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Introduction: IMbassador250 was a prospective phase III international multicenter trial enrolling 759 men with mCRPC who had prior progression on abiraterone, with or without prior taxane, randomizing to enzalutamide +/- atezolizumab. For this retrospective biomarker study, we hypothesized that decreases in ctDNA after 6 weeks of therapy, as measured from a novel low-pass, whole genome methylation sequencing assay from Foundation Medicine, will have greater discriminatory power to distinguish overall survival (OS) than PSA alone in a post-abiraterone mCRPC setting. Methods: Pre-treatment and C3D1 plasma samples from IMbassador250 were sequenced using a novel research assay that examines global copy number changes and methylation patterns through low pass, whole genome sequencing from Foundation Medicine. Kinetic changes in ctDNA were estimated between pre-treatment and C3D1 timepoints and patients were dichotomized into significant decreases vs. not using a predefined cutoff. PSA was examined as both 50% reduction from baseline to disease progression as well as a cutoff that matched the prevalence captured by the ctDNA reduction group at C3D1. Cox proportional hazards were calculated from Kaplan-Meier survival plots of overall survival between the reduction vs. no reduction groups. Results: Stratifying OS according to PSA 50% reduction from baseline to disease progression yielded an HR = 2.71 (95%CI:2.04-3.62). 370 patients (48%) had available ctDNA at both C1D1 and C3D1, and the median OS (mOS) in the reduction vs. non-reduction groups were 17.4 vs. 9.1 months, respectively (HR of 3.01; 95%CI:1.96-4.64). Evaluation of PSA reduction at C3D1 in the patients with available ctDNA yielded mOS of 16.3 and 9.5 months in the reduction vs. non-reduction groups, respectively (HR=2.70; 95%CI:1.77-4.12). Spearman’s correlation of ctDNA fold change between the research assay and an orthogonal FDA approved liquid biopsy assay was 0.95. Discussion: In this study, early ctDNA kinetic changes provided numerically superior estimation of overall survival compared to PSA in mCRPC patients receiving enzalutamide +/- atezolizumab in the post-abiraterone setting. Furthermore, ctDNA kinetic changes through C3D1 were apparent mostly prior to both PSA 50 and radiographic progression (6 weeks vs mean 3.3 months), providing a non-invasive strategy that is independent of PSA for monitoring therapy response when the disease is less AR dependent. Citation Format: Christopher Sweeney, Chang Xu, Jie He, Amanda Young, Alexander Robertson, Russell Petry, Daniel Zollinger, Alexander Fine, Neil Peterman, Eliana Polisecki, Tyler Warner, Kobe Yuen, Yanmei Huang, Zoe Assaf, Ryon Graf, Sanjeev Mariathasan, Priti Hegde, David Fabrizio, Thomas Powles. Evaluation of circulating tumor DNA kinetics as a prognostic biomarker for overall survival in metastatic castrate resistant prostate cancer using a novel methylation sequencing research assay [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3362.

SARS-CoV-2 remdesivir resistance mutations have been generated in vitro but have not been reported in patients receiving treatment with the antiviral agent. We present a case of an immunocompromised patient with acquired B-cell deficiency who developed an indolent, protracted course of SARS-CoV-2 infection. Remdesivir therapy alleviated symptoms and produced a transient virologic response, but her course was complicated by recrudescence of high-grade viral shedding. Whole genome sequencing identified a mutation, E802D, in the nsp12 RNA-dependent RNA polymerase, which was not present in pre-treatment specimens. In vitro experiments demonstrated that the mutation conferred a ∼6-fold increase in remdesivir IC50 but resulted in a fitness cost in the absence of remdesivir. Sustained clinical and virologic response was achieved after treatment with casirivimab-imdevimab. Although the fitness cost observed in vitro may limit the risk posed by E802D, this case illustrates the importance of monitoring for remdesivir resistance and the potential benefit of combinatorial therapies in immunocompromised patients with SARS-CoV-2 infection.

Supervising medical students to develop a research project can be challenging. A cohort of medical students were encouraged to focus their project ideas on a story of someone whose medical problem was of interest to them and use it to develop their research project.

Soft tissue pressure injuries are localised injuries to surface and deep tissue, caused by sustained compression of skin and muscle between a bony area of the body, and for example, a hospital mattress or medical device. Prolonged cell deformation is known to reduce the structural integrity of the cell cytoskeleton, leading to cascade of cell death, inflammation, oedema and oxidative stress, factors that are like exacerbated by inadequate blood flow and oxygen delivery. Numerous secondary factors are thought to accelerate this cascade, including systemic hypoxia and changes in tissue temperature. By examining the responses of various skin viability markers, both during and after the application of temperature and pressure stimuli, the present study aims to expand understanding of the secondary factors affecting pressure ulcers onset and progression. In the present study, a custom skin deformation device, with an area of 33cm2, was used to apply a combination of pressures (6, 20 and 40mmHg) and temperatures (33, 33, 38°C) at the sacrum of four healthy volunteers (data collection ongoing). A laser doppler flowmetry probe, embedded into the skin deformation device, was used to measure baseline skin blood flow, skin blood flow under pressure, and reactive hyperaemia (RH) on pressure release. All measurements were calculated as a percentage of heat-induced maximal cutaneous vascular conductance (%CVCmax). Changes in stratum corneum and epidermal hydration were calculated using the difference in tissue electrical capacitance (corneometry) measurements before and after skin deformation. The results indicated a significant difference in loaded skin blood flow between the pressures of 6-20mmHg (p=0.045), and 6-40mmHg (p=0.018), decreasing from 30.5 ± 9.1 %CVCmax to 21.8 ± 9.0 %CVCmax and 17.5 ± 6.7 %CVCmax respectively. Furthermore, there was a significant increase (p=0.030) from 16.9 ± 8.2 %CVCmax to 29.8 ± 5.4 %CVCmax in loaded skin blood flow, between the temperatures of 28-38°C. Finally, blood flow saw a significant (p=0.005) increase on pressure release, from a loaded average of 19.7 ± 8.2 %CVCmax to an unloaded average of 29.0 ± 12.0 %CVCmax, however there was no significant effect of pressure level or temperature on reactive hyperemia. Changes in stratum corneum hydration between 28-33°C (p=0.044), and 28-38°C (p=0.019), increased from 20.8 ± 11.3% to 38.8 ± 12.7% and 48.5 ± 15.5% respectively. Differing pressures and temperatures had no significant effect on epidermal hydration. Initial indications from the present study suggest low local tissue temperature reduces tissue blood flow under pressure, thereby potentially reducing oxygen transport to, and metabolites away from, areas of loaded tissue. However, increased local temperature results in greater moisture accumulation on the surface layer of the cutaneous tissues, potentially resulting in a lower structural integrity, and when combined with a higher metabolism, may result in a faster rate of tissue breakdown. On balance, a neutral skin temperature may be best skin to balance the harmful effects pressure on tissue viability, but further investigation is required to fully understand the influence of temperature on each aspect of the pressure injury cascade, including cell cytoskeleton integrity, inflammation, and oedema, as well as blood flow dynamics, oxygen delivery, cell metabolism and oxidative stress.

Spelling variation in historical text negatively impacts the performance of naturallanguage processing techniques, so normalisation is an important pre-processingstep. Current methods fall some way short of perfect accuracy, often requiringlarge amounts of training data to be effective, and are rarely evaluated againsta wide range of historical sources. This thesis evaluates three models: a HiddenMarkov Model, which has not been previously used for historical text normalisation; a soft attention Neural Network model, which has previously only been evaluated on a single German dataset; and a hard attention Neural Network model,which is adapted from work on morphological inflection and applied here to historical text normalisation for the first time. Each is evaluated against multipledatasets taken from prior work on historical text normalisation. This facilitatesdirect comparison of this work to that existing work. The hard attention NeuralNetwork model achieves state-of-the-art normalisation accuracy in all datasets,even when the volume of training data is restricted. This work will be of particular interest to researchers working with noisy historical data which they wouldlike to explore using modern computational techniques.

Languages in earlier stages of development differ from their modern analogues, reflecting syntactic, semantic and morphological changes over time. The study of these and other phenomena is the major concern of historical linguistics. The development of literacy and advances in technology mean that human language has often been reserved in physical form. Whilst these artefacts will eventually include video and sound recordings, the current life blood of historical linguistics is text. The written word is the de facto source of evidence for earlier stages of languages and “the first-order witnesses to the more distance linguistic past are written texts.” (Lass, 1997) This dissertation proposes and evaluates a method for identifying spelling variants in historical documents.

Background and Aims Little is known about small-bowel (SB) capsule endoscopy (CE) in patients with a history of gastric surgery. This study aims to evaluate the feasibility and diagnostic yield (DY) of orally ingested SB-CE in patients with surgically altered gastric anatomy. Methods Twenty-four European centers retrospectively identified patients who had SB-CE after total or subtotal gastrectomy. The primary outcome was the DY of SB-CE (intermediate P1 to highly P2 relevant findings). Secondary outcomes were gastric and SB transit times, completion, cleanliness, and adverse event rates. Results Studied were 248 procedures from 243 patients (mean age, 62 years) with a history of partial gastrectomy (Billroth I, 13.1%; Billroth II, 34.6%), total gastrectomy (7.4%), Whipple procedure (12.8%), sleeve gastrectomy (7.2%), or gastric bypass surgery (24.7%). Obscure GI bleeding was the most frequent indication (85.1%). SB completion rate was 84.3%. One capsule retention in the SB was noted (adverse event rate, .4%). Median SB transit time was 286 minutes (interquartile range [235; 387]). Cleanliness was rated as adequate in 92.1% of procedures. After exclusion of abnormalities found at the upper anastomotic site, the DY was 43.6%, with inflammatory/ulcerated lesions observed more frequently (23.4%) than vascular lesions (21.0%). Conclusions SB-CE seems to be feasible and safe in selected patients with a history of major gastric surgery and comes with a high DY. The spectrum of abnormal SB findings in these patients may be different from what is known from the literature in nonoperated patients.

Much has been written about the benefits of green infrastructure, but securing the resources necessary for its development and long-term maintenance is often difficult. This article’s premise is that, in general, people and organisations will take action to provide those resources when they can see value accruing to them; therefore narratives of value generation and capture (our definition of business models) are required to motivate and support that action. This article explores the application of soft systems methodology to the wicked problem of business model development in the context of a social enterprise, using a case study based on a piece of green infrastructure in the city of Birmingham, UK, called The Lost World. The research involved a workshop with several of The Lost World’s key stakeholders and aimed at identifying: The Lost World’s scope as a business; its potential value streams; and how they might be realised in a social enterprise. Analysis of the findings shows that while stakeholders can identify opportunities for their organisations, bringing those opportunities to fruition is difficult. The research demonstrates a compelling need for social entrepreneurs to act as catalysts and long-term enablers of the formulation and maintenance of businesses and business models—vital missing actors in the ambition to transform cityscapes.

Introduction Microscopic colitis (MC) is still perceived to be an ‘uncommon’ condition1. Despite significant impact on quality of life1, many aspects of the patient journey remain unclear. A National MC Disease Registry is being developed with the aim of gathering data on epidemiology, variations in clinical practice and patient journey. The secondary aim is to generate academic and clinical data to help create more stream-lined MC Services, improving patient care and outcomes. Methods Retrospective data was collected across 6 Scottish (2 DGHs/4 University teaching) units. Once identified from Pathology databases, further data was collected from electronic records. Results In total, 527 patients were enrolled on the registry; of whom, 54 were excluded due to incomplete information. Out of 473 patients [Collagenous colitis 328(69%), Lymphocytic colitis 127(27%), 18 unspecified (4%)] included in the analysis, 358(76%) were female, aged 20–96 (median 67) years. Watery diarrhoea (463, 98%) and abdominal pain (111, 23%) were predominant symptoms. Weight loss was noted in 115(24%). Eight (2%) patients developed complications; 2 adverse drug reactions, 1 colorectal malignancy and 3 required surgical intervention for intractable symptoms related to MC. Variations were noted in the following areas: Patient journey: Whilst 230(49%) were referred directly to Gastroenterology, 109(23%) were referred initially to Surgery– with subsequent referral to Gastroenterology following colonoscopy. This led to delay in therapy initiation in a proportion of patients. In one unit, average length of symptoms at diagnosis was 5.7 months, with an average length of 9.1 months to see Gastroenterology. Medications: There was no evidence of medication review in 121(26%) patients. Reducing-dose Budesonide was the first line treatment in 205(43%). Though 174(37%) did not require initial medical therapy; of these 18(10%) required subsequent treatment with Budesonide. There are 4(1%) patients on biologics and 4(1%) patients on immunomodulators specifically for MC– all of which were treated with budesonide first line. Follow-up: A majority, 337(71%) were followed-up in clinic, with 260(77%) later discharged. Relapse was noted in 118(25%) patients. Conclusions Initial findings from the first MC Registry in the UK demonstrate variability in referral pathway, patient journey and management. Data suggests association with alarm features and significant complications. Reference Townsend T, Campbell F, O’Toole P, et al. Microscopic colitis: diagnosis and management. Frontline Gastroenterology 2019;10(4):388–93

Systematic reviews, which entail the extraction of data from large numbers of scientific documents, are an ideal avenue for the application of machine learning. They are vital to many fields of science and philanthropy, but are very time-consuming and require experts. Yet the three main stages of a systematic review are easily done automatically: searching for documents can be done via APIs and scrapers, selection of relevant documents can be done via binary classification, and extraction of data can be done via sequence-labelling classification. Despite the promise of automation for this field, little research exists that examines the various ways to automate each of these tasks. We construct a pipeline that automates each of these aspects, and experiment with many human-time vs. system quality trade-offs. We test the ability of classifiers to work well on small amounts of data and to generalise to data from countries not represented in the training data. We test different types of data extraction with varying difficulty in annotation, and five different neural architectures to do the extraction. We find that we can get surprising accuracy and generalisability of the whole pipeline system with only 2 weeks of human-expert annotation, which is only 15% of the time it takes to do the whole review manually and can be repeated and extended to new data with no additional effort., Comment: In EMNLP 2020 Scholarly Document Processing Workshop

Organic semiconductors have attracted considerable attention due to their applications in low-cost (opto)electronic devices. Many successful organic materials utilize blends of several types of molecules that contribute different functions (e.g., serving as donors and acceptors in solar cells). In blends, the local environment, which is inherently heterogeneous, strongly influences the (opto)electronic performance and photostability. We use functionalized fluorinated pentacene (F8 TCHS-Pn) molecules as single-molecule probes of the nanoscale environment in blends containing donor and acceptor molecules incorporated into a polymer (PMMA) matrix. Single F8 TCHS-Pn donor (D) molecules were imaged in PMMA in the presence of functionalized indenofluorene (TIPS-IF) or PCBM acceptor (A) molecules using wide-field fluorescence microscopy at various concentrations. Long-lived dark states attributed to a reversible formation of an endoperoxide (TCHS-EPO) were observed, and the EPO formation and reversal processes, ...

In standard practice, estimations of populations of fungal spores on gridded membrane filter discs are made from spore loads in arbitrarily selected groups or rows of grids (quadrats). We used the resting spores of Synchytrium endobioticum to examine actual/expected spore ratio. The ratios showed unacceptable divergences, and are characterized by an aggregated spore distribution. The fractal diversity index of the quadrats is inversely related the loga of the population numbers. The analysis gives values for the appropriate spore number per quadrat and the quadrat pattern to yield the best actual/expected ratio.

Recording the home languages of schoolchildren has long been acknowledged as a useful way of mapping community multilingualism. However, the need to process large quantities of data on many different languages has meant that in order to assess the vitality of community languages, researchers have had to rely on schoolchildren's self-reported language preference and proficiency. Moreover, large scale data collection among minors poses ethical and data protection issues. We describe a pilot study carried out in Manchester, England, in which a method was tested to record home language proficiency based on rapid, anonymous speech acts. These were correlated with respondents’ self-reported exposure to their home languages. The results indicate that different factors can play a role in language maintenance in different communities, and that home language maintenance does not have an adverse effect on proficiency in the majority language.

BackgroundPatients presenting with chest pain represent a significant proportion of attendances to the ED. The History, ECG, Age, Risk Factors and Troponin (HEART) Score is validated for the risk stratification of suspected ischaemic chest pain within the ED. The goal of this research was to establish the interoperator reliability of the HEART Score as performed in the ED by different grades of doctor and nurse.MethodologyPatients with suspected ischaemic chest pain presenting to the ED of an inner city, London Hospital, were recruited prospectively between January and May 2016. Patients that had been enrolled in the study were interviewed by clinicians from four different categories: senior doctor, junior doctor, senior nurse and junior nurse. Clinicians, blinded to other raters’ results, calculated the HEART Scores for each patient with the assistance of a pocket-sized HEART Score card. The intraclass correlation coefficient (ICC) was calculated as the primary measure of reliability. 120 patients were required to achieve a desired power of 80%.Results88 complete comparisons were obtained. There were no significant differences between the distributions of HEART Scores for each clinician group (p=0.95). The ICC for the overall HEART Score was 0.91 (95% CI 0.87 to 0.93). The ICC for troponin and age were ‘1’, for ‘history’ 0.41 (95% CI 0.30 to 0.52), ‘ECG’ 0.64 (95% CI 0.54 to0.73) and ‘risk factors’ 0.84 (95% CI 0.79 to 0.89).ConclusionThis study demonstrates very strong overall interoperator reliability between the four groups of clinicians studied. This suggests that the HEART Score is reproducible when used by different professional groups and grade of clinician.

We highlight several issues in the evaluation of historical text normalization systems that make it hard to tell how well these systems would actually work in practice---i.e., for new datasets or languages; in comparison to more na\"ive systems; or as a preprocessing step for downstream NLP tools. We illustrate these issues and exemplify our proposed evaluation practices by comparing two neural models against a na\"ive baseline system. We show that the neural models generalize well to unseen words in tests on five languages; nevertheless, they provide no clear benefit over the na\"ive baseline for downstream POS tagging of an English historical collection. We conclude that future work should include more rigorous evaluation, including both intrinsic and extrinsic measures where possible., Comment: Accepted to NAACL 2018

Introduction In 2014, our centre reported experience showing a high diagnostic yield (DY) of capsule endoscopy (CE) in octogenarians, although sinister lesions were rare and little change in management was made2. Based on our subsequent experience, this study seeks to establish if this still holds true. Methods A prospectively-maintained CE database of patients who underwent CE from 2005–2017 was interrogated for patients>80 years old. Data were extracted on CE indications, findings and outcomes. The capsule examination was considered to have DY if the findings accounted for the patient’s presentation. Results 164 CE procedures were performed in 150 patients≥80 years, mean age 84.1 years (range 80.0–96.2, 99F/65M). Indications for CE were iron deficiency anaemia (IDA) (82), obscure gastrointestinal bleeding (OGIB) (63), possible IBD (6), suspected malignancy/lymphoma (4) and others (10). 12 (8%) underwent more than 1 CE. 23 were excluded with incomplete data. 5 patients died of unrelated pathologies over the study period. The overall DY of CE in this cohort was 75/141 (53.2%). The findings were: angioectasias (46), small bowel masses (10, including polyps and nodular bleeding lesions), portal hypertensive/NSAID/other enteropathies (9), small bowel inflammation (3), small bowel varices (2), GAVE (2), duodenal ulcer (1) and caecal bleeding (1). 59/141 (41.8%) patients had normal CE findings; another 7/141 (4.9%) had findings of unclear clinical significance. Of the 10 (7.1%) patients with possible small bowel masses seen on CE, 5 were not followed up due to frailty and the presence of more likely causes of IDA/OGIB (e. g. significant gastritis). 2 underwent double-balloon enteroscopy with no lesion found. 1 patient was felt likely to have inflammatory bowel disease and treated. 1 patient had repeat CE with similar benign appearances and was discharged. Only 1 patient had a suspicious-looking obstructive and bleeding lesion; he returned to Australia and underwent follow-up there. There were 7 patients≥90 years old. All underwent CE for OGIB/IDA. 3 patients had angioectasias with active bleeding; 2 were treated with APC and one managed conservatively. 1 patient had small duodenal angioectasias of unclear significance. In 2 patients, the small bowel was normal but gastric ulcers/significant gastritis were deemed the likely cause of blood loss. There was 1 oesophageal retention with no further CE. Conclusion In this age group, 90% (145/162) were referred with IDA/OGIB, with DY 53.2%. Angioectasias were the main significant findings. However, although a gastrointestinal source of blood loss was frequently found, there was rarely a change to management required, advisable or possible based on the CE result.

Introduction Upper GI bleeding remains an important cause of morbidity and mortality. Mortality rates in non-variceal upper GI bleeding have remained relatively static over recent decades despite an ever-increasing range of therapeutic options. Interventional radiology (IR) has become an increasingly available tool for management of upper GI bleeding when endoscopic haemostasis has failed. However, literature is lacking surrounding the technical success and long term outcomes of mesenteric embolisation in patients with non-variceal upper GI haemorrhage. We therefore wished to assess the overall technical efficacy and outcomes of interventional radiology in patients presenting with upper GI haemorrhage who had undergone initial endoscopy at the Royal Infirmary of Edinburgh. Methods We retrospectively analysed the interventional radiology database for all patients who had undergone embolisation procedures. We then focussed on patients who had presented with non-variceal haemorrhage and assessed their outcomes using computer-based records. Patients were followed up for a minimum of 1 year. Results Data were available from 2007 onward. We assessed patient’s mortality outcomes at 30 days and 1 year. In total, 24 patients had undergone mesenteric embolisation for non-variceal upper GI haemorrhage (15 female, 9 males). Median age was 72 (range 52–96). Over half of patients (14 of 24, 58.3%) had an ASA grade of III or IV (figure 1). 19 of 24 had information available to calculate Glasgow-Blatchford score, with a median score of 15 (figure 2). Mean length of hospital stay in survivors was 31.75 days (5–148). 23 lesions were located in the duodenum, 1 in the oesophagus. There were 2 Dieulafoy lesions, 1 tumour vessel, 1 unclear bleeding point and 20 ulcers with varying stigmata. 5 patients had already undergone surgical management of their bleeding lesion prior to IR. IR was technically successful in 22 of 24 patients. 4 out of 24 patients rebled following embolisation. No patients developed an acute kidney injury following angiography. 6 out of 24 (25%) of patients died within 30 days of their IR procedure (figure 3). 8 out of 24 (33%) died within 1 year. 3 of these were due to bleeding, 3 due to sepsis and 2 due to malignancies (figure 4). Conclusions Mesenteric embolisation in patients with significant non-variceal upper GI bleeding has high technical success rates with low rebleeding rates, in a patient population that often is elderly with significant comorbidity. Approximately one third of patients who undergo interventional radiology procedures for non-variceal upper GI haemorrhage will be dead at 1 year; the majority from non-bleeding related causes.

This paper discusses relativization strategies used by South Asian languages, with the focus falling on relative-correlative constructions. The bi-clausal relative-correlative structure is believed to be native to Indo-Aryan languages and has been replicated by Austroasiatic, Dravidian and Tibeto-Burman languages of South Asia through contact and convergence, despite the non-Indic languages of the region already having a participial relativization strategy at their disposal. Various permutations of the relative-correlative construction are discussed and compared to the participial relativization strategies of South Asian languages, and functional reasons are proposed for its widespread diffusion and distribution. Accepted version