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 Il-10-/- mice. In contrast, mouse-to-mouse transfer of mouse-adapted human IBD patient microbiota transferred with high efficiency and low compositional variability resulting in highly consistent and reproducible colitis phenotypes in recipient Il-10-/- mice. Human-to-mouse FMT caused a population bottleneck with reassembly of microbiota composition that was host inflammatory environment specific. Mouse-adaptation in the inflamed Il-10-/- host reassembled a more aggressive microbiota that induced more severe colitis in serial transplant to Il-10-/- mice than the distinct microbiota reassembled in non-inflamed WT hosts. Our findings support a model of IBD pathogenesis in which host inflammation promotes aggressive resident bacteria, which further drives a feed-forward process of dysbiosis exacerbated gut inflammation. This model implies that effective management of IBD requires treating both the dysregulated host immune response and aggressive inflammation-driven microbiota. We propose that our mouse-adapted human microbiota model is an optimized, reproducible, and rigorous system to study human microbiome-driven disease phenotypes, which may be generalized to mouse models of other human microbiota-modulated diseases, including metabolic syndrome/obesity, diabetes, autoimmune diseases, and cancer.

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. Herein we review studies that have leveraged MAB technologies to deliver novel insights into the TME of NSCLC.

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. Included patients were identified using institutional registries; demographics, staging, treatment history, and clinical outcomes were collected. Kaplan-Meier methods were used to assess progression-free survival (PFS) and overall survival (OS). Ninety-seven patients, treated between 2006 and 2022, were included; 61.9% had intrahepatic cholangiocarcinoma. At the time of analysis, there had been 91 deaths. Median PFS from initiating 3L palliative systemic therapy (mPFS3) was 3.1 months (95%CI 2.0-4.1), while mOS3 was 6.4 months (95%CI 5.5-7.3); mOS1 was 26.9 months (95%CI 23.6-30.2). Among patients with a therapy-targeted molecular aberration (10.3%; n = 10; all received in 3L), mOS3 was significantly improved versus all other included patients (12.5 vs. 5.9 months; p = 0.02). No differences in OS1 were demonstrated between anatomical subtypes. Fourth-line systemic therapy was received by 19.6% of patients (n = 19). This international multicentre analysis documents systemic therapy use in this select patient group, and provides a benchmark of outcomes for future trial design.

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. Towards that aim, we first estimated the frequency characteristics of movement artifacts under various static and dynamic experimental conditions. We found that the extent of the movement artifact depended on the nature of the movement and varied from person to person. Our study's highest movement artifact frequency for the stand position was 10 Hz, tiptoe 22, walk 32, run 23, jump from box 41, and jump up and down 40 Hz. Secondly, using a 40 Hz highpass filter, we cut out most of the frequencies belonging to the movement artifacts. Finally, we checked whether the latencies and amplitudes of reflex and direct muscle responses were still observed in the highpass-filtered sEMG. We showed that the 40 Hz highpass filter did not significantly alter reflex and direct muscle variables. Therefore, we recommend that researchers who use sEMG under similar conditions employ the recommended level of highpass filtering to reduce movement artifacts from their records. However, suppose different movement conditions are used. In that case, it is best to estimate the frequency characteristics of the movement artifact before applying any highpass filtering to minimize movement artifacts and their harmonics from sEMG.

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. This retrospective case series aims to explore the current management strategies with particular emphasis on the use of PARP inhibitors and outcomes, as well as identification of other prognostic indicators. METHODS: A total of 39 ovarian cancer patients with brain metastases were identified from eight cancer centres in the UK. Clinical characteristics, details of management, and survival data were collected. RESULTS: A total of 14/39 had BM as their first site of relapse. The majority (29 patients) received systemic treatments in addition to local radiotherapy (RT)/surgery. Nineteen patients had BRCA mutations (one somatic), one had a RAD51C mutation, and eighteen were BRCA wild type; one was unknown. A total of 14/39 patients received maintenance PARP inhibitors. As is well known, patients who received PARPi had consistently better outcomes. This was no different for those who received PARPi as part of the management of their BM. Platinum sensitivity and receiving more than one modality of therapy (e.g., radiation +/- chemotherapy and PARPi) for BM were also good prognostic indicators. Median PFS/OS for those treated with chemotherapy and either RT or surgery, then PARP inhibitor maintenance, have not been reached after a median of 33 months follow up. CONCLUSIONS: As with abdominal relapse, maintenance treatment with PARP inhibitors also has a valuable role in managing BMs in EOC patients.

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 London Medical Repository from 1822 to 1825. His greatest work was The Dictionary of Practical Medicine written entirely by himself which was completed between 1832 and 1858. More than 10,000 copies of the dictionary were sold and its author became world famous during his lifetime. In 1833, Copland was elected a Fellow of the Royal Society and from 1837 onwards he played a prominent role in the proceedings of The Royal College of Physicians. This article shows how his extensive professional and literary work was combined with an unusual private life.

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, My Residence at the Court of the Amir.

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. Materials and methods: 51 consecutive lung SABR plans received 54 Gy in 3 fractions (54 Gy/3 Fr), 55 Gy/5 Fr or 60 Gy/8 Fr. Plans were developed according to 2016 UK SABR consortium guidelines, which did not specify PCI or PDS; these values were retrospectively calculated. As PCI varies from 0 to an optimum of 1, inverse PCI (invPCI) was used for calculations. Results: PTV-adjusted PDS tolerances were met in 80.4% of studied plans. A near-perfect positive correlation between invPCI and PDS (R2 = 0.978) was found - stronger than between invPCI and the previously-used RTOG-CI (R2 = 0.915). Conclusions: The strong invPCI-PDS correlation is likely dependent on adequate PTV coverage, present in our cohort. This supports the UK SABR Consortium's adoption of PDS provided PTV coverage is ensured. Plan conformity should be confirmed by visual slice-by-slice review.

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. Therefore, the majority of patients with pCCA will require systemic treatment for advanced disease. The prognosis with cytotoxic chemotherapy remains poor, driving interest in therapies targeted to the molecular nature of a given patient's cancer. In recent years, the search for efficacious targeted therapies has been fuelled both by whole-genome and epigenomic studies, looking to uncover the molecular landscape of CCA, and by specifically testing for aberrations where established therapies exist in other indications. This review aims to provide a focus on the current molecular characterisation of pCCA, targeted therapies applicable to pCCA, and future directions in applying personalised medicine to this difficult-to-treat malignancy.

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. Defining resectability in PDAC is problematic; multiple differing definitions exist. Multidisciplinary input, both in initial assessment of resectability and in supervision of multimodality therapy, is therefore advised. European and North American guidelines recommend the use of neoadjuvant chemotherapy in borderline resectable (BR)-PDAC. Similar regimens may be applied in locally advanced (LA)-PDAC with the aim of improving potential access to curative-intent resection, but appropriate patient selection is key due to significant rates of recurrence after excision of LA disease. Upfront surgery and adjuvant chemotherapy remain standard-of-care in clearly resectable PDAC, but multiple trials evaluating the use of neoadjuvant therapy in this and other localised settings are ongoing.

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. Primary outcomes evaluated before and after QI implementation were incidence of outbreaks and severe COVID-19 illness defined as COVID-19-related death or hospitalization. Secondary outcomes included the proportion of patients identified in the pre-symptomatic/asymptomatic phase on surveillance rRT-PCR screening and the incidence and longevity of SARS-CoV-2 antibody response. RESULTS: Following the implementation of the QI project, there were no further outbreaks. Pre- and post-implementation comparison showed a significant reduction in COVID-19-related mortality and hospitalization (26 vs. 13 events, respectively, p < 0.001). Surveillance rRT-PCR screening identified 39 asymptomatic or pre-symptomatic cases out of a total of 59 rRT-PCR-positive patients (39/59, 66%). SARS-CoV-2 antibody levels were detected in 72/74 (97%) rRT-PCR-positive patients. Amongst rRT-PCR-positive patients diagnosed before August 2020, 96% had detectable antibodies until January 2021 (days from the rRT-PCR test to last antibody testing, 245-280). CONCLUSIONS: Systematic implementation of a bundle of IPC measures using QI methodology and surveillance rRT-PCR eliminated outbreaks in HD facilities. Most HD patients mount and sustain antibody response to COVID-19 for over 8 months.

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. While the interaction between respiration and the heart is well characterized, the extent to which systolic and diastolic indices are affected by inspiration is unknown. Our objective was to understand how inspiratory pressure affects the hemodynamic assessment of cardiac function. To do this, we developed custom software to assess and separate indices of systolic and diastolic function into inspiratory, early expiratory, and late expiratory phases of respiration. We then compared cardiac parameters during normal breathing and with various respiratory loads. Variations in inspiratory pressure had a small impact on systolic pressure and function. Conversely, diastolic pressure strongly correlated with negative inspiratory pressure. Cardiac pressures were less affected by respiration during expiration; late expiration was the most stable respiratory phase. In conclusion, inspiration is a large confounding influence on diastolic pressure, but minimally affects systolic pressure. Performing cardiac hemodynamic analysis by accounting for respiratory phase yields more accuracy and analytic confidence to the assessment of diastolic 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. Here we describe the results of our baseline and follow up occupational exposure audit in a renal centre in the North West of England following the implementation of a multifaceted IPC bundle.

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 (38.4% of our HD population) to temporarily convert to twice-weekly haemodialysis immediately prior to the peak of the COVID-19 pandemic in our area. Changes in pre-dialysis weight, systolic blood pressure (SBP) and biochemistry were recorded weekly throughout the 4-week project. Hyperkalaemic patients (serum potassium > 6.0 mmol/L) were treated with a potassium binder, sodium bicarbonate and received responsive dietary advice. RESULTS: There were 12 deaths (5 due to COVID-19) in the HD population, 6 of which were in the twice weekly HD group; no deaths were definitively associated with change of dialysis protocol. A further 19 patients were either hospitalised and/or developed COVID-19 and thus transferred back to thrice weekly dialysis as per protocol. 113 (68.1%) were still receiving twice-weekly HD by the end of the 4-week project. Indications for transfer back to thrice weekly were; fluid overload (19), persistent hyperkalaemia (4), patient request (4) and compliance (1). There were statistically significant increases in SBP and pre-dialysis potassium during the project. CONCLUSIONS: Short term conversion of a large but selected HD population to twice-weekly dialysis sessions was possible and safe. This approach could help mitigate COVID-19 transmission amongst dialysis patients in centres with similar organisational pressures.

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. METHODS: 918 waitlisted patients were grouped based on presence or absence of Diabetes or Cardio-Vascular Disease (CVD): Group-1 (255 DM-/CVD-/NISS-), Group-2 (368 DM-/CVD-/NISS+) and Group-3 (295 with DM or CVD). RESULTS: Group-2 patients had longer 'time-to-listing' (5.5months in Group-1 vs 6.9months in 'Normal-NISS' vs 9.9months in 'Abnormal-NISS', p<0.01) but none with 'Abnormal-NISS' needed coronary revascularization before listing. NISS was followed by revascularization in 8 Group-3 patients (3%). In multi-variate analyses, there was no association of NISS on death or MACE in listed patients. During follow up, Transplantation was the most significant factor associated with improved outcomes in all subgroups (HR:0.97, p<0.001). 135 patients were considered unsuitable for waitlisting, with NISS influencing management in 11 of these patients (8%). CONCLUSIONS: Pre-kidney transplant evaluation with NISS influenced clinical management in 19 of 1053 (2%) patients. Screening with NISS added limited benefit but contributes to significant delays in listing and adding resource implications. Further studies are needed to assess clinical and cost effectiveness of NISS in pretransplant evaluation to optimize outcomes and resources.

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 (BRCA), and is now recommended as maintenance treatment in patients with platinum-sensitive relapse of ovarian cancer. It has been shown to increase progression-free survival. We present a case of a 68-year-old woman with brain metastases from high-grade serous ovarian cancer who has remained free of disease progression for longer than 17 months with niraparib use as maintenance treatment after second-line chemotherapy.

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. This chemical differentiation was partially consistent with previous models of oxide fluxing, alloy sulfidation, NiO micro-channel diffusion, and synergistic dissolution mechanisms. Broad shallow pits or uniform attack morphologies were consistent with prior studies performed in high >100 ppm pSO2 environments. Higher Mo experimental alloys trended toward more degradation, producing 100 µm thick scales with distinct Al(Cr)S-rich inner layers or 500 µm thick NiO. The aggressive behavior in these environments supports the need for LTHC-resistant coatings for single crystal superalloys.

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. Many patients will still present via the acute take and therefore acute physicians need to be aware of the role of the acute oncology teams and management of oncology emergencies. This article discusses the role of the acute oncology team, management of acute oncology emergencies, namely neutropenic sepsis, metastatic spinal cord compression and superior vena cava obstruction, and important points for acute teams to consider.

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. Abundant H3K27me3 deposition at pro-memory genes occurred late during TE cell development, probably from diminished transcription factor FOXO1 expression. These results outline a temporal model for loss of memory cell potential through selective epigenetic silencing of pro-memory genes in effector T cells.

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. Human Trm cells in the gut and BM were enriched in Tsp cells that were predominantly in the G0 stage of the cell cycle. Moreover, in histone 2B-GFP mice, the 2B-GFP label was retained in Tsp cells, indicative of a slow-cycling phenotype. Human Tsp cells displayed a distinct gene-expression profile that was enriched for genes overexpressed in Trm cells. In mice, proteins encoded by Tsp signature genes, including nuclear receptor subfamily 4 group A member 1 (NR4A1) and ATP-binding cassette (ABC) transporters, influenced the function and differentiation of Trm cells. Responses to adoptive transfer of human Tsp cells into immune-deficient mice and plerixafor therapy suggested that human Tsp cell mobilization could be manipulated as a potential cellular therapy. These data identify a distinct subset of human T cells with a quiescent/slow-cycling phenotype, propensity for tissue enrichment, and potential to mobilize into circulation, which may be harnessed for adoptive cellular therapy.