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Congratulations to Kennedy Institute Group Leader Dr Anjali Kusumbe who has been awarded prestigious funding from the European Research Council to investigate the link between blood vessels and tumour metastasis in bone.
Obesity increases the odds of intervertebral disc herniation and spinal stenosis; an MRI study of 1634 low back pain patients.
PURPOSE: The objective of this study was to examine the relationships between BMI and intervertebral disc degeneration (DD), disc herniation (DH) and spinal stenosis (SS) using a large, prospectively recruited and heterogeneous patient population. METHODS: Patients were recruited through the European Genodisc Study. An experienced radiologist scored MRI images for DD, DH and SS. Multivariate linear and logistic regression analyses were used to model the relationship between these variables and BMI with adjustment for patient and MRI confounders. RESULTS: We analysed 1684 patients with a mean age of 51 years and BMI of 27.2 kg/m2. The mean DD score was 2.6 (out of 5) with greater DD severity with increasing age (R2 = 0.44). In the fully adjusted model, a 10-year increase in age and a 5 kg/m2 increase in BMI were associated, respectively, with a 0.31-unit [95% CI 0.29,0.34] and 0.04-unit [CI 0.01,0.07] increase in degeneration. Age (OR 1.23 [CI 1.06,1.43]) and BMI (OR 2.60 [CI 2.28,2.96]) were positively associated with SS. For DH, age was a negative predictor (OR 0.70 [CI 0.64,0.76]) but for BMI (OR 1.19 [CI 1.07,1.33]), the association was positive. BMI was the strongest predictor of all three features in the upper lumbar spine. CONCLUSIONS: While an increase in BMI was associated with only a slight increase in DD, it was a stronger predictor for DH and SS, particularly in the upper lumbar discs, suggesting weight loss could be a useful strategy for helping prevent disorders associated with these pathologies.
Spatiotemporal signal space separation for regions of interest: Application for extracting neuromagnetic responses evoked by deep brain stimulation.
Magnetoencephalography (MEG) recordings are often contaminated by interference that can exceed the amplitude of physiological brain activity by several orders of magnitude. Furthermore, the activity of interference sources may spatially extend (known as source leakage) into the activity of brain signals of interest, resulting in source estimation inaccuracies. This problem is particularly apparent when using MEG to interrogate the effects of brain stimulation on large-scale cortical networks. In this technical report, we develop a novel denoising approach for suppressing the leakage of interference source activity into the activity representing a brain region of interest. This approach leverages spatial and temporal domain projectors for signal arising from prespecified anatomical regions of interest. We apply this denoising approach to reconstruct simulated evoked response topographies to deep brain stimulation (DBS) in a phantom recording. We highlight the advantages of our approach compared to the benchmark-spatiotemporal signal space separation-and show that it can more accurately reveal brain stimulation-evoked response topographies. Finally, we apply our method to MEG recordings from a single patient with Parkinson's disease, to reveal early cortical-evoked responses to DBS of the subthalamic nucleus.
Increased interleukin-26 in the peripheral joints of patients with axial spondyloarthritis and psoriatic arthritis, co-localizing with CD68-positive synoviocytes.
OBJECTIVES: IL26 levels are elevated in the blood and synovial fluid of patients with inflammatory arthritis. IL26 can be produced by Th17 cells and locally within joints by tissue-resident cells. IL26 induces osteoblast mineralization in vitro. As osteoproliferation and Th17 cells are important factors in the pathogenesis of axial spondyloarthritis (axSpA), we aimed to clarify the cellular sources of IL26 in spondyloarthritis. METHODS: Serum, peripheral blood mononuclear cells (n = 15-35) and synovial tissue (n = 3-9) of adult patients with axSpA, psoriatic arthritis (PsA) and rheumatoid arthritis (RA) and healthy controls (HCs, n = 5) were evaluated by ELISA, flow cytometry including PrimeFlow assay, immunohistochemistry and immunofluorescence and quantitative PCR. RESULTS: Synovial tissue of axSpA patients shows significantly more IL26-positive cells than that of HCs (p < 0.01), but numbers are also elevated in PsA and RA patients. Immunofluorescence shows co-localization of IL26 with CD68, but not with CD3, SMA, CD163, cadherin-11, or CD90. IL26 is elevated in the serum of RA and PsA (but not axSpA) patients compared with HCs (p < 0.001 and p < 0.01). However, peripheral blood CD4+ T cells from axSpA and PsA patients show higher positivity for IL26 in the PrimeFlow assay compared with HCs. CD4+ memory T cells from axSpA patients produce more IL26 under Th17-favoring conditions (IL-1β and IL-23) than cells from PsA and RA patients or HCs. CONCLUSION: IL26 production is increased in the synovial tissue of SpA and can be localized to CD68+ macrophage-like synoviocytes, whereas circulating IL26+ Th17 cells are only modestly enriched. Considering the osteoproliferative properties of IL26, this offers new therapeutic options independent of Th17 pathways.
Effect of a 2-week interruption in methotrexate treatment on COVID-19 vaccine response in people with immune-mediated inflammatory diseases (VROOM study): a randomised, open label, superiority trial.
BACKGROUND: Methotrexate is the first-line treatment for immune-mediated inflammatory diseases and reduces vaccine-induced immunity. We evaluated if a 2-week interruption of methotrexate treatment immediately after COVID-19 booster vaccination improved antibody response against the S1 receptor binding domain (S1-RBD) of the SARS-CoV-2 spike protein and live SARS-CoV-2 neutralisation compared with uninterrupted treatment in patients with immune-mediated inflammatory diseases. METHOD: We did a multicentre, open-label, parallel-group, randomised, superiority trial in secondary-care rheumatology and dermatology clinics in 26 hospitals in the UK. Adults (aged ≥18 years) with immune-mediated inflammatory diseases taking methotrexate (≤25 mg per week) for at least 3 months, who had received two primary vaccine doses from the UK COVID-19 vaccination programme were eligible. Participants were randomly assigned (1:1) using a centralised validated computer program, to temporarily suspend methotrexate treatment for 2 weeks immediately after COVID-19 booster vaccination or continue treatment as usual. The primary outcome was S1-RBD antibody titres 4 weeks after COVID-19 booster vaccination and was assessed masked to group assignment. All randomly assigned patients were included in primary and safety analyses. This trial is registered with ISRCTN, ISRCTN11442263; following a pre-planned interim analysis, recruitment was stopped early. FINDING: Between Sept 30, 2021, and March 7, 2022, we screened 685 individuals, of whom 383 were randomly assigned: to either suspend methotrexate (n=191; mean age 58·8 years [SD 12·5], 118 [62%] women and 73 [38%] men) or to continue methotrexate (n=192; mean age 59·3 years [11·9], 117 [61%] women and 75 [39%] men). At 4 weeks, the geometric mean S1-RBD antibody titre was 25 413 U/mL (95% CI 22 227-29 056) in the suspend methotrexate group and 12 326 U/mL (10 538-14 418) in the continue methotrexate group with a geometric mean ratio (GMR) of 2·08 (95% CI 1·59-2·70; p<0·0001). No intervention-related serious adverse events occurred. INTERPRETATION: 2-week interruption of methotrexate treatment in people with immune-mediated inflammatory diseases enhanced antibody responses after COVID-19 booster vaccination that were sustained at 12 weeks and 26 weeks. There was a temporary increase in inflammatory disease flares, mostly self-managed. The choice to suspend methotrexate should be individualised based on disease status and vulnerability to severe outcomes from COVID-19. FUNDING: National Institute for Health and Care Research.
Gene therapy for choroideremia using an adeno-associated viral vector encoding Rab escort protein 1: the REGENERATE open-label trial
Background Choroideremia is an X-linked inherited retinal degeneration that begins in childhood with nyctalopia and loss of peripheral vision, and gradually progresses to blindness in adulthood. Choroideremia is caused by null mutations in the CHM gene, which encodes Rab escort protein 1. Objective Assessment of the efficacy and safety of a single subretinal injection of an adeno-associated virus serotype 2 vector encoding Rab escort protein 1 in patients with choroideremia. Design Multicentre open-label clinical trial of a gene therapy for choroideremia using an adeno-associated virus serotype 2-Rab escort protein 1 vector. Setting This study (NCT02407678) was conducted at two NHS eye hospitals in the UK. Participants Males aged 18 years or above, having a clinical diagnosis of choroideremia with genetic confirmation of CHM gene mutation or molecular confirmation of Rab escort protein 1 protein deficiency and having best corrected visual acuity better than or equal to 6/60 (20/200; LogMAR 1.0). Intervention Adeno-associated virus serotype 2-Rab escort protein 1 vector suspension (1 × 1012 vector particles per ml) was supplied by Nightstar Therapeutics (London, UK), now part of Biogen Inc. (Cambridge, MA, USA). Up to 0.1 ml of adeno-associated virus serotype 2-Rab escort protein 1 vector suspension, corresponding to a dose of up to 1 × 1011 vector particles, was administered to the treated eye by subretinal injection. Selection of treated eyes was randomised in participants having relatively symmetrical retinal degeneration. Main outcome measures The primary safety-related outcome was change from baseline in best corrected visual acuity in treated eyes at 24 months post treatment, with prospective efficacy evaluated by comparative change from baseline in best corrected visual acuity in treated and untreated contralateral (control) eyes. Secondary outcomes included comparative change from baseline in mean retinal sensitivity (microperimetry) and retinal anatomy (area of autofluorescence) in treated and control eyes. Visual assessments were conducted by masked assessors. Results The primary efficacy-related outcome (comparative change from baseline in best corrected visual acuity in treated and control eyes at 24 months post treatment) was not statistically different between treated eyes (−2.63 letters, standard error of the mean 2.76) and control eyes (+2.67 letters, standard error of the mean 0.768) in all 30 participants (p = 0.08). Greater loss of visual fields, possibly surgery-induced, was observed in treated eyes. Six serious adverse events were reported in the treated eyes of four participants: one surgery-related and two inflammation-related serious adverse events involving clinically significant decreases in best corrected visual acuity, and three serious adverse events in one participant involving reduction in central retinal sensitivity, but with best corrected visual acuity remaining stable. Limitations No evidence of possible efficacy of the intervention was observed, as a meaningful difference in comparative change from baseline in best corrected visual acuity in treated and control eyes was not discernible at 24 months post treatment. As choroideremia is a very slow degeneration, best corrected visual acuity in control eyes did not decline significantly during the assessment period. Conclusion Although this study has not presented evidence that reduction in visual fields caused by the intervention would be justified by the possible rescue of best corrected visual acuity, a more definitive assessment may be provided by long-term monitoring of trial participants in an observational study (NCT03584165). Trial registration This study is registered as ISRCTN15602229 (www.isrctn.com/) and NCT02407678 (https://clinicaltrials.gov/). Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 12/66/35) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 9. See the NIHR Funding and Awards website for further award information.
Preclinical characterization of ISB 1342, a CD38 × CD3 T-cell engager for relapsed/refractory multiple myeloma.
Although treatment of multiple myeloma (MM) with daratumumab significantly extends the patient's lifespan, resistance to therapy is inevitable. ISB 1342 was designed to target MM cells from patients with relapsed/refractory MM (r/r MM) displaying lower sensitivity to daratumumab. ISB 1342 is a bispecific antibody with a high-affinity Fab binding to CD38 on tumor cells on a different epitope than daratumumab and a detuned scFv domain affinity binding to CD3ε on T cells, to mitigate the risk of life-threatening cytokine release syndrome, using the Bispecific Engagement by Antibodies based on the TCR (BEAT) platform. In vitro, ISB 1342 efficiently killed cell lines with different levels of CD38, including those with a lower sensitivity to daratumumab. In a killing assay where multiple modes of action were enabled, ISB 1342 showed higher cytotoxicity toward MM cells compared with daratumumab. This activity was retained when used in sequential or concomitant combinations with daratumumab. The efficacy of ISB 1342 was maintained in daratumumab-treated bone marrow patient samples showing lower sensitivity to daratumumab. ISB 1342 induced complete tumor control in 2 therapeutic mouse models, unlike daratumumab. Finally, in cynomolgus monkeys, ISB 1342 displayed an acceptable toxicology profile. These data suggest that ISB 1342 may be an option in patients with r/r MM refractory to prior anti-CD38 bivalent monoclonal antibody therapies. It is currently being developed in a phase 1 clinical study.
Post-resolution macrophages shape long-term tissue immunity and integrity in a mouse model of pneumococcal pneumonia.
Resolving inflammation is thought to return the affected tissue back to homoeostasis but recent evidence supports a non-linear model of resolution involving a phase of prolonged immune activity. Here we show that within days following resolution of Streptococcus pneumoniae-triggered lung inflammation, there is an influx of antigen specific lymphocytes with a memory and tissue-resident phenotype as well as macrophages bearing alveolar or interstitial phenotype. The transcriptome of these macrophages shows enrichment of genes associated with prostaglandin biosynthesis and genes that drive T cell chemotaxis and differentiation. Therapeutic depletion of post-resolution macrophages, inhibition of prostaglandin E2 (PGE2) synthesis or treatment with an EP4 antagonist, MF498, reduce numbers of lung CD4+/CD44+/CD62L+ and CD4+/CD44+/CD62L-/CD27+ T cells as well as their expression of the α-integrin, CD103. The T cells fail to reappear and reactivate upon secondary challenge for up to six weeks following primary infection. Concomitantly, EP4 antagonism through MF498 causes accumulation of lung macrophages and marked tissue fibrosis. Our study thus shows that PGE2 signalling, predominantly via EP4, plays an important role during the second wave of immune activity following resolution of inflammation. This secondary immune activation drives local tissue-resident T cell development while limiting tissue injury.
Eight years into the horizon of aspirational maternal and newborn health pledges: a nationwide cross-sectional exploration of the Burundian EmONC network capacity and budget deficits.
OBJECTIVE: The Burundian emergency obstetric and neonatal care (EmONC) programme, which was initiated in 2017 and supported by a specific policy, does not appear to reverse maternal and newborn mortality trends. Our study examined the capacity challenges facing participating EmONC facilities and developed alternative investment proposals to improve their readiness paying particular attention to EmONC professionals, physical infrastructure, and capital equipment. DESIGN: Cross-sectional study. SETTING: Burundian EmONC facilities (n=112). PARTICIPANTS: We examined EmONC policy documents, consulted 12 maternal and newborn health experts and 23 stakeholders and policymakers, surveyed all EmONC facilities (n=112), and collected cost data from the Ministry of Health and local suppliers in Burundi. We developed three context-specific EmONC resource benchmark standards by facility type; the Burundian policy norms and the expert minimum and maximum suggested thresholds; and used these alternatives to estimate EmONC resource gaps. We forecasted three corresponding budget estimates needed to address prevailing deficits taking a government perspective for a 5-year EmONC investment strategy. Additionally, we explored relationships between EmONC professionals and selected measures of service delivery using bivariate analyses and graphically. RESULTS: The lowest EmONC resource benchmark revealed that 95% of basic EmONC and all comprehensive EmONC facilities lack corresponding sets of human resources and 90% of all facilities need additional physical infrastructure and capital equipment. Assessed against the highest benchmark which proposes the most progressive set of standards for the prevailing workloads, Burundi would require 162 more medical doctors, 1005 midwives and nurses, 132 delivery rooms, 191 delivery tables, 678 and 156 maternity and newborn care beds, and 395 incubators amounting to US$32.9 million additional budget for 5 years. CONCLUSION: We demonstrated that Burundian EmONC facilities face enormous capacity challenges equivalent to US$32.9 million funding gap for 5 years; averagely approximating to 5.96% total health budget increase annually.
Clinical assessment and management of lumbar spinal stenosis: clinical dilemmas and considerations for surgical referral.
Lumbar spinal stenosis is the leading indication for spine surgery in older adults. Surgery is recommended in clinical guidelines if non-surgical treatments have been provided with insufficient benefit. The difficulty for clinicians is that the current number of randomised controlled trials is low, which creates uncertainty about which treatments to provide. For non-surgical clinicians this paucity of data leads to a clinical dilemma of whether to continue managing the patient or refer to a spine surgeon. This Viewpoint aims to provide an update on the assessment of lumbar spinal stenosis, treatment recommendations, indications for referral to a spine surgeon, and current clinical dilemmas facing non-surgical clinicians and spinal surgeons.
Cementing Techniques In Knee Surgery (CeTIKS): a UK expert consensus study.
AIMS: Aseptic loosening is the most common cause of failure following cemented total knee arthroplasty (TKA), and has been linked to poor cementation technique. We aimed to develop a consensus on the optimal technique for component cementation in TKA. METHODS: A UK-based, three-round, online modified Delphi Expert Consensus Study was completed focusing on cementation technique in TKA. Experts were identified as having a minimum of five years' consultant experience in the NHS and fulfilling any one of the following criteria: a 'high volume' knee arthroplasty practice (> 150 TKAs per annum) as identified from the National joint Registry of England, Wales, Northern Ireland and the Isle of Man; a senior author of at least five peer reviewed articles related to TKA in the previous five years; a surgeon who is named trainer for a post-certificate of comletion of training fellowship in TKA. RESULTS: In total, 81 experts (round 1) and 80 experts (round 2 and 3) completed the Delphi Study. Four domains with a total of 24 statements were identified. 100% consensus was reached within the cement preparation, pressurization, and cement curing domains. 90% consensus was reached within the cement application domain. Consensus was not reached with only one statement regarding the handling of cement during initial application to the tibial and/or femoral bone surfaces. CONCLUSION: The Cementing Techniques In Knee Surgery (CeTIKS) Delphi consensus study presents comprehensive recommendations on the optimal technique for component cementing in TKA. Expert opinion has a place in the hierarchy of evidence and, until better evidence is available these recommendations should be considered when cementing a TKA.
Blood RNA-sequencing across the continuum of ANA-positive autoimmunity reveals insights into initiating immunopathology.
OBJECTIVE: Mechanisms underpinning clinical evolution to systemic lupus erythematosus (SLE) from preceding antinuclear antibodies (ANA) positivity are poorly understood. This study aimed to understand blood immune cell transcriptional signatures associated with subclinical ANA positivity, and progression or non-progression to SLE. METHODS: Bulk RNA-sequencing of peripheral blood mononuclear cells isolated at baseline from 35 ANA positive (ANA+) subjects with non-diagnostic symptoms was analysed using differential gene expression, weighted gene co-expression network analysis, deconvolution of cell subsets and functional enrichment analyses. ANA+ subjects, including those progressing to classifiable SLE at 12 months (n=15) and those with stable subclinical ANA positivity (n=20), were compared with 15 healthy subjects and 18 patients with SLE. RESULTS: ANA+ subjects demonstrated extensive transcriptomic dysregulation compared with healthy controls with reduced CD4+naïve T-cells and resting NK cells, but higher activated dendritic cells. B-cell lymphopenia was evident in SLE but not ANA+ subjects. Two-thirds of dysregulated genes were common to ANA+ progressors and non-progressors. ANA+ progressors showed elevated modular interferon signature in which constituent genes were inducible by both type I interferon (IFN-I) and type II interferon (IFN-II) in vitro. Baseline downregulation of mitochondrial oxidative phosphorylation complex I components significantly associated with progression to SLE but did not directly correlate with IFN modular activity. Non-progressors demonstrated more diverse cytokine profiles. CONCLUSIONS: ANA positivity, irrespective of clinical trajectory, is profoundly dysregulated and transcriptomically closer to SLE than to healthy immune function. Metabolic derangements and IFN-I activation occur early in the ANA+ preclinical phase and associated with diverging transcriptomic profiles which distinguish subsequent clinical evolution.
Fracture Risk and Health Profiles Differ According to Relationship Status: Findings from the Hertfordshire Cohort Study.
Registry studies have suggested associations between relationship status and fracture risk. We considered associations between relationship status and incident fracture in the Hertfordshire Cohort Study, comprising community-dwelling older adults, and explored associations between socioeconomic and lifestyle factors with relationship status. 2997 participants completed a baseline questionnaire (1998-2004) and clinic visit. Participants were followed up until December 2018 using Hospital Episode Statistics, which report clinical outcomes using codes from the 10th revision of the International Classification of Diseases (ICD-10); these codes were used to ascertain incident fractures. Relationship status (not currently married/cohabiting vs currently married/cohabiting) at baseline was examined in relation to incident fracture using Cox regression. Associations between baseline characteristics and relationship status were examined using logistic regression. Mean baseline age was 66.2 years. 80% were married/cohabiting at baseline; 15% had an incident fracture (mean (SD) follow-up duration: 14.4 (4.5) years). The following were related to greater likelihood of not being married/cohabiting: older age (women only); higher BMI (women only); current smoking; high alcohol consumption (men only); poorer diet quality (men only); lower physical activity; leaving school before age 15 (women only); and not owning one's home. Those not married/cohabiting had greater risk of incident fracture compared to those who were (age-adjusted hazard ratios (95% CI) 1.58 (1.06, 2.38) among men, 1.35 (1.06, 1.72) among women); associations were attenuated after accounting for the above factors associated with relationship status in the corresponding sex. This suggests that differences in health profiles and lifestyle according to relationship status may explain the association between relationship status and fracture risk.
Estimating dose-response relationships for vitamin D with coronary heart disease, stroke, and all-cause mortality: observational and Mendelian randomisation analyses.
BACKGROUND: Randomised trials of vitamin D supplementation for cardiovascular disease and all-cause mortality have generally reported null findings. However, generalisability of results to individuals with low vitamin D status is unclear. We aimed to characterise dose-response relationships between 25-hydroxyvitamin D (25[OH]D) concentrations and risk of coronary heart disease, stroke, and all-cause mortality in observational and Mendelian randomisation frameworks. METHODS: Observational analyses were undertaken using data from 33 prospective studies comprising 500 962 individuals with no known history of coronary heart disease or stroke at baseline. Mendelian randomisation analyses were performed in four population-based cohort studies (UK Biobank, EPIC-CVD, and two Copenhagen population-based studies) comprising 386 406 middle-aged individuals of European ancestries, including 33 546 people who developed coronary heart disease, 18 166 people who had a stroke, and 27 885 people who died. Primary outcomes were coronary heart disease, defined as fatal ischaemic heart disease (International Classification of Diseases 10th revision code I20-I25) or non-fatal myocardial infarction (I21-I23); stroke, defined as any cerebrovascular disease (I60-I69); and all-cause mortality. FINDINGS: Observational analyses suggested inverse associations between incident coronary heart disease, stroke, and all-cause mortality outcomes with 25(OH)D concentration at low 25(OH)D concentrations. In population-wide genetic analyses, there were no associations of genetically predicted 25(OH)D with coronary heart disease (odds ratio [OR] per 10 nmol/L higher genetically-predicted 25(OH)D concentration 0·98, 95% CI 0·95-1·01), stroke (1·01, [0·97-1·05]), or all-cause mortality (0·99, 0·95-1·02). Null findings were also observed in genetic analyses for cause-specific mortality outcomes, and in stratified genetic analyses for all outcomes at all observed levels of 25(OH)D concentrations. INTERPRETATION: Stratified Mendelian randomisation analyses suggest a lack of causal relationship for 25(OH)D concentrations with both cardiovascular and mortality outcomes for individuals at all levels of 25(OH)D. Our findings suggest that substantial reductions in mortality and cardiovascular morbidity due to long-term low-dose vitamin D supplementation are unlikely even if targeted at individuals with low vitamin D status. FUNDING: British Heart Foundation, Medical Research Council, National Institute for Health Research, Health Data Research UK, Cancer Research UK, and International Agency for Research on Cancer.
Influence of vitamin D supplementation on growth, body composition, pubertal development and spirometry in South African schoolchildren: a randomised controlled trial (ViDiKids).
OBJECTIVE: To determine whether weekly oral vitamin D supplementation influences growth, body composition, pubertal development or spirometric outcomes in South African schoolchildren. DESIGN: Phase 3 double-blind randomised placebo-controlled trial. SETTING: Socioeconomically disadvantaged peri-urban district of Cape Town, South Africa. PARTICIPANTS: 1682 children of black African ancestry attending government primary schools and aged 6-11 years at baseline. INTERVENTIONS: Oral vitamin D3 (10 000 IU/week) versus placebo for 3 years. MAIN OUTCOME MEASURES: Height-for-age and body mass index-for-age, measured in all participants; Tanner scores for pubertal development, spirometric lung volumes and body composition, measured in a subset of 450 children who additionally took part in a nested substudy. RESULTS: Mean serum 25-hydroxyvitamin D3 concentration at 3-year follow-up was higher among children randomised to receive vitamin D versus placebo (104.3 vs 64.7 nmol/L, respectively; mean difference (MD) 39.7 nmol/L, 95% CI 37.6 to 41.9 nmol/L). No statistically significant differences in height-for-age z-score (adjusted MD (aMD) -0.08, 95% CI -0.19 to 0.03) or body mass index-for-age z-score (aMD -0.04, 95% CI -0.16 to 0.07) were seen between vitamin D versus placebo groups at follow-up. Among substudy participants, allocation to vitamin D versus placebo did not influence pubertal development scores, % predicted forced expiratory volume in 1 s (FEV1), % predicted forced vital capacity (FVC), % predicted FEV1/FVC, fat mass or fat-free mass. CONCLUSIONS: Weekly oral administration of 10 000 IU vitamin D3 boosted vitamin D status but did not influence growth, body composition, pubertal development or spirometric outcomes in South African schoolchildren. TRIAL REGISTRATION NUMBERS: ClinicalTrials.gov NCT02880982, South African National Clinical Trials Register DOH-27-0916-5527.
Immune responses and clinical outcomes after COVID-19 vaccination in patients with liver disease and liver transplant recipients.
BACKGROUND & AIMS: Comparative assessments of immunogenicity following different COVID-19 vaccines in patients with distinct liver diseases are lacking. SARS-CoV-2-specific T-cell and antibody responses were evaluated longitudinally after one to three vaccine doses, with long-term follow-up for COVID-19-related clinical outcomes. METHODS: A total of 849 participants (355 with cirrhosis, 74 with autoimmune hepatitis [AIH], 36 with vascular liver disease [VLD], 257 liver transplant recipients [LTRs] and 127 healthy controls [HCs]) were recruited from four countries. Standardised immune assays were performed pre and post three vaccine doses (V1-3). RESULTS: In the total cohort, there were incremental increases in antibody titres after each vaccine dose (p <0.0001). Factors associated with reduced antibody responses were age and LT, whereas heterologous vaccination, prior COVID-19 and mRNA platforms were associated with greater responses. Although antibody titres decreased between post-V2 and pre-V3 (p = 0.012), patients with AIH, VLD, and cirrhosis had equivalent antibody responses to HCs post-V3. LTRs had lower and more heterogenous antibody titres than other groups, including post-V3 where 9% had no detectable antibodies; this was heavily influenced by intensity of immunosuppression. Vaccination increased T-cell IFNγ responses in all groups except LTRs. Patients with liver disease had lower functional antibody responses against nine Omicron subvariants and reduced T-cell responses to Omicron BA.1-specific peptides compared to wild-type. 122 cases of breakthrough COVID-19 were reported of which 5/122 (4%) were severe. Of the severe cases, 4/5 (80%) occurred in LTRs and 2/5 (40%) had no serological response post-V2. CONCLUSION: After three COVID-19 vaccines, patients with liver disease generally develop robust antibody and T-cell responses to vaccination and have mild COVID-19. However, LTRs have sustained no/low antibody titres and appear most vulnerable to severe disease. IMPACT AND IMPLICATIONS: Standardised assessments of the immune response to different COVID-19 vaccines in patients with liver disease are lacking. We performed antibody and T-cell assays at multiple timepoints following up to three vaccine doses in a large cohort of patients with a range of liver conditions. Overall, the three most widely available vaccine platforms were immunogenic and appeared to protect against severe breakthrough COVID-19. This will provide reassurance to patients with chronic liver disease who were deemed at high risk of severe COVID-19 during the pre-vaccination era, however, liver transplant recipients had the lowest antibody titres and remained vulnerable to severe breakthrough infection. We also characterise the immune response to multiple SARS-CoV-2 variants and describe the interaction between disease type, severity, and vaccine platform. These insights may prove useful in the event of future viral infections which also require rapid vaccine development and delivery to patients with liver disease.
Training needs for staff providing remote services in general practice: a mixed-methods study.
BACKGROUND: Contemporary general practice includes many kinds of remote encounter. The rise in telephone, video and online modalities for triage and clinical care requires clinicians and support staff to be trained, both individually and as teams, but evidence-based competencies have not previously been produced for general practice. AIM: To identify training needs, core competencies, and learning methods for staff providing remote encounters. DESIGN AND SETTING: Mixed-methods study in UK general practice. METHOD: Data were collated from longitudinal ethnographic case studies of 12 general practices; a multi-stakeholder workshop; interviews with policymakers, training providers, and trainees; published research; and grey literature (such as training materials and surveys). Data were coded thematically and analysed using theories of individual and team learning. RESULTS: Learning to provide remote services occurred in the context of high workload, understaffing, and complex workflows. Low confidence and perceived unmet training needs were common. Training priorities for novice clinicians included basic technological skills, triage, ethics (for privacy and consent), and communication and clinical skills. Established clinicians' training priorities include advanced communication skills (for example, maintaining rapport and attentiveness), working within the limits of technologies, making complex judgements, coordinating multi-professional care in a distributed environment, and training others. Much existing training is didactic and technology focused. While basic knowledge was often gained using such methods, the ability and confidence to make complex judgements were usually acquired through experience, informal discussions, and on-the-job methods such as shadowing. Whole-team training was valued but rarely available. A draft set of competencies is offered based on the findings. CONCLUSION: The knowledge needed to deliver high-quality remote encounters to diverse patient groups is complex, collective, and organisationally embedded. The vital role of non-didactic training, for example, joint clinical sessions, case-based discussions, and in-person, whole-team, on-the-job training, needs to be recognised.