Cardiorespiratory Optimisation By Arteriovenous fistula Ligation after renal Transplantation (COBALT): study protocol for a multicentre randomised interventional feasibility trial.

INTRODUCTION: Cardiovascular events are a major cause of mortality following successful kidney transplantation.Arteriovenous fistulas (AVFs) are considered the best option for haemodialysis, but may contribute to this excess mortality because they promote adverse cardiac remodelling and ventricular hypertrophy. This raises the question whether recipients with a well-functioning kidney transplant should undergo elective AVF ligation. METHODS AND ANALYSIS: The COBALT feasibility study is a multicentre interventional randomised controlled trial (RCT) that will randomise renal transplant patients with stable graft function and a working AVF on a 1:1 basis to standard care (continued conservative management) or to AVF ligation. All patients will perform cardiopulmonary exercise testing (CPET) on recruitment and 6 months later. Daily functioning and quality of life will be additionally assessed by questionnaire completion and objective measure of physical activity. The primary outcome-the proportion of approached patients who complete the study (incorporating rates of consent, receipt of allocated intervention and completion of both CPETs without withdrawal)-will determine progression to a full-scale RCT. Design of the proposed RCT will be informed by an embedded qualitative assessment of participant and healthcare professional involvement. ETHICS AND DISSEMINATION: This study has been approved by the East Midlands-Derby Research Ethics Committee (22/EM/0002) and the Health Research Authority. The results of this work will be disseminated academically through presentation at national and international renal meetings and via open access, peer-reviewed outputs. Existing networks of renal patient groups will also be used to disseminate the study findings to other key stakeholders. TRIAL REGISTRATION NUMBER: ISRCTN49033491.

T cell Allorecognition Pathways in Solid Organ Transplantation.

Transplantation is unusual in that T cells can recognize alloantigen by at least two distinct pathways: as intact MHC alloantigen on the surface of donor cells via the direct pathway; and as self-restricted processed alloantigen via the indirect pathway. Direct pathway responses are viewed as strong but short-lived and hence responsible for acute rejection, whereas indirect pathway responses are typically thought to be much longer lasting and mediate the progression of chronic rejection. However, this is based on surprisingly scant experimental evidence, and the recent demonstration that MHC alloantigen can be re-presented intact on recipient dendritic cells-the semi-direct pathway-suggests that the conventional view may be an oversimplification. We review recent advances in our understanding of how the different T cell allorecognition pathways are triggered, consider how this generates effector alloantibody and cytotoxic CD8 T cell alloresponses and assess how these responses contribute to early and late allograft rejection. We further discuss how this knowledge may inform development of cellular and pharmacological therapies that aim to improve transplant outcomes, with focus on the use of induced regulatory T cells with indirect allospecificity and on the development of immunometabolic strategies. KEY POINTS Acute allograft rejection is likely mediated by indirect and direct pathway CD4 T cell alloresponses.Chronic allograft rejection is largely mediated by indirect pathway CD4 T cell responses. Direct pathway recognition of cross-dressed endothelial derived MHC class II alloantigen may also contribute to chronic rejection, but the extent of this contribution is unknown.Late indirect pathway CD4 T cell responses will be composed of heterogeneous populations of allopeptide specific T helper cell subsets that recognize different alloantigens and are at various stages of effector and memory differentiation.Knowledge of the precise indirect pathway CD4 T cell responses active at late time points in a particular individual will likely inform the development of alloantigen-specific cellular therapies and will guide immunometabolic modulation.

Evaluation of surgical approaches to anatomical segmentectomies: the transition to minimal invasive surgery improves hospital outcomes.

BACKGROUND: We aim to evaluate the transition process from open to video-assisted thoracoscopic surgery (VATS) anatomical segmentectomies in a regional thoracic surgical unit. METHODS: In a retrospective study from January 2013 to December 2015, we identified all anatomical segmentectomies performed in our unit. Pre, peri and postoperative data were compared between the three years (2013, 2014 and 2015) and according to operative approach. Thoracotomy after VATS intraoperative biopsy was considered a conversion for the purposes of the study. RESULTS: A total of 86 consecutive cases [56 females and 30 males, median age 70 years (range, 43 to 83 years); median FEV1 of 78% predicted (range, 41% to 126%)] were included. There was a significant change in the surgical approach with time. Fifty-two cases underwent VATS (73% via single-port) and 34 open surgeries, including nine conversions. There were no postoperative deaths in the VATS group and one in the open group. Operative outcomes were similar over time with no haemorrhagic events, equivalent R1 resection and nodal stations explored in all lymph node positive patients. In node negative cases however, open surgery was associated with more extensive mediastinal exploration. Patients in 2015 had a shorter hospital stay in comparison to those in previous years [median 4 days (range, 1-15 days) vs. median 6 days (range, 3-27 days), P=0.01]. There were no differences in the incidence of complications or readmissions to hospital over time. CONCLUSIONS: The transition over a short period of time from open to single-port VATS segmentectomy has allowed us to significantly reduce postoperative hospital stay without compromising operative or postoperative outcomes.

Low rates of neurocognitive impairment are observed in neuro-asymptomatic HIV-infected subjects on effective antiretroviral therapy.

BACKGROUND: Few studies investigating the rate of neurocognitive (NC) impairment in effectively treated neuro-asymptomatic HIV-infected subjects have been performed. METHODS: We assessed NC function via a computerized cognitive test in HIV-infected subjects on stable combination antiretroviral therapy (cART) with plasma HIV RNA<50 copies/mL for at least 3 months. Neurologically symptomatic subjects were excluded. Current cART was evaluated for drug class (protease inhibitor [PI]- vs non-nucleoside reverse transcriptase inhibitor [NNRTI]-based) and Clinical Penetration Effectiveness (CPE) score. NC impairment was defined as a NC domain score>1 SD below mean age-matched population scores in at least 2 cognitive domains and global NC composite z-score calculated. Associations between NC scores and clinical parameters were evaluated using linear regression. RESULTS: 101 (88% male) subjects participated. Median (IQR) age was 53 (43-62) years, with current CD4+ 525 (373-710) and nadir CD4+ 185 (83-260) cells/µL. 25 subjects (25%) had chronic hepatitis C. Median (IQR) CPE score was 1.5 (1.5-2.5), and 53% were receiving NNRTI-based cART. Overall 19 (19%) subjects had NC impairment. No association between presence of NC impairment and clinical parameters were observed (P>.14, all values). Poorer global NC composite z-score was independently associated with lower nadir CD4+ lymphocyte count (P=.04) and older age (P<.001) but not other study parameters (P>.10 all values). CONCLUSION: In neuro-asymptomatic HIV-infected adults on stable cART, rates of NC impairment are low. HIV disease status (lower nadir CD4+ count) and older age, but not CPE score or cART drug class, are associated with poorer NC performance.

Epidermal growth factor receptor status in early stage breast cancer is associated with cellular proliferation but not cross-talk.

The epidermal growth factor receptor (EGFR) is a therapeutic target in a number of settings in solid malignancies, but its role in breast cancer has remained unclear and controversial. In 810 primary breast cancers derived from patients suitable for cytotoxic chemotherapy, EGFR was prospectively measured and interactions with tumour and clinical correlates were tested to observe whether postulated cross-talk mechanisms are likely to modulate breast cancer metastasis and proliferation. A minority (79 tumours, 9.8%) were EGFR positive; in a multivariate analysis the likelihood of being EGFR positive was significantly increased for patients with grade 3 disease, compared with grade 1 (OR 15.6; 95% CI 2 to 122, p=0.0001), and for oestrogen receptor-negative status compared with positive (OR 24.1; 95% CI 12.7 to 46.00, p=0.0001). EGFR expression may play a role in breast cancer proliferation, but appears unlikely to modify tumour pathology via postulated mechanisms of oestrogen receptor/EGFR-mediated cross-talk.