Immune checkpoint inhibitor-induced cholangitis-a three-case series.

Over the last decade, immune checkpoint inhibitors (ICIs) have dramatically improved the systemic treatment of multiple solid tumour types. However, they can also induce inflammation in an extensive range of normal tissues types. The entity of ICI-induced cholangitis is rare and has not been widely described.

Mouse adaptation of human inflammatory bowel diseases microbiota enhances colonization efficiency and alters microbiome aggressiveness depending on the recipient colonic inflammatory environment.

Background: Understanding the cause vs consequence relationship of gut inflammation and microbial dysbiosis in inflammatory bowel diseases (IBD) requires a reproducible mouse model of human-microbiota-driven experimental colitis.

Results: Our study demonstrated that human fecal microbiota transplant (FMT) transfer efficiency is an underappreciated source of experimental variability in human microbiota-associated (HMA) mice. Pooled human IBD patient fecal microbiota engrafted germ-free (GF) mice with low amplicon sequence variant (ASV)-level transfer efficiency, resulting in high recipient-to-recipient variation of microbiota composition and colitis severity in HMA Il-10 mice.

Mouse Adaptation of Human Inflammatory Bowel Diseases Microbiota Enhances Colonization Efficiency and Alters Microbiome Aggressiveness Depending on Recipient Colonic Inflammatory Environment.

Understanding the cause vs consequence relationship of gut inflammation and microbial dysbiosis in inflammatory bowel diseases (IBD) requires a reproducible mouse model of human-microbiota-driven experimental colitis. Our study demonstrated that human fecal microbiota transplant (FMT) transfer efficiency is an underappreciated source of experimental variability in human microbiota associated (HMA) mice. Pooled human IBD patient fecal microbiota engrafted germ-free (GF) mice with low amplicon sequence variant (ASV)-level transfer efficiency, resulting in high recipient-to-recipient variation of microbiota composition and colitis severity in HMA mice.

Advancing Understanding of Non-Small Cell Lung Cancer with Multiplexed Antibody-Based Spatial Imaging Technologies.

Non-small cell lung cancer (NSCLC) remains a cause of significant morbidity and mortality, despite significant advances made in its treatment using immune checkpoint inhibitors (ICIs) over the last decade; while a minority experience prolonged responses with ICIs, benefit is limited for most patients. The development of multiplexed antibody-based (MAB) spatial tissue imaging technologies has revolutionised analysis of the tumour microenvironment (TME), enabling identification of a wide range of cell types and subtypes, and analysis of the spatial relationships and interactions between them. Such study has the potential to translate into a greater understanding of treatment susceptibility and resistance, factors influencing prognosis and recurrence risk, and identification of novel therapeutic approaches and rational treatment combinations to improve patient outcomes in the clinic.

Third-Line Palliative Systemic Therapy for Advanced Biliary Tract Cancer: Multicentre Review of Patterns of Care and Outcomes.

Phase 3 trials have established standard first-line (1L) and 2L systemic therapy options for patients with advanced biliary cancer (ABC). However, a standard 3L treatment remains undefined. Clinical practice and outcomes for 3L systemic therapy in patients with ABC were therefore evaluated from three academic centres.

Estimating and minimizing movement artifacts in surface electromyogram.

While recording surface electromyography [sEMG], it is possible to record the electrical activities coming from the muscles and transients in the half-cell potential at the electrode-electrolyte interface due to micromovements of the electrode-skin interface. Separating the two sources of electrical activity usually fails due to the overlapping frequency characteristics of the signals. This paper aims to develop a method that detects movement artifacts and suggests a minimization technique.

Description of a Retrospective Cohort of Epithelial Ovarian Cancer Patients with Brain Metastases: Evaluation of the Role of PARP Inhibitors in this Setting.

Background: The incidence of brain metastases (BM) in patients with epithelial ovarian cancer (EOC) is low: 0.3-11%. The onset of BM has been regarded as a late event with limited treatment options and poor prognosis.

A single centre evaluation of the 2019 UK SABR consortium guidelines for primary lung cancer: correlation between Prescription Dose Spillage and inverse Paddick Conformity Index.

Background: The aim of the study was to determine level of agreement between RTOG Conformity Index (RTOG-CI), Paddick Conformity Index (PCI) and Prescription Dose Spillage (PDS) in describing lung stereotactic ablative radiotherapy (SABR) plan conformity; to elucidate any limitations, in practice, of PCI and PDS. International Commission on Radiation Units and Measurements report 91 (ICRU 91) aimed to reduce inconsistencies in dose prescription and normalisation between centres by specifying SABR reporting rules, and suggested using PCI. UK SABR Consortium 2019 guidelines adopted PDS to measure plan quality, but not the PCI.

Targeted Therapies for Perihilar Cholangiocarcinoma.

Perihilar cholangiocarcinoma (pCCA) is the anatomical sub-group of biliary tract cancer (BTC) arising between the second-order intrahepatic bile ducts and the cystic duct. Together with distal and intrahepatic cholangiocarcinoma (dCCA and iCCA; originating distal to, and proximal to this, respectively), gallbladder cancer (GBC) and ampulla of Vater carcinoma (AVC), these clinicopathologically and molecularly distinct entities comprise biliary tract cancer (BTC). Most pCCAs are unresectable at diagnosis, and for those with resectable disease, surgery is extensive, and recurrence is common.

Clinical challenges associated with utility of neoadjuvant treatment in patients with pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is an increasingly common cancer with a persistently poor prognosis, and only approximately 20% of patients are clearly anatomically resectable at diagnosis. Historically, a paucity of effective therapy made it inappropriate to forego the traditional gold standard of upfront surgery in favour of neoadjuvant treatment; however, modern combination chemotherapy regimens have made neoadjuvant therapy increasingly viable. As its use has expanded, the rationale for neoadjuvant therapy has evolved from one of 'downstaging' to one of early treatment of micro-metastases and selection of patients with favourable tumour biology for resection.

A Quality Improvement Project to Minimize COVID-19 Infections in Patients Receiving Haemodialysis and the Role of Routine Surveillance Using Nose and Throat Swabs for SARS-CoV-2 rRT-PCR and Serum Antibody Testing.

Background: Patients receiving in-centre haemodialysis (ICHD) are highly vulnerable to COVID-19.

Objective: We created a quality improvement (QI) project aimed to eliminate outbreaks of COVID-19 in haemodialysis units and evaluated the utility of surveillance rRT-PCR test and SARS-CoV-2 serum antibodies for prompt identification of patients infected with COVID-19.

Methods: A multifaceted QI programme including a bundle of infection prevention control (IPC) measures was implemented across 5 ICHD units following the first wave of the pandemic in June 2020.

A new approach to improve the hemodynamic assessment of cardiac function independent of respiratory influence.

Cardiovascular and respiratory systems are anatomically and functionally linked; inspiration produces negative intrathoracic pressures that act on the heart and alter cardiac function. Inspiratory pressures increase with heart failure and can exceed the magnitude of ventricular pressure during diastole. Accordingly, respiratory pressures may be a confounding factor to assessing cardiac function.

Occupational exposure of healthcare workers to COVID-19 and infection prevention control measures in haemodialysis facilities in North West of England.

COVID-19 infection rates in haemodialysis (HD) facilities are extremely high and are attributed to the high burden of comorbidities of HD patients coupled with inability to self-isolate needing thrice weekly attendance for HD treatment. Healthcare workers (HCW) in HD facilities are at risk of occupational exposure to COVID-19. Infection prevention control (IPC) measures were introduced during the pandemic aiming at reducing transmission and occupational exposure risk of COVID-19.

Dr James Copland (1791-1870) and his Dictionary of Practical Medicine.

Dr James Copland (1791-1870) was born in the Orkney Islands and studied medicine at Edinburgh where he graduated in 1815. The following year was spent in Paris to acquire knowledge of the latest developments in pathology and he then travelled for a year along the coast of West Africa gaining practical experience of treating tropical diseases. After establishing his medical practice in London, which eventually became extremely successful, he contributed to medical journals and also became editor of the from 1822 to 1825.

Dr JA Gray (1858-1929)-Surgeon to HH The Amir of Afghanistan.

Dr Gray was an assistant medical officer at the Islington Workhouse when he was offered the dangerous but well-paid post as surgeon to the Amir of Afghanistan in August 1888. He arrived in Afghanistan in March 1889 and continued in the post until June 1893. He described his experiences in his book,

Safely reducing haemodialysis frequency during the COVID-19 pandemic.

Background: Patients undergoing haemodialysis (HD) are at higher risk of developing worse outcomes if they contract COVID-19. In our renal service we reduced HD frequency from thrice to twice-weekly in selected patients with the primary aim of reducing COVID 19 exposure and transmission between HD patients.

Methods: Dialysis unit nephrologists identified 166 suitable patients (38.

Non-invasive cardiac stress studies may not offer significant benefit in pre-kidney transplant evaluation: A retrospective cohort study.

Background: Screening with cardiac non-invasive stress studies (NISS) prior to listing for kidney transplantation can help in identifying treatable coronary disease and is considered an integral part of pre-kidney transplant evaluation. However, few studies assessed their effectiveness in all patients evaluated for transplantation in clinical practice. To evaluate the role of NISS in pre-kidney transplant evaluation we analyzed their impact prior to waitlisting in 1053 adult CKD-5 patients consecutively evaluated in Greater Manchester, UK during a 6-year period.

Niraparib as maintenance therapy in a patient with ovarian cancer and brain metastases.

Ovarian cancer is the second the most common gynaecological malignancy in developed countries. 70% of patients relapse in the first 3 years following debulking surgery and first-line chemotherapy. Niraparib is a poly adenosine diphosphate ribose polymerase inhibitor which uses the concept of synthetic lethality in the presence of a mutation in the breast cancer susceptibility gene (), and is now recommended as maintenance treatment in patients with platinum-sensitive relapse of ovarian cancer.

Low Temperature Hot Corrosion Screening of Single Crystal Superalloys.

Single crystal superalloys were screened in Type II molten (Na,K)-sulfate hot corrosion re-coat tests in air +300 ppm SO₂ at 700 °C. They exhibited large 20⁻40 mg/cm² weight changes, repeated spallation, and non-protective, 25⁻50 μm thick corrosion layers after 300 h of testing. Scale cross sections revealed dual outer Ni(Co)O and inner Al(Cr)S-rich corrosion layers.

Management of oncological emergencies on the acute take.

In 2008, recommendations from the National Confidential Enquiry into Patient Outcome and Death identified large variations in the quality and safety of delivery of systemic anti-cancer therapy. In 49% of cases it was felt there was room for improvement and in 27% of cases treatment actually caused or hastened death. Every hospital with an emergency department and/or specialist oncology beds should therefore have a fully functioning acute oncology service to align acute oncology with urgent care.

Polycomb Repressive Complex 2-Mediated Chromatin Repression Guides Effector CD8 T Cell Terminal Differentiation and Loss of Multipotency.

Understanding immunological memory formation depends on elucidating how multipotent memory precursor (MP) cells maintain developmental plasticity and longevity to provide long-term immunity while other effector cells develop into terminally differentiated effector (TE) cells with limited survival. Profiling active (H3K27ac) and repressed (H3K27me3) chromatin in naive, MP, and TE CD8 T cells during viral infection revealed increased H3K27me3 deposition at numerous pro-memory and pro-survival genes in TE relative to MP cells, indicative of fate restriction, but permissive chromatin at both pro-memory and pro-effector genes in MP cells, indicative of multipotency. Polycomb repressive complex 2 deficiency impaired clonal expansion and TE cell differentiation, but minimally impacted CD8 memory T cell maturation.

Disambiguate: An open-source application for disambiguating two species in next generation sequencing data from grafted samples.

Grafting of cell lines and primary tumours is a crucial step in the drug development process between cell line studies and clinical trials. is a program for computationally separating the sequencing reads of two species derived from grafted samples. operates on DNA or RNA-seq alignments to the two species and separates the components at very high sensitivity and specificity as illustrated in artificially mixed human-mouse samples.

ABC transporters and NR4A1 identify a quiescent subset of tissue-resident memory T cells.

Immune surveillance in tissues is mediated by a long-lived subset of tissue-resident memory T cells (Trm cells). A putative subset of tissue-resident long-lived stem cells is characterized by the ability to efflux Hoechst dyes and is referred to as side population (SP) cells. Here, we have characterized a subset of SP T cells (Tsp cells) that exhibit a quiescent (G0) phenotype in humans and mice.

The Interleukin-2-mTORc1 Kinase Axis Defines the Signaling, Differentiation, and Metabolism of T Helper 1 and Follicular B Helper T Cells.

The differentiation of CD4(+) helper T cell subsets with diverse effector functions is accompanied by changes in metabolism required to meet their bioenergetic demands. We find that follicular B helper T (Tfh) cells exhibited less proliferation, glycolysis, and mitochondrial respiration, accompanied by reduced mTOR kinase activity compared to T helper 1 (Th1) cells in response to acute viral infection. IL-2-mediated activation of the Akt kinase and mTORc1 signaling was both necessary and sufficient to shift differentiation away from Tfh cells, instead promoting that of Th1 cells.

Production of IL-10 by CD4(+) regulatory T cells during the resolution of infection promotes the maturation of memory CD8(+) T cells.

Memory CD8(+) T cells are critical for host defense upon reexposure to intracellular pathogens. We found that interleukin 10 (IL-10) derived from CD4(+) regulatory T cells (Treg cells) was necessary for the maturation of memory CD8(+) T cells following acute infection with lymphocytic choriomeningitis virus (LCMV). Treg cell-derived IL-10 was most important during the resolution phase, calming inflammation and the activation state of dendritic cells.