Tarlton's News Out of Purgatory (1590): a modern spelling edition with introduction and commentary

This thesis is a modern-spelling edition of Tarlton's News Out of Purgatory, based on the British Library's copy of the first edition of 1590, with occasional emendations from the second and third editions, and including a full collation of the three early editions. The Introduction offers studies of various aspects of the work, including the bibliographical background of the piece, and descriptions of surviving copies; the life and legend of Richard Tarlton; the background of the genre of 'News from Hell', to which the work belongs, and examination of works in that genre which immediately followed the publication of Tarlton's News Out of Purgatory; and the sources of the pamphlet, and the author's adaptation and development of them. There is a study of the work published in response to Tarlton's News Out of Purgatory in 1590, The Cobler of Caunterburie; an investigation into the question of the identity of the author, including consideration of claims that have been made for various writers, and, finally, a short critical appreciation of the work. There is a full Commentary on the text, including glosses of obscure and archaic words, textual notes, explanations of references in the work, and, as part of the investigation into the authorship, echoes of the works of contemporary writers

Testicular microlithiasis imaging and follow-up: guidelines of the ESUR scrotal imaging subcommittee

The subcommittee on scrotal imaging, appointed by the board of the European Society of Urogenital Radiology (ESUR), have produced guidelines on imaging and follow-up in testicular microlithiasis (TML)

Are youth mentoring programs good value-for-money? An evaluation of the Big Brothers Big Sisters Melbourne Program

Background : The Big Brothers Big Sisters (BBBS) program matches vulnerable young people with a trained, supervised adult volunteer as mentor. The young people are typically seriously disadvantaged, with multiple psychosocial problems.Methods : Threshold analysis was undertaken to determine whether investment in the program was a worthwhile use of limited public funds. The potential cost savings were based on US estimates of life-time costs associated with high-risk youth who drop out-of-school and become adult criminals. The intervention was modelled for children aged 10&ndash;14 years residing in Melbourne in 2004.Results : If the program serviced 2,208 of the most vulnerable young people, it would cost AUD 39.5 M. Assuming 50% were high-risk, the associated costs of their adult criminality would be AUD 3.3 billion. To break even, the program would need to avert high-risk behaviours in only 1.3% (14/1,104) of participants.Conclusion : This indicative evaluation suggests that the BBBS program represents excellent \u27value for money\u27.<br /

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication

Testicular Germ Cell Tumours&mdash;The Role of Conventional Ultrasound

Testicular tumours are the most common tumours found in young males and germ cell tumours account for 95% of testicular tumours. Ultrasound is the first-line radiological investigation for imaging of the testis. This article outlines how to undertake an ultrasound examination, including optimal patient position, scanning technique and imaging parameters. Classification of germ cell tumours is provided, and salient imaging features of different tumours are described. Difficulties and pitfalls of ultrasound are described, including tumours found after a trauma presentation, orchitis causing diagnostic difficulties and imaging of small testicular lesions. Other uses of ultrasound are outlined, including looking for a primary testicular tumour following the discovery of retroperitoneal lymph nodes, imaging when tumour-makers increase, local recurrence in the scrotum, and for solid organ biopsy in metastatic disease. Conclusion: Ultrasound remains the first-line of investigation for imaging of the testis, and conventional ultrasound still plays a large role in imaging. On ultrasound alone, accurate morphological characterisation of tumours remains a challenge, despite the imaging features that can be seen in different tumour types. Therefore, histology following orchidectomy of a germ cell tumour remains the gold standard for accurate tumour characterisation

Investigation and assessment of adrenal incidentalomas

With the increasing volume of diagnostic imaging undertaken in an ageing population, adrenal incidentalomas (AIs) are increasingly commonly seen. These masses are most likely to be benign, but a small proportion may be malignant. Similarly, they are usually non-functional, but ∼14% are functional, ie hormone-secreting tumours. Clinical, biochemical and radiological assessment is mandated to stratify patients into those requiring radiological surveillance, medical management or surgical intervention or who can be discharged. Mass characteristics on cross-sectional (CT/MRI) imaging influence the need for radiological surveillance. Functional tumours where excess cortisol, aldosterone or catecholamine are secreted should be excluded, with mild autonomous cortisol secretion (MACS) and primary aldosteronism (PA) as the two most common functional states. MACS and PA are associated with an increased risk of cardiometabolic disease (eg hypertension, type 2 diabetes) and cardiovascular morbidity/mortality (eg coronary heart disease). Multidisciplinary management is critical for selected cases; the majority of adrenal incidentalomas only require a single assessment

RXC008 suppresses fibrosis in a DSS model as measured by histopathology and magnetic resonance imaging

Background: A common and untreatable complication of Crohn’s disease (CD) is the development of intestinal fibrostenosis; it is estimated that 50% of Crohn’s patients will experience fibrosis within 10 years of diagnosis and repeated surgical intervention is currently the only treatment option. ROCK is a serine/threonine kinase that plays a fundamental role in fibrosis and inhibitors of ROCK have been shown to suppress fibrosis in numerous animal models. RXC008 is a GI restricted, potent and selective ROCK1/2 inhibitor with the potential to treat fibrostenosis. Methods: RXC008 was examined for anti-fibrotic efficacy in a chronic 9-week DSS colitis model of intestinal fibrosis with RNAseq, histology, magnetization transfer (MT) and texture analysis entropy (TA-entropy) of magnetic resonance imaging (MRI) used to measure the extent of fibrosis. Results: The MT-MRI and TA-entropy assessments correlated with the histopathology scores with TA-entropy proving superior to MT-MRI for quantifying the progression of fibrosis throughout the experiment. RXC008 was able to strongly suppress fibrosis in the DSS colitis model as measured by both histology and TA-entropy; in addition, multiple pro-fibrotic and tissue remodelling genes were modulated by RXC008. Conclusions: MRI TA-entropy is a highly promising non-invasive surrogate markers of intestinal fibrosis that has the potential to revolutionise clinical assessment of fibrostenosis in Crohn’s patients and measure efficacious effects of new treatments. RXC008 shows great promise as an anti-fibrotic therapy to for fibrostenosis demonstrating strong efficacy as measured by both histopathology and MRI TA-entropy. RXC008 is being developed for phase I clinical assessment in H2 2023