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Perspectum Diagnostics – a spinout from the Radcliffe Department of Medicine – has reinvested money in the University of Oxford, to fund a three year multicentre European health economic study into methods of diagnosing fatty liver disease. This first of three payments totaling €759,999, is part of a €3.4m project, won by Perspectum in the H2020 grant competition.
Standardisation of Definition and Management for Bleeding Disorder of Unknown Cause: Communication from the SSC of the ISTH.
In many patients referred with significant bleeding phenotype, laboratory testing fails to define any hemostatic abnormalities. Clinical practise with respect to diagnosis and management of this patient cohort poses significant clinical challenges. We recommend that bleeding history in these patients should be objectively assessed using the ISTH bleeding assessment tool (BAT). Patients with increased BAT scores should progress to hemostasis laboratory testing. To diagnose BDUC, normal complete blood count, prothrombin time, activated partial thromboplastin time, thrombin time, von Willebrand factor antigen, von Willebrand factor function; coagulation factors VIII, IX and XI and platelet light transmission aggregometry (LTA) should be the minimum laboratory assessment. In some laboratories, additional specialized haemostasis testing may be performed and identify other rare causes of bleeding. We recommend that patients with a significant bleeding phenotype but normal laboratory investigations should be registered with a diagnosis of 'Bleeding disorder of unknown cause (BDUC)' in preference to other terminology. Global haemostatic tests and markers of fibrinolysis demonstrate variable abnormalities, and their clinical significance remains uncertain. Targeted genomic sequencing examining candidate hemostatic genes has a low diagnostic yield. Underlying BDUC should be considered in patients with heavy menstrual bleeding since delays in diagnosis often extend to many years and negatively impact quality of life. Treatment options for BDUC patients include tranexamic acid, desmopressin and platelet transfusions.
Effects of ranolazine on the arrhythmic substrate in hypertrophic cardiomyopathy.
Introduction: Hypertrophic cardiomyopathy (HCM) is a leading cause of lethal arrhythmias in the young. Although the arrhythmic substrate has been hypothesised to be amenable to late Na+ block with ranolazine, the specific mechanisms are not fully understood. Therefore, this study aimed to investigate the substrate mechanisms of safety and antiarrhythmic efficacy of ranolazine in HCM. Methods: Computational models of human tissue and ventricles were used to simulate the electrophysiological behaviour of diseased HCM myocardium for variable degrees of repolarisation impairment, validated against in vitro and clinical recordings. S1-S2 pacing protocols were used to quantify arrhythmic risk in scenarios of (i) untreated HCM-remodelled myocardium and (ii) myocardium treated with 3µM, 6µM and 10µM ranolazine, for variable repolarisation heterogeneity sizes and pacing rates. ECGs were derived from biventricular simulations to identify ECG biomarkers linked to antiarrhythmic effects. Results: 10µM ranolazine given to models manifesting ventricular tachycardia (VT) at baseline led to a 40% reduction in number of VT episodes on pooled analysis of >40,000 re-entry inducibility simulations. Antiarrhythmic efficacy and safety were dependent on the degree of repolarisation impairment, with optimal benefit in models with maximum JTc interval <370 ms. Ranolazine increased risk of VT only in models with severe-extreme repolarisation impairment. Conclusion: Ranolazine efficacy and safety may be critically dependent upon the degree of repolarisation impairment in HCM. For moderate repolarisation impairment, reductions in refractoriness heterogeneity by ranolazine may prevent conduction blocks and re-entry. With severe-extreme disease substrates, reductions of the refractory period can increase re-entry sustainability.
Risk of severe COVID-19 outcomes after autumn 2022 COVID-19 booster vaccinations: a pooled analysis of national prospective cohort studies involving 7.4 million adults in England, Northern Ireland, Scotland and Wales.
BACKGROUND: UK COVID-19 vaccination policy has evolved to offering COVID-19 booster doses to individuals at increased risk of severe Illness from COVID-19. Building on our analyses of vaccine effectiveness of first, second and initial booster doses, we aimed to identify individuals at increased risk of severe outcomes (i.e., COVID-19 related hospitalisation or death) post the autumn 2022 booster dose. METHODS: We undertook a national population-based cohort analysis across all four UK nations through linked primary care, vaccination, hospitalisation and mortality data. We included individuals who received autumn 2022 booster doses of BNT162b2 (Comirnaty) or mRNA-1273 (Spikevax) during the period September 1, 2022 to December 31, 2022 to investigate the risk of severe COVID-19 outcomes. Cox proportional hazard models were used to estimate adjusted hazard ratios (aHR) and 95% confidence intervals (CIs) for the association between demographic and clinical factors and severe COVID-19 outcomes after the autumn booster dose. Analyses were adjusted for age, sex, body mass index (BMI), deprivation, urban/rural areas and comorbidities. Stratified analyses were conducted by vaccine type. We then conducted a fixed-effect meta-analysis to combine results across the four UK nations. FINDINGS: Between September 1, 2022 and December 31, 2022, 7,451,890 individuals ≥18 years received an autumn booster dose. 3500 had severe COVID-19 outcomes (2.9 events per 1000 person-years). Being male (male vs female, aHR 1.41 (1.32-1.51)), older adults (≥80 years vs 18-49 years; 10.43 (8.06-13.50)), underweight (BMI <18.5 vs BMI 25.0-29.9; 2.94 (2.51-3.44)), those with comorbidities (≥5 comorbidities vs none; 9.45 (8.15-10.96)) had a higher risk of COVID-19 hospitalisation or death after the autumn booster dose. Those with a larger household size (≥11 people within household vs 2 people; 1.56 (1.23-1.98)) and from more deprived areas (most deprived vs least deprived quintile; 1.35 (1.21-1.51)) had modestly higher risks. We also observed at least a two-fold increase in risk for those with various chronic neurological conditions, including Down's syndrome, immunodeficiency, chronic kidney disease, cancer, chronic respiratory disease, or cardiovascular disease. INTERPRETATION: Males, older individuals, underweight individuals, those with an increasing number of comorbidities, from a larger household or more deprived areas, and those with specific underlying health conditions remained at increased risk of COVID-19 hospitalisation and death after the autumn 2022 vaccine booster dose. There is now a need to focus on these risk groups for investigating immunogenicity and efficacy of further booster doses or therapeutics. FUNDING: National Core Studies-Immunity, UK Research and Innovation (Medical Research Council and Economic and Social Research Council), Health Data Research UK, the Scottish Government, and the University of Edinburgh.
Professionals’ views on providing personalized recurrence risks for de novo mutations: implications for genetic counseling
When an apparent de novo (new) genetic change has been identified as the cause of a serious genetic condition in a child, many couples would like to know the risk of this happening again in a future pregnancy. Current practice provides families with a population average risk of 1-2%. However, this figure is not accurate for any specific couple, and yet, they are asked to make decisions about having another child and/or whether to have prenatal testing. The PREcision Genetic Counselling And REproduction (PREGCARE) study is a new personalized assessment strategy that refines a couple’s recurrence risk prior to a new pregnancy, by analysing several samples from the parent-child trio (blood, saliva, swabs and father’s sperm) using Deep-Sequencing and haplotyping. Overall, this approach can reassure ~2/3 of couples who have a negligible (<0.1%) recurrence risk and focus support on those at higher risk (i.e. when mosaicism is identified in one of the parents). Here we present a qualitative interview study with UK clinical genetics professionals (n=20), which investigate the potential implications of introducing such a strategy in genetics clinics. While thematic analysis of the interviews indicated perceived clinical utility, it also indicates a need to prepare couples for the psychosocial implications of parent-of-origin information and to support their understanding of the assessment being offered. When dealing with personalized reproductive risk, a traditional non-directive approach may not meet the needs of practitioner and client(s) and shared decision-making provides an additional framework that may relieve some patient burden. Further qualitative investigation with couples is planned.
Fine-mapping analysis including over 254,000 East Asian and European descendants identifies 136 putative colorectal cancer susceptibility genes.
Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development.
Impact of prior lenalidomide or proteasome inhibitor exposure on the effectiveness of ixazomib-lenalidomide-dexamethasone for relapsed/refractory multiple myeloma: A pooled analysis from the INSURE study.
OBJECTIVES: To characterize the impact of prior exposure and refractoriness to lenalidomide or proteasome inhibitors (PIs) on the effectiveness and safety of ixazomib-lenalidomide-dexamethasone (IRd) in relapsed/refractory multiple myeloma (RRMM). METHODS: INSURE is a pooled analysis of adult RRMM patients who had received IRd in ≥2 line of therapy from three studies: INSIGHT MM, UVEA-IXA, and REMIX. RESULTS: Overall, 391/100/68 were lenalidomide-naïve/-exposed/-refractory and 37/411/110 were PI-naïve/-exposed/-refractory. Median duration of therapy (DOT) was 15.3/15.6/4.7 months and median progression-free survival (PFS) was 21.6/25.8/5.6 months in lenalidomide-naïve/exposed/refractory patients. Median DOT and PFS in PI-naïve/exposed/refractory patients were 20.4/15.2/6.9 months and not reached/19.8/11.4 months, respectively. The proportion of lenalidomide-naïve/exposed/refractory patients in INSIGHT and UVEA-IXA who discontinued a study drug due to adverse events (AEs) was ixazomib, 31.6/28.2/28.0% and 18.6/6.7/10.5%; lenalidomide, 21.9/28.2/16.0% and 16.1/6.7/10.5%; dexamethasone, 18.4/20.5/16.0% and 10.6/0/10.5%, respectively. The proportion of PI-naïve/exposed/refractory patients in INSIGHT and UVEA-IXA who discontinued a study drug due to AEs was: ixazomib, 44.4/28.8/27.8% and 22.2/16.7/15.7%; lenalidomide, 33.3/22.0/19.4% and 16.7/15.9/11.8%; dexamethasone, 33.3/17.4/16.7% and 16.7/9.5/7.8%, respectively. REMIX AE discontinuation rates were unavailable. CONCLUSION: IRd appeared to be effective in RRMM patients in routine clinical practice regardless of prior lenalidomide or PI exposure, with better outcomes seen in lenalidomide- and/or PI-nonrefractory versus refractory patients.
A review and analysis of outcomes in randomized clinical trials of plasma transfusion in patients with bleeding or for the prevention of bleeding: The BEST collaborative study.
BACKGROUND: Previous systematic reviews have revealed an inconsistency of outcome definitions as a major barrier in providing evidence-based guidance for the use of plasma transfusion to prevent or treat bleeding. We reviewed and analyzed outcomes in randomized controlled trials (RCTs) to provide a methodology for describing and classifying outcomes. STUDY DESIGN AND METHODS: RCTs involving transfusion of plasma published after 2000 were identified from a prior review (Yang 2012) and combined with an updated systematic literature search of multiple databases (July 1, 2011 to January 17, 2023). Inclusion of publications, data extraction, and risk of bias assessments were performed in duplicate. (PROSPERO registration number is: CRD42020158581). RESULTS: In total, 5579 citations were identified in the new systematic search and 22 were included. Six additional trials were identified from the previous review, resulting in a total of 28 trials: 23 therapeutic and five prophylactic studies. An increasing number of studies in the setting of major bleeding such as in cardiovascular surgery and trauma were identified. Eighty-seven outcomes were reported with a mean of 11 (min-max. 4-32) per study. There was substantial variation in outcomes used with a preponderance of surrogate measures for clinical effect such as laboratory parameters and blood usage. CONCLUSION: There is an expanding literature on plasma transfusion to inform guidelines. However, considerable heterogeneity of reported outcomes constrains comparisons. A core outcome set should be developed for plasma transfusion studies. Standardization of outcomes will motivate better study design, facilitate comparison, and improve clinical relevance for future trials of plasma transfusion.
Large-scale phenotyping of patients with long COVID post-hospitalization reveals mechanistic subtypes of disease.
One in ten severe acute respiratory syndrome coronavirus 2 infections result in prolonged symptoms termed long coronavirus disease (COVID), yet disease phenotypes and mechanisms are poorly understood1. Here we profiled 368 plasma proteins in 657 participants ≥3 months following hospitalization. Of these, 426 had at least one long COVID symptom and 233 had fully recovered. Elevated markers of myeloid inflammation and complement activation were associated with long COVID. IL-1R2, MATN2 and COLEC12 were associated with cardiorespiratory symptoms, fatigue and anxiety/depression; MATN2, CSF3 and C1QA were elevated in gastrointestinal symptoms and C1QA was elevated in cognitive impairment. Additional markers of alterations in nerve tissue repair (SPON-1 and NFASC) were elevated in those with cognitive impairment and SCG3, suggestive of brain-gut axis disturbance, was elevated in gastrointestinal symptoms. Severe acute respiratory syndrome coronavirus 2-specific immunoglobulin G (IgG) was persistently elevated in some individuals with long COVID, but virus was not detected in sputum. Analysis of inflammatory markers in nasal fluids showed no association with symptoms. Our study aimed to understand inflammatory processes that underlie long COVID and was not designed for biomarker discovery. Our findings suggest that specific inflammatory pathways related to tissue damage are implicated in subtypes of long COVID, which might be targeted in future therapeutic trials.
Adult Human, but Not Rodent, Spermatogonial Stem Cells Retain States with a Foetal-like Signature
Spermatogenesis involves a complex process of cellular differentiation maintained by spermatogonial stem cells (SSCs). Being critical to male reproduction, it is generally assumed that spermatogenesis starts and ends in equivalent transcriptional states in related species. Based on single-cell gene expression profiling, it has been proposed that undifferentiated human spermatogonia can be subclassified into four heterogenous subtypes, termed states 0, 0A, 0B, and 1. To increase the resolution of the undifferentiated compartment and trace the origin of the spermatogenic trajectory, we re-analysed the single-cell (sc) RNA-sequencing libraries of 34 post-pubescent human testes to generate an integrated atlas of germ cell differentiation. We then used this atlas to perform comparative analyses of the putative SSC transcriptome both across human development (using 28 foetal and pre-pubertal scRNA-seq libraries) and across species (including data from sheep, pig, buffalo, rhesus and cynomolgus macaque, rat, and mouse). Alongside its detailed characterisation, we show that the transcriptional heterogeneity of the undifferentiated spermatogonial cell compartment varies not only between species but across development. Our findings associate ‘state 0B’ with a suppressive transcriptomic programme that, in adult humans, acts to functionally oppose proliferation and maintain cells in a ready-to-react state. Consistent with this conclusion, we show that human foetal germ cells—which are mitotically arrested—can be characterised solely as state 0B. While germ cells with a state 0B signature are also present in foetal mice (and are likely conserved at this stage throughout mammals), they are not maintained into adulthood. We conjecture that in rodents, the foetal-like state 0B differentiates at birth into the renewing SSC population, whereas in humans it is maintained as a reserve population, supporting testicular homeostasis over a longer reproductive lifespan while reducing mutagenic load. Together, these results suggest that SSCs adopt differing evolutionary strategies across species to ensure fertility and genome integrity over vastly differing life histories and reproductive timeframes.
The pRb/RBL2-E2F1/4-GCN5 axis regulates cancer stem cell formation and G0 phase entry/exit by paracrine mechanisms.
The lethality, chemoresistance and metastatic characteristics of cancers are associated with phenotypically plastic cancer stem cells (CSCs). How the non-cell autonomous signalling pathways and cell-autonomous transcriptional machinery orchestrate the stem cell-like characteristics of CSCs is still poorly understood. Here we use a quantitative proteomic approach for identifying secreted proteins of CSCs in pancreatic cancer. We uncover that the cell-autonomous E2F1/4-pRb/RBL2 axis balances non-cell-autonomous signalling in healthy ductal cells but becomes deregulated upon KRAS mutation. E2F1 and E2F4 induce whereas pRb/RBL2 reduce WNT ligand expression (e.g. WNT7A, WNT7B, WNT10A, WNT4) thereby regulating self-renewal, chemoresistance and invasiveness of CSCs in both PDAC and breast cancer, and fibroblast proliferation. Screening for epigenetic enzymes identifies GCN5 as a regulator of CSCs that deposits H3K9ac onto WNT promoters and enhancers. Collectively, paracrine signalling pathways are controlled by the E2F-GCN5-RB axis in diverse cancers and this could be a therapeutic target for eliminating CSCs.
Pathways to optical STED microscopy
AbstractOptical far-field microscopy such as confocal fluorescence microscopy is a very popular technique for investigating the living cell. Unfortunately, its spatial resolution is limited to around 200 nm, impeding the imaging of small molecular assemblies. Recent decades have seen the development of optical nanoscopy, optical far-field microscopy with a spatial resolution down to molecular scales. STED microscopy was the first of such nanoscopy techniques. Despite the fact, that it in principle only requires the addition of a strong STED laser to a conventional microscope, STED nanoscopy was for a long time considered as a very complex technique, impossible to be applicable as a turn-key technique in everyday biological research. However, recent years has seen important improvements of the STED nanoscopy approach which have significantly simplified the setup. These developments mainly followed from optimization of fluorescent labels, laser technology and optical simplifications. As a result, STED microscopy setups have got more compact and have been realized on commercial instruments, allowing access to lessexperienced users in open imaging facilities. Here, we give a brief overview of the recent improvements in STED microscopy that made these important developments possible