National Institutes For Health Research Research Articles

Role of NIH in the Ending the HIV Epidemic in the US Initiative: Research Improving Practice.

In 2019, approximately 1.2 M persons were living with HIV and an estimated 34,800 new HIV infections occurred in the United States (U.S.). Significant disparities in HIV burden exist among persons of color, those with male-to-male sexual contact, young people, and persons experiencing barriers to consistent uptake of HIV interventions and services. These disparities are the root of major gaps in coverage of HIV testing, linkage to prevention and treatment, adherence, and retention in services in the United States. These gaps help fuel the American HIV epidemic. The Ending the HIV Epidemic in the U.S. Initiative (EHE) is built on 4 decades of federal domestic and international responses to HIV/AIDS. As the largest health research agency in the world, the National Institutes for Health (NIH) funds extensive basic, clinical, translational, and implementation HIV research that is crucial to achieving HIV epidemic control. Addressing the gaps and meeting EHE milestones will be accomplished in part through a combination of adaptation, implementation, and scale-up of existing HIV interventions. New discoveries will also be needed to create improved and novel diagnostics, monitor viral loads, and develop new prevention and treatment tools and approaches. HIV implementation research is essential to demonstrate the most effective strategies to facilitate the adaptation, adoption, and integration of evidence-based HIV interventions in real-world settings. This article outlines current NIH research plans to reduce and identify new HIV infections, improve treatment coverage and outcomes among persons with HIV, and effectively respond to HIV transmission outbreaks in the United States.

Implementation of non-communicable disease policies from 2015 to 2020: a geopolitical analysis of 194 countries

Non-communicable diseases (NCDs) are the leading cause of morbidity and mortality globally. We aimed to analyse trends in implementation of WHO-recommended population-level policies and associations with national geopolitical characteristics. We calculated cross-sectional NCD policy implementation scores for all 194 WHO member states from the 2015, 2017, and 2020 WHO progress monitor reports, and examined changes over time as well as average implementation by geographical and geopolitical region and income level. We developed a framework of indicators of national characteristics hypothesised to influence policy implementation, including democracy, corporate permeation (an indicator of corporate influence), NCD burden, and risk factor prevalence. We used multivariate regression models to test our hypotheses. On average, countries had fully implemented a third (32·8%, SD 18·2) of the 19 policies in 2020. Using aggregate policy scores, which include partially implemented policies, mean implementation had increased from 39·0% (SD 19·3) in 2015 to 45·9% (19·2) in 2017 and 47·0% (19·8) in 2020. Implementation was lowest for policies relating to alcohol, tobacco, and unhealthy foods, and had reversed for a third of all policies. Low-income and less democratic countries had the lowest policy implementation. Our model explained 64·8% of variance in implementation scores. For every unit increase in corporate permeation, implementation decreased by 5·0% (95% CI -8·0 to -1·9, p=0·0017), and for every 1% increase in NCD mortality burden, implementation increased by 0·9% (0·2 to 1·6, p=0·014). Democracy was positively associated with policy implementation, but only in countries with low corporate permeation. Implementation of NCD policies is uneven, but broadly improving over time. Urgent action is needed to boost implementation of policies targeting corporate vectors of NCDs, and to support countries facing high corporate permeation. The National Institutes for Health Research, the Swedish Research Council, the Fulbright Commission, and the Swedish Society of Medicine.

Efficacy of ChAdOx1 nCoV-19 (AZD1222) Vaccine Against SARS-CoV-2 VOC 202012/01 (B.1.1.7)

Background: A new variant of SARS-CoV-2, B.1.1.7, emerged as the dominant cause of COVID-19infection in the United Kingdom from November 2020 with a transmission advantage over the previous variants of the virus. Here we report efficacy of the adenoviral vector vaccine, ChAdOx1 nCoV-19, against this variant in comparison with non-B.1.1.7 lineages.Methods: Volunteers enrolled in phase II/III vaccine efficacy studies in the United Kingdom and randomised 1:1 to receive ChAdOx1 nCoV-19 or a MenACWY control vaccine, providedupper airway swabs every week during the trial and also if they developed possible symptomatic COVID-19 infection. Swabs were tested by nucleic acid amplification test (NAAT) for SARS-CoV-2, and positive samples were sequenced through the COVID-19Genomics UK consortium (COG UK). NAAT data were used to assess the duration ofdetectable viral RNA in diagnostic specimens and the viral load. Anti-spike IgG wasmeasured by ELISA at baseline, 14 and 28 days after prime and 28 days after boostervaccination. Neutralising antibody responses were measured using a live virus neutralisation assay against the B.1.1.7 and Victoria lineages of the virus. The efficacy analysis included symptomatic COVID-19 in seronegative participants with a NAAT positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cut-off on Jan 14, 2021. Vaccine efficacy was calculated as 1 − relative risk derived from a robust Poisson regression model. This study is ongoing and is registered with ClinicalTrials.gov NCT04400838 and ISRCTN 15281137.5Findings: Between 1st October 2020 and 14th January 2021, 499 participants developed Covid-19infection. 1524 NAAT positive nose/throat swabs were collected from these participants during the trial. Of these, 323 swabs from 256 participants were successfully sequenced.ChAdOx1 nCoV-19 recipients had a significantly lower viral load as represented byminimum PCR Ct value (pInterpretation: Efficacy of ChAdOx1 nCoV-19 against the B.1.1.7 variant of SARS-CoV-2 is similar to the efficacy of the vaccine against other lineages. Furthermore, vaccination with ChAdOx1 nCoV-19 results in a reduction in the duration of shedding and viral load, which may translate into a material impact on transmission of disease.Trial Registration Number: This study is ongoing and is registered with ClinicalTrials.gov NCT04400838 and ISRCTN 15281137.Funding: The clinical trial was funded by UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, NIHR OxfordBiomedical Research Centre, Thames Valley and South Midlands NIHR Clinical Research Network, and AstraZeneca. COG-UK is supported by funding from the Medical Research Council (MRC) part of UK Research & Innovation (UKRI), the National Institute of Health Research (NIHR) and Genome Research Limited, operating as the Wellcome SangerInstitute. Computational work was supported by the Wellcome Trust Core Award Grant Number 203141/Z/16/Z with funding from the NIHR Oxford BRC.Conflict of Interest: Oxford University has entered into a partnership with AstraZeneca for further development of ChAdOx1 nCoV-19. AstraZeneca reviewed the data from the study and the final manuscript before submission, but the authors retained editorial control. SCG is cofounder of Vaccitech (collaborators in the early development of this vaccine candidate) and named as an inventor on a patent covering use of ChAdOx1-vectored vaccines (PCT/GB2012/000467) and a patent application covering this SARS-CoV-2 vaccine. TL is named as an inventor on a patentapplication covering this SARS-CoV-2 vaccine and was consultant to Vaccitech. PMF is a consultant to Vaccitech. AJP is Chair of the UK Department of Health and Social Care’s JCVI, but does not participate in policy advice on coronavirus vaccines, and is a member of the WHO Strategic Advisory Group of Experts (SAGE). AJP and SNF are NIHR SeniorInvestigators. AVSH is a cofounder of and consultant to Vaccitech and is named as aninventor on a patent covering design and use of ChAdOx1-vectored vaccines(PCT/GB2012/000467). MDS reports grants from Janssen, GlaxoSmithKline, Medimmune,Novavax, and MCM Vaccine and grants and non-financial support from Pfizer outside of the submitted work. CG reports personal fees from the Duke Human Vaccine Institute outside of the submitted work. ADD reports grants and personal fees from AstraZeneca outside of the submitted work. SNF reports grants from Janssen and Valneva, outside the submitted work.TLV and JV are employees of AstraZeneca. All other authors declare no competing interests.The views expressed in this publication are those of the authors and not necessarily those of the National Institute for Health Research or the Department of Health and Social Care.Ethical Approval: The study was sponsored by the University of Oxford (Oxford, UK) and approved in the UK by the Medicines and Healthcare products Regulatory Agency (MHRA) reference 21584/0428/001-0001 and the South-Central Berkshire Research Ethics Committee reference 20/SC/0179.

Safety and Immunogenicity of the ChAdox1 nCoV-19 (AZD1222) Vaccine Against SARS-CoV-2 in HIV Infection

Background: The ChAdOx1 nCoV-19 (AZD1222) vaccine is immunogenic and protects against COVID-19. However, data on vaccine immunogenicity are needed for the 40 million people living with HIV (PWH), who may have less functional immunity and more associated co-morbidities than the general population. Methods: Between the 5th and 24th November 2020, 54 adults with HIV, aged 18-55 years, were enrolled into a single arm open label vaccination study within the protocol of the larger phase 2/3 COV002 trial. A prime-boost regimen of ChAdOx1 nCoV-19, with two doses (5 × 1010 vp) was given 4-6 weeks apart. All participants were on antiretroviral therapy (ART) with undetectable plasma HIV viral loads and CD4+ T cell counts >350 cells/µl at enrolment. Data were captured on adverse events. Humoral responses were measured by anti-spike IgG ELISA and antibody-mediated live virus neutralisation. Cell-mediated immune responses were measured by ex-vivo interferon-γ enzyme-linked immunospot assay (ELISpot) and T cell proliferation. All outcomes were compared with a HIV uninfected group from the main COV002 study.Findings: 54 participants with HIV (median age 42.5 years (IQR 37.2-49.8)) received two doses of ChAdOx1 nCoV-19. Median CD4+ T cell count at enrolment was 694 cells/µl (IQR 562-864). Results are reported for 56 days of follow-up. Local and systemic reactions occurring during the first 7 days after prime vaccination included pain at the injection site (49%), fatigue (47%), headache (47%), malaise (34%), chills (23%), and muscle or (36%) joint pain (9%), the frequencies of which were similar to the HIV-negative participants. There were no serious adverse events. Anti-spike IgG responses by ELISA peaked at Day 42 (median 1440 ELISA units, IQR 704-2728) and were sustained out to Day 56. There was no correlation with CD4+ T cell count or age and the magnitude of the anti-spike IgG response at Day 56 (P>0.05 for both). ELISpot and T cell proliferative responses peaked between Day 14 and 28 after prime and were sustained through to Day 56. When compared to participants without HIV there was no statistical difference in magnitude or persistence of SARS-CoV-2 spike-specific humoral or cellular responses (P>0.05 for all analyses).Interpretation: In this study of PWH, vaccination with ChAdOx1 nCoV-19 was well tolerated and there was no difference in humoral and cell-mediated immune responses compared to an adult cohort without HIV who received the same vaccination regime. Trial Registration: Trial Registration number is NCT04400838. Funding: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midlands NIHR Clinical Research Network, and AstraZeneca. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.Declaration of Interest: Oxford University has entered into a partnership with AstraZeneca for further development of ChAdOx1 nCoV-19 (AZD1222). AstraZeneca reviewed the data from the study and the final manuscript before 474 submission, but the authors retained editorial control. SCG is cofounder of Vaccitech (a collaborator in the early development of this vaccine candidate) and named as an inventor on a patent covering use of ChAdOx1-vectored vaccines (PCT/GB2012/000467) and a patent application covering this SARS-CoV-2 vaccine. TL is named as an inventor on a patent application covering this SARS-CoV-2 vaccine and was consultant to Vaccitech. PMF is a consultant to Vaccitech. AJP is Chair of the UK Department of Health and Social Care’s JCVI, but does not participate in policy advice on coronavirus vaccines, and is a member of the WHO Strategic Advisory Group of Experts (SAGE). AVSH is a cofounder of and consultant to Vaccitech and is named as an inventor on a patent covering design and use of ChAdOx1-vectored vaccines (PCT/GB2012/000467).Ethical Approval: Written informed consent was obtained from all participants, and the trial was done in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. This study was approved in the UK by the Medicines and Healthcare products Regulatory Agency (reference 21584/0424/001-0001) and the South Central Berkshire Research Ethics Committee (reference 20/SC/0145). Vaccine use was authorised by Genetically Modified Organisms Safety Committees at each participating site.

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK

SummaryBackgroundA safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials.MethodsThis analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674.FindingsBetween April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0–75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4–97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8–80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3–4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation.InterpretationChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials.FundingUK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, Bill & Melinda Gates Foundation, Lemann Foundation, Rede D’Or, Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca.

Safety and immunogenicity of ChAdOx1 nCoV-19 vaccine administered in a prime-boost regimen in young and old adults (COV002): a single-blind, randomised, controlled, phase 2/3 trial

Safety and immunogenicity of ChAdOx1 nCoV-19 vaccine administered in a prime-boost regimen in young and old adults (COV002): a single-blind, randomised, controlled, phase 2/3 trial

ELFIN, the United Kingdom preterm lactoferrin trial: interpretation and future questions 1.

Results from previous studies have suggested that supplemental bovine lactoferrin (BLF) given to preterm infants (<32weeks gestation) reduces late-onset sepsis (LOS) and necrotising enterocolitis (NEC). The Enteral Lactoferrin in Neonates (ELFIN) study, performed in the UK, aimed to further address this issue with a well powered double-blind placebo controlled trial of >2200 preterm infants. The results from ELFIN did not demonstrate a reduction in LOS or NEC, or several other clinically important measures. Of the 1093 infants, 316 (29%) in the intervention group developed late-onset sepsis versus 334 (31%) of 1089 in the control group, with an adjusted risk ratio of 0.95 (95%CI = 0.86-1.04; p= 0.233). Reasons for the differences in ELFIN trial results and other studies may include population differences, the routine use of antifungal prophylaxis in the UK, timing of administration of the lactoferrin in relation to disease onset, or specific properties of the lactoferrin used in the different trials. The UK National Institutes for Health Research funded "Mechanisms Affecting the Guts of Preterm Infants in Enteral feeding trials" (MAGPIE) study is further exploring the use of lactoferrin, and the results should be available soon.

Corrigendum: Genome-wide association analysis identifies novel blood pressure loci and offers biological insights into cardiovascular risk.

HRW, CPC, MR, MRB, PBM, MB and MJC were funded by the National Institutes for Health Research (NIHR) as part of the portfolio of translational research of the NIHR Biomedical Research Unit at Barts and The London School of Medicine and Dentistry. HG was funded by the NIHR Imperial College Health Care NHS Trust and Imperial College London Biomedical Research Centre. MR was a recipient from China Scholarship Council (No. 2011632047). BM holds an MRC eMedLab Medical Bioinformatics Career Development Fellowship, funded from award MR/L016311/1. JMMH was funded by the UK Medical Research Council (G0800270), British Heart Foundation (SP/09/002), UK National Institute for Health Research Cambridge Biomedical Research Centre, European Research Council (268834), European Commission Framework Programme 7 (HEALTH-F2-2012-279233). BK holds a British Heart Foundation Personal Chair (CH/13/2/30154). NJS holds a chair funded by the British Heart Foundation and is a NIHR Senior Investigator. FD was funded by the MRC Unit at the University of Bristol (MC_UU_12013/1-9). PSu was funded by the UK Medical Research Council (G0800270). CL and AK were funded by the NHLBI intramural funding. CNC was funded by the National Institutes of Health (HL113933, HL124262). PVDH was funded by the ZonMw grant 90.700.441, Marie Sklodowska-Curie GF (call: H2020- MSCA-IF-2014, Project ID: 661395). NV was supported by Marie Sklodowska-Curie GF grant (661395) and ICIN-NHI. NP received funding from the UK National Institute for Health Research Biomedical Research Centre at Imperial College Healthcare NHS Trust and Imperial College London and also from his Senior Investigator Award. PS was supported by the NIHR Biomedical Research Centre at Imperial College Healthcare NHS Trust and Imperial College London. ST was supported by the NIHR Biomedical Research Centre at Imperial College Healthcare NHS Trust and Imperial College London. PFO received funding from the UK Medical Research Council (MR/N015746/1) and the Wellcome Trust (109863/Z/15/Z). IK was supported by the EU PhenoMeNal project (Horizon 2020, 654241). AC was funded by the National Institutes of Health (HL128782, HL086694). MF was supported by the Wellcome Trust core award (090532/Z/09/Z) and the BHF Centre of Research Excellence, Oxford (RE/13/1/30181). CH was funded by an MRC core grant for QTL in Health and Disease programme. Some of this work used the ALICE and SPECTRE High Performance Computing Facilities at the University of Leicester. MJC is a National Institute for Health Research (NIHR) senior investigator. PE is a National Institute for Health Research (NIHR) senior investigator and acknowledges support from the NIHR Biomedical Research Centre at Imperial College Healthcare NHS Trust and Imperial College London, and the NIHR Health Protection Research Unit in Health Impact of Environmental Hazards (HPRU-2012-10141). As director of the MRC-PHE Centre for Environment and Health, PE acknowledges support from the Medical Research Council and Public Health England (MR/L01341X/1). This work used the computing resources of the UK MEDical BIOinformatics partnership - aggregation, integration, visualisation and analysis of large, complex data (UK MED-BIO) which is supported by the Medical Research Council (MR/L01632X/1). This research was supported by the British Heart Foundation (grant SP/13/2/30111). Project title: Large-scale comprehensive genotyping of UK Biobank for cardiometabolic traits and diseases: UK CardioMetabolic Consortium (UKCMC).

Abstracts from the 2017 Annual Scientific Meeting of the British and Irish Hypertension Society (BIHS).

National Institutes for Health Research (NIHR), portfolio of translational research of the NIHR Biomedical Research Centre at Barts. London School of Medicine and Dentistry, Queen Mary University of London .

Mechanisms Affecting the Gut of Preterm Infants in Enteral Feeding Trials.

Large randomized controlled trials (RCTs) in preterm infants offer unique opportunities for mechanistic evaluation of the risk factors leading to serious diseases, as well as the actions of interventions designed to prevent them. Necrotizing enterocolitis (NEC) a serious inflammatory gut condition and late-onset sepsis (LOS) are common feeding and nutrition-related problems that may cause death or serious long-term morbidity and are key outcomes in two current UK National Institutes for Health Research (NIHR) trials. Speed of increasing milk feeds trial (SIFT) randomized preterm infants to different rates of increases in milk feeds with a primary outcome of survival without disability at 2 years corrected age. Enteral lactoferrin in neonates (ELFIN) randomizes infants to supplemental enteral lactoferrin or placebo with a primary outcome of LOS. This is a protocol for the mechanisms affecting the gut of preterm infants in enteral feeding trials (MAGPIE) study and is funded by the UK NIHR Efficacy and Mechanistic Evaluation programme. MAGPIE will recruit ~480 preterm infants who were enrolled in SIFT or ELFIN. Participation in MAGPIE does not change the main trial protocols and uses non-invasive sampling of stool and urine, along with any residual resected gut tissue if infants required surgery. Trial interventions may involve effects on gut microbes, metabolites (e.g., short-chain fatty acids), and aspects of host immune function. Current hypotheses suggest that NEC and/or LOS are due to a dysregulated immune system in the context of gut dysbiosis, but mechanisms have not been systematically studied within large RCTs. Microbiomic analysis will use next-generation sequencing, and metabolites will be assessed by mass spectrometry to detect volatile organic and other compounds produced by microbes or the host. We will explore differences between disease cases and controls, as well as exploring the actions of trial interventions. Impacts of this research are multiple: translation of knowledge of mechanisms promoting gut health may explain outcomes or suggest alternate strategies to improve health. Results may identify new non-invasive diagnostic or monitoring techniques, preventative or treatment strategies for NEC or LOS, or provide data useful for risk stratification in future studies. Mechanistic evaluation might be especially informative where there are not clear effects on the primary outcome (ISRCTN 12554594).

Cost-effective recruitment methods for a large randomised trial in people with diabetes: A Study of Cardiovascular Events iN Diabetes (ASCEND)

BackgroundClinical trials require cost-effective methods for identifying, randomising, and following large numbers of people in order to generate reliable evidence. ASCEND (A Study of Cardiovascular Events iN Diabetes) is a randomised ‘2 × 2 factorial design’ study of aspirin and omega-3 fatty acid supplements for the primary prevention of cardiovascular events in people with diabetes; this study used central disease registers and a mail-based approach to identify, randomise, and follow 15,000 people. In collaboration with UK consultants and general practitioners (GPs), researchers identified potentially eligible people with diabetes from centrally held registers (e.g. for retinopathy screening) and GP-held disease registers. Permission was obtained under section 251 of the National Health Service Act 2006 (previously section 60 of the NHS act 2001) to allow invitation letters to be generated centrally in the name of the holder of the register. In addition, with the collaboration of the National Institutes for Health Research (NIHR) Diabetes and Primary Care Research Networks (DRN and PCRN), general practices sent pre-assembled invitation packs to people with a diagnosis of diabetes. Invitation packs included a cover letter, screening questionnaire (with consent form), information leaflet, and a Freepost envelope. Eligible patients entered a 2-month, pre-randomisation, run-in phase on placebo tablets and were only randomised if they completed a randomisation form and remained willing and eligible at the end of the run-in. Follow-up is ongoing, using mail-based approaches that are being supplemented by central registry data.ResultsInformation on approximately 600,000 people listed on 58 centrally held diabetes registers was obtained, and 300,188 potentially eligible patients were invited to join the study. In addition, 785 GP practices mailed invitations to 120,875 patients. A further 2,340 potential study participants were identified via other routes. In total, 423,403 people with diabetes were invited to take part; 26,462 entered the 2-month, pre-randomisation, run-in phase; and 15,480 were randomised.ConclusionIf sufficient numbers of potentially eligible patients can be identified centrally and the trial treatments do not require participants to attend clinics, the recruitment and follow-up of patients by mail is feasible and cost-effective. Wider use of these methods could allow more, large, randomised trials to be undertaken successfully and cost-effectively.Trial registrationCurrent Controlled Trials, ISRCTN60635500, registered on 14 July 2005Electronic supplementary materialThe online version of this article (doi:10.1186/s13063-016-1354-9) contains supplementary material, which is available to authorized users.

Role of IGSF10 mutations in self-limited delayed puberty

BackgroundAbnormal timing of puberty affects over 4% of adolescents and is associated with adverse health and psychosocial outcomes. Previous studies estimate that 60–80% of variation in the timing of pubertal onset is genetically determined. However, little is known about the genetic control of human puberty. Self-limited delayed puberty segregates in an autosomal dominant pattern; our study aimed to identify novel genetic regulators of disease in these patients. MethodsWe performed whole-exome sequencing in 18 families with self-limited delayed puberty from our cohort, followed by candidate gene sequencing in a further 42 families. The functional consequences of the identified mutations in one candidate gene were interrogated via expression of wild type and mutant proteins in mammalian cells. For this gene we defined tissue expression in human and mouse embryos. The effects of gene knockdown were assessed via in-vitro neuronal migration assays, and in vivo with a transgenic zebrafish model. FindingsIn ten unrelated families, we identified four rare mutations in IGSF10 in individuals with self-limited delayed puberty (adjusted p value after rare variant burden testing=3·4 × 10–2). The identified mutations were in evolutionarily conserved positions, and two mutations resulted in intracellular retention with failure in secretion of the N-terminal fragment of the protein. IGSF10 mRNA was strongly expressed in the nasal mesenchyme in mouse and human embryos during migration of gonadotropin-releasing hormone (GnRH) neurons from their nasal origin towards the hypothalamus. IGSF10 knockdown caused reduced migration of immature GnRH neurons in the in-vitro analysis, and perturbed migration and extension of GnRH neurons in the zebrafish model. InterpretationOur findings strongly support the contention that mutations in IGSF10 cause delayed puberty in human beings, through misregulation of GnRH neuronal migration during embryonic development. FundingWellcome Trust (102745), Rosetrees Trust (M222), and the Barts and the London Charity (417/1551) (SH); Biotechnology and Biological Sciences Research Council (BB/L002671/1) (LG and GB); LD is partly supported by the Academy of Finland (14135); National Institutes for Health Research (NIHR) (MB, HW, and CC); Medical Research Council (MR/K021613/1) (AD); Telethon Foundation (GP13142) (AC); VA is partly supported by a COST STSM (BM1105-16145) and a travel grant sponsored by Development (The Company of Biologists Ltd).

Activity of Bruton's tyrosine-kinase inhibitor ibrutinib in patients with CD117-positive acute myeloid leukaemia: a mechanistic study using patient-derived blast cells

Roughly 80% of patients with acute myeloid leukaemia have high activity of Bruton's tyrosine-kinase (BTK) in their blast cells compared with normal haemopoietic cells, rendering the cells sensitive to the oral BTK inhibitor ibrutinib in vitro. We aimed to develop the biological understanding of the BTK pathway in acute myeloid leukaemia to identify clinically relevant diagnostic information that might define a subset of patients that should respond to ibrutinib treatment. We obtained acute myeloid leukaemia blast cells from unselected patients attending our UK hospital between Feb 19, 2010, and Jan 20, 2014. We isolated primary acute myeloid leukaemia blast cells from heparinised blood and human peripheral blood mononuclear cells to establish the activity of BTK in response to CD117 activation. Furthermore, we investigated the effects of ibrutinib on CD117-induced BTK activation, downstream signalling, adhesion to primary bone-marrow mesenchymal stromal cells, and proliferation of primary acute myeloid leukaemia blast cells. We used the Mann-Whitney U test to compare results between groups. We obtained acute myeloid leukaemia blast cells from 29 patients. Ibrutinib significantly inhibited CD117-mediated proliferation of primary acute myeloid leukaemia blast cells (p=0·028). CD117 activation increased BTK activity by inducing phosphorylated BTK in patients with CD117-positive acute myeloid leukaemia. Furthermore, ibrutinib inhibited CD117-induced activity of BTK and downstream kinases at a concentration of 100 nM or more. CD117-mediated adhesion of CD117-expressing blast cells to bone-marrow stromal cells was significantly inhibited by Ibrutinib at 500 nM (p=0·028) INTERPRETATION: As first-in-man clinical trials of ibrutinib in patients with acute myeloid leukaemia commence, the data suggest not all patients will respond. Our findings show that BTK has specific pro-tumoural biological actions downstream of surface CD117 activation, which are inhibited by ibrutinib. Accordingly, we propose that patients with acute myeloid leukaemia whose blast cells express CD117 should be considered for forthcoming clinical trials of ibrutinib. Worldwide Cancer Research, The Big C, UK National Institutes for Health Research, the Humane Research Trust, the Department of Higher Education and Research of the Libyan Government, and Norwich Research Park.

Gene and Cell Therapy Funding Opportunities in Horizon 2020: An Overview for 2014–2015

Gene and Cell Therapy Funding Opportunities in Horizon 2020: An Overview for 2014–2015