion of IgM and IgA clones was observed. In contrast, after vaccination the proportion of BCRs bearing IgD/M isotypes increased, SHM was unchanged and expansion of IgG clones was prominent. Infection generated a broad distribution of SARS-CoV-2-specific clones predicted to target the spike protein whilst vaccination produced a more focused response mainly targeting the spike’s receptor-binding domain. These findings offer insights into how different immune exposure to SARS-CoV-2 impacts upon BCR repertoire development, potentially informing vaccine strategies.Funding: We are grateful to CVC Capital Partners, the Evelyn Trust (20/75), Addenbrooke's Charitable Trust, Cambridge University Hospitals (12/20A), the NIHR Cambridge Biomedical Research Centre, and the UKRI/NIHR through the UK Coronavirus Immunology Consortium (UK-CIC) for their financial support. Further support: K.G.C.S.: Wellcome Investigator Award (200871/Z/16/Z); C.H.: Wellcome COVID-19 Rapid Response DCF and the Fondation Botnar; N.M.: MRC (CSF MR/P008801/1), NHSBT (WPA15-02), and Addenbrooke's Charitable Trust, (grant ref. to 900239 NJM); I.G.G.: Wellcome Senior Fellowship and Wellcome grant (Ref: 207498/Z/17/Z); N.M. was funded by the MRC (CSF MR/P008801/1), NHSBT (WPA15-02) and Addenbrooke’s Charitable Trust (grant ref. to 900239 NJM); RKG is supported by a Wellcome Trust Senior Fellowship in Clinical Science (WT108082AIA). Z.K.T. and M.R.C. are supported by a Medical Research Council Human Cell Atlas Research Grant (MR/S035842/1). M.R.C is supported by an NIHR Research Professorship (RP-2017-08-ST2- 002). P.K. is the recipient of a Jacquot Research Entry Scholarship of the Royal Australasian College of Physicians Foundation. W.M.R. is funded by the Wellcome Trust (216382/Z/19/Z). We would like to thank the NIHR Cambridge Clinical Research Facility outreach team for enrolment of patients; the NIHR Cambridge Biomedical Research Centre Cell Phenotyping Hub and the CRUK Cambridge Institute flow cytometry core facility for flow and mass cytometry; and the Cambridge NIHR BRC Stratified Medicine Core Laboratory NGS Hub (supported by an MRC Clinical Infrastructure Award) for BCR sequencing. Declaration of Interests: The authors declare they have no competing interests.Ethics Approval Statement: Ethical approval was obtained from the East of England – Cambridge Central Research Ethics Committee (“NIHR BioResource” REC ref 17/EE/0025, and “Genetic variation AND Altered Leucocyte Function in health and disease - GANDALF” REC ref 08/H0308/176). All participants provided informed consent.

Influenza, Shingles and Pneumococcal Vaccine Uptake, Offer and Refusal in Adult Populations at High-Risk for COVID-19: A UK Population-Based Cohort Study

Background: As COVID-19 vaccination programs are being rolled out globally, we studied the ethnic, deprivation, household size and comorbidity ‘patterning’ of existing vaccination programs in populations at high-risk for COVID-19, to inform risk-stratified vaccination strategies and mitigate health inequalities. Methods: A population-level cohort study of UK adults aged 65 years or older, using a large primary care database. We used multivariable logistic regression to assess uptake of influenza, pneumococcal and shingles vaccination across ethnic groups, deprivation quintile, household size, and comorbidities, computing odds ratios (OR) adjusted for age, sex, demographics, body mass index and smoking. Offers and refusals of each vaccination type were analysed in those not receiving them. Findings: The cohort comprised 2,054,463 patients from 1,318 general practices. 1,452,014 (70.7%) patients received influenza vaccine, 1,391,228 (67.7%) received pneumococcal vaccine, and 690,783 (53.4%) received shingles vaccine. Compared to Whites, influenza vaccination uptake was lower in Pakistani (adjusted odds ratio (OR) 0.82; 99% confidence interval: 0.74-0.90), Black Caribbean (OR 0.46; 0.43-0.48), Black African (OR 0.63; 0.58-0.68), Chinese (OR 0.70; 0.64-0.76) and ‘Other ethnic group’ (OR 0.65; 0.63-0.69). The Black Caribbean group had higher vaccination refusal than the White group for influenza vaccination (OR 1.17; 1.05-1.30). Vaccination uptake was lower among the more deprived and those living in household sizes above 3 or more persons, with some significant interactions between ethnicity and comorbidities. Uptake of all three vaccines was higher in those with asthma, COPD, type 2 diabetes, hypertension and learning disability, whilst lower in those with dementia. Interpretation: Whilst uptake and refusal of influenza, shingles and pneumococcal vaccination are patterned by ethnicity, deprivation, household size and comorbidities, vaccination offer is mostly patterned by comorbidities. This information can inform national policies to ensure equitable implementation of COVID-19 vaccination programs to avoid exacerbating health inequalities.Funding Statement: This project was funded by the Medical Research Council (Grant Ref: MR/V027778/1).Declaration of Interests: PST reports previous consultation with AstraZeneca and Duke-NUS outside the submitted work. KK is a Member of the Scientific Advisory Group for Emergencies (SAGE), Member of Independent SAGE, Director of the University of Leicester Centre for Black Minority Health and Trustee of the south Asian Health Foundation. JHC is a member of several SAGE committees and chair of the risk stratification subgroup of the NERVTAG. She is unpaid director of QResearch and founder and former medical director of ClinRisk Ltd (outside the submitted work). MP, AKC, HDM, DS, TAR, FZ, BRS, SJG, CC, CG have no interests to declare.

Maternal Obesity Before Pregnancy Predicts Offspring Blood Pressure at 18 Years of Age – A Causal Mediation Analysis

Background: Hypertension is the second most common pediatric chronic disease in Westernized countries. Understanding the natural history of hypertension is key to identifying prevention strategies. The present study will examine the relationship between maternal pre-pregnancy body mass index (BMI) and the possible mediating role of growth throughout childhood and adolescence on offspring blood pressure at 18 years. Methods: We performed multivariable regression and causal mediation analyses within 3217 mother - offspring pairs from the Avon Longitudinal Study of Parents and Children (ALSAPC) prospective birth cohort. The main exposure was maternal pre-pregnancy BMI. Latent trajectory analysis (LTA) was used to quantify the mediating variable of offspring BMI Z scores from 7 to 18 years of age. The main outcome was offspring blood pressure at 18 years of age categorized as normal or elevated as per the 2017 American Academy of Pediatrics guidelines. Findings: At 18 years of age, among 3217 offspring, 676 (21%) were overweight or obese, 865 (27%) had elevated blood pressure, and 510 (16%) were hypertensive. LTA identified five distinct offspring BMI trajectories. Multivariable logistic regression revealed that for every 1 unit increase in maternal BMI the risk of elevated blood pressure at 18 years of age increased by 5% (aOR: 1.05, 95% CI: 1.03 – 1.07; p <0.001) and this effect was reduced after adjusting for offspring BMI trajectory (aOR: 1.03, 95% CI: 1.00 – 1.05; p = 0.017). Causal mediation analysis confirmed offspring BMI trajectory as a mediator, accounting for 46% of the total effect of maternal BMI on elevated offspring blood pressure (aOR 1.22; 95% CI: 1.07-1.39). Interpretation: Maternal BMI prior to pregnancy is associated with an increased risk of elevated blood pressure in offspring at 18 years of age and is largely mediated by offspring BMI trajectory throughout childhood and adolescence. Funding Statement: The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. A comprehensive list of grants funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf). JMM was supported by a Canadian Institute of Health Research (CIHR) Applied Public Health Chair, MBA holds a Tier 2 Canada Research Chair (CRC) in the Developmental Origins of Chronic Disease. JMM holds grants from the CIHR, Diabetes Canada, the Heart and Stroke Foundation (HSF), the Cosmopolitan Foundation, and the Lawson Foundation. AD currently has research funding from CIHR, Research Manitoba and CHRIM. MBA holds grants from the CIHR, The Bill and Melinda Gates Foundation, the Canada Foundation for Innovation, the Garfield G. Weston Foundation, Prolacta Biosciences, Mitacs, the Canadian Institutes for Advanced Research, the Children’s Hospital Foundation of Manitoba, and Research Manitoba; NB and Drs JMM, MBA and AD were also supported by a Research Manitoba grant to the DEVOTION research cluster. Declaration of Interests: None of the authors report potential or actual conflicts of interest. All authors have completed and submitted a Conflict of Interest Statement. Ethics Approval Statement: Ethical approval was obtained from the ALSPAC Law and Ethics Committee and the Biomedical Research Ethics Board at the University of Manitoba. Informed consent for the use of data collected via questionnaires and clinics was obtained from participants following the recommendations of the ALSPAC Ethics and Law Committee at the time.

Effect of HIV Infection on Growth and Bone Density in Peripubertal Children in the Era of Antiretroviral Therapy: A Cross-Sectional Study in Zimbabwe

Background: Poor linear growth and pubertal delay, both common in children with HIV (CWH) in sub-Saharan Africa, may affect adolescent bone accrual and future fragility fracture risk. We investigated the association of HIV with size-adjusted bone density in peri-pubertal children in Zimbabwe. Methods: CWH aged 8-16 years taking ART for ≥2 years from public-sector HIV clinics in Harare, and HIV-uninfected children from schools in the same catchment area, were recruited into a cross-sectional study. Sociodemographic, clinical and anthropometric data were collected. Outcomes were dual-energy X-ray absorptiometry (DXA) measured total-body less-head bone mineral content-for-lean mass adjusted for height (TBLH-BMCLBM) and lumbar spine bone mineral apparent density (LS-BMAD). Linear regression models using multiple imputation for missing data, assessed relationships between risk factors and DXA measures by HIV status, and interaction by sex and pubertal (Tanner) stage. Findings: We recruited 303 CWH and 306 without HIV, mean (SD) age 12.5 (2.5) years and 50% female. Mean ART duration was 7.9 (2.6) years; for 34% ART included tenofovir disproxil fumarate (TDF). The prevalence of low TBLH-BMCLBM and LS-BMAD (Z-Score<-2) was higher in children with than without HIV (10.4% vs. 6.2%, p=0.066; 14.3% vs. 5.8%, p=0.001 respectively). HIV and male sex were associated with earlier Tanner stage. The negative effects of HIV on TBLH-BMCLBM and LS-BMAD were more pronounced with pubertal maturation, particularly in females. Among CWH, years of TDF exposure and orphanhood were strongly associated with lower TBLH-BMCLBM Z-Score in both unadjusted and adjusted analyses. Current TDF use was associated with 0.40 (95%CI 0.07, 0.73; p=0.018) and 0.31 (0.07, 0.69; p=0.110) lower TBLH-BMCLBM and LS-BMAD Z-Scores respectively. Interpretation: Despite ART, HIV is associated with substantial skeletal deficits by the end of puberty. The size of bone deficits associated with TDF and its widespread use in children in sub-Saharan Africa raise concern for future adult fracture risk. Funding Statement: Wellcome Trust. Declaration of Interests: RR (206764/Z/17/Z) RAF (206316/Z/17/Z) are funded by the Wellcome Trust. CK is funded by a National Institute of Health (NIH) Fogarty Trent Fellowship. AMR is partially supported by the UK Medical Research Council (MRC) and the UK Department for International Development (DFID) under the MRC/DFID Concordat agreement which is also part of the EDCTP2 programme supported by the European Union Grant Ref: MR/R010161/1. All other authors declare no competing interests. Ethics Approval Statement: Ethical and governance approvals were granted by the London School of Hygiene and Tropical Medicine Ethics Committee (Ref: 15333), the Institutional Review Board of the Biomedical Research and Training Institute in Harare (Ref: AP145/2018), the Joint Research Ethics Committee for University of Zimbabwe College of Health Sciences and the Parirenyatwa Group of Hospitals (Ref: 11/18), Harare Central Hospital Ethics Committee (Ref: 170118/04), the Medical Research Council of Zimbabwe (Ref: MRCZ/A/2297) and the Ministry of Primary and Secondary Education Zimbabwe (Ref: C/426/Harare). Guardians provided written informed consent and children provided written assent.

Markov chain simulation for multilevel Monte Carlo

AJ was supported by an AcRF tier 2 grant: R-155-000-161-112. AJ is affiliated with the Risk Management Institute, the Center for Quantitative Finance and the OR & Analytics cluster at NUS. AJ was supported by a KAUST CRG4 grant ref: 2584. KJHL was supported by the University of Manchester School of Mathematics.

Puberty timing and adiposity change across childhood and adolescence: disentangling cause and consequence.

STUDY QUESTIONIs earlier puberty more likely a result of adiposity gain in childhood than a cause of adiposity gain in adulthood?SUMMARY ANSWERPre-pubertal fat mass is associated with earlier puberty timing but puberty timing is not associated with post-pubertal fat mass change.WHAT IS KNOWN ALREADYAge at puberty onset has decreased substantially in the last several decades. Whether reducing childhood adiposity prevents earlier puberty and if early puberty prevention itself also has additional independent benefits for prevention of adult adiposity is not well understood.STUDY DESIGN, SIZE, DURATIONProspective birth cohort study of 4176 participants born in 1991/1992 with 18 232 repeated measures of fat mass from age 9 to 18 years.PARTICIPANTS/MATERIALS, SETTING, METHODSWe used repeated measures of height from 5 to 20 years to identify puberty timing (age at peak height velocity, aPHV) and repeated measures of directly measured fat mass from age 9 to 18 years, from a contemporary UK birth cohort study to model fat mass trajectories by chronological age and by time before and after puberty onset. We then examined associations of these trajectories with puberty timing separately in females and males.MAIN RESULTS AND THE ROLE OF CHANCEIn models by chronological age, a 1-year later aPHV was associated with 20.5% (95% confidence interval (CI): 18.6–22.4%) and 23.4% (95% (CI): 21.3–25.5%) lower fat mass in females and males, respectively, at 9 years. These differences were smaller at age 18 years: 7.8% (95% (CI): 5.9–9.6%) and 12.4% (95% (CI): 9.6–15.2%) lower fat mass in females and males per year later aPHV. Trajectories of fat mass by time before and after puberty provided strong evidence for an association of pre-pubertal fat mass with puberty timing, and little evidence of an association of puberty timing with post-pubertal fat mass change. The role of chance is likely to be small in this study given the large sample sizes available.LIMITATIONS, REASONS FOR CAUTIONParticipants included in our analyses were more socially advantaged than those excluded. The findings of this work may not apply to non-White populations and further work examining associations of puberty timing and fat mass in other ethnicities is required.WIDER IMPLICATIONS OF THE FINDINGSPrevious research has relied on self-reported measures of puberty timing such as age of voice breaking in males, has lacked data on pre-and post-pubertal adiposity together and relied predominantly on indirect measures of adiposity such as BMI. This has led to conflicting results on the nature and direction of the association between puberty timing and adiposity in females and males. Our work provides important clarity on this, suggesting that prevention of adiposity in childhood is key for prevention of early puberty, adult adiposity and associated cardiovascular risk. In contrast, our findings suggest that prevention of early puberty without prevention of childhood adiposity would have little impact on prevention of adult adiposity.STUDY FUNDING/COMPETING INTEREST(S)The UK Medical Research Council and Wellcome (Grant ref: 102215/2/13/2) and the University of Bristol provide core support for Avon Longitudinal Study of Parents and Children (ALSPAC). L.M.O.K. is supported by a UK Medical Research Council Population Health Scientist fellowship (MR/M014509/1) and a Health Research Board (HRB) of Ireland Emerging Investigator Award (EIA-FA-2019-007 SCaRLeT). J.A.B. is supported by the Elizabeth Blackwell Institute for Health Research, University of Bristol and the Wellcome Trust Institutional Strategic Support Fund (204813/Z/16/Z). L.D.H. and A.F. are supported by Career Development Awards from the UK Medical Research Council (grants MR/M020894/1 and MR/M009351/1, respectively). All authors work in a unit that receives funds from the UK Medical Research Council (grant MC_UU_00011/3, MC_UU_00011/6). No competing interests to declare.TRIAL REGISTRATION NUMBERN/A.

Data for action on early childhood development

Data for action on early childhood development

Birth shock! What role might arts engagement have to play in antenatal and postnatal care?

This article shares research findings for an Arts and Humanities Research Council project called The Birth Project (grant ref. AH/K003364/1). The Birth Project has been particularly interested to explore women’s personal experience of birth and the transition to motherhood using the arts, within a participatory arts framework. It ran experiential art-based groups for mothers and a further group for birthing professionals, each over a twelve-week period to solicit in-depth qualitative data. An innovative aspect of this endeavour has been the use of film as research data, as a means of answering the research questions (through selective editing) and as the primary mode of dissemination of the research results. Results elaborated and summarized here explore the ways women and birthing professionals found the intervention useful. The project analyses the distinctive contribution of the arts and concludes that arts engagement can play a vital role in both antenatal and postnatal care.

The helical arrangement of nitrilase enzymes determines their substrate size

Nitrilases are commercially important biocatalysts found in diverse taxa that catalyse the hydrolysis of nitriles to amides and acids. In vitro they form rings, terminating spirals or long filaments that seem to be necessary for activity. In vivo, NIT1 assemblies have been observed in Arabidopsis. Substrate size is correlated with the helical twist of nitrilase filaments and can be altered by changing a single residue by site‐directed mutagenesis or by mixing with an excess of enzyme in a different helical conformation. We have determined the first close‐to‐atomic resolution structure of an active nitrilase by cryo‐EM and identified substrate‐specifying residues for site saturation directed evolution. In silico docking of the substrate, β‐L‐cyanoalanine, into the binding pocket led to the identification of a loop that limits the maximum length of a bound substrate and shifts position as a function of helical twist. We propose that the overall size of the binding pocket is specified by this loop, while binding pocket residues alter selectivity for different functional groups. We propose that this mechanism allows nitrilases to rapidly neofunctionalise according to cellular requirements.Support or Funding InformationWe acknowledge Diamond for access and support of the Cryo‐EM facilities at the UK national electron bio‐imaging centre (eBIC), (proposal EM20975‐1), funded by the Wellcome Trust, MRC, and BBSRC. Y. Qayiya, N. Arendse, M. Jaffer, B. Weber, and S. Neumann for technical assistance. This work was funded by the South Africa/Germany Cooperation in Science and Technology Joint Research Grant, the Deutsche Forschungsgemeinschaft (PI 424/1, PI 424/3), Research Career Advancement Fellowship from the National Research Foundation of South Africa (92556) and GCRF‐START (UK Science and Technology Facilities Council grant ref. ST/R002754/1).