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Antibody testing for COVID-19: A report from the National COVID Scientific Advisory Panel.
Background: The COVID-19 pandemic caused >1 million infections during January-March 2020. There is an urgent need for reliable antibody detection approaches to support diagnosis, vaccine development, safe release of individuals from quarantine, and population lock-down exit strategies. We set out to evaluate the performance of ELISA and lateral flow immunoassay (LFIA) devices. Methods: We tested plasma for COVID (severe acute respiratory syndrome coronavirus 2; SARS-CoV-2) IgM and IgG antibodies by ELISA and using nine different LFIA devices. We used a panel of plasma samples from individuals who have had confirmed COVID infection based on a PCR result (n=40), and pre-pandemic negative control samples banked in the UK prior to December-2019 (n=142). Results: ELISA detected IgM or IgG in 34/40 individuals with a confirmed history of COVID infection (sensitivity 85%, 95%CI 70-94%), vs. 0/50 pre-pandemic controls (specificity 100% [95%CI 93-100%]). IgG levels were detected in 31/31 COVID-positive individuals tested ≥10 days after symptom onset (sensitivity 100%, 95%CI 89-100%). IgG titres rose during the 3 weeks post symptom onset and began to fall by 8 weeks, but remained above the detection threshold. Point estimates for the sensitivity of LFIA devices ranged from 55-70% versus RT-PCR and 65-85% versus ELISA, with specificity 95-100% and 93-100% respectively. Within the limits of the study size, the performance of most LFIA devices was similar. Conclusions: Currently available commercial LFIA devices do not perform sufficiently well for individual patient applications. However, ELISA can be calibrated to be specific for detecting and quantifying SARS-CoV-2 IgM and IgG and is highly sensitive for IgG from 10 days following first symptoms.
Developing a framework for tracking antimicrobial resistance gene movement in a persistent environmental reservoir.
Mobile genetic elements are key to the global emergence of antibiotic resistance. We successfully reconstructed the complete bacterial genome and plasmid assemblies of isolates sharing the same bla KPC carbapenemase gene to understand evolution over time in six confined hospital drains over five years. From 82 isolates we identified 14 unique strains from 10 species with 113 bla KPC-carrying plasmids across 16 distinct replicon types. To assess dynamic gene movement, we introduced the 'Composite-Sample Complex', a novel mathematical approach to using probability to capture the directional movement of antimicrobial resistance genes. The Composite Sample Complex accounts for the co-occurrence of both plasmids and chromosomes within an isolate, and highlights likely gene donors and recipients. From the validated model, we demonstrate frequent transposition events of bla KPC from plasmids to other plasmids, as well as integration into the bacterial chromosome within specific drains. We present a novel approach to estimate the directional movement of antimicrobial resistance via gene mobilization.
Utilization of Proteomic Measures for Early Detection of Drug Benefits and Adverse Effects.
Recognition of benefits and adverse effects of therapies in earlier clinical trial phases could improve the safety, efficiency, and cost of clinical trials. Using four clinical trials representing a diverse set of diseases and drug classes (EXSCEL: exenatide/GLP-1 RA, SUGAR-DM-HF: empagliflozin/SGLT2i, PRADA: epirubicin/anthracycline, and AMPLE: abatacept/immunomodulator and adalimumab/TNF inhibitor), we hypothesized that previously validated proteomic measures for cardiometabolic outcomes could enable the detection of beneficial and adverse drug effects in fewer participants over a shorter follow-up period. Changes in SomaSignalTM proteomic tests over time in response to treatment were assessed in the EXSCEL (baseline vs 1 year; once-weekly exenatide (EQW) (n) = 1812 vs control (n) = 1787), SUGAR-DM-HF (baseline vs 12 weeks and 36 weeks; empagliflozin (n) = 45 vs control (n) = 52), AMPLE (baseline vs 85 days and 1 year; abatacept (n) = 210, adalimumab (n) = 222), and PRADA (baseline vs 7-10 days and 3 months, n = 120) trial. Improvement of cardiovascular risk and cardiometabolic traits with EQW was detectable within 1 year (P = .002) in sample sizes significantly smaller than the original study. Cardio- and kidney-protective (P = .06, P = .037) effects of empagliflozin were detectable within 36 weeks in a small sample size (n ∼ 50). Abatacept and adalimumab treatment demonstrated significant improvements in cardiovascular risk (P ≤ .001, P ≤ .001) and cardiorespiratory fitness (P ≤ .001, P ≤ .001) within 85 days. In contrast, anthracycline treatment led to significant increases in heart failure mortality risk (P ≤ 0.001) and cardiovascular risk (P = .004) after the first cycle of chemotherapy treatment. These findings provide preliminary evidence that proteomics may provide a powerful tool for optimizing drug pipelines by predicting the effects of novel therapeutics in smaller, shorter trials.
Paediatric meningitis in the conjugate vaccine era and a novel clinical decision model to predict bacterial aetiology.
OBJECTIVES: The aims of this study were to assess aetiology and clinical characteristics in childhood meningitis, and develop clinical decision rules to distinguish bacterial meningitis from other similar clinical syndromes. METHODS: Children aged <16 years hospitalised with suspected meningitis/encephalitis were included, and prospectively recruited at 31 UK hospitals. Meningitis was defined as identification of bacteria/viruses from cerebrospinal fluid (CSF) and/or a raised CSF white blood cell count. New clinical decision rules were developed to distinguish bacterial from viral meningitis and those of alternative aetiology. RESULTS: The cohort included 3002 children (median age 2·4 months); 1101/3002 (36·7%) had meningitis, including 180 bacterial, 423 viral and 280 with no pathogen identified. Enterovirus was the most common pathogen in those aged <6 months and 10-16 years, with Neisseria meningitidis and/or Streptococcus pneumoniae commonest at age 6 months to 9 years. The Bacterial Meningitis Score had a negative predictive value of 95·3%. We developed two clinical decision rules, that could be used either before (sensitivity 82%, specificity 71%) or after lumbar puncture (sensitivity 84%, specificity 93%), to determine risk of bacterial meningitis. CONCLUSIONS: Bacterial meningitis comprised 6% of children with suspected meningitis/encephalitis. Our clinical decision rules provide potential novel approaches to assist with identifying children with bacterial meningitis. FUNDING: This study was funded by the Meningitis Research Foundation, Pfizer and the NIHR Programme Grants for Applied Research.
Adult T cell leukaemia/lymphoma (ATL) in pregnancy: A UK case series.
INTRODUCTION: Chronic infection with human T-cell lymphotropic virus type-1 (HTLV-1) may result in aggressive adult T-cell leukaemia/lymphoma (ATL) in 4-6% carriers. The majority of this risk arises in carriers infected during infancy, and so each infant has ∼25% lifetime risk. Other risk factors include a family history of ATL. Antenatal HTLV-1 screening is not undertaken in the UK. METHODS: Here we describe four cases of ATL diagnosed during pregnancy and describe strategies to minimise HTLV-1 transmission to neonates. RESULTS/CONCLUSION: These cases highlight undiagnosed HTLV-1 in pregnancy which allows ongoing mother to child vertical transmission and risk of future ATL. We recommend the UK National Screening Committee incorporate HTLV-1 serology into antenatal screening.
Effects of intensive blood pressure treatment on orthostatic hypertension: individual level meta-analysis.
OBJECTIVE: To determine the effects of intensive blood pressure treatment on orthostatic hypertension. DESIGN: Systematic review and individual participant data meta-analysis. DATA SOURCES: MEDLINE, Embase, and Cochrane CENTRAL databases through 13 November 2023. INCLUSION CRITERIA: Population: ≥500 adults, age ≥18 years with hypertension or elevated blood pressure; intervention: randomized trials of more intensive antihypertensive drug treatment (lower blood pressure goal or active agent) with duration ≥6 months; control: less intensive antihypertensive drug treatment (higher blood pressure goal or placebo); outcome: measured standing blood pressure. MAIN OUTCOMES: Orthostatic hypertension, defined as an increase in systolic blood pressure ≥20 mm Hg or diastolic blood pressure ≥10 mm Hg after changing from sitting to standing. DATA SYNTHESIS: Two investigators independently abstracted articles. Individual participant data from nine trials identified during the systematic review were appended together as a single dataset. RESULTS: Of 31 124 participants with 315 497 standing blood pressure assessments, 9% had orthostatic hypotension (that is, a drop in blood pressure after standing of systolic ≥20 mm Hg or diastolic ≥10 mm Hg), 17% had orthostatic hypertension, and 3.2% had both a rise in systolic blood pressure and standing blood pressure ≥140 mm Hg at baseline. The effects of more intensive treatment were similar across trials with odds ratios for orthostatic hypertension ranging from 0.85 to 1.08 (I2=38.0%). During follow-up, 17% of patients assigned to more intensive treatment had orthostatic hypertension, whereas 19% of those assigned less intensive treatment had orthostatic hypertension. Compared with less intensive treatment, the risk of orthostatic hypertension was lower with more intensive blood pressure treatment (odds ratio 0.93, 95% confidence interval 0.90 to 0.96). Effects were greater among non-black versus black adults (odds ratio 0.86 v 0.97; P for interaction=0.003) and adults without diabetes versus those with diabetes (0.88 v 0.96; P for interaction=0.05) but did not differ by age ≥75 years, sex, baseline seated blood pressure ≥130/≥80 mm Hg, obesity, stage 3 kidney disease, stroke, cardiovascular disease, standing systolic blood pressure ≥140 mm Hg, or pre-randomization orthostatic hypertension (P for interactions ≥0.05). CONCLUSIONS: In this pooled cohort of adults with elevated blood pressure or hypertension, orthostatic hypertension was common and more intensive blood pressure treatment modestly reduced the occurrence of orthostatic hypertension. These findings suggest that approaches generally used for seated hypertension may also prevent hypertension on standing. STUDY REGISTRATION: Prospero CRD42020153753 (original proposal).
Ribosome phenotypes for rapid classification of antibiotic-susceptible and resistant strains of Escherichia coli.
Rapid antibiotic susceptibility tests (ASTs) are an increasingly important part of clinical care as antimicrobial resistance (AMR) becomes more common in bacterial infections. Here, we use the spatial distribution of fluorescently labelled ribosomes to detect intracellular changes associated with antibiotic susceptibility in E. coli cells using a convolutional neural network (CNN). By using ribosome-targeting probes, one fluorescence image provides data for cell segmentation and susceptibility phenotyping. Using 60,382 cells from an antibiotic-susceptible laboratory strain of E. coli, we showed that antibiotics with different mechanisms of action result in distinct ribosome phenotypes, which can be identified by a CNN with high accuracy (99%, 98%, 95%, and 99% for ciprofloxacin, gentamicin, chloramphenicol, and carbenicillin). With 6 E. coli strains isolated from bloodstream infections, we used 34,205 images of ribosome phenotypes to train a CNN that could classify susceptible cells with 91% accuracy and resistant cells with 99% accuracy. Such accuracies correspond to the ability to differentiate susceptible and resistant samples with 99% confidence with just 2 cells, meaning that this method could eliminate lengthy culturing steps and could determine susceptibility with 30 min of antibiotic treatment. The ribosome phenotype method should also be able to identify phenotypes in other strains and species.
Identification of plasma proteomic markers underlying polygenic risk of type 2 diabetes and related comorbidities.
Genomics can provide insight into the etiology of type 2 diabetes and its comorbidities, but assigning functionality to non-coding variants remains challenging. Polygenic scores, which aggregate variant effects, can uncover mechanisms when paired with molecular data. Here, we test polygenic scores for type 2 diabetes and cardiometabolic comorbidities for associations with 2,922 circulating proteins in the UK Biobank. The genome-wide type 2 diabetes polygenic score associates with 617 proteins, of which 75% also associate with another cardiometabolic score. Partitioned type 2 diabetes scores, which capture distinct disease biology, associate with 342 proteins (20% unique). In this work, we identify key pathways (e.g., complement cascade), potential therapeutic targets (e.g., FAM3D in type 2 diabetes), and biomarkers of diabetic comorbidities (e.g., EFEMP1 and IGFBP2) through causal inference, pathway enrichment, and Cox regression of clinical trial outcomes. Our results are available via an interactive portal ( https://public.cgr.astrazeneca.com/t2d-pgs/v1/ ).
Characteristics and outcomes of neonates hospitalised with SARS-CoV-2 infection in the UK by variant: a prospective national cohort study.
OBJECTIVE: Neonatal infection with wildtype SARS-CoV-2 is rare and good outcomes predominate. We investigated neonatal outcomes using national population-level data to describe the impact of different SARS-CoV-2 variants. DESIGN: Prospective population-based cohort study. SETTING: Neonatal, paediatric and paediatric intensive care inpatient care settings in the UK. PATIENTS: Neonates (first 28 days after birth) with confirmed SARS-CoV-2 infection who received inpatient care, March 2020 to April 2022. Neonates were identified through active national surveillance with linkage to national SARS-CoV-2 testing data, routinely recorded neonatal data, paediatric intensive care data and obstetric and perinatal mortality surveillance data. OUTCOMES: Presenting signs, clinical course, severe disease requiring respiratory support are presented by the dominant SARS-CoV-2 variant in circulation at the time. RESULTS: 344 neonates with SARS-CoV-2 infection received inpatient care; breakdown by dominant variant: 146 wildtype, 123 alpha, 57 delta and 18 omicron. Overall, 44.7% (153/342) neonates required respiratory support; short-term outcomes were good with 93.6% (322/344) of neonates discharged home. Eleven neonates died: seven unrelated to SARS-CoV-2 infection, four were attributed to neonatal SARS-CoV-2 infection (case fatality 4/344, 1.2% 95% CI 0.3% to 3.0%) of which three were born preterm due to maternal COVID-19. More neonates were born very preterm (23/54) and required invasive ventilation (27/57) when delta variant was predominant, and all four SARS-CoV-2-related deaths occurred in this period. CONCLUSIONS: Inpatient care for neonates with SARS-CoV-2 was uncommon. Although rare, severe neonatal illness was more common during the delta variant period, potentially reflecting more severe maternal disease and associated preterm birth. TRIAL REGISTRATION NUMBER: ISRCTN60033461.
Genomic investigations of unexplained acute hepatitis in children.
Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children.
HIV Nef-mediated CD4 down-regulation is adaptor protein complex 2 dependent.
Nef is a crucial viral protein for HIV to replicate at high titers and in the development of AIDS. One Nef function is down-regulating CD4 from the cell surface, which correlates with Nef-enhanced viral pathogenicity. Nef down-regulates CD4 by linking CD4 to clathrin-coated pits. However, the mechanistic connection between the C-terminal dileucine motif of Nef and the component(s) of the clathrin-coated pits has not been pinpointed. In this report we used two AP-2 complex-specific inhibitors: a dominant negative mutant of Eps15 (Eps15DIII) that binds to the alpha subunit of AP-2 complex and a small interference RNA that is specific for the mu2 subunit of AP-2 complex. We show that both HIV Nef- and SIV Nef-mediated CD4 down-regulations were profoundly blocked by the synergistic effect of Eps15DIII and RNA interference of AP-2 expression. The results demonstrate that HIV/SIV Nef-mediated CD4 down-regulation is AP-2 dependent. We also show that the PMA-induced CD4 down-regulation was blocked by these two inhibitors. Therefore, PMA-induced CD4 down-regulation is also AP-2 dependent. The results demonstrate that, like the tyrosine sorting motif-dependent endocytosis (for which the transferrin receptor and the epidermal growth factor receptor are the two prototypes), dileucine sorting motif-dependent endocytosis of Nef and CD4 are also AP-2 dependent.
Polygenic prediction of occupational status GWAS elucidates genetic and environmental interplay in intergenerational transmission, careers and health in UK Biobank.
Socioeconomic status (SES) impacts health and life-course outcomes. This genome-wide association study (GWAS) of sociologically informed occupational status measures (ISEI, SIOPS, CAMSIS) using the UK Biobank (N = 273,157) identified 106 independent single-nucleotide polymorphisms of which 8 are novel to the study of SES. Genetic correlations with educational attainment (rg = 0.96-0.97) and income (rg = 0.81-0.91) point to a common genetic factor for SES. We observed a 54-57% reduction in within-family predictions compared with population-based predictions, attributed to indirect parental effects (22-27% attenuation) and assortative mating (21-27%) following our calculations. Using polygenic scores from population predictions of 5-10% (incremental R2 = 0.023-0.097 across different approaches and occupational status measures), we showed that (1) cognitive and non-cognitive traits, including scholastic and occupational motivation and aspiration, link polygenic scores to occupational status and (2) 62% of the intergenerational transmission of occupational status cannot be ascribed to genetic inheritance of common variants but other factors such as family environments. Finally, links between genetics, occupation, career trajectory and health are interrelated with parental occupational status.
Building the capacity of young professionals in family planning to publish: Insights from the ICFP2022 WHO scientific writing, mentoring and coaching course.
OBJECTIVES: We describe the development, delivery, and evaluation of a program to support junior professionals to publish their work in a scientific journal. STUDY DESIGN: Conference delegates with an accepted abstract at the International Conference on Family Planning (ICFP), self-identifying as junior professionals and from a low- or middle-income country (LMIC) or working predominantly in LMIC settings, were eligible for the program. The program involved: (1) Four face-to-face workshops at ICFP from the 14th to 17th of November 2022; (2) mentoring meetings at ICFP; (3) a six-month post-conference online coaching program; and (4) post-conference learning webinars from December 2022 to May 2023. We used online surveys to assess the participants' reactions, learning, and behaviour changes to the workshops and the online coaching program. We present participants' self-reported progress towards achieving a scientific publication. RESULTS: Sixty-seven participants from 29 countries participated in the workshops, and 40 attended the post-conference program. Workshops were rated positively, though the in-conference mentoring program faced challenges, including low attendance. The post-conference program was highly rated, with most participants engaging well with coaching and the webinars. At the end of the six-month program, 31 (46%) participants reported some progress in manuscript writing, with five completed manuscripts submitted. CONCLUSIONS: Scientific writing is a complex skill, and whilst our program had several positive elements, our participants faced many challenges completing their manuscripts within six months. The post-conference coaching and webinar program was rated highly, emphasising the need for ongoing support. IMPLICATIONS: Future programs should address this and other difficulties we highlight.