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Background & Aims: Inflammatory bowel disease (IBD) causes a marked increase in the number of T cells in the intestinal mucosa. Debate exists about whether these excess cells arise from local clonal proliferation or recruitment from the periphery. Methods: CD8+ T cells were sorted from colon biopsy specimens and blood for T-cell receptor (TCR) β-chain sequencing. Biopsy specimens from inflamed or uninflamed colon from ulcerative colitis or Crohn’s disease cohorts were compared with colon biopsy specimens from people without IBD, as well as with autologous blood α4β7+, α4β7- effector/memory, terminal effector/memory CD45RA+ T cell, and mucosal-associated invariant T-cell CD8 subpopulations. Results: CD8 TCR diversity in mucosa and blood did not correlate with inflammation. Repertoire overlap between any 2 distinct locations of a given person’s colon was consistently high, although often lower between inflamed and uninflamed sites. CD8 TCR repertoires overlapped between the colon and each peripheral blood subpopulation studied, with the highest overlap seen for integrin α4β7+ T cells. Inflamed tissue consistently overlapped more than uninflamed tissue with each blood subpopulation. Conclusions: CD8 T-cell clones are spread homogenously throughout the length of the colon. Although TCR repertoire overlap is greater within than between inflamed and uninflamed colon segments, a similar TCR diversity in both argues against local clonal expansion being the main source of excess cytotoxic T cells in inflamed mucosa. Rather, the increased TCR overlap observed between blood and inflamed mucosa supports the significance of T-cell trafficking in IBD pathogenesis, particularly concerning α4β7+ T-cell populations.

Intro: Acinetobacter baumannii is a Gram-negative coccobacillus that has become a major nosocomial pathogen and a common isolate in Malaysian hospitals. One of the features that enabled A. baumannii to gain clinical prominence is its remarkable ability to rapidly acquire and develop resistance to nearly all classes of antibiotics. In this study, whole genome sequencing was carried out on thirty-six A. baumannii clinical isolates from Hospital Sultanah Nur Zahirah, the main tertiary hospital in Terengganu, Malaysia, from the years 2017 and 2018. Methods: Antimicrobial resistance profiles of the A. baumannii isolates were determined by disk diffusion. Whole genome sequencing was performed on the Illumina platform and the sequences were assembled using UniCycler. Findings: Majority of the isolates (n = 30) were carbapenem as well as multidrug resistant (MDR; i.e., resistant towards three of more antimicrobial classes). The sequence type 2 (ST2) of the A. baumannii Global Clone 2 (GC2) lineage was predominant (n = 27) and all ST2 isolates were MDR. Phylogenetic analysis indicated that these ST2 isolates were very closely related. Nearly all the MDR isolates (n = 29) harboured the blaOXA-23 acquired carbapenemase gene with the remaining one MDR isolate, A. baumannii AC1839 harbouring two acquired carbapenemase genes, blaOXA-58, and blaNDM-1. AC1839 was however typed as ST1278/ST515 and was not of the GC2 lineage. Several MDR isolates also harboured broad spectrum β-lactamases with more than half (n = 19) carrying the blaTEM-1D gene and two MDR isolates harbouring the blaCARB-5-like gene. Majority of the isolates (n = 34) harboured the Acinetobacterderived single-variant cephalosporinase gene, blaADC-25, which is likely responsible for cephalosporin resistance. Resistance genes for aminoglycosides, macrolides, sulphonomides, and tetracyclines were also identified from the genome sequences of these A. baumannii isolates. Conclusion: Whole genome sequencing has revealed that the multidrugresistant ST2 clone harbouring the acquired blaOXA-23 carbapenemase gene is the predominant A. baumannii clone in Terengganu.

Intro: Acinetobacter oleivorans is an environmental isolate that has rarely been reported to cause human infections, unlike the more notorious nosocomial pathogen, Acinetobacter baumannii. In this study, two clinical isolates of A. oleivorans from Hospital Sultanah Nur Zahirah in Terengganu were subjected to whole genome sequencing and the resulting sequences analysed. Methods: A. oleivorans AC1583 and AC1885 were both isolated from the sputum of infected patients with pneumonia in 2015 and 2018, respectively. The isolates were initially identified as A. oleivorans by rpoB gene sequencing. Antimicrobial susceptibility was tested using a panel of 21 antibiotics encompassing 8 antimicrobial classes. Genome sequencing was performed on the Illumina HiSeq platform and assembled using Unicycler v.0.4.8. Findings: AC1583 was susceptible to all tested antibiotics whereas AC1885 only displayed resistance to trimethoprim/sulfamethoxazole. The assembled genome size for AC1583 was 4,200,796 bp and 4,287,299 bp for AC1885. Multilocus sequence typing (MLST) using the Pasteur scheme indicated that AC1583 and AC1885 were typed as ST1616 and ST1617, respectively. Phylogenetic analysis showed that AC1583 and AC1885 were closely related to clinical isolates from Japan (A. oleivorans TUM15450) and the United States (A. oleivorans ACIN00177), respectively. Several virulence-associated genes were identified from the genome sequences of AC1583 and AC1885, and these include exotoxin genes such as phospholipase C and catalase, various genes for biofilm formation, immune modulation, and heme utilisation. AC1583 also harboured a small 8,731 bp plasmid, pAC1583-1, that was identical with a putative virulence- associated plasmid initially found in A. baumannii which harboured genes encoding a tonB-dependent receptor and sel1 repeat protein. This plasmid was absent in AC1885, which harboured a 11,715 bp cryptic plasmid designated pAC1885-1 instead. Conclusion: Despite its susceptibility to most antimicrobials, A. oleivorans was still capable of causing infections due likely to its carriage of several virulence factors and thus warrants vigilance.

Maintaining adherence to treatment for tuberculosis (TB) is essential if the disease is to be eliminated. As part of formative research to develop an intervention to improve adherence, we documented the lived experiences of adults receiving anti-TB treatment (ATT) in three UK cities and examined how personal, social, and structural circumstances interacted to impact on individuals’ adherence to treatment. Using a topic guide that explored social circumstances and experiences of TB care, we conducted in-depth interviews with 18 adults (six women) who were being or had been treated for TB (patients) and four adults (all women) who were caring for a friend, relative, or partner being treated for TB (caregivers). We analysed transcripts using an adapted framework method that classified factors affecting adherence as personal, social, structural, health systems, or treatment-related. Eleven of 18 patients were born outside the UK (in South, Central, and East Asia, and Eastern and Southern Africa); among the seven who were UK-born, four were Black, Asian, or Minority Ethnic and three were White British. TB and its treatment were often disruptive: in addition to debilitating symptoms and side effects of ATT, participants faced job insecurity, unstable housing, stigma, social isolation, worsening mental health, and damaged relationships. Those who had a strong support network, stable employment, a routine that could easily be adapted, a trusting relationship with their TB team, and clear understanding of the need for treatment reported finding it easier to adhere to ATT. Changes in circumstances sometimes had dramatic effects on an individual’s ability to take ATT; participants described how the impact of certain acute events (e.g., the onset of side effects or fatigue, episodes of stigmatisation, loss of income) were amplified by their timing or through their interaction with other elements of the individual’s life. We suggest that the dynamic and fluctuating nature of these factors necessitates comprehensive and regular review of needs and potential problems, conducted before and during ATT; this, coupled with supportive measures that consider (and seek to mitigate) the influence of social and structural factors, may help improve adherence.

Introduction: CD8 encephalitis is a relatively recently described condition in the setting of HIV infection. It is becoming increasingly recognised in recent years though is still likely underdiagnosed. Methods: We present three cases of encephalitis in HIV-positive black African females initially presenting with neurological pathology. Two cases concern recent presentations of patients attending HIV services at a large tertiary referral hospital and the third case involves a retrospective analysis of an archived case. Results and discussion: MRI brain demonstrated periventricular white matter changes in 2 cases and a cerebellar lesion in the third case. CSF examination revealed lymphocytosis and elevated protein levels. CSF HIV viral load analysis showed viral escape along with new antiretroviral drug resistance mutations. CSF flow cytometry studies demonstrated a reversed CD4:CD8 ratio with a high CD8+ cells percentage. All patients had EBV DNA detected in their CSF. Brain biopsy in two patients confirmed CD8 encephalitis and also revealed isolated cells demonstrating EBV positivity by in-situ hybridization using EBER (Epstein–Barr virus-encoded small RNAs). Treatment with steroids and ART optimisation led to significant clinical and radiological improvements in all cases. Discussion: CD8 encephalitis should be considered as a cause of neurological symptoms and confusion in the HIV-positive patient, particularly if poor ART adherence or viral resistance are suspected. Brain biopsy should be considered in HIV-positive patients with encephalopathy of uncertain cause. Early treatment with high-dose corticosteroids when suspecting this diagnosis is essential for a favourable outcome. The prognosis is variable but can be favourable even following severe encephalopathy. The presence of new INSTI mutations in the CSF but absent peripherally in two INSTI-era patients is a novel finding for this case series in the context of CD8 encephalitis. The role played by EBV in this disease remains unclear and warrants further investigation.

The approximate number system (ANS) enables organisms to represent the approximate number of items in an observed collection, quickly and independently of natural language. Recently, it has been proposed that the ANS goes beyond representing natural numbers by extracting and representing rational numbers (Clarke & Beck, 2021a). Prior work demonstrates that adults and children discriminate ratios in an approximate and ratio-dependent manner, consistent with the hallmarks of the ANS. Here, we use a well-known "connectedness illusion" to provide evidence that these ratio-dependent ratio discriminations are (a) based on the perceived number of items in seen displays (and not just non-numerical confounds), (b) are not dependent on verbal working memory, or explicit counting routines, and (c) involve representations with a part-whole (or subset-superset) format, like a fraction, rather than a part-part format, like a ratio. These results vindicate key predictions of the hypothesis that the ANS represents rational numbers., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Virtual reality (VR) holds unmeasured potential as a multicomponent tool for managing chronic pain by adapting conventional in-person biopsychosocial pain management strategies into one virtual space. We review recent evidence showcasing the successful integration of cognitive behavioural therapy, mindfulness-based stress reduction, embodiment techniques, and physical therapy into VR environments, demonstrating positive outcomes in patients with chronic pain. We propose that future clinical and basic research build on this by integrating pain neuroscience techniques to help better understand pathophysiological pain mechanisms and treatment response. This could help facilitate early assessment and personalised treatment of chronic pain using a VR-based biopsychosocial approach., (Copyright © 2024 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Objectives: Calcitonin gene-related peptide monoclonal antibodies (CGRP mAbs) are novel high-cost treatments for the prevention of migraine. This study presents data on utilization, expenditure, and treatment patterns with CGRP mAbs available under a managed access protocol in Ireland, to a cohort of treatment refractory patients (failed 3 or more previous treatments) with chronic migraine., Methods: Data were extracted from the Primary Care Reimbursement Service High Tech claims database and special drug request online system and analyzed using Microsoft Excel and SAS. Treatment persistence was evaluated by refill patterns, and adherence was evaluated using the proportion of days covered method. Expenditure data were extracted directly from the database., Results: Between September 1, 2021 and April 30, 2023, 1517 applications for reimbursement approval for a CGRP mAb were received; 1458 (96.1%) were approved for reimbursement. Total expenditure on CGRP mAbs in year 1 (September 1, 2021 to August 31, 2022) was €3.2 million. The majority of patients initiated treatment with fremanezumab (60.8%) or erenumab (37.1%). Almost 90% of patients were considered adherent, and treatment persistence was high, with more than 75% of patients receiving more than 12 months of treatment in our 18-month study time frame., Conclusions: This study demonstrates the importance of active health technology management, after reimbursement, in enabling cost-effective use of high-cost treatments while providing budget certainty for the healthcare payer. High levels of adherence and persistence suggest that treatment is successfully targeted in situations which unmet clinical need is greatest., Competing Interests: Author Disclosures Author disclosure forms can be accessed below in the Supplemental Material section., (Copyright © 2024. Published by Elsevier Inc.)

It is often assumed that adaptation - a temporary change in sensitivity to a perceptual dimension following exposure to that dimension - is a litmus test for what is and is not a "primary visual attribute". Thus, papers purporting to find evidence of number adaptation motivate a claim of great significance: That number is something that can be seen in much the way that canonical visual features, like color, contrast, size, and speed, can. Fifteen years after its reported discovery, number adaptation's existence seems to be nearly undisputed, with dozens of papers documenting support for the phenomenon. The aim of this paper is to offer a counterweight - to critically assess the evidence for and against number adaptation. After surveying the many reasons for thinking that number adaptation exists, we introduce several lesser-known reasons to be skeptical. We then advance an alternative account - the old news hypothesis - which can accommodate previously published findings while explaining various (otherwise unexplained) anomalies in the existing literature. Next, we describe the results of eight pre-registered experiments which pit our novel old news hypothesis against the received number adaptation hypothesis. Collectively, the results of these experiments undermine the number adaptation hypothesis on several fronts, whilst consistently supporting the old news hypothesis. More broadly our work raises questions about the status of adaptation itself as a means of discerning what is and is not a visual attribute., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier B.V.)

Background: Stability skills (e.g., static/dynamic balance) are a precursor for other movement skill development (e.g., jumping, catching). However, young children consistently demonstrate low stability and movement skill ability. There is therefore a need to develop effective strategies to improve stability skills in early childhood., Aim: To pilot the effect of a home-based gamified stability skills intervention on 4-5-year-old children's physical skills, self-perceptions and cognitions., Methods: One-hundred-and-eleven 4-5-year-old children participated from three schools. Two schools were allocated into the intervention group (n = 66 children, 33 boys) and one to the control group (n = 45 children, 25 boys). Stability, fundamental movement skills, perceived motor competence, and cognition were assessed at baseline and at post-intervention. The intervention group was given a booklet detailing the 12-week gamified stability skill intervention. The control group participated in their usual weekly activities., Results: A series of ANCOVAs controlling for baseline values demonstrated significantly higher stability skills (F(1,93) = 24.79, p < 0.001, partial η 2  = 0.212), fundamental movement skills (F(1,94) = 15.5, p = < 0.001, partial η 2  = 0.139), perceived motor competence (F(1,96) = 5.48, p = 0.021, partial η 2  = 0.054) and cognition (F(1,96) = 15.5, p = < 0.001, partial η 2  = 0.139) at post-test for the intervention versus control groups., Discussion: This study demonstrates that a home-based, gamified, stability skills intervention enhances stability skills, fundamental movement skills, perceived motor competence and cognition in children aged 4-5-years old., Competing Interests: Declaration of competing interest The information reported in this manuscript was supported via a small research grant from the British Academy., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Competing Interests: We declare no competing interests.

Background: This study was conducted to determine the association between fluid balance metrics and mortality and other postoperative outcomes after neonatal cardiac operation in a contemporary multicenter cohort., Methods: This was an observational cohort study across 22 hospitals in neonates (≤30 days) undergoing cardiac operation. We explored overall percentage fluid overload, postoperative day 1 percentage fluid overload, peak percentage fluid overload, and time to first negative daily fluid balance. The primary outcome was in-hospital mortality. Secondary outcomes included postoperative duration of mechanical ventilation and intensive care unit (ICU) and hospital length of stay. Multivariable logistic or negative binomial regression was used to determine independent associations between fluid overload variables and each outcome., Results: The cohort included 2223 patients. In-hospital mortality was 3.9% (n = 87). Overall median peak percentage fluid overload was 4.9% (interquartile range, 0.4%-10.5%). Peak percentage fluid overload and postoperative day 1 percentage fluid overload were not associated with primary or secondary outcomes. Hospital resource utilization increased on each successive day of not achieving a first negative daily fluid balance and was characterized by longer duration of mechanical ventilation (incidence rate ratio, 1.11; 95% CI, 1.08-1.14), ICU length of stay (incidence rate ratio, 1.08; 95% CI, 1.03-1.12), and hospital length of stay (incidence rate ratio, 1.09; 95% CI, 1.05-1.13)., Conclusions: Time to first negative daily fluid balance, but not percentage fluid overload, is associated with improved postoperative outcomes in neonates after cardiac operation. Specific treatments to achieve an early negative fluid balance may decrease postoperative care durations., (Copyright © 2022 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Growth is often impaired in infants with congenital heart disease. Poor growth has been associated with worse neurodevelopment, abnormal behavioral state, and longer time to hospital discharge. Nutritional interventions, drug therapy, and surgical palliation have varying degrees of success enhancing growth. Passive range of motion (PROM) improves somatic growth in preterm infants and is safe and feasible in infants with hypoplastic left heart syndrome (HLHS), after their first palliative surgery (Norwood procedure)., Methods: This multicenter, Phase III randomized control trial of a 21-day PROM exercise or standard of care evaluates growth in infants with HLHS after the Norwood procedure. Growth (weight-, height- and head circumference-for-age z-scores) will be compared at 4 months of age or at the pre-superior cavopulmonary connection evaluation visit, whichever comes first. Secondary outcomes include neonatal neurobehavioral patterns, neurodevelopmental assessment, and bone mineral density. Eligibility include diagnosis of HLHS or other single right ventricle anomaly, birth at ≥37 weeks gestation and Norwood procedure at <30 days of age, and family consent. Infants with known chromosomal or recognizable phenotypic syndromes associated with growth failure, listed for transplant, or expected to be discharged within 14 days of screening are excluded., Conclusions: The TEAM 4 Growth trial will make an important contribution to understanding the role of PROM on growth, neurobehavior, neurodevelopment, and BMD in infants with complex cardiac anomalies, who are at high risk for growth failure and developmental concerns., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Epidermal growth factor receptor gene (EGFR) exon 20 insertion (ex20-ins) mutations are an uncommon and heterogeneous group of non-small cell lung cancers (NSCLCs), resistant to conventional EGFR tyrosine kinase inhibitors (TKIs). Characteristics and outcomes of patients with EGFR ex20-ins have not been fully established; we sought to clarify them using a multinational patient database., Patients and Methods: Patients with NSCLC from six Australian institutions with EGFR exon 20 mutations (ex20-mut), excluding T790M, were retrospectively reviewed. Clinical characteristics and outcomes with systemic treatments were collected and analyzed using comparative statistics., Results: Among 109 patients with ex20-mut, 61% were females and 75% were Caucasians. More males presented with de novo metastatic disease (84% vs. 51%; P = .002). Central nervous system (48%) and liver (24%) metastases were common within metastatic patients (n = 86). Thirty-nine patients received platinum-based chemotherapy (PBC) and achieved a 43% objective response rate (ORR), median progression-free survival (mPFS) of 6.9 months, and median overall survival (mOS) of 31.0 months. Twenty-three of the patients with ex20-ins received conventional TKIs, resulting in an ORR of 13%, mPFS of 3.4 months (95% confidence interval [CI], 1.91-6.25), and mOS of 31.0 months (95% CI, 15.09-not reached). Nine patients with S786I mutations received TKIs, resulting in an ORR of 50%, mPFS of 18.2 months (2.79-not reached), and mOS of 33.4 months (95% CI, 16.14-not reached). Twenty-three patients received immune checkpoint inhibitor monotherapy (ICIm), resulting in an ORR of 4%, mPFS of 2.6 months (95% CI, 1.91-4.83), and mOS of 30.8 months (95% CI, 17.62-41.62)., Conclusion: Although phenotypically similar to patients with common EGFR mutations, patients with EGFR ex20-mut had worse survival, perhaps due to the lack of targeted therapies. Chemotherapy was superior to conventional EGFR TKIs in patients with EGFR ex20-ins, although there was moderate activity of TKIs in S768I mutations. ICIm was ineffective., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Pancreatic cancer is the 8th commonest cancer and the 5th commonest cause of cancer-related death in Australia, with a 9% average 5-year survival. This study aims to investigate the effects of neoadjuvant treatment on overall survival (OS) and recurrence-free survival (RFS) in borderline resectable (BRPC) and locally advanced (LAPC) pancreatic adenocarcinoma followed by curative resection., Materials and Methods: Prospectively-collected demographic, medical, surgical and pathological data of patients with BRPC and LAPC treated with both neoadjuvant therapy (NAT) and surgery at a single tertiary referral centre in Australia were reviewed and analysed., Results: Between 2012 and 2018, 60 patients, 34 with BRPC and 26 with LAPC, were treated with NAT followed by curative resection. The commonest neoadjuvant chemotherapy regimens were Gemcitabine + Abraxane (51.7%) and FOLFIRINOX (35.0%), with 48.3% of patients additionally receiving neoadjuvant radiotherapy. Median RFS was 30 months and median OS was 35 months. On multivariable analysis, inferior OS was predicted by enlarged loco-regional lymph nodes on initial computed tomography (p = 0.032), larger tumour size post-NAT (p = 0.006) and Common Terminology Criteria for Adverse Events post-NAT toxicity greater than grade 2 (p = 0.015). LAPC patients received more neoadjuvant chemotherapy (p = 0.008) and radiotherapy (p = 0.021) than BRPC and achieved a superior pathological response (p = 0.010)., Conclusion: Patients who respond to NAT likely have a favourable disease biology and will progress well following resection. It is these patients who should be selected for more aggressive upfront management, and those with resistant disease should be spared from high-risk surgery., Competing Interests: Declaration of competing interest None., (Copyright © 2021 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

The threat posed by invasive non-native species worldwide requires a global approach to identify which introduced species are likely to pose an elevated risk of impact to native species and ecosystems. To inform policy, stakeholders and management decisions on global threats to aquatic ecosystems, 195 assessors representing 120 risk assessment areas across all six inhabited continents screened 819 non-native species from 15 groups of aquatic organisms (freshwater, brackish, marine plants and animals) using the Aquatic Species Invasiveness Screening Kit. This multi-lingual decision-support tool for the risk screening of aquatic organisms provides assessors with risk scores for a species under current and future climate change conditions that, following a statistically based calibration, permits the accurate classification of species into high-, medium- and low-risk categories under current and predicted climate conditions. The 1730 screenings undertaken encompassed wide geographical areas (regions, political entities, parts thereof, water bodies, river basins, lake drainage basins, and marine regions), which permitted thresholds to be identified for almost all aquatic organismal groups screened as well as for tropical, temperate and continental climate classes, and for tropical and temperate marine ecoregions. In total, 33 species were identified as posing a 'very high risk' of being or becoming invasive, and the scores of several of these species under current climate increased under future climate conditions, primarily due to their wide thermal tolerances. The risk thresholds determined for taxonomic groups and climate zones provide a basis against which area-specific or climate-based calibrated thresholds may be interpreted. In turn, the risk rankings help decision-makers identify which species require an immediate 'rapid' management action (e.g. eradication, control) to avoid or mitigate adverse impacts, which require a full risk assessment, and which are to be restricted or banned with regard to importation and/or sale as ornamental or aquarium/fishery enhancement., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Total arterial coronary revascularization for three coronary territory disease can be achieved with a second arterial conduit joined to the left internal mammary artery as a Y graft, by using either a radial artery (RAY) or a second mammary artery (BIMAY)., Methods: Patients undergoing total arterial revascularization for three coronary territory disease were identified from two cardiac surgical databases (in Sydney and Melbourne, Australia) using Society of Thoracic Surgeons-based definitions. BIMAY-treated patients underwent surgery between 1994 and 2009, mostly using an age-limited protocol, whereas RAY-treated patients underwent surgery between 1996 and 2003 without age limits. All-cause mortality data were acquired from the national death registry, and survival was estimated by the Kaplan-Meier method. Propensity score matching was performed using 13 variables. Given the age imbalance between the groups, the primary comparison was performed for age 66 years or younger., Results: Overall, 1896 patients underwent RAY procedures, and 720 patients underwent BIMAY operations. Older age at surgery was the strongest independent predictor of mortality, with a hazard ratio of 2.06, and a 95% confidence interval of 1.93, 2.22 (P < .001). After propensity score matching, we identified 299 pairs of patients 66 years of age or younger with no preoperative or operative differences and similar ages at surgery: RAY 56.4 ± 7.0 years of age vs BIMAY 56.4 ± 6.8 years of age (P = .96). The RAY group had 4.0 ± 0.9 grafts, and the BIMAY group had 3.9 ± 0.9 grafts (P = .814). All-cause mortality was not different, with the proportion surviving at 15 years at 74.9% for the RAY group vs 76.2% for the BIMAY group (P = .211)., Conclusions: Survival was not different between the RAY and BIMAY groups for total arterial revascularization of three coronary territory bypass grafting., (Copyright © 2021 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Risk factors for further bleeding and ischemic events after acute coronary syndrome (ACS) often overlap. Little is known about sex-based differences in the management and outcomes of ACS patients according to their combined bleeding-ischemic risk., Methods: All ACS hospitalizations in the United Kingdom (2010-2017) were retrospectively analyzed, stratified by sex and bleeding-ischemic risk combination (using CRUSADE and GRACE scores). Multivariable logistic regression was performed to examine association between risk-groups and 1) receipt of guideline-recommended management and 2) in-hospital outcomes., Results: Of 584,360 patients, a third of males (32.3%) and females (32.6%) were in the dual high-risk group (High CRUSADE- High GRACE). In comparison to the dual low-risk group (Low CRUSADE-Low GRACE), the dual high-risk patients of both sexes were 59-83% less likely to receive inpatient revascularisation (PCI or CABG) and 50% less likely to receive dual antiplatelet therapy (DAPT) on discharge, with a significant increase in odds of MACE (~8 to 9-fold), all-cause and cardiac mortality (25 to 35-fold), and bleeding (78-91%). The greatest difference in management and clinical outcomes between sexes was found in the dual-high risk group where females were less likely to receive guideline-recommended therapy (revascularisation and DAPT), compared to males, and were more likely to experience MACE, all-cause and cardiac mortality., Conclusion: ACS patients with dual high-risk for bleeding and recurrent ischemia, especially females, are less likely to receive guideline-recommended therapy and experience significantly worse outcomes. Novel strategies are needed to effectively manage this highly prevalent, complex patient group and address the under-treatment of females., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: The optimum transfusion strategy in patients with fractured neck of femur is uncertain, particularly if there is coexisting cardiovascular disease., Methods: We conducted a prospective, single-centre, randomised feasibility trial of two transfusion strategies. We randomly assigned patients undergoing surgery for fractured neck of femur to a restrictive (haemoglobin, 70-90 g L -1 ) or liberal (haemoglobin, 90-110 g L -1 ) transfusion strategy throughout their hospitalisation. Feasibility outcomes included: enrolment rate, protocol compliance, difference in haemoglobin, and blood exposure. The primary clinical outcome was myocardial injury using troponin estimations. Secondary outcomes included major adverse cardiac events, postoperative complications, duration of hospitalisation, mortality, and quality of life., Results: We enrolled 200 (22%) of 907 eligible patients, and 62 (31%) showed decreased haemoglobin (to 90 g L -1 or less) and were thus exposed to the intervention. The overall protocol compliance was 81% in the liberal group and 64% in the restrictive group. Haemoglobin concentrations were similar preoperatively and at postoperative day 1 but lower in the restrictive group on day 2 (mean difference [MD], 7.0 g L -1 ; 95% confidence interval [CI], 1.6-12.4). Lowest haemoglobin within 30 days/before discharge was lower in the restrictive group (MD, 5.3 g L -1 ; 95% CI, 1.7-9.0). Overall, 58% of patients in the restrictive group received no transfusion compared with 4% in the liberal group (difference in proportion, 54.5%; 95% CI, 36.8-72.2). The proportion with the primary clinical outcome was 14/26 (54%, liberal) vs 24/34 (71%, restrictive), and the difference in proportion was -16.7% (95% CI, -41.3 to 7.8; P=0.18)., Conclusion: A clinical trial of two transfusion strategies in hip fracture with a clinically relevant cardiac outcome is feasible., Clinical Trial Registration: NCT03407573., (Copyright © 2020 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

The updated RCN Competence Framework for orthopaedic and trauma practitioners was published in 2019 following completion of a 2 year project undertaken by a working group of representatives from England, Northern Ireland, Scotland and Wales. Expert musculoskeletal practitioners, including an allied health professional and working across the lifespan in varying domains of orthopaedic and trauma practice, collaborated to produce a working document applicable to trauma and orthopaedic (T&O) practitioners from all NHS (UK) pay bands. The 2019 document builds on the original and subsequent versions (2005 and 2012), importing new evidence and reformatting it so that it is contemporary and easily cross referenced with the NMC Code (2018). The restructure includes an example of a learning contract demonstrating how the framework can be applied in practice, whether for self-learning, or in conjunction with the revalidation process. This paper reflects on and describes the process undertaken by the working group in the development and restructuring of the 2019 framework, including its evaluation to date and planned in the future., (Crown Copyright © 2020. Published by Elsevier Ltd. All rights reserved.)

Background: This multicentre, randomised, double-blinded, placebo-controlled, phase II/III trial aimed to evaluate an oral THC:CBD (tetrahydrocannabinol:cannabidiol) cannabis extract for prevention of refractory chemotherapy-induced nausea and vomiting (CINV). Here we report the phase II component results., Patients and Methods: Eligible patients experienced CINV during moderate-to-high emetogenic intravenous chemotherapy despite guideline-consistent antiemetic prophylaxis. Study treatment consisted of one cycle of 1-4 self-titrated capsules of oral THC 2.5 mg/CBD 2.5 mg (TN-TC11M) three times daily, from days -1 to 5, and 1 cycle of matching placebo in a crossover design, then blinded patient preference for a third cycle. The primary end point was the proportion of participants with complete response during 0-120 h from chemotherapy. A total of 80 participants provided 80% power to detect a 20% absolute improvement with a two-sided P value of 0.1., Results: A total of 81 participants were randomised; 72 completing two cycles were included in the efficacy analyses and 78 not withdrawing consent were included in safety analyses. Median age was 55 years (range 29-80 years); 78% were female. Complete response was improved with THC:CBD from 14% to 25% (relative risk 1.77, 90% confidence interval 1.12-2.79, P = 0.041), with similar effects on absence of emesis, use of rescue medications, absence of significant nausea, and summary scores for the Functional Living Index-Emesis (FLIE). Thirty-one percent experienced moderate or severe cannabinoid-related adverse events such as sedation, dizziness, or disorientation, but 83% of participants preferred cannabis to placebo. No serious adverse events were attributed to THC:CBD., Conclusion: The addition of oral THC:CBD to standard antiemetics was associated with less nausea and vomiting but additional side-effects. Most participants preferred THC:CBD to placebo. Based on these promising results, we plan to recruit an additional 170 participants to complete accrual for the definitive, phase III, parallel group analysis., Trial Registration: Australian New Zealand Clinical Trials Registry ACTRN12616001036404; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=370473&isReview=true., Competing Interests: Disclosure PG: Research funding to institution—ASLAN Pharmaceuticals (Inst), Boston Biomedical (Inst), Eisai (Inst), Eisai (Inst), Five Prime (Inst), Genentech (Inst), Gilead Sciences (Inst), Halozyme (Inst), Medimmune, MSD (Inst), Pfizer (Inst), Pfizer (Inst), Specialised Therapeutics, Tigermed (Inst), Tilray (Inst), Zucero. MS: Research funding to institution—Amgen (Inst), Astellas Pharma (Inst), AstraZeneca (Inst), Bayer (Inst), Bionomics (Inst), Bristol-Myers Squibb (Inst), Celgene (Inst), Medivation (Inst), Merck Sharp & Dohme (Inst), Pfizer (Inst), Roche (Inst), Sanofi (Inst), Tilray (Inst); Travel, Accommodations, Expenses—Medivation/Pfizer. NL: Consulting or Advisory Role—Camurus, Indivior, Mundipharma; Speakers' Bureau—PCM Healthcare Ltd; Research funding to institution—Camurus (Inst). AM: Travel, Accommodations, Expenses—Roche. AT: Travel, Accommodations, Expenses—Ipsen. JS: Research funding to institution—AbbVie (Inst), Amgen (Inst), Astellas Pharma (Inst), AstraZeneca (Inst), Bayer (Inst), Bristol-Myers Squibb (Inst), Merck Serono (Inst), Pfizer (Inst), Roche (Inst). RM: Research funding to institution—Edwards Life Sciences (Inst). IO: Consulting or Advisory Role—Aucentra, Con Ca Pty Ltd, VieCure; Speakers' Bureau—Pierre Fabre (Inst). IM: Honoraria—Janssen; Patents, Royalties, Other Intellectual Property—Kinoxis Therapeutics. CG: Honoraria—Novotech; Consulting or Advisory Role—AbbVie (Inst), Bristol-Myers Squibb (Inst), Ipsen (Inst), Merck Sharp & Dohme (Inst), Novotech, Pfizer (Inst); Research funding to institution—Amgen (Inst), Bristol-Myers Squibb (Inst), Merck Sharp & Dohme (Inst); Travel, Accommodations, Expenses—Astellas Pharma, Astellas Pharma, Merck Sharp & Dohme. SC: Employment—GenesisCare; Stock and Other Ownership Interests—GenesisCare; Honoraria—Tetra Health; Consulting or Advisory Role—All Vascular, AstraZeneca/MedImmune, Bayer, Ipsen, Merck; Speakers' Bureau—Merck, Novartis/Ipsen; Travel, Accommodations, Expenses—Bristol-Myers Squibb, MedLab. All remaining authors have declared no conflicts of interest., (Copyright © 2020 European Society for Medical Oncology. All rights reserved.)

Background: A previous randomised controlled trial (RCT) by our group found that robotic assisted unicompartmental knee arthroplasty (UKA) surgery was significantly more accurate than conventional instrumentation. The aim of this study was to determine whether a low-cost novel PSI design could deliver the same level of accuracy as the robot in the same time efficient manner as conventional instruments., Methods: Thirty patients undergoing medial UKA took part. Tibial component position was planned using a low dose CT-scan, and compared to a day 1 postoperative CT-scan to determine the difference between the planned and achieved positions. Operations were performed by one expert surgeon using PSI (Embody, London, UK)., Results: The mean absolute difference between planned and achieved tibial implant positions using PSI was 2.0° (SD 1.0°) in the coronal plane, 1.8° (SD 1.5) in the sagittal plane, and 4.5° (SD 3.3) in the axial plane. These results were not significantly different to the 13 historical robotic cases (mean difference 0.5°, 0.5°, and 1.7°, p = 0.1907, 0.2867 and 0.1049 respectively). PSI mean operating time was on average 62 min shorter than the robotic group (p < 0.0001) and 40 min shorter than the conventional instrument group (p < 0.0001). No complications were reported., Conclusions: In conclusion, this clinical trial demonstrates that for tibial component positioning in UKA, a novel design PSI guide in the hands of an expert surgeon, can safely deliver comparable accuracy to a robotic system, whilst being significantly faster than conventional instruments. NIHR Clinical Research Network Reference: 16100., (Crown Copyright © 2019. Published by Elsevier B.V. All rights reserved.)

CD23 is involved in a myriad of immune reactions. It is not only a receptor for IgE, but also functions in the regulation of IgE synthesis, isotype switching in B cells, and induction of the inflammatory response. These effector functions of CD23 arise through its interaction with another leukocyte-specific cell surface receptor - the β 2 integrin subfamily. It has been shown that CD23 is also capable of interacting with the β 3 and β 5 integrin β-subunit of integrins via a basic RKC motif in a metal cation-independent fashion. In this study the interaction was probed for whether or not the RKC motif governs the interaction between CD23 and the α X β 2 integrin as well. This was done by performing bioinformatic docking predictions between CD23 and α X β 2 integrin αI domain and SPR spectroscopy analysis of the interaction. This revealed that in the absence of cations, the RKC motif is involved in interaction with the integrin αI domain. However, in the presence of divalent metal cations the interaction showed the involvement of a novel acidic motif within the CD23 protein. This same pattern of interaction was seen in docking predictions between CD23 and the β 3 I-like domain. This study thus presents an alternative site as a possible contributor to the CD23-integrin interaction exhibiting cation-dependence., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Purpose: Anorexia nervosa (AN) is a chronic and life-threatening eating disorder that can have a considerable negative impact on the growing skeleton. We hypothesized that the long-term impact on bone health may persist even after normalization of body weight., Methods: 41 females (mean age 21.2 ± 2.9 years) with a history of adolescent-onset AN attended a follow-up bone health assessment at 5 years (T5, n = 28) or 10 years (T10, n = 13) after their first AN-related hospital admission. Assessment included dual-energy x-ray absorptiometry measurements of the total body, lumbar spine, and proximal femur, peripheral quantitative computed tomography at the radius and tibia, anthropometric measurements, serum biochemistry, fracture history, and a patient questionnaire., Results: A recovery in body weight and BMI was seen for both the T5 and T10 cohorts (BMI at intake 16.6, BMI at T5-T10 21.2-21.3). Dual-energy x-ray absorptiometry body composition indicated a recovery of fat mass and lean tissue mass. Total BMD was unaffected, but reductions were seen at the femoral neck and arms. Peripheral quantitative computed tomography showed reduced trabecular and cortical bone in the radius, and cortical thinning in the tibia. AN patients showed a statistically significant reduction in measures of radiographic bone health at follow up, although not to a degree that necessitated clinical intervention. Serum insulin-like growth factor 1 was also positively correlated with total BMD and BMC measures. While fracture risk was not increased, a subset of participants (8%) showed multiple (>4) fractures., Conclusion: A longitudinal study of adolescent AN showed persisting negative effects on bone health., (Crown Copyright © 2018. Published by Elsevier Inc. All rights reserved.)

Background: Up to 60% of patients who undergo curative-intent pancreatic ductal adenocarcinoma (PDAC) resection experience disease recurrence within six months. We recently published a systematic review of prognostic immunohistochemical biomarkers in PDAC and shortlisted a panel of those reported with the highest level of evidence, including p53, p16, Ca-125, S100A4, FOXC1, EGFR, mesothelin, CD24 and UPAR. This study aims to discover and validate the prognostic significance of a combinatorial panel of tumor biomarkers in patients with resected PDAC., Methods: Patients who underwent PDAC resection were included from a single institution discovery cohort and a multi-institutional validation cohort. Tumors in the discovery cohort were stained immunohistochemically for all nine shortlisted biomarkers. Biomarkers significantly associated with overall survival (OS) were reevaluated as a combinatorial panel in both discovery and validation cohorts for its prognostic significance., Results: 224 and 191 patients were included in the discovery and validation cohorts, respectively. In both cohorts, S100A4, Ca-125 and mesothelin expression were associated with shorter OS. In both cohorts, the number of these biomarkers expressed was significantly associated with OS (discovery cohort 36.8 vs. 26.4 vs 16.3 vs 12.8 months, P < 0.001; validation cohort 25.2 vs 18.3 vs 13.6 vs 11.9 months, P = 0.008 for expression of zero, one, two and three biomarkers, respectively). On multivariable analysis, expression of at least one of three biomarkers was independently associated with shorter OS., Conclusion: Combinations of S100A4, Ca-125 and mesothelin expression stratify survival after resection of localized PDAC. Co-expression of all three biomarkers is associated with the poorest prognostic outcome., (Copyright © 2018. Published by Elsevier Ltd.)

EEG biomarkers have shown promise in predicting non-response to stimulant medication in ADHD and could serve as translational biomarkers. This study aimed to replicate and extend previous EEG biomarkers. The international Study to Predict Optimized Treatment for ADHD (iSPOT-A), a multi-center, international, prospective open-label trial, enrolled 336 children and adolescents with ADHD (11.9 yrs; 245 males; prescribed methylphenidate) and 158 healthy children. Treatment response was established after six weeks using the clinician rated ADHD-Rating Scale-IV. Theta/Beta ratio (TBR) and alpha peak frequency (APF) were assessed at baseline as predictors for treatment outcome. No differences between ADHD and controls were found for TBR and APF. 62% of the ADHD group was classified as a responder. Responders did not differ from non-responders in age, medication dosage, and baseline severity of ADHD symptoms. Male-adolescent non-responders exhibited a low frontal APF (Fz: R = 9.2 Hz vs. NR = 8.1 Hz; ES = 0.83), whereas no effects were found for TBR. A low APF in male adolescents was associated with non-response to methylphenidate, replicating earlier work. Our data suggest that the typical maturational EEG changes observed in ADHD responders and controls are absent in non-responders to methylphenidate and these typical changes start emerging in adolescence., Clinical Trials Registration: www.clinicaltrials.gov; NCT00863499 (https://clinicaltrials.gov/ct2/show/NCT00863499)., (Copyright © 2018. Published by Elsevier B.V.)

Background: The neutrophil to lymphocyte ratio (NLR) is closely linked to mortality in patients with cardiovascular disease. We investigated whether NLR is associated with early clinical outcomes in patients with acute ischemic stroke., Methods: We collated data from a tertiary hospital's stroke registry including admitted patients with a first-ever acute ischemic stroke within 72 h of onset. White blood cell counts and peripheral differential counts were measured on admission. Early clinical outcomes were in-hospital mortality and disability at discharge assessed by the modified Rankin scale (mRS)., Results: Among 1131 stroke patients, 454 patients were included and classified into tertile groups based on NLR on admission. Patients in higher tertiles of NLR were likely to have severe neurologic deficit at discharge. Higher NLR tertiles were associated with an unfavourable shift of mRS score (p < .0001). This association remained significant after adjustment for clinical and laboratory variables including age, sex, hypertension, hypercholesterolemia, atrial fibrillation, stroke severity, and glucose level (p = .032 for trend). However, risk of death or major disability (score of 3-6 on mRS) and in-hospital mortality were not significantly different across NLR tertile groups., Conclusions: In patients with acute ischemic stroke, NLR was predictive of short-term functional outcome., (Crown Copyright © 2018. Published by Elsevier B.V. All rights reserved.)

Question: In people who have undergone cardiac surgery via median sternotomy, does modifying usual sternal precautions to make them less restrictive improve physical function, pain, kinesiophobia and health-related quality of life?, Design: Two-centre, randomised, controlled trial with concealed allocation, blinded assessors and intention-to-treat analysis., Participants: Seventy-two adults who had undergone cardiac surgery via a median sternotomy were included., Intervention: Participants were randomly allocated to one of two groups at 4 (SD 1) days after surgery. The control group received the usual advice to restrict their upper limb use for 4 to 6 weeks (ie, restrictive sternal precautions). The experimental group received advice to use pain and discomfort as the safe limits for their upper limb use during daily activities (ie, less restrictive precautions) for the same period. Both groups received postoperative individualised education in hospital and via weekly telephone calls for 6 weeks., Outcome Measures: The primary outcome was physical function assessed by the Short Physical Performance Battery. Secondary outcomes included upper limb function, pain, kinesophobia, and health-related quality of life. Outcomes were measured before hospital discharge and at 4 and 12 weeks postoperatively. Adherence to sternal precautions was recorded., Results: There were no statistically significant differences in physical function between the groups at 4 weeks (MD 1.0, 95% CI -0.2 to 2.3) and 12 weeks (MD 0.4, 95% CI -0.9 to 1.6) postoperatively. There were no statistically significant between-group differences in secondary outcomes., Conclusion: Modified (ie, less restrictive) sternal precautions for people following cardiac surgery had similar effects on physical recovery, pain and health-related quality of life as usual restrictive sternal precautions. Similar outcomes can be anticipated regardless of whether people following cardiac surgery are managed with traditional or modified sternal precautions., Trial Registration: Australian and New Zealand Clinical Trials Registry ANZCTRN12615000968572. [Katijjahbe MA, Granger CL, Denehy L, Royse A, Royse C, Bates R, Logie S, Nur Ayub MA, Clarke S, El-Ansary D (2018) Standard restrictive sternal precautions and modified sternal precautions had similar effects in people after cardiac surgery via median sternotomy ('SMART' Trial): a randomised trial. Journal of Physiotherapy 64: 97-106]., (Crown Copyright © 2018. Published by Elsevier B.V. All rights reserved.)