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O'Connell, P.

Publications and source records attributed to O'Connell, P..

2 recordsLinked to original sources

Deep-learning Based Pathological Assessment of Frozen Procurement Kidney Biopsies Predicts Graft Loss and Guides Organ Utilization: A Large-scale Retrospective Study

BackgroundLesion scores on procurement donor biopsies are commonly used to guide organ utilization. However, frozen sections present challenges for histological scoring, leading to inter- and intra-observer variability and inappropriate discard. MethodsWe constructed deep-learning based models to recognize kidney tissue compartments in H&E stained sections from procurement biopsies performed at 583 hospitals nationwide in year 2011-2020. The models were trained and tested respectively on 11473 and 3986 images sliced from 100 slides. We then extracted whole-slide abnormality features from 2431 kidneys, and correlated with pathologists scores and transplant outcomes. Finally, a Kidney Donor Quality Score (KDQS) incorporating digital features and the Kidney Donor Profile Index (KDPI) was derived and used in combination with recipient demographic and peri-transplant characteristics to predict graft loss or assist organ utilization. ResultsOur model accurately identified 96% and 91% of normal/sclerotic glomeruli respectively; 94% of arteries/arterial intimal fibrosis regions; 90% of tubules. Three whole-slide features (Sclerotic Glomeruli%, Arterial Intimal Fibrosis%, and Interstitial Fibrosis%) demonstrated strong correlations with corresponding pathologists scores (n=2431), but had superior associations with post-transplant eGFR (n=2033) and graft loss (n=1560). The combination of KDQS and other factors predicted 1- and 4-year graft loss (discovery: n=520, validation: n=1040). Finally, by matching 398 discarded kidneys due to "biopsy findings" to transplanted population, the matched transplants from discarded KDQS<4 group (110/398, 27.6%) showed similar graft survival rate to unmatched transplanted kidneys (2-, 5-year survival rate: 97%, 86%). KDQS [&ge;] 7 (37/398, 9.3%) and 1-year survival model score [&ge;] 0.55 were determined to identify possible discards (PPV=0.92). ConclusionThis deep-learning based approach provides automatic and reliable pathological assessment of procurement kidney biopsies, which could facilitate graft loss risk stratification and organ utilization. Translational StatementThis deep-learning based approach provides rapid but more objective, sensitive and reliable assessment of deceased-donor kidneys before transplantation, and improves the prognostic value of procurement biopsies, thus could potentially reduce inappropriate discard and stratify patients needing monitoring or preventative measures after transplantation. The pipeline can be integrated into various types of scanners and conveniently generates report after slide scanning. Such report can be used in conjunction with pathologists report or independently for centers lacking renal pathologists.

bioinformatics↗

Novel metabolic role for CD47 in pancreatic β-cell insulin secretion and islet transplant outcomes

Diabetes is a global public health burden and is characterized clinically by a relative or absolute insulin deficiency. Therapeutic agents that stimulate and improve insulin secretion and insulin sensitivity are in high demand as diabetic treatment. CD47 is a cell surface glycoprotein implicated in multiple cellular functions, including recognition of self, angiogenesis, and nitric oxide signaling, however its role in the regulation of insulin secretion remains unknown. For the first time we demonstrate that CD47 receptor signaling inhibits insulin release from {beta}-cells and that it can be pharmacologically exploited to boost insulin secretion. CD47 depletion stimulates insulin granule exocytosis via activation of the Rho GTPase Cdc42. CD47 deficiency improved glucose clearance and insulin sensitivity in mice. CD47 blockade enhanced islet transplantation efficiency and improved outcomes. Further, anti-CD47 antibody treatment delayed the onset of diabetes in non-obese diabetic mice and protected them from overt diabetes. Our findings identify CD47 as a previously unrecognized regulator of insulin secretion and its manipulation in {beta}-cells offers a novel therapeutic opportunity for diabetes and islet transplantation by correcting insulin deficiency. One Sentence SummaryCD47 limits insulin secretion and islet transplant outcomes

physiology↗