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GSK3358699 is a mononuclear myeloid-targeted bromodomain and extra-terminal domain (BET) family inhibitor which demonstrates immunomodulatory effects in vitro. This phase 1, randomized, first-in-human study evaluated the safety, pharmacokinetics, and pharmacodynamics of GSK3358699 in healthy male participants (NCT03426995).Part A (N = 23) included three dose-escalating periods of 1-40 mg of GSK3358699 or placebo in two cohorts in a single ascending-dose crossover design. Part C (N = 25) was planned as an initial dose of 10 mg of GSK3358699 or placebo daily for 14 days followed by selected doses in four sequential cohorts.In part A, exposure to GSK3358699 and its metabolite GSK3206944 generally increased with increasing doses. The median initial half-life ranged from 0.7 to 1.1 (GSK3358699) and 2.1 to 2.9 (GSK3206944) hours after a single dose of 1-40 mg. GSK3206944 concentrations in monocytes were quantifiable at 1-hour post-dose following 10 mg of GSK3358699 and 1 and 4 hours post-dose following 20-40 mg. Mean predicted percentage inhibition of ex vivo lipopolysaccharide-induced monocyte chemoattractant protein (MCP)-1 reached 75% with 40 mg of GSK3358699. GSK3358699 did not inhibit interleukin (IL)-6 and tumour necrosis factor (TNF). The most common adverse event (AE) was headache. Four AEs of nonsustained ventricular tachycardia were observed across parts A and C. One serious AE of atrial fibrillation (part C) required hospitalization.Single doses of GSK3358699 are generally well tolerated with significant metabolite concentrations detected in target cells. A complete assessment of pharmacodynamics was limited by assay variability. A causal relationship could not be excluded for cardiac-related AEs, resulting in an inability to identify a suitable repeat-dose regimen and study termination.

Significance IgG antibodies are a key component of adaptive humoral immunity but can cause organ damage if they bind self-antigen, as occurs in the autoimmune disease systemic lupus erythematosus (SLE). Many of the proinflammatory effects of IgG are mediated by ligating Fcγ receptors (FcγRs) expressed by tissue-resident leukocytes such as macrophages. One of the most serious complications of SLE is kidney inflammation: lupus nephritis. Here we show that IgG ligation of FcγRs on macrophages in the kidney leads to a change in their metabolism, resulting in a switch toward glycolysis. Administration of a glycolysis inhibitor attenuated IgG-associated kidney macrophage activation, proinflammatory cytokine secretion, and kidney inflammation. Therefore, manipulating macrophage metabolism may be a useful therapeutic strategy in lupus nephritis., IgG antibodies cause inflammation and organ damage in autoimmune diseases such as systemic lupus erythematosus (SLE). We investigated the metabolic profile of macrophages isolated from inflamed tissues in immune complex (IC)-associated diseases, including SLE and rheumatoid arthritis, and following IgG Fcγ receptor cross-linking. We found that human and mouse macrophages undergo a switch to glycolysis in response to IgG IC stimulation, mirroring macrophage metabolic changes in inflamed tissue in vivo. This metabolic reprogramming was required to generate a number of proinflammatory mediators, including IL-1β, and was dependent on mTOR and hypoxia-inducible factor (HIF)1α. Inhibition of glycolysis, or genetic depletion of HIF1α, attenuated IgG IC-induced activation of macrophages in vitro, including primary human kidney macrophages. In vivo, glycolysis inhibition led to a reduction in kidney macrophage IL-1β and reduced neutrophil recruitment in a murine model of antibody-mediated nephritis. Together, our data reveal the molecular mechanisms underpinning FcγR-mediated metabolic reprogramming in macrophages and suggest a therapeutic strategy for autoantibody-induced inflammation, including lupus nephritis.

Introduction: Hyperbaric oxygen treatment (HBOT) may be complicated by oxygen toxicity seizures, which typically occur with hyperbaric partial pressures of oxygen exceeding 203 kPa (2 atmospheres absolute). All other hyperbaric units in Australia exclusively use a multiplace chamber when treating with United States Navy Treatment Table 6 (USN TT6) due to this perceived risk. The purpose of this study was to determine the safety of a monoplace chamber when treating decompression illness (DCI) with USN TT6. Methods: A retrospective review of the medical records of all patients treated at Fiona Stanley Hospital Hyperbaric Medicine Unit with USN TT6 between November 2014 and June 2020 was undertaken. These data were combined with previous results from studies performed at our hyperbaric unit at Fremantle Hospital from 1989 to 2014, creating a data set covering a 30-year period. Results: One thousand treatments with USN TT6 were performed between 1989 and 2020; 331 in a monoplace chamber and 669 in a multiplace chamber. Four seizures occurred: a rate of 0.59% (1/167) in a multiplace chamber; and none in a monoplace chamber, indicating no statistically significant difference between seizures in a monoplace versus multiplace chamber (P = 0.31). Conclusions: The rate of oxygen toxicity seizures in a monoplace chamber is not significantly higher than for treatment in the multiplace chamber. We conclude that using the monoplace chamber for USN TT6 in selected patients poses an acceptably low seizure risk.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infections have a devastating effect on patients receiving hemodialysis. To what extent infection-induced antibody responses are maintained, or protective, is unknown. This study describes the evolution of antibodies against the SARS-CoV-2 spike protein in a cohort of 990 patients on hemodialysis. During the first wave of the pandemic, 26% of patients had developed antispike SARS-CoV-2 antibodies. Fewer PCR-confirmed second-wave infections were observed in patients with pre-existing antibodies (4.2%) than those without antibodies (11.4%). This study shows that SARS-CoV-2 antibodies in patients on hemodialysis are well maintained and associate with reduced risk of subsequent SARS-CoV-2 infection.

(Howard AE, Buzzacott P, Gawthrope IC, Banham ND. Effect of antiplatelet and/or anticoagulation medication on the risk of tympanic barotrauma in hyperbaric oxygen therapy patients, and development of a predictive model. Diving and Hyperbaric Medicine. 2020 December 31;50(4):338–342. doi: 10.28920/dhm50.4.338-342. PMID: 33325013.) Introduction: Middle ear barotrauma (MEBt) is a common side effect of hyperbaric oxygen treatment (HBOT) and can result in pain, hearing loss, tinnitus and otorrhagia. The use of antiplatelet/anticoagulant drugs is thought to increase the risk and severity of MEBt during HBOT. Methods: Single centre, retrospective observational cohort study of all patients treated with HBOT over a 4-year period (between 01 January 2015 to 31 December 2018) looking at the incidence of MEBt and the concurrent use of antiplatelet and/or anticoagulant drugs. MEBt was assessed by direct otoscopy of the tympanic membrane post-HBOT and scored using the modified Teed classification. Multivariate modelling assessed the relationship between antiplatelet and/or anticoagulation drug use, age, sex, and MEBt during HBOT. Results: There was no evidence that antiplatelet and/or anticoagulation drugs increase the risk of tympanic barotrauma in HBOT patients. The prevalence of MEBt was higher in female patients than in males (χ2 P = 0.004), and increased with age (χ2 P = 0.048). No MEBt was recorded in patients undergoing recompression therapy for decompression sickness or cerebral arterial gas embolism. Conclusions: In this retrospective single-centre study, antiplatelet and/or anticoagulation drugs did not affect the risk of MEBt, but both age and sex did, with greater prevalence of MEBt among older patients and females compared with younger patients and males. A predictive model, requiring further validation, may be helpful in assessing the likelihood of MEBt in patients undergoing HBOT.

Background Aboriginal and Torres Strait Islander Australians have poorer cancer outcomes than other Australians. Comparatively little is known of the type and amount of cancer treatment provided to Aboriginal and Torres Strait Islander people and the consequences for cancer survival. This study quantifies the influence of surgical, systemic and radiotherapy treatment on risk of cancer death among matched cohorts of cancer cases and, the comparative exposure of cohorts to these treatments. Methods Cancers registered among Aboriginal South Australians in 1990–2010 (N = 777) were matched with randomly selected non-Indigenous cases by sex, birth and diagnostic year, and primary site, then linked to administrative cancer treatment for the period from 2 months before to 13 months after diagnosis. Competing risk regression summarised associations of Indigenous status, geographic remoteness, comorbidities, cancer stage and treatment exposure with risk of cancer death. Results Fewer Aboriginal cases had localised disease at diagnosis (37.2% versus 50.2%) and they were less likely to: experience hospitalisation with cancer diagnosis, unadjusted odds ratio (UOR) = 0.76; 95%CI = 0.59–0.98; have surgery UOR = 0.65; 95%CI = 0.53–0.80; systemic therapies UOR = 0.64; 95%CI = 0.52–0.78; or radiotherapy, UOR = 0.76; 95%CI = 0.63–0.94. Localised disease carried lower risk of cancer death compared to advanced cases receiving surgery or systemic therapies, SHR = 0.34; 95%CI = 0.25–0.47 and SHR = 0.35; 95%CI = 0.25–0.48. Advanced disease and no treatment carried higher risk of cancer death, SHR = 1.82; 95%CI = 1.26–2.63. Conclusion The effects of treatment did not differ between Aboriginal and non-Indigenous cohorts. However, comparatively less exposure to surgical and systemic treatments among Aboriginal cancer cases further complicated the disadvantages associated with geographic remoteness, advanced stage of disease and co-morbid conditions at diagnosis and add to disparities in cancer death. System level responses to improving access, utilisation and quality of effective treatments are needed to improve survival after cancer diagnosis.

Background Low pH suppresses the proliferation and cytotoxic activity of CD8+ cytotoxic and natural killer lymphocytes. The hypoxia-regulated transmembrane protein, carbonic anhydrase CA9, converts carbon dioxide produced by the Krebs cycle to bicarbonate and protons that acidify the extracellular milieu. We examined whether CA9 is also involved in intratumoural immunosuppression pathways. Methods A series of 98 tissue samples of primary non-small-cell lung carcinomas (NSCLC) from patients treated with surgery were analysed for the expression of CA9 and programmed-death ligand PD-L1 by cancer cells, and of FOXP3 by tumour-infiltrating lymphocytes (TILs). Results There was no direct association of CA9 with PD-L1 expression or the density of TILs in the tumour stroma, but CA9 was directly related to the extent of FOXP3+ TIL density (p = 0.008). Double-stratification survival analysis showed that patients with high CA9 expression and low TIL score had significantly poorer survival compared with all other groups (p Conclusion The study provides a basis for testing CA9 as a marker of resistance to immune-checkpoint inhibitors and as a therapeutic target to enhance the efficacy of immunotherapy.

Aim: The aim of this paper is to describe the implementation and evaluation of the Growing Strong Brains® (GSB) toolkit in a remote Aboriginal community in Western Australia (WA) over a 2-year period, 2018–2019. Background: Ngala, a community service organisation in WA, developed the GSB toolkit in 2014, a culturally appropriate and interactive resource to build knowledge of early childhood development within Aboriginal communities. This was in response to evidence that a higher percentage of children in Aboriginal communities were developmentally vulnerable compared to the rest of the population. The GSB toolkit promotes awareness and understanding of early brain development pre-birth and in the early years of a child’s life. Methods: The project was underpinned by participatory action research (PAR). Reflective PAR review cycles (n = 5) monitored local community engagement, navigated challenges and utilised community strengths. Fifty-nine local service providers attended a 2-day formal training. Data were collected by using various methods throughout the project, including feedback following training, focus groups, surveys, one-on-one interviews using yarning techniques and reflective feedback from the Project Lead. Findings: Establishing local Aboriginal project staff was pivotal to the success of the project. When delivering services for and with Aboriginal people, it is essential that cultural competence, safety and decision-making is carried through from planning to implementation and evaluation, and involves genuine, respectful and authentic relationships. Sufficient time allocation directed towards building relationships with other service providers and local community members needs to be considered and built into future projects. The Growing Strong Brains® project is embedded within the local community, and anticipated implementation outcomes were achieved. The support of the local people and service providers was beyond expectation, enabling the building of local capacity, and the development of a common understanding of the key messages from the GSB toolkit to allow integration throughout all levels of the community. This project has been important to build on the strategies necessary to introduce, implement and evaluate the GSB toolkit in other remote Aboriginal communities.

Process mining is a well-established discipline with applications in many industry sectors, including healthcare. To date, few publications have considered the context in which processes execute. Little consideration has been given as to how contextual data (exogenous data) can be practically included for process mining analysis, beyond including case or event attributes in a typical event log. We show that the combination of process data (endogenous) and exogenous data can generate insights not possible with standard process mining techniques. Our contributions are a framework for process mining with exogenous data and new analyses, where exogenous data and process behaviour are linked to process outcomes. Our new analyses visualise exogenous data, highlighting the trends and variations, to show where overlaps or distinctions exist between outcomes. We applied our analyses in a healthcare setting and show that clinicians could extract insights about differences in patients' vital signs (exogenous data) relevant to clinical outcomes. We present two evaluations, using a publicly available data set, MIMIC-III, to demonstrate the applicability of our analysis. These evaluations show that process mining can integrate large amounts of physiologic data and interventions, with resulting discrimination and conversion to clinically interpretable information.

This paper explores, analyses, and documents the experiences of Afghan-Australians who arrived in Australia as refugees and were granted citizenship after living in Australia for several years. This research adopted a mixed method of qualitative and quantitative approaches and surveyed 102 people, interviewed 13 participants, and conducted two focus-groups within its research design. Analysis of data indicates that former Afghan refugees gradually settled down and integrated within Australian society. They value safety and security, open democracy and orderly society of Australia, as well as accessing to education and healthcare services and opportunity for social mobility. However, since the integration is a long process, they are also facing some challenges in this area. Findings of this study show that Afghan-Australians require more support from Australian governments to overcome some of these challenges particularly securing employment within their area of interests and professional occupations that they have qualifications and experiences from Afghanistan. They are also experiencing broader challenges in the area of socio-cultural issues within Australian society. Since the Afghan community is an emerging community in Western Australia, they require more support from local government to enhance their ethnic cohesion and solidarity.

ELTD1 is expressed in endothelial and vascular smooth muscle cells and has a role in angiogenesis. It has been classified as an adhesion GPCR, but as yet, no ligand has been identified and its function remains unknown. To establish its role, ELTD1 was overexpressed in endothelial cells. Expression and consequently ligand independent activation of ELTD1 results in endothelial-mesenchymal transistion (EndMT) with a loss of cell-cell contact, formation of stress fibres and mature focal adhesions and an increased expression of smooth muscle actin. The effect was pro-angiogenic, increasing Matrigel network formation and endothelial sprouting. RNA-Seq analysis after the cells had undergone EndMT revealed large increases in chemokines and cytokines involved in regulating immune response. Gene set enrichment analysis of the data identified a number of pathways involved in myofibroblast biology suggesting that the endothelial cells had undergone a type II EMT. This type of EMT is involved in wound repair and is closely associated with inflammation implicating ELTD1 in these processes.

No abstract available.

Background: Aboriginal people with cancer experience worse outcomes than other Australians for a range of complex and interrelated reasons. A younger age at diagnosis, higher likelihood of more advanced cancer or cancer type with poorer prognosis, geographic isolation and cultural and language diversity mean that patient pathways are potentially more complex for Aboriginal people with cancer. In addition, variation in the quality and acceptability of care may influence cancer outcomes. Objective: This study sought to understand how care coordination influences Aboriginal people's experiences of cancer treatment. Methods: Interviews with 29 Aboriginal patients or cancer survivors, 11 carers and 22 service providers were carried out. Interviews were semi-structured and sought to elicit experiences of cancer and the health-care system. The manifest content of the cancer narratives was entered onto a cancer pathway mapping tool and underlying themes were identified inductively. Results: The practice of cancer care coordination was found to address the needs of Aboriginal patients and their families/carers in 4 main areas: "navigating the health system" "information and communication" "things to manage at home" and "cultural safety". Conclusions: The CanDAD findings indicate that, when the need for cancer care coordination is met, it facilitated continuity of care in a range of ways that may potentially improve cancer outcomes. However, the need remains unmet for many. Findings support the importance of dedicated care coordination to enable Aboriginal people to receive adequate and appropriate patient-centred care, so that the unacceptable disparity in cancer outcomes between Aboriginal and non-Aboriginal people can be addressed. Refereed/Peer-reviewed

Background: Aboriginal Australians have poorer cancer survival than other Australians. Diagnoses at later stages and correlates of remote area living influence, but do not fully explain, these disparities. Little is known of the prevalence and influence of comorbid conditions experienced by Aboriginal people, including their effect on cancer survival. This study quantifies hospital recorded comorbidities using the Elixhauser Comorbidity Index (ECI), examines their influence on risk of cancer death, then considers effect variation by Aboriginality. Methods: Cancers diagnosed among Aboriginal South Australians in 1990–2010 (N = 777) were matched with randomly selected non-Aboriginal cases by birth year, diagnostic year, sex, and primary site, then linked to administrative hospital records to the time of diagnosis. Competing risk regression summarised associations of Aboriginal status, stage, geographic attributes and comorbidities with risk of cancer death. Results: A threshold of four or more ECI conditions was associated with increased risk of cancer death (sub-hazard ratio SHR 1.66, 95%CI 1.11-2.46). Alternatively, the presence of any one of a subset of ECI conditions was associated with similarly increased risk (SHR = 1.62, 95%CI 1.23-2.14). The observed effects did not differ between Aboriginal and matched non-Aboriginal cases. However, Aboriginal cases experienced three times higher exposure than non-Aboriginal to four or more ECI conditions (14.2% versus 4.5%) and greater exposure to the subset of ECI conditions (20.7% versus 8.0%). Conclusion: Comorbidities at diagnosis increased the risk of cancer death in addition to risks associated with Aboriginality, remoteness of residence and disease stage at diagnosis. The Aboriginal cohort experienced comparatively greater exposure to comorbidities which adds to disparities in cancer outcomes. Refereed/Peer-reviewed

Four studies reveal that offering diversity awards (i.e., awards for applicants from marginalized groups) has unintentionally negative implications for equity. Across the four studies, applicants from marginalized groups were more likely to select the more lucrative award when two unrestricted awards were offered (Study 1: adults from racial groups underrepresented in U.S. colleges who were recruited from Amazon Mechanical Turk, N = 168; Studies 2–4: college women, N range = 152–628). However, the presence of a less lucrative diversity award caused applicants to apply for and prioritize diversity awards over more lucrative unrestricted awards. Fit, or how much applicants felt the award was for someone like them, mediated their increased likelihood of applying for diversity awards over unrestricted awards. These findings suggest that diversity awards may inadvertently siphon applicants from marginalized groups out of application pools for unrestricted awards. Greater examination of unrestricted awards is needed to increase their attractiveness and fit, especially in instances when diversity awards are also offered.

Introduction: Oxygen toxicity seizures (OTS) are a well-recognised complication of hyperbaric oxygen treatment (HBOT). As such, seizure-like activity during HBOT is usually presumed to be a result of central nervous system oxygen toxicity (CNS-OT). Four cases are reported here where causes other than CNS-OT were determined as being the likely cause of the seizure; causes we have labelled ‘OTS mimics’. Through review of the current literature, and our hyperbaric medicine unit’s experience to date, we aimed to highlight the relevance of these OTS mimics, as the potential for significant morbidity and mortality exists with incorrect diagnoses. Methods: A retrospective review of the medical records of all patients treated at the Fiona Stanley Hospital and Fremantle Hospital hyperbaric medicine units who had a seizure during HBOT between November 1989 and June 2020. These events were reviewed to determine whether causes for seizures other than oxygen toxicity were evident. Results: Four OTS mimics were identified: posterior reversible encephalopathy syndrome, pethidine toxicity, previous subarachnoid haemorrhage with resultant epilepsy, and severe hypoglycaemia. Conclusions: This case series highlights the need for caution when diagnosing an apparent OTS. Multiple conditions may mimic the signs and symptoms of oxygen toxicity. This creates scope for misdiagnosis, with potential for consequent morbidity and mortality. A pragmatic approach is necessary to any patient exhibiting seizure-like activity during HBOT, with suspicion for other underlying pathologies.

Objectives To determine if a specific intervention reduces the composite of progression of patients with COVID-19-related disease to organ failure or death as measured by time to incidence of any one of the following: death, invasive mechanical ventilation, ECMO, cardiovascular organ support (inotropes or balloon pump), or renal failure (estimated Cockcroft Gault creatinine clearance Trial design Randomised, parallel arm, open-label, adaptive platform Phase 2/3 trial of potential disease modifying therapies in patients with late stage 1/stage 2 COVID-19-related disease, with a diagnosis based either on a positive assay or high suspicion of COVID-19 infection by clinical, laboratory and radiological assessment. Participants Patients aged 18 and over, with a clinical picture strongly suggestive of COVID-19-related disease (with/without a positive COVID-19 test) AND a risk count (as defined below) >3 OR ≥3 if risk count includes “Radiographic severity score >3”. A risk count is calculated by the following features on admission (1 point for each): radiographic severity score >3, male gender, non-white ethnicity, diabetes, hypertension, neutrophils >8.0 x109/L, age >40 years and CRP >40 mg/L. Patients should be considered an appropriate subject for intervention with immunomodulatory or other disease modifying agents in the opinion of the investigator and are able to swallow capsules or tablets. The complete inclusion and exclusion criteria as detailed in the Additional file 1 should be fulfilled. Drug specific inclusion and exclusion criteria will also be applied to the active arms. Patients will be enrolled prior to the need for invasive mechanical ventilation, cardiac or renal support. Participants will be recruited across multiple centres in the UK including initially at Cambridge University Hospitals NHS Foundation Trust and St George’s University NHS Foundation Trust. Other centres will be approached internationally in view of the evolving pandemic. Intervention and comparator There is increasing evidence of the role of immunomodulation in altering the course of COVID-19. Additionally, various groups have demonstrated the presence of pulmonary shunting in patients with COVID-19 as well as other cardiovascular complications. TACTIC-E will assess the efficacy of the novel immunomodulatory agent EDP1815 versus the approved cardio-pulmonary drugs, Dapagliflozin in combination with Ambrisentan versus the prevailing standard of care. EDP1815 will be given as 2 capsules twice daily (1.6 x 1011 cells) for up to 7 days with the option to extend up to 14 days at the discretion of the principal investigator or their delegate, if the patient is felt to be clinically responding to treatment, is tolerating treatment, and is judged to be likely to benefit from a longer treatment course. Ambrisentan 5mg and Dapagliflozin 10mg will be given in combination once daily orally for up to maximum of 14 days. Patients will be randomised in a 1:1:1 ratio across treatments. Each active arm will be compared with standard of care alone. Additional arms may be added as the trial progresses. No comparisons will be made between active arms in this platform trial. Main outcomes The primary outcome is the incidence (from baseline up to Day 14) to the occurrence of the any one of the following events: death, invasive mechanical ventilation, extra corporeal membrane oxygenation, cardiovascular organ support (inotropes or balloon pump), or renal failure (estimated Cockcroft Gault creatinine clearance Randomisation Eligible patients will be randomised using a central web-based randomisation service (Sealed Envelope) in a 1:1:1 ratio, stratified by site to one of the treatment arms or standard of care. Blinding (masking) This is an open-label trial. Data analysis will not be blinded. Numbers to be randomised (sample size) There is no fixed sample size for this study. There will be an early biomarker-based futility analysis performed at a point during the study. If this biomarker futility analysis is not conclusive, then a second futility analysis based on clinical endpoints will be performed after approximately 125 patients have been recruited per arm. Provisionally, further analyses of clinical endpoints will be performed after 229 patients per active arm and later 469 patients per arm have been recruited. Further additional analyses may be triggered by the independent data monitoring committee. Trial Status TACTIC-E Protocol version number 1.0 date May 27th, 2020. Recruitment starts on the 3rd of July 2020. The end trial date will be 18 months after the last patient’s last visit and cannot be accurately predicted at this time. Trial registration Registered on EU Clinical Trials Register EudraCT Number: 2020-002229-27 registered: 9 June 2020. The trial was also registered on ClinicalTrials.gov (NCT04393246) on 19 May 2020. Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Purpose Nemiralisib, a phosphoinositide 3-kinase δ inhibitor, is being investigated as an immunomodulatory agent with anti-inflammatory properties in chronic obstructive pulmonary disease. This study evaluated the pharmacokinetic (PK) properties and safety of a new formulation of nemiralisib that contains 0.4% magnesium stearate. Methods In this randomized, double-blind, parallel-group study, healthy individuals received a single dose of 500 or 750 μg of nemiralisib administered via the Ellipta dry powder inhaler (DPI) (n = 6 in each treatment group). Aerodynamic particle size distribution (APSD) data comparing previous and new formulations were available before the study. Serial PK analyses for plasma exposure and safety assessments were performed during the first 24 h after dosing, with follow-up measurements on days 3 and 6 in clinic. Findings APSD had increases of approximately 6-fold and 2-fold in very fine particle mass and fine particle mass over the previous (Diskus) formulation. In humans, systemic exposure (AUC) was greater after inhalation of 750 versus 500 μg of nemiralisib (AUC0–t: 17,200 h∙pg/mL; 95% CI, 10,900–27,200 h∙pg/mL and 13,100; 95% CI, 8130–21,000 h∙pg/mL, respectively). A low frequency of individual adverse events and no serious adverse events were reported after both doses. Implications After single-dose inhalation of 500 and 750 μg of nemiralisib from the Ellipta DPI in healthy individuals, plasma PK data were well defined, and as predicted based on previous PK and APSD data, exposure was increased with the new formulation. Nemiralisib was well tolerated with no new safety issues identified. These data supported progression of nemiralisib to a Phase IIb study in patients with chronic obstructive pulmonary disease. ClinicalTrials.gov identifier: NCT03189589 .

The sorting of specific cell populations is an established tool in biological research, with new applications demanding greater cell throughput, sterility and elimination of cross-contamination. Here we report 'vortex-actuated cell sorting' (VACS), a new technique that deflects cells individually, via the generation of a transient microfluidic vortex by a thermal vapour bubble: a novel mechanism, which is able to sort cells based on fluorescently-labelled molecular markers. Using in silico simulation and experiments on beads, an immortal cell line and human peripheral blood mononuclear cells (PBMCs), we demonstrate high-purity and high-recovery sorting with input rates up to 104 cells per s and switching speeds comparable to existing techniques (>40 kHz). A tiny footprint (1 × 0.25 mm) affords miniaturization and the potential to achieve multiplexing: a crucial step in increasing processing rate. Simple construction using biocompatible materials potentially minimizes cost of fabrication and permits single-use sterile cartridges. We believe VACS potentially enables parallel sorting at throughputs relevant to cell therapy, liquid biopsy and phenotypic screening.

Funder: Rhodes Scholarships; doi: http://dx.doi.org/10.13039/501100000697, Funder: Clarendon Scholarship, Funder: Ernest Oppenheimer Memorial Trust; doi: http://dx.doi.org/10.13039/501100009978, Funder: European Union (European Social Fund), Funder: Free State of Saxony, Funder: Cancer Research UK; doi: http://dx.doi.org/10.13039/501100000289, Funder: Breast Cancer Research Foundation; doi: http://dx.doi.org/10.13039/100001006, ADGRL4/ELTD1 is an orphan adhesion GPCR (aGPCR) expressed in endothelial cells that regulates tumour angiogenesis. The majority of aGPCRs are orphan receptors. The Stachel Hypothesis proposes a mechanism for aGPCR activation, in which aGPCRs contain a tethered agonist (termed Stachel) C-terminal to the GPCR-proteolytic site (GPS) cleavage point which, when exposed, initiates canonical GPCR signalling. This has been shown in a growing number of aGPCRs. We tested this hypothesis on ADGRL4/ELTD1 by designing full length (FL) and C-terminal fragment (CTF) ADGRL4/ELTD1 constructs, and a range of potential Stachel peptides. Constructs were transfected into HEK293T cells and HTRF FRET, luciferase-reporter and Alphascreen GPCR signalling assays were performed. A stable ADGRL4/ELTD1 overexpressing HUVEC line was additionally generated and angiogenesis assays, signalling assays and transcriptional profiling were performed. ADGRL4/ELTD1 has the lowest GC content in the aGPCR family and codon optimisation significantly increased its expression. FL and CTF ADGRL4/ELTD1 constructs, as well as Stachel peptides, did not activate canonical GPCR signalling. Furthermore, stable overexpression of ADGRL4/ELTD1 in HUVECs induced sprouting angiogenesis, lowered in vitro anastomoses, and decreased proliferation, without activating canonical GPCR signalling or MAPK/ERK, PI3K/AKT, JNK, JAK/HIF-1α, beta catenin or STAT3 pathways. Overexpression upregulated ANTXR1, SLC39A6, HBB, CHRNA, ELMOD1, JAG1 and downregulated DLL4, KIT, CCL15, CYP26B1. ADGRL4/ELTD1 specifically regulates the endothelial tip-cell phenotype through yet undefined signalling pathways.

ELTD1/ADGRL4 expression is increased in the vasculature of a number of tumor types and this correlates with a good prognosis. Expression has also been reported in some tumor cells with high expression correlating with a good prognosis in hepatocellular carcinoma (HCC) and a poor prognosis in glioblastoma. Here we show that 35% of primary human breast tumors stain positively for ELTD1, with 9% having high expression that correlates with improved relapse-free survival. Using immunocompetent, syngeneic mouse breast cancer models we found that tumors expressing recombinant murine Eltd1 grew faster than controls, with an enhanced ability to metastasize and promote systemic immune effects. The Eltd1-expressing tumors had larger and better perfused vessels and tumor–endothelial cell interaction led to the release of proangiogenic and immune-modulating factors. M2-like macrophages increased in the stroma along with expression of programmed death-ligand 1 (PD-L1) on tumor and immune cells, to create an immunosuppressive microenvironment that allowed Eltd1-regulated tumor growth in the presence of an NY-ESO-1–specific immune response. Eltd1-positive tumors also responded better to chemotherapy which could explain the relationship to a good prognosis observed in primary human cases. Thus, ELTD1 expression may enhance delivery of therapeutic antibodies to reverse the immunosuppression and increase response to chemotherapy and radiotherapy in this subset of tumors. ELTD1 may be useful as a selection marker for such therapies. Implications: ELTD1 expression in mouse breast tumors creates an immunosuppressive microenvironment and increases vessel size and perfusion. Its expression may enhance the delivery of therapies targeting the immune system.

BackgroundIn contrast with the setting of acute myocardial infarction, there are limited data regarding the impact of diabetes mellitus on clinical outcomes in contemporary cohorts of patients with chronic coronary syndromes. We aimed to investigate the prevalence and prognostic impact of diabetes according to geographical regions and ethnicity.Methods and resultsCLARIFY is an observational registry of patients with chronic coronary syndromes, enrolled across 45 countries in Europe, Asia, America, Middle East, Australia, and Africa in 2009–2010, and followed up yearly for 5 years. Chronic coronary syndromes were defined by ≥1 of the following criteria: prior myocardial infarction, evidence of coronary stenosis >50%, proven symptomatic myocardial ischaemia, or prior revascularization procedure.Among 32 694 patients, 9502 (29%) had diabetes, with a regional prevalence ranging from below 20% in Northern Europe to ∼60% in the Gulf countries. In a multivariable-adjusted Cox proportional hazards model, diabetes was associated with increased risks for the primary outcome (cardiovascular death, myocardial infarction, or stroke) with an adjusted hazard ratio of 1.28 (95% confidence interval 1.18, 1.39) and for all secondary outcomes (all-cause and cardiovascular mortality, myocardial infarction, stroke, heart failure, and coronary revascularization). Differences on outcomes according to geography and ethnicity were modest.ConclusionIn patients with chronic coronary syndromes, diabetes is independently associated with mortality and cardiovascular events, including heart failure, which is not accounted by demographics, prior medical history, left ventricular ejection fraction, or use of secondary prevention medication. This is observed across multiple geographic regions and ethnicities, despite marked disparities in the prevalence of diabetes.ClinicalTrials identifierISRCTN43070564

ObjectivesTo quantify emergency department (ED) presentations by individuals within vulnerable populations compared with other adults and the extent to which these are potentially preventable.DesignPeriod prevalence study from 2005-2006 to 2010–2011.SettingPerson-linked, ED administrative records for public hospitals in South Australia.ParticipantsAdults aged 20 or more in South Australia’s metropolitan area presenting to ED and categorised as Refugee and Asylum Seeker Countries of birth (RASC); Aboriginal; those aged 75 years or more; or All others.Main outcome measuresUnadjusted rates of ambulatory care sensitive condition (ACSC), general practitioner (GP)–type presentations and associated direct ED costs among mutually exclusive groups of individuals.ResultsDisparity between RASC and All others was greatest for GP-type presentations (423.7 and 240.1 persons per 1000 population, respectively) with excess costs of $A106 573 (95% CI $A98 775 to $A114 371) per 1000 population. Aboriginal had highest acute ACSC presenter rates (125.8 against 51.6 per 1000 population) with twice the risk of multiple presentations and $A108 701 (95% CI $A374 to $A123 029) per 1000 excess costs. Those aged 75 or more had highest chronic ACSC presenter rates (119.7vs21.1 per 1000), threefold risk of further presentations (incidence rate ratio 3.20, 95% CI 3.14 to 3.26) and excess cost of $A385 (95% CI $A178 160 to $A184 609) per 1000 population.ConclusionsVulnerable groups had excess ED presentations for a range of issues potentially better addressed through primary and community healthcare. The observed differences suggest inequities in the uptake of effective primary and community care and represent a source of excess cost to the public hospital system.

Background: Australian health surveys occasionally include health utility measures in describing health related quality of life (HRQoL) across the general population. However, the HRQoL of specific population groups, such as Aboriginal and Torres Strait Islander (respectfully referred to as Aboriginal), are poorly understood. Our analysis describes HRQoL utility among Aboriginal South Australians by examining the characteristics of respondents completing HRQoL questioning, the relationship between HRQoL and respondent characteristics, then considers reported HRQoL utility in the wider population context. Methods: Population weighted and self-reported HRQoL was measured using SF-6D, as derived from the SF-12version 2, in the South Australian Aboriginal Health Survey’s face to face interviews with 399 respondents aged 15or more in 2010/11. Results: Mean HRQoL utility was 0.77 (95% CIs 0.76–0.79) with marked variations by gender (females 0.03, 95% CIs0.00–0.06 lower than males), age (with ages 55 or more 0.08, 95% CIs 0.02–0.14 lower than 15–35 years) and number of chronic health conditions (3 or more conditions 0.14, 95% CIs 0.09–0.19 lower than those with 0 conditions). A pattern of response to HRQoL questions was also evident. Response was less likely among respondents speaking Aboriginal languages at home, living in non-urban settings, and experiencing multiple chronic health conditions. Conclusions: The SF-6D provides useful information on the HRQoL of Aboriginal South Australians. However, non-completion was pronounced among respondents speaking traditional languages and experiencing more chronic health conditions. Improved participation of vulnerable and health compromised respondents through culturally safe and relevant self-reporting HRQoL utility instruments is needed. Refereed/Peer-reviewed

Background: Australia’s Aboriginal and Torres Strait Islander women have poorer survival and twice the disease burden from breast cancer compared to other Australian women. These disparities are influenced, but not fully explained, by more diagnoses at later stages. Incorporating breast screening, hospital and out of hospital treatment and cancer registry records into a person-linked data system can improve our understanding of breast cancer outcomes. We focussed one such system on a population-based cohort of Aboriginal women in South Australia diagnosed with breast cancer and a matched cohort of non-Aboriginal women with breast cancer. We quantify Aboriginal and non-Aboriginal women’s contact with publicly funded screening mammograms; quantify exposure to a selection of cancer treatment modalities; then assess the relationship between screening, treatment and the subsequent risk of breast cancer death. Methods: Breast cancers registered among Aboriginal women in South Australia in 1990–2010 (N = 77) were matched with a random selection of non-Aboriginal women by birth and diagnostic year, then linked to screening records, and treatment 2 months before and 13 months after diagnosis. Competing risk regression summarised associations of Aboriginality, breast screening, cancer stage and treatment with risk of breast cancer death. Results: Aboriginal women were less likely to have breast screening (OR = 0.37, 95%CIs 0.19–0.73); systemic therapies(OR = 0.49, 95%CIs 0.24–0.97); and, surgical intervention (OR = 0.35, 95%CIs 0.15–0.83). Where surgery occurred,mastectomy was more common among Aboriginal women (OR = 2.58, 1.22–5.46). Each of these factors influenced the risk of cancer death, reported as sub-hazard ratios (SHR). Regional spread disease (SHR = 34.23 95%CIs 6.76–13.40) and distant spread (SHR = 49.67 95% CIs 6.79–363.51) carried more risk than localised disease (Reference SHR = 1). Breast screening reduced the risk (SHR = 0.07 95%CIs 0.01–0.83). So too did receipt of systemic therapy (SHR = 0.06 95%CIs 0.01–0.41) and surgical treatments (SHR = 0.17 95% CIs 0.04–0.74). In the presence of adjustment for these factors,Aboriginality did not further explain the risk of breast cancer death. Conclusion: Under-exposure to screening and treatment of Aboriginal women with breast cancers in South Australia contributed to excess cancer deaths. Improved access, utilisation and quality of effective treatments is needed to improve survival after breast cancer diagnosis. Refereed/Peer-reviewed

Aims To report long-term outcomes of patients treated with stereotactic ablative radiotherapy (SABR) for early stage, peripherally located non-small cell lung cancer. Materials and methods Data were collected retrospectively between September 2009 and May 2019. Electronic medical records were reviewed for baseline characteristics, treatment details and outcomes. All patients were treated according to local protocol based on the national UK SABR Consortium guidelines. Risk-adapted treatment schedules were used depending on the size and the location of the tumour (54 Gy in three fractions, 55 Gy in five fractions, 60 Gy in eight fractions or 50 Gy in 10 fractions). Overall survival outcomes were evaluated using the Kaplan–Meier method. Results In total, 412 patients were included in the analysis. The median age was 76 years (range 48–93 years). Histological confirmation was obtained in 233 cases (56.6%). The median overall survival for all patients was 42.3 months (95% confidence interval 37.3–47.3 months), with 3- and 5-year overall survival of 52.8% and 37.3%, respectively. For biopsy-proven patients (56.6%), 3- and 5-year overall survival was 57.3% and 40.1%, respectively. With respect to overall survival, univariate and multivariate analysis revealed no significant difference in survival by technique (volume-modulated arc therapy versus conformal; three-dimensional computed tomography versus four-dimensional computed tomography), tumour location, smoking status at first contact, pre-treatment tumour stage or pre-treatment standardised uptake value. Survival was poorer for patients who received the 50 Gy in 10 fractions schedule. Treatment was very well tolerated with very low rates of grade 3–4 toxicity (1%). Conclusions SABR for peripherally located, medically inoperable non-small cell lung cancer can be safely and effectively implemented in a non-academic institution with appropriate equipment and training. Overall survival outcomes and toxicity rates are comparable with internationally published studies. Patients treated with 50 Gy in 10 fractions had a poorer survival outcome.

Objectives To determine if a specific immunomodulatory intervention reduces progression of COVID-19-related disease to organ failure or death, compared to standard of care (SoC). Trial design Randomised, parallel 3-arm (1:1:1 ratio), open-label, Phase IV platform trial of immunomodulatory therapies in patients with late stage 1 or stage 2 COVID-19-related disease, with a diagnosis based either on a positive assay or high suspicion of COVID-19 infection by clinical and/or radiological assessment. Participants Patients aged 18 and over, with a clinical picture strongly suggestive of COVID-19-related disease (with/without a positive COVID-19 test) AND a Risk count (as defined below) >3 OR ≥3 if risk count includes “Radiographic severity score >3”. A risk count is calculated by the following features on admission (1 point for each): radiographic severity score >3, male gender, non-white ethnicity, diabetes, hypertension, neutrophils >8.0 x109/L, age >40 years and CRP >40 mg/L. Patients should be considered an appropriate subject for intervention with immunomodulatory therapies in the opinion of the investigator and be able to be maintained on venous thromboembolism prophylaxis during the inpatient dosing period, according to local guidelines. The complete inclusion and exclusion criteria as detailed in the additional file 1 should be fulfilled. Patients will be enrolled prior to the need for invasive mechanical ventilation, cardiac or renal support. Participants will be recruited across multiple centres including initially at Cambridge University Hospitals NHS Foundation Trust, King’s College Hospital NHS Foundation Trust, Guy’s and St Thomas’ NHS Foundation Trust, University Hospital of Wales, Gloucestershire Royal Hospitals NHS Foundation Trust and The Royal Wolverhampton NHS Trust. Intervention and comparator Each active comparator arm will be compared against standard of care (SoC). The immunomodulatory drugs were selected from a panel of licenced candidates by a drug evaluation committee, which considered potential efficacy, potential toxicity, scalability and novelty of each strategy. The initial active arms comprise baricitinib and ravulizumab. Baricitinib will be given 4 mg orally (once daily (OD)) on days 1-14 or until day of discharge. The dose will be reduced to 2 mg OD for patients aged > 75 years and those with an estimated Cockcroft Gault creatinine clearance of 30-60 ml/min. Ravulizumab will be administered intravenously once according to the licensed weight-based dosing regimen (see Additional file 1). Each active arm will be compared with standard of care alone. No comparisons will be made between active arms in this platform trial. Main outcomes The primary outcome is the incidence (from baseline up to Day 14) of any one of the events (whichever comes first): death, invasive mechanical ventilation, extra corporeal membrane oxygenation, cardiovascular organ support (inotropes or balloon pump), or renal failure (estimated Cockcroft Gault creatinine clearance Randomisation Eligible patients will be randomised using a central web-based randomisation service (Sealed Envelope) in a 1:1:1 ratio, stratified by site to one of the treatment arms or SoC. Blinding (masking) This is an open-label trial. Data analysis will not be blinded. Numbers to be randomised (sample size) There is no fixed sample size for this study. Serial interim analyses will be triggered by an Independent Data Monitoring Committee (IDMC), including analysis after 125 patients are recruited to each arm, 375 in total assuming 3 arms. Additional interim analyses are projected after 229 patients per arm, and potentially then after 469 per arm, but additional analyses may be triggered by the IDMC. Trial Status TACTIC-R Protocol version number 2.0 date May 20, 2020, recruitment began May 7, 2020 and the end trial will be the date 18 months after the last patient’s last visit. The recruitment end date cannot yet be accurately predicted. Trial registration Registered on EU Clinical Trials Register EudraCT Number: 2020-001354-22 Registered: 6 May 2020 It was registered on ClinicalTrials.gov (NCT04390464) and on ISRCTN (ISRCTN11188345) Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

(Ashton C, Banham N, Needham M. Acute spontaneous spinal cord infarction: Utilisation of hyperbaric oxygen treatment, cerebrospinal fluid drainage and pentoxifylline. Diving and Hyperbaric Medicine. 2020 December 20;50(4):325–331. doi: 10.28920/dhm50.4.325-331. PMID: 33325011.) Introduction: Spinal cord infarction (SCI) is a potentially devastating disorder presenting with an acute anterior spinal artery syndrome, accounting for an estimated 1% of stroke presentations. Aetiologies include aortic surgical complications, systemic hypotension, fibrocartilaginous embolism and vascular malformations. Diagnosis is clinical combined with restriction on diffusion-weighted magnetic resonance imaging (MRI). There are no treatment guidelines for non-perioperative cases although there is limited literature regarding potential therapies, including hyperbaric oxygen treatment (HBOT) and cerebrospinal fluid (CSF) drainage. We describe 13 cases of acute SCI, five receiving HBOT, and three also receiving pentoxifylline and drainage of lumbar CSF. Methods: Data for all patients with MRI-proven SCI at Fiona Stanley Hospital from 2014–2019 were reviewed. Results: Thirteen patients, median age 57 years (31–74), 54% female, were identified. Aetiologies: two fibrocartilaginous emboli; seven likely atherosclerotic; two thromboembolic; two cryptogenic. All presented with flaccid paraplegia except one with Brown-Sequard syndrome. Levels ranged from C4 to T11. Five patients received HBOT within a median time of 40 hours from symptom onset, with an average 15 treatments (10−20). Three of these received triple therapy (HBOT, pentoxifylline, CSF drainage) and had median Medical Research Council manual muscle testing power of 5, median modified Rankin Score (mRS) of 1 and American Spinal Injury Association (ASIA) score of D on discharge, compared with 2 power, mRS 3.5 and ASIA B in those who did not. Conclusions: SCI can be severely disabling. Triple therapy with pentoxifylline, CSF drainage and HBOT may reduce disability and further prospective trials are required.

Thymocyte selection-associated high-mobility group box (TOX) is a DNA-binding factor that is able to regulate transcription by modifying local chromatin structure and modulating the formation of multi-protein complexes. TOX has multiple roles in the development of the adaptive immune system including development of CD4 T cells, NK cells and lymph node organogenesis. However very few antibodies recognizing this molecule have been reported and no extensive study of the expression of TOX in reactive and neoplastic lymphoid tissue has been performed to date. In the present study, we have investigated TOX expression in normal and neoplastic lymphoid tissues using a novel rat monoclonal antibody that recognizes its target molecule in paraffin-embedded tissue sections. A large series of normal tissues and B- and T-cell lymphomas was studied, using whole sections and tissue microarrays. We found that the majority of precursor B/T lymphoblastic, follicular and diffuse large B-cell lymphomas, nodular lymphocyte-predominant Hodgkin lymphomas and angioimmunoblastic T-cell lymphomas strongly expressed the TOX protein. Burkitt and mantle cell lymphomas showed TOX expression in a small percentage of cases. TOX was not found in the majority of chronic lymphocytic leukemia, myelomas, marginal zone lymphomas and classical Hodgkin lymphomas. In conclusion, we describe for the first time the expression of TOX in normal and neoplastic lymphoid tissues. The co-expression of TOX and PD-1 identified in normal and neoplastic T cells is consistent with recent studies identifying TOX as a critical regulator of T-cell exhaustion and a potential immunotherapy target. Its differential expression may be of diagnostic relevance in the differential diagnosis of follicular lymphoma, the identification of the phenotype of diffuse large B-cell lymphoma and the recognition of peripheral T-cell lymphoma with a follicular helper T phenotype. This work was supported by grants from the Plan Nacional de I+D+I, co-financed by the ISCIII-Subdireccion General de Evaluacion and the Fondo Europeo de Desarrollo Regional (FEDER), CIBERONC -CB16/12/00291 (MAP), and Programs of R&D activities among research groups of the Community of Madrid in Biomedicine (B2017/BMD-3778) (MAP, GR, JFGG). All funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Sí

Background Comorbidity is known to increase risk of death in cancer patients, both Aboriginal and non-Aboriginal. The means of measuring comorbidity to assess risk of death has not been studied in any depth in Aboriginal patients in Australia. In this study, conventional and customized comorbidity indices were used to investigate effects of comorbidity on cancer survival by Aboriginal status and to determine whether comorbidity explains survival disparities. Methods A retrospective cohort study was undertaken using linked population-based South Australian Cancer Registry and hospital inpatient data for 777 Aboriginal people diagnosed with primary cancer between 1990 and 2010 and 777 randomly selected non-Aboriginal controls matched by sex, birth year, diagnosis year and tumour type. A customised comorbidity index was developed by examining associations of comorbid conditions with 1-year all-cause mortality within the Aboriginal and non-Aboriginal patient groups separately using Cox proportional hazard model, adjusting for age, stage, sex and primary site. The adjusted hazard ratios for comorbid conditions were used as weights for these conditions in index development. The comorbidity index score for combined analyses was the sum of the weights across the comorbid conditions for each case from the two groups. Results The two most prevalent comorbidities in the Aboriginal cohort were “uncomplicated” hypertension (13.5%) and diabetes without complications (10.8%), yet in non-Aboriginal people, the comorbidities were “uncomplicated” hypertension (7.1%) and chronic obstructive pulmonary disease (4.4%). Higher comorbidity scores were associated with higher all-cause and cancer-specific mortality. The new index showed minor improvements in predictive ability and model fit when compared with three common generic comparison indices. After accounting for the competing risk of other deaths, stage at diagnosis, socioeconomic status, area remoteness and comorbidity, the increased risk of cancer death in Aboriginal people remained. Conclusions Our new customised index performed at least as well, although not markedly better than the generic indices. We conclude that in broad terms, the generic indices are reasonably effective for adjusting for comorbidity when comparing survival outcomes by Aboriginal status. Irrespective of the index used, comorbidity has a negative impact on cancer-specific survival, but this does not fully explain the lower survival in Aboriginal patients.

Summary Background B cells produce alloantibodies and activate alloreactive T cells, negatively affecting kidney transplant survival. By contrast, regulatory B cells are associated with transplant tolerance. Immunotherapies are needed that inhibit B-cell effector function, including antibody secretion, while sparing regulators and minimising infection risk. B lymphocyte stimulator (BLyS) is a cytokine that promotes B-cell activation and has not previously been targeted in kidney transplant recipients. We aimed to determine the safety and activity of an anti-BLyS antibody, belimumab, in addition to standard-of-care immunosuppression in adult kidney transplant recipients. We used an experimental medicine study design with multiple secondary and exploratory endpoints to gain further insight into the effect of belimumab on the generation of de-novo IgG and on the regulatory B-cell compartment. Methods We undertook a double-blind, randomised, placebo-controlled phase 2 trial of belimumab, in addition to standard-of-care immunosuppression (basiliximab, mycophenolate mofetil, tacrolimus, and prednisolone) at two centres, Addenbrooke's Hospital, Cambridge, UK, and Guy's and St Thomas' Hospital, London, UK. Participants were eligible if they were aged 18–75 years and receiving a kidney transplant and were planned to receive standard-of-care immunosuppression. Participants were randomly assigned (1:1) to receive either intravenous belimumab 10 mg per kg bodyweight or placebo, given at day 0, 14, and 28, and then every 4 weeks for a total of seven infusions. The co-primary endpoints were safety and change in the concentration of naive B cells from baseline to week 24, both of which were analysed in all patients who received a transplant and at least one dose of drug or placebo (the modified intention-to-treat [mITT] population). This trial has been completed and is registered with ClinicalTrials.gov, NCT01536379, and EudraCT, 2011–006215–56. Findings Between Sept 13, 2013, and Feb 8, 2015, of 303 patients assessed for eligibility, 28 kidney transplant recipients were randomly assigned to receive belimumab (n=14) or placebo (n=14). 25 patients (12 [86%] patients assigned to the belimumab group and 13 [93%] patients assigned to the placebo group) received a transplant and were included in the mITT population. We observed similar proportions of adverse events in the belimumab and placebo groups, including serious infections (one [8%] of 12 in the belimumab group and five [38%] of 13 in the placebo group during the 6-month on-treatment phase; and none in the belimumab group and two [15%] in the placebo group during the 6-month follow-up). In the on-treatment phase, one patient in the placebo group died because of fatal myocardial infarction and acute cardiac failure. The co-primary endpoint of a reduction in naive B cells from baseline to week 24 was not met. Treatment with belimumab did not significantly reduce the number of naive B cells from baseline to week 24 (adjusted mean difference between the belimumab and placebo treatment groups −34·4 cells per μL, 95% CI −109·5 to 40·7). Interpretation Belimumab might be a useful adjunct to standard-of-care immunosuppression in renal transplantation, with no major increased risk of infection and potential beneficial effects on humoral alloimmunity. Funding GlaxoSmithKline.

Background Our laboratory identified ADGRL4/ELTD1, an orphan GPCR belonging to the adhesion GPCR (aGPCR) family, as a novel regulator of angiogenesis and a potential anti-cancer therapeutic target. Little is known about how ADGRL4/ELTD1 (and aGPCRs in general) function, a problem compounded by a lack of known ligands or means of activation. With this in mind, we turned to computational evolutionary biology with the aim of better understanding ADGRL4/ELTD1. Results We identified ADGRL4/ELTD1 as a highly conserved early angiogenic gene which emerged in the first true vertebrates (bony fish) approximately 435 million years ago (mya), evolving alongside key angiogenic genes VEGFR2 and DLL4. We identified 3 evolutionary ADGRL4/ELTD1 variants based on EGF domain deletions with variant 2 first emerging 101 mya (95% CI 96–105) in Afrotheria and 82 mya (95% CI 76–89) in Primates. Additionally, conservation mapping across all orthologues reveals highest level conservation in EGF Ca binding domain 1, suggesting that this motif plays an essential role, as well as specific regions of the GAIN domain, GPS motif and 7TM domain, suggesting possible activation mechanisms and ligand binding positions. Additionally, we found that ADGRL4/ELTD1 (a member aGPCR family 1) is possibly ancestral to members of aGPCR family 2. Conclusion This work establishes ADGRL4/ELTD1’s evolution, sheds light on its possible activation and ligand binding zones, and establishes the first temporal references for the emergence of ADGRL4/ELTD1 variants during vertebrate evolution. Our approach is applicable to the greater aGPCR family and opens up new avenues for future experimental work. Electronic supplementary material The online version of this article (10.1186/s12862-019-1445-9) contains supplementary material, which is available to authorized users.

The role of Notch signaling and its ligand JAGGED1 (JAG1) in tumor biology has been firmly established, making them appealing therapeutic targets for cancer treatment. Here, we report the development and characterization of human/rat-specific JAG1-neutralizing mAbs. Epitope mapping identified their binding to the Notch receptor interaction site within the JAG1 Delta/Serrate/Lag2 domain, where E228D substitution prevented effective binding to the murine Jag1 ortholog. These antibodies were able to specifically inhibit JAG1-Notch binding in vitro, downregulate Notch signaling in cancer cells, and block the heterotypic JAG1-mediated Notch signaling between endothelial and vascular smooth muscle cells. Functionally, in vitro treatment impaired three-dimensional growth of breast cancer cell spheroids, in association with a reduction in cancer stem cell number. In vivo testing showed variable effects on human xenograft growth when only tumor-expressed JAG1 was targeted (mouse models) but a more robust effect when stromal-expressed Jag1 was also targeted (rat MDA-MB-231 xenograft model). Importantly, treatment of established triple receptor-negative breast cancer brain metastasis in rats showed a significant reduction in neoplastic growth. MRI imaging demonstrated that this was associated with a substantial improvement in blood–brain barrier function and tumor perfusion. Lastly, JAG1-targeting antibody treatment did not cause any detectable toxicity, further supporting its clinical potential for cancer therapy.

Purpose/Aim: Regulatory FOXP3+ T-cells control the cytotoxic activity of effector cells and may have an essential role in the development of immune tolerance in cancer patients. Programed death ligand 1 PD-L1, expressed on cancer cell membranes also blocks the cytotoxic activity of PD1+ cytotoxic lymphocytes. Materials and Methods: We assessed the immunohistochemical detection of these immune-tolerance related markers in a series of 98 non-small cell lung carcinomas (NSCLC) treated with surgery. The Tumor Infiltration Lymphocyte TIL density (mean number per x400 optical field) and the percentage of FOXP3+ TILs were assessed. Results: PD-L1 expression was directly linked with the TIL density (p = 0.01) and with the extent of infiltration with FOXP3+ TILs, named as the FIL-score (p = 0.01). FIL-score was significantly higher in stage I disease (p = 0.04). IL6 expression was linked with high TIL-score. A low TIL-score, characterizing immune deficient tumors defined a significantly poorer prognosis subgroup of patients (p = 0.03). Stratification of these tumors according to the FIL-score showed that FOXP3 expression by TILs correlated with an even a poorer prognosis in univariate (p = 0.007; median survival 14 vs. 44 months, respectively) and in multivariate analysis (p = 0.01, hazard ratio 4.3). Conclusion: Tumor stroma infiltration by FOXP3+ Tregs is an early event in the progression of NSCLC. Low lymphocytic infiltration defines poor prognosis, which becomes worse when the small numbers of infiltrating lymphocytes characterizing these tumors contain FOXP3 + Tregs. Furthermore, the direct association of FOXP3+ Treg infiltration density with PD-L1 expression by cancer cells implies a co-ordinated immune-suppressive activity in NSCLC.

Objective. To determine whether hindsight bias impacts on retrospective case note review using a five point scoring system based on modern clinical governance toolkits. Design. Survey. Setting. Clinicians of varying grades invited to complete a short internet survey. Participants. Ninety three clinicians were invited to complete an anonymous survey in which they reviewed three case vignettes for the purposes of a fictional clinical governance meeting. For each vignette, participants were randomised to an outcome in which the patient made a full recovery or alternatively died shortly after discharge. Main outcome measure. Participants submit scores from 1 to 5 to indicate the quality of care provided to patients prior to their discharge. These scores were compared to determine whether judgements about the quality of antecedent care were biased by the description of a patient death. Results. In two out of three case vignettes clinicians exhibited marked hindsight bias. In a case of a patient with a swollen leg, identical antecedent care was scored as poor by participants when the patient died the next day, but good when the patient recovered (p

T-cell receptor mimic (TCRm) antibodies have expanded the repertoire of antigens targetable by monoclonal antibodies, to include peptides derived from intracellular proteins that are presented by major histocompatibility complex class I (MHC-I) molecules on the cell surface. We have previously used this approach to target p53, which represents a valuable target for cancer immunotherapy because of the high frequency of its deregulation by mutation or other mechanisms. The T1-116C TCRm antibody targets the wild type p5365-73 peptide (RMPEAAPPV) presented by HLA-A*0201 (HLA-A2) and exhibited in vivo efficacy against triple receptor negative breast cancer xenografts. Here we report a comprehensive mutational analysis of the p53 RMPEAAPPV peptide to assess the T1-116C epitope and its peptide specificity. Antibody binding absolutely required the N-terminal arginine residue, while amino acids in the center of the peptide contributed little to specificity. Data mining the immune epitope database with the T1-116C binding consensus and validation of peptide recognition using the T2 stabilization assay identified additional tumor antigens targeted by T1-116C, including WT1, gp100, Tyrosinase and NY-ESO-1. Most peptides recognized by T1-116C were conserved in mice and human HLA-A2 transgenic mice showed no toxicity when treated with T1-116C in vivo. We conclude that comprehensive validation of TCRm antibody target specificity is critical for assessing their safety profile.

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of mature B-cell lymphoma. While the majority of patients are cured with immunochemotherapy incorporating the anti-CD20 monoclonal antibody rituximab (R-CHOP), relapsed and refractory patients still have a dismal prognosis. DLBCL subtypes including an aggressive activated B-cell-like (ABC) and a more favorable prognosis germinal center-like (GCB) DLBCL have been identified by gene expression profiling and are characterized by distinct genetic abnormalities and oncogenic pathways. This identification of novel molecular targets is now enabling clinical trials to evaluate more effective personalized approaches to DLBCL therapy. The forkhead transcription factor FOXP1 is highly expressed in the ABC-DLBCL gene signature and has been extensively studied within the context of DLBCL for more than a decade. Here, we review the significance of FOXP1 in the pathogenesis of DLBCL, summarizing data supporting its utility as a prognostic and subtyping marker, its targeting by genetic aberrations, the importance of specific isoforms, and emerging data demonstrating a functional role in lymphoma biology. FOXP1 is one of the critical transcription factors whose deregulated expression makes important contributions to DLBCL pathogenesis. Thus, FOXP1 warrants further study as a potential theranostic in ABC-DLBCL.

Principles of mechanical ventilation #### Modes of mechanical ventilation Recommendation 1. Pressure-targeted ventilators are the devices of choice for acute NIV (Grade B). Good practice points #### Choice of interface for NIV Recommendation 2. A full face mask (FFM) should usually be the first type of interface used (Grade D). Good practice points #### Indications for and contra-indications to NIV in AHRF Recommendation 3. The presence of adverse features increase the risk of NIV failure and should prompt consideration of placement in high dependency unit (HDU)/intensive care unit (ICU) (Grade C). Good practice points #### Monitoring during NIV Good practice points #### Supplemental oxygen therapy with NIV Recommendations 4. Oxygen enrichment should be adjusted to achieve SaO2 88–92% in all causes of acute hypercapnic respiratory failure (AHRF) treated by NIV (Grade A). 5. Oxygen should be entrained as close to the patient as possible (Grade C). Good practice points

Notch is a highly conserved signaling system that allows neighboring cells to communicate, thereby controlling their differentiation, proliferation and apoptosis, with the outcome of its activation being highly dependent on signal strength and cell type. As such, there is growing evidence that disturbances in physiological Notch signaling contribute to cancer development and growth through various mechanisms. Notch was first reported to contribute to tumorigenesis in the early 90s, through identification of the involvement of the Notch1 gene in the chromosomal translocation t(7;9)(q34;q34.3), found in a small subset of T-cell acute lymphoblastic leukemia. Since then, Notch mutations and aberrant Notch signaling have been reported in numerous other precursor and mature hematological malignancies, of both myeloid and lymphoid origin, as well as many epithelial tumor types. Of note, Notch has been reported to have both oncogenic and tumor suppressor roles, dependent on the cancer cell type. In this review, we will first give a general description of the Notch signaling pathway, and its physiologic role in hematopoiesis. Next, we will review the role of aberrant Notch signaling in several hematological malignancies. Finally, we will discuss current and potential future therapeutic approaches targeting this pathway.

Background/Aim: This study tested the utility of retrospectively staging cancer registry data for comparing stage and stage-specific survivals of Aboriginal and non-Aboriginal people. Differences by area level factors were also explored. Methods: This test dataset comprised 950 Aboriginal cases and all other cases recorded on the South Australian cancer registry with a 1977–2010 diagnosis. A sub-set of 777 Aboriginal cases diagnosed in 1990–2010 were matched with randomly selected non-Aboriginal cases by year of birth, diagnostic year, sex, and primary site of cancer. Competing risk regression summarised associations of Aboriginal status, stage, and geographic attributes with risk of cancer death. Results: Aboriginal cases were 10 years younger at diagnosis, more likely to present in recent diagnostic years, to be resident of remote areas, and have primary cancer sites of head & neck, lung, liver and cervix. Risk of cancer death was associated in the matched analysis with more advanced stage at diagnosis. More Aboriginal than non-Aboriginal cases had distant metastases at diagnosis (31.3% vs 22.0, p < 0.001). After adjusting for stage, remote-living Aboriginal residents had higher risks of cancer death than Aboriginal residents of metropolitan areas. Non-Aboriginal cases had the lowest risk of cancer death. Conclusion: Retrospective staging proved to be feasible using registry data. Results indicated more advanced stages for Aboriginal than matched non-Aboriginal cases. Aboriginal people had higher risks of cancer death, which persisted after adjusting for stage, and applied irrespective of remoteness of residence, with highest risk of death occurring among Aboriginal people from remote areas. Refereed/Peer-reviewed

In Australia, Aboriginal and Torres Strait Islander People carry a greater burden of cancerrelated mortality than non-Aboriginal Australians. The Cancer Data and Aboriginal Disparities Project aims to develop and test an integrated, comprehensive cancer monitoring and surveillance system capable of incorporating epidemiological and narrative data to address disparities and advocate for clinical system change. Methods and analysis: The Advanced Cancer Data System will integrate routinely collected unit record data from the South Australian Population Cancer Registry and a range of other data sources for a retrospective cohort of indigenous people with cancers diagnosed from 1990 to 2010. A randomly drawn non-Aboriginal cohort will be matched by primary cancer site, sex, age and year at diagnosis. Cross-Tabulations and regression analyses will examine the extent to which demographic attributes, cancer stage and survival vary between the cohorts. Narratives from Aboriginal people with cancer, their families, carers and service providers will be collected and analysed using patient pathway mapping and thematic analysis. Statements from the narratives will structure both a concept mapping process of rating, sorting and prioritising issues, focusing on issues of importance and feasibility, and the development of a real-Time Aboriginal Cancer Measure of Experience for ongoing linkage with epidemiological data in the Advanced Cancer Data System. Aboriginal Community engagement underpins this Project. Ethics and dissemination: The research has been approved by relevant local and national ethics committees. Findings will be disseminated in local andinternational peer-reviewed journals and conference presentations. In addition, the research will provide data for knowledge translation activities across thepartner organisations and feed directly into the Statewide Cancer Control Plan. It will provide a mechanism for monitoring and evaluating theimplementation of the recommendations in these documents. Refereed/Peer-reviewed

Huntingtin-interacting protein 1-related (HIP1R) is an endocytic protein involved in receptor trafficking, including regulating cell surface expression of receptor tyrosine kinases. We have previously shown that low HIP1R protein expression was associated with poorer survival in diffuse large B-cell lymphoma (DLBCL) patients from Denmark treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). In this multicenter study, we extend these findings and validate the prognostic and subtyping utility of HIP1R expression at both transcript and protein level. Using data mining on three independent transcriptomic datasets of DLBCL, HIP1R transcript was preferentially expressed in germinal center B-cell (GCB)-like DLBCL subtype (Phi/HIP1R lo phenotype) exhibited poorer OS (P=0.0038) and PFS (P=0.0134). Multivariate analysis showed that HIP1Rhi/HIP1R lo subgroup of patients exhibited inferior OS and PFS (P

BACKGROUND: B cells produce alloantibodies and activate alloreactive T cells, negatively affecting kidney transplant survival. By contrast, regulatory B cells are associated with transplant tolerance. Immunotherapies are needed that inhibit B-cell effector function, including antibody secretion, while sparing regulators and minimising infection risk. B lymphocyte stimulator (BLyS) is a cytokine that promotes B-cell activation and has not previously been targeted in kidney transplant recipients. We aimed to determine the safety and activity of an anti-BLyS antibody, belimumab, in addition to standard-of-care immunosuppression in adult kidney transplant recipients. We used an experimental medicine study design with multiple secondary and exploratory endpoints to gain further insight into the effect of belimumab on the generation of de-novo IgG and on the regulatory B-cell compartment. METHODS: We undertook a double-blind, randomised, placebo-controlled phase 2 trial of belimumab, in addition to standard-of-care immunosuppression (basiliximab, mycophenolate mofetil, tacrolimus, and prednisolone) at two centres, Addenbrooke's Hospital, Cambridge, UK, and Guy's and St Thomas' Hospital, London, UK. Participants were eligible if they were aged 18-75 years and receiving a kidney transplant and were planned to receive standard-of-care immunosuppression. Participants were randomly assigned (1:1) to receive either intravenous belimumab 10 mg per kg bodyweight or placebo, given at day 0, 14, and 28, and then every 4 weeks for a total of seven infusions. The co-primary endpoints were safety and change in the concentration of naive B cells from baseline to week 24, both of which were analysed in all patients who received a transplant and at least one dose of drug or placebo (the modified intention-to-treat [mITT] population). This trial has been completed and is registered with ClinicalTrials.gov, NCT01536379, and EudraCT, 2011-006215-56. FINDINGS: Between Sept 13, 2013, and Feb 8, 2015, of 303 patients assessed for eligibility, 28 kidney transplant recipients were randomly assigned to receive belimumab (n=14) or placebo (n=14). 25 patients (12 [86%] patients assigned to the belimumab group and 13 [93%] patients assigned to the placebo group) received a transplant and were included in the mITT population. We observed similar proportions of adverse events in the belimumab and placebo groups, including serious infections (one [8%] of 12 in the belimumab group and five [38%] of 13 in the placebo group during the 6-month on-treatment phase; and none in the belimumab group and two [15%] in the placebo group during the 6-month follow-up). In the on-treatment phase, one patient in the placebo group died because of fatal myocardial infarction and acute cardiac failure. The co-primary endpoint of a reduction in naive B cells from baseline to week 24 was not met. Treatment with belimumab did not significantly reduce the number of naive B cells from baseline to week 24 (adjusted mean difference between the belimumab and placebo treatment groups -34·4 cells per μL, 95% CI -109·5 to 40·7). INTERPRETATION: Belimumab might be a useful adjunct to standard-of-care immunosuppression in renal transplantation, with no major increased risk of infection and potential beneficial effects on humoral alloimmunity. FUNDING: GlaxoSmithKline.

Streptococcus pneumoniae is a major cause of pneumonia and a leading cause of death world-wide. Antibody-mediated immune responses can confer protection against repeated exposure to S. pneumoniae, yet vaccines offer only partial protection. Patients with Activated PI3Kδ Syndrome (APDS) are highly susceptible to S. pneumoniae. We generated a conditional knock-in mouse model of this disease and identify a CD19+B220− B cell subset that is induced by PI3Kδ signaling, resides in the lungs, and is correlated with increased susceptibility to S. pneumoniae during early phases of infection via an antibody-independent mechanism. We show that an inhaled PI3Kδ inhibitor improves survival rates following S. pneumoniae infection in wild-type mice and in mice with activated PI3Kδ. These results suggest that a subset of B cells in the lung can promote the severity of S. pneumoniae infection, representing a potential therapeutic target., Antibody mediated immune responses to Streptococcus pneumoniae are crucial for the immune response to infection. Here the authors show hyper-activation of PI3Kδ promotes development of a subset of B cells that exacerbate infection in an antibody-independent manner and can be reversed by therapeutic targeting in vivo.

The realisation of human potential for development requires age-specific investment throughout the 8000 days of childhood and adolescence. Focus on the first 1000 days is an essential but insufficient investment. Intervention is also required in three later phases: the middle childhood growth and consolidation phase (5-9 years), when infection and malnutrition constrain growth, and mortality is higher than previously recognised; the adolescent growth spurt (10-14 years), when substantial changes place commensurate demands on good diet and health; and the adolescent phase of growth and consolidation (15-19 years), when new responses are needed to support brain maturation, intense social engagement, and emotional control. Two cost-efficient packages, one delivered through schools and one focusing on later adolescence, would provide phase-specific support across the life cycle, securing the gains of investment in the first 1000 days, enabling substantial catch-up from early growth failure, and leveraging improved learning from concomitant education investments. Refereed/Peer-reviewed

The FOXP1 (forkhead box P1) transcription factor is a marker of poor prognosis in diffuse large B-cell lymphoma (DLBCL). Here microarray analysis of FOXP1-silenced DLBCL cell lines identified differential regulation of immune response signatures and major histocompatibility complex class II (MHC II) genes as some of the most significant differences between germinal center B-cell (GCB)-like DLBCL with full-length FOXP1 protein expression versus activated B-cell (ABC)-like DLBCL expressing predominantly short FOXP1 isoforms. In an independent primary DLBCL microarray data set, multiple MHC II genes, including human leukocyte antigen DR alpha chain (HLA-DRA), were inversely correlated with FOXP1 transcript expression (P

Contains fulltext : 171662.pdf (Publisher’s version ) (Open Access) Antibodies are widely exploited as research/diagnostic tools and therapeutics. Despite providing exciting research opportunities, the multitude of available antibodies also offers a bewildering array of choice. Importantly, not all companies comply with the highest standards, and thus many reagents fail basic validation tests. The responsibility for antibodies being fit for purpose rests, surprisingly, with their user. This paper condenses the extensive experience of the European Monoclonal Antibody Network to help researchers identify antibodies specific for their target antigen. A stepwise strategy is provided for prioritising antibodies and making informed decisions regarding further essential validation requirements. Web-based antibody validation guides provide practical approaches for testing antibody activity and specificity. We aim to enable researchers with little or no prior experience of antibody characterization to understand how to determine the suitability of their antibody for its intended purpose, enabling both time and cost effective generation of high quality antibody-based data fit for publication.