A web-based tool for real-time adequacy assessment of kidney biopsies.

The escalating incidence of kidney biopsies providing insufficient tissue for diagnosis poses a dual challenge, straining the healthcare system and jeopardizing patients who may require rebiopsy or face the prospect of an inaccurate diagnosis due to an unsampled disease. Here, we introduce a web-based tool that can provide real-time, quantitative assessment of kidney biopsy adequacy directly from photographs taken with a smartphone camera. The software tool was developed using a deep learning-driven automated segmentation technique, trained on a dataset comprising nephropathologist-confirmed annotations of the kidney cortex on digital biopsy images. Our framework demonstrated favorable performance in segmenting the cortex via 5-fold cross-validation (Dice coefficient: 0.788±0.130) (n=100). Offering a bedside tool for kidney biopsy adequacy assessment has the potential to provide real-time guidance to the physicians performing medical kidney biopsies, reducing the necessity for re-biopsies. Our tool can be accessed through our web-based platform: http://www.biopsyadequacy.org.

Non-insulinoma pancreatogenous hypoglycemia syndrome due to nesidioblastosis following bariatric Roux-en-Y gastric bypass.

A 56-year-old woman with past medical history significant for bariatric Roux-en-Y gastric bypass 3 years prior presented for evaluation of an 8-month history of severe hypoglycemia relieved by intake of carbohydrates associated with syncopal episodes. Inpatient workup revealed endogenous hyperinsulinemia concerning for insulinoma vs. nesidioblastosis. She successfully underwent pancreaticoduodenectomy (Whipple procedure), and pathology report confirmed scattered low-grade intraepithelial neoplasia within the pancreatic parenchyma consistent with nesidioblastosis. The patient has had satisfactory control of glucose levels 30 days out from surgery.

Percutaneous Cholecystostomy Tubes versus Medical Management for Acute Cholecystitis.

BACKGROUND: Cholecystitis is one of the most common infections treated surgically in the United States. Surgical risk is prohibitive in some patients, leading to alternative therapeutic strategies, including medical management (antibiotics) with or without percutaneous cholecystostomy tube (PCT) drainage. MATERIALS AND METHODS: Using the Healthcare Cost and Utilization Project (HCUP) National Readmission Database (NRD), we performed a retrospective review to compare medically managed patients with or without PCT placement by evaluating 60-day readmissions rates, health care costs, and hospital length of stay (LOS). Both study groups were matched using the Elixhauser comorbidity index, age, and sex. Univariate and multivariate statistical analyses were performed using STATA. RESULTS: 776,766 patients were included in the analysis. The population receiving PCT placement was on average 16 years older (69.9 vs 53.6 years; P < .01), less likely to be female (40.7% vs 59.3%; P < .01), and had almost twice as many comorbidities (3.36 vs 1.81; P < .01) compared to the population receiving medical management. After matching our data to account for these incongruities, PCT patients were still 10.4 times more likely to be readmitted, had a 11.6% increase in the cost of care, and a 37.6% increase in LOS compared to those managed medically. DISCUSSION: Percutaneous cholecystostomy tube placement for cholecystitis is associated with a higher readmission rate, increased charges, and increased LOS compared to antibiotic therapy alone, even after correcting for age, sex, and comorbidities.

The Impact of Deceased Donor Liver Extraction Time on Early Allograft Function in Adult Liver Transplant Recipients.

BACKGROUND: In liver transplantation, both cold and warm ischemia times are known to impact early graft function. The extraction time is a period during the initial phase of organ cooling which occurs during deceased donor procurement. During this time, the organ is at risk of suboptimal cooling. Whether donor extraction time, the time from donor aortic cross-clamp to removal of the donor organ from the body cavity has an effect on early graft function is not known. METHODS: We investigated the effect of donor extraction time on early graft function in 292 recipients of liver grafts procured locally and transplanted at our center between June 2012 and December 2016. Early graft function was assessed using the model of early allograft function score in a multivariable regression model including donor extraction time, cold ischemia time, warm ischemia time, donor risk index, and terminal donor sodium. RESULTS: Donor extraction time had an independent effect on early graft function measured by the model of early allograft function score (coefficient, 0.021; 95% confidence interval, 0.007-0.035; P < 0.01; for each minute increase of donor extraction time). Besides donor extraction time, cold ischemia time, warm ischemia time, and donor risk index had a significant effect on early graft function. CONCLUSIONS: We demonstrate an independent effect of donor extraction time on graft function after liver transplantation. Efforts to minimize donor extraction time could improve early graft function in liver transplantation.

DNA-PKcs controls calcineurin mediated IL-2 production in T lymphocytes.

Loss of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) activity in mammals results in severe combined immuno-deficiency (SCID). This SCID phenotype has been postulated to be due solely to the function of DNA-PKcs in V(D)J recombination, a process critical for lymphocyte maturation. However; we show that DNA-PKcs is required for IL-2 production via regulation of the calcineurin signaling pathway. Reducing DNA-PKcs activity in activated T cells either by shRNA or an inhibitor significantly reduced IL-2 production by blocking calcineurin activity and the translocation of NFAT into the nucleus. Additionally, we show that DNA-PKcs exerts its effect on calcineurin by altering the expression of the endogenous calcineurin inhibitor Cabin1 through activation of the kinase CHK2, a known Cabin1 regulator. The discovery of DNA-PKcs as a potent regulator of IL-2 production will drive continued investigation of small molecule inhibition of this enzyme within the clinic.

A Formula to Calculate Standard Liver Volume Using Thoracoabdominal Circumference.

BACKGROUND: With the use of split liver grafts as well as living donor liver transplantation (LDLT) it is imperative to know the minimum graft volume to avoid complications. Most current formulas to predict standard liver volume (SLV) rely on weight-based measures that are likely inaccurate in the setting of cirrhosis. Therefore, we sought to create a formula for estimating SLV without weight-based covariates. METHODS: LDLT donors underwent computed tomography scan volumetric evaluation of their livers. An optimal formula for calculating SLV using the anthropomorphic measure thoracoabdominal circumference (TAC) was determined using leave-one-out cross-validation. The ability of this formula to correctly predict liver volume was checked against other existing formulas by analysis of variance. The ability of the formula to predict small grafts in LDLT was evaluated by exact logistic regression. RESULTS: The optimal formula using TAC was determined to be SLV = (TAC × 3.5816) - (Age × 3.9844) - (Sex × 109.7386) - 934.5949. When compared to historic formulas, the current formula was the only one which was not significantly different than computed tomography determined liver volumes when compared by analysis of variance with Dunnett posttest. When evaluating the ability of the formula to predict small for size syndrome, many (10/16) of the formulas tested had significant results by exact logistic regression, with our formula predicting small for size syndrome with an odds ratio of 7.94 (95% confidence interval, 1.23-91.36; P = 0.025). CONCLUSION: We report a formula for calculating SLV that does not rely on weight-based variables that has good ability to predict SLV and identify patients with potentially small grafts.

Proteomic Identification of DNA-PK Involvement within the RET Signaling Pathway.

Constitutive activation of the Rearranged during Transfection (RET) proto-oncogene leads to the development of MEN2A medullary thyroid cancer (MTC). The relatively clear genotype/phenotype relationship seen with RET mutations and the development of MEN2A is unusual in the fact that a single gene activity can drive the progression towards metastatic disease. Despite knowing the oncogene responsible for MEN2A, MTC, like most tumors of neural crest origin, remains largely resistant to chemotherapy. Constitutive activation of RET in a SK-N-MC cell line model reduces cell sensitivity to chemotherapy. In an attempt to identify components of the machinery responsible for the observed RET induced chemoresistance, we performed a proteomic screen of histones and associated proteins in cells with a constitutively active RET signaling pathway. The proteomic approach identified DNA-PKcs, a DNA damage response protein, as a target of the RET signaling pathway. Active DNA-PKcs, which is phosphorylated at site serine 2056 and localized to chromatin, was elevated within our model. Treatment with the RET inhibitor RPI-1 significantly reduced s2056 phosphorylation in RET cells as well as in a human medullary thyroid cancer cell line. Additionally, inhibition of DNA-PKcs activity diminished the chemoresistance observed in both cell lines. Importantly, we show that activated DNA-PKcs is elevated in medullary thyroid tumor samples and that expression correlates with expression of RET in thyroid tumors. These results highlight one mechanism by which RET signaling likely primes cells for rapid response to DNA damage and suggests DNA-PKcs as an additional target in MTC.