Severe acute myositis and myocarditis on initiation of 6-weekly pembrolizumab post-COVID-19 mRNA vaccination.

We describe three cases of critical acute myositis with myocarditis occurring within 22 days of each other at a single institution, all within 1 month of receiving the initial cycle of the anti-PD-1 drug pembrolizumab. Analysis of T cell receptor repertoires from peripheral blood and tissues revealed a high degree of clonal expansion and public clones between cases, with several T cell clones expanded within the skeletal muscle putatively recognizing viral epitopes. All patients had recently received a COVID-19 mRNA booster vaccine prior to treatment and were positive for SARS-CoV2 Spike antibody. In conclusion, we report a series of unusually severe myositis and myocarditis following PD-1 blockade and the COVID-19 mRNA vaccination.

Disaster day: a simulation-based competition for educating emergency medicine residents and medical students on disaster medicine.

BACKGROUND: Disaster medicine is a growing field within the specialty of emergency medicine, but educational training typically focuses on hospital drills or other educational strategies, such as didactics, simulation, or tabletop exercises. With the success of gamification in other medical education applications, we sought to investigate if a novel gamified curricular innovation would lead to improved test performance and confidence in the ability to manage a real mass casualty incident (MCI). METHODS: This was a prospective observational study of medical students and emergency medicine residents who participated in a 4-h simulation-based competition consisting of 4 unique stations. Each station had learning objectives associated with the content taught. Learners completed a pre-event survey, followed by participation in the competitive gamification event, and subsequently completed a post-event survey. Differences between pre- and post-event responses were matched and analyzed using paired and unpaired t tests for medical knowledge assessments, the Mann-Whitney U test for perceptions of confidence in the ability to manage an MCI event, and descriptive statistics provided on perceptions of the effectiveness of this educational strategy. RESULTS: We analyzed data from 49 learners with matched (and unmatched) pre- and post-event survey responses. There was a statistically significant increase in medical knowledge assessment scores in both unmatched group means and available matched data (47 to 69%, p < 0.01, and 50 to 69%, p < 0.05). Self-reported confidence in the ability to handle an MCI scenario also significantly increased (p < 0.01). Finally, 100% of respondents indicated they "agreed" or "strongly agreed" that the event was an effective education tool for disaster preparedness and training. CONCLUSIONS: In this study, we found that learners perceived a novel gamification event as an effective educational tool, which led to improved learner knowledge and self-reported confidence in the ability to manage a real MCI.

A Non-Classical Presentation of Erythema Migrans in a 51-Year-Old Woman With Early Manifestation of Lyme Neuroborreliosis (Bannwarth Syndrome).

The authors present a case of a 51-year-old female who presented to the emergency department with general malaise, headache, neck stiffness, and an expanding rash consistent with Lyme neuroborreliosis. In this case report, the clinical presentation, diagnosis, and management of Lyme neuroborreliosis and different presentations of erythema migrans are discussed.

Coronial postmortem reports and indirect COVID-19 pandemic-related mortality.

AIMS: Widespread disruption of healthcare services and excess mortality not directly attributed to COVID-19 occurred between March and May 2020. We undertook the first UK multicentre study of coroners' autopsies before and during this period using postmortem reports. METHODS: We reviewed reports of non-forensic coroners' autopsies performed during the first COVID-19 lockdown (23 March to 8 May 2020), and the same period in 2018. Deaths were categorised as natural non-COVID-19, COVID-19-related, non-natural (suicide, drug and alcohol-related, traumatic, other). We provided opinion regarding whether delayed access to medical care or changes in behaviour due to lockdown were a potential factor in deaths. RESULTS: Seven centres covering nine coronial jurisdictions submitted a total of 1100 coroners' autopsies (498 in 2018, 602 in 2020). In only 54 autopsies was death attributed to COVID-19 (9%). We identified a significant increase in cases where delays in accessing medical care potentially contributed to death (10 in 2018, 44 in 2020). Lockdown was a contributing factor in a proportion of suicides (24%) and drug and alcohol-related deaths (12%). CONCLUSIONS: Postmortem reports have considerable utility in evaluating excess mortality due to healthcare and wider societal disruption during a pandemic. They provide information at an individual case level that is not available from assessment of death certification data. Detailed evaluation of coroners' autopsy reports, supported by appropriate regulatory oversight, is recommended to mitigate disruption and indirect causes of mortality in future pandemics. Maintaining access to healthcare, including substance misuse and mental health services, is an important consideration.

Acute Myopericarditis in the Post COVID-19 Recovery Phase.

The COVID-19 viral infection, caused by the novel coronavirus severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is a currently ongoing global pandemic that, as of mid-October, 2020, has resulted in more than 38.7 million confirmed cases globally and has caused more than 1.1 million fatalities. COVID-19 infection is associated with severe life threatening respiratory and cardiac complications such as acute respiratory distress syndrome (ARDS), pneumonia, shock, cardiac arrhythmias, myocardial infarction and heart failure, particularly in the acute infectious stage. Acute myopericarditis is another reported cardiac complication of COVID-19. Case reports have been limited in reporting the effects of COVID-19 in the post-symptomatic period. In this article, we present a case of acute myopericarditis resulting 6 to 8 weeks after testing positive for COVID-19. Here we will breakdown the initial emergency department (ED) presentation, with particular attention to the electrocardiogram (ECG) findings of acute myopericarditis. This case, to the our best knowledge and after an extensive literature review, depicts the first case of myopericarditis in the post COVID-19 infection recovery phase.

Greater utility of molecular subtype rather than epithelial-to-mesenchymal transition (EMT) markers for prognosis in high-risk non-muscle-invasive (HGT1) bladder cancer.

Approximately 75% of bladder cancers are non-muscle invasive (NMIBC). Of these, up to 53% of cases progress to life-threatening muscle-invasive bladder cancer (MIBC). Patients with high-grade stage T1 (HGT1) NMIBC frequently undergo radical cystectomy (RC), although this represents overtreatment for many. Identification of progressors versus non-progressors could spare unnecessary treatment. Recent studies have confirmed that urothelial carcinoma is composed of two main molecular subtypes, basal and luminal, with 12% of basal tumours exhibiting epithelial-to-mesenchymal transition (EMT). Levels of immune cell infiltration have been shown to be subtype-specific. Here, we performed immunohistochemistry (IHC) for 11 antibodies relating to molecular subtypes or EMT in 26 cases of HGT1 urothelial carcinoma cases with 6 matched samples subsequently obtained at cystectomy (n = 6; 1 muscle-invasive, 5 non-muscle-invasive; 3 = pTis, 1 = pT1, 1 = pTa) and at recurrence (n = 2, pT2). RNAScope was also conducted in a subset. Expression patterns in HGT1 specimens versus MIBC (pT2+) were examined, and correlated with disease-specific survival (DSS). Levels of stromal tumour-infiltrating lymphocytes (sTILs) were assessed manually to determine whether lymphocyte infiltration was associated with DSS and whether differences existed between HGT1 and MIBC. Molecular subtype markers demonstrated increased prognostic potential compared to the EMT markers assessed. Increased expression of the luminal markers FOXA1 and SCUBE2, were found to be significantly associated with better DFS. No EMT markers were significantly associated with DFS. In areas of non-invasive papillary urothelial carcinoma, but not invasive carcinoma, sTIL levels were found to be significantly associated with DFS. While differences were observed between HGT1 cases that progressed versus those that did not, a larger cohort study is required for validation of these findings. Taken together, an emphasis on molecular subtype markers, rather than EMT markers, may be preferable when studying biomarkers of HGT1 urothelial carcinoma in the future.

The important role of the histopathologist in clinical trials: challenges and approaches to tackle them.

High-quality histopathology is essential for the success of clinical trials. Histopathologists have a detailed understanding of tumour biology and mechanisms of disease, as well as practical knowledge of optimal tissue handling and logistical service requirements for study delivery, such as biomarker evaluation, tissue acquisition and turnaround times. As such, histopathologist input is essential throughout every stage of research and clinical trials, from concept development and study design to trial delivery, analysis and dissemination of results. Patient recruitment to trials takes place among all healthcare settings, meaning that histopathologists make an invaluable contribution to clinical trials as part of their routine day-to-day work that often goes unrecognised. More complex evaluation of surgical specimens in the neoadjuvant setting and ever-expanding minimum data sets add to the workload of every histopathologist, not just academic pathologists in tertiary centres. This is occurring against a backdrop of increasing workload pressures and a worldwide shortage of histopathologists and biomedical scientists. Providing essential histopathology support for trials at grassroots level requires funding for adequate resources including histopathologist time, education and training, biomedical scientist and administrative support and greater recognition of the contribution made by histopathology. This paper will discuss the many ways in which histopathologists are involved in clinical trials and the challenges faced in meeting the additional demands posed by trial participation and potential ways to address this, with a special emphasis on the UK model and the Cellular-Molecular Pathology Initiative (CM-Path).

Mineral processing simulation based-environmental life cycle assessment for rare earth project development: A case study on the Songwe Hill project.

Rare earth elements (REE), including neodymium, praseodymium, and dysprosium are used in a range of low-carbon technologies, such as electric vehicles and wind turbines, and demand for these REE is forecast to grow. This study demonstrates that a process simulation-based life cycle assessment (LCA) carried out at the early stages of a REE project, such as at the pre-feasibility stage, can inform subsequent decision making during the development of the project and help reduce its environmental impacts. As new REE supply chains are established and new mines are opened. It is important that the environmental consequences of different production options are examined in a life cycle context in order that the environment footprint of these raw materials is kept as low as possible. Here, we present a cradle-to-gate and process simulation-based life cycle assessment (LCA) for a potential new supply of REE at Songwe Hill in Malawi. We examine different project options including energy selection and a comparison of on-site acid regeneration versus virgin acid consumption which were being considered for the project. The LCA results show that the global warming potential of producing 1 kg of rare earth oxide (REO) from Songwe Hill is between 17 and 87 kg CO2-eq. A scenario that combines on-site acid regeneration with off-peak hydroelectric and photovoltaic energy gives the lowest global warming potential and performs well in other impact categories. This approach can equally well be applied to all other types of ore deposits and should be considered as a routine addition to all pre-feasibility studies.

The use of digital pathology and image analysis in clinical trials.

Digital pathology and image analysis potentially provide greater accuracy, reproducibility and standardisation of pathology-based trial entry criteria and endpoints, alongside extracting new insights from both existing and novel features. Image analysis has great potential to identify, extract and quantify features in greater detail in comparison to pathologist assessment, which may produce improved prediction models or perform tasks beyond manual capability. In this article, we provide an overview of the utility of such technologies in clinical trials and provide a discussion of the potential applications, current challenges, limitations and remaining unanswered questions that require addressing prior to routine adoption in such studies. We reiterate the value of central review of pathology in clinical trials, and discuss inherent logistical, cost and performance advantages of using a digital approach. The current and emerging regulatory landscape is outlined. The role of digital platforms and remote learning to improve the training and performance of clinical trial pathologists is discussed. The impact of image analysis on quantitative tissue morphometrics in key areas such as standardisation of immunohistochemical stain interpretation, assessment of tumour cellularity prior to molecular analytical applications and the assessment of novel histological features is described. The standardisation of digital image production, establishment of criteria for digital pathology use in pre-clinical and clinical studies, establishment of performance criteria for image analysis algorithms and liaison with regulatory bodies to facilitate incorporation of image analysis applications into clinical practice are key issues to be addressed to improve digital pathology incorporation into clinical trials.

Deep learning for detecting tumour-infiltrating lymphocytes in testicular germ cell tumours.

AIMS: To evaluate if a deep learning algorithm can be trained to identify tumour-infiltrating lymphocytes (TILs) in tissue samples of testicular germ cell tumours and to assess whether the TIL counts correlate with relapse status of the patient. METHODS: TILs were manually annotated in 259 tumour regions from 28 whole-slide images (WSIs) of H&E-stained tissue samples. A deep learning algorithm was trained on half of the regions and tested on the other half. The algorithm was further applied to larger areas of tumour WSIs from 89 patients and correlated with clinicopathological data. RESULTS: A correlation coefficient of 0.89 was achieved when comparing the algorithm with the manual TIL count in the test set of images in which TILs were present (n=47). In the WSI regions from the 89 patient samples, the median TIL density was 1009/mm2. In seminomas, none of the relapsed patients belonged to the highest TIL density tertile (>2011/mm2). TIL quantifications performed visually by three pathologists on the same tumours were not significantly associated with outcome. The average interobserver agreement between the pathologists when assigning a patient into TIL tertiles was 0.32 (Kappa test) compared with 0.35 between the algorithm and the experts, respectively. A higher TIL density was associated with a lower clinical tumour stage, seminoma histology and lack of lymphovascular invasion. CONCLUSIONS: Deep learning-based image analysis can be used for detecting TILs in testicular germ cell cancer more objectively and it has potential for use as a prognostic marker for disease relapse.

Peritoneal disease in breast cancer: a specific entity with an extremely poor prognosis.

BACKGROUND: Peritoneal metastases are now a significant cause of morbidity and mortality in patients with advanced breast cancer. There are few published data regarding the prognosis, clinical characteristics and management of individuals with peritoneal metastases from breast cancer. METHODS: The electronic database at Imperial College Healthcare NHS Trust (Charing Cross Hospital) was searched for the terms 'breast', 'cancer' or 'tumour', 'peritoneal' and 'ascites' from 2000 to 2008. Those with confirmed peritoneal disease from breast cancer, as described on ultrasound or staging CT reports with a clinico-pathologic confirmed diagnosis, were included. RESULTS: A total of 1628 patients were screened and initially 168 patients were identified. A subsequent total of 44 individuals (2.7% of the cohort) were defined as having breast cancer with peritoneal secondaries and were included in the analysis. Of these, the majority (77%) had invasive ductal carcinomas (IDCs). While the median survival from the diagnosis of metastatic breast cancer measured 20.5 months (range 0.1-125 months), the median survival of patients with peritoneal disease was 1.56 months (range 0.2-27 months). CONCLUSIONS: These data demonstrate that the median survival of patients with peritoneal breast cancer metastasis is surprisingly poor, with only a minority surviving more than 6 months. A specific association with invasive lobular carcinoma (ILC) was not observed. The dismal outcome of these individuals, despite further active therapy, merits their inclusion into clinical trials designed specifically for this group of patients.

Exploring possible mechanisms for primary bile acid malabsorption: evidence for different regulation of ileal bile acid transporter transcripts in chronic diarrhoea.

OBJECTIVES: Chronic diarrhoea resulting from primary idiopathic bile acid malabsorption (IBAM) is common, but its aetiology is largely unknown. We investigated possible mechanisms, first looking for common sequence variations in the cytoplasmic ileal bile acid-binding protein (IBABP, gene symbol FABP6), and secondly, determining the expression of ileal mucosal transcripts for the apical sodium-linked bile acid transporter (ASBT), IBABP, the putative basolateral transporters, OSTalpha and OSTbeta, and regulatory factors. METHODS: Genomic DNA was prepared from two cohorts of patients and two control groups; the promoter and exonic regions of FABP6 were sequenced. In intestinal biopsies, transcript expression was measured by quantitative real time-PCR, using ileum from 17 patients and 21 controls. RESULTS: Sequence variations were identified in FABP6, but overall frequencies were similar in patients and controls. Transcripts of ASBT and IBABP, but not OSTalpha and OSTbeta, were expressed at higher levels in ileum than duodenum. The transcription factors farnesoid-X-receptor (FXR) and liver-receptor-homologue (LRH-1) were also more abundant in ileum, as was fibroblast growth factor 19 (FGF19), unlike short heterodimer partner (SHP), c-Fos, or CDX2. No significant differences in mean or median values were found between the groups for any of these transcripts. However, findings on regression analysis suggested that these transporters differ in their regulation, particularly in the relationships of CDX2, LRH-1 and FXR with OSTalpha. CONCLUSION: Most cases of IBAM are unlikely to be caused by genetic variation in FABP6 or by major differences in transporter transcript expression. Our evidence indicates that other factors, such as regulation of expression of the basolateral bile acid transporter, should be considered as possible causes.