Citations

Context.— Distinguishing between renal oncocytic tumors, such as renal oncocytoma (RO), and a subset of tumors with overlapping characteristics, including the recently identified low-grade oncocytic tumor (LOT), can present a diagnostic challenge for pathologists owing to shared histopathologic features. Objective.— To develop an automatic computational classifier for stratifying whole slide images of biopsy and resection specimens into 2 distinct groups: RO and LOT. Design.— A total of 269 whole slide images from 125 cases across 6 institutions were collected. A weakly supervised attention-based multiple-instance–learning deep learning (DL) model was trained and initially evaluated through 5-fold cross validation with case-level stratification, followed by validation using an independent holdout data set. Quantitative performance evaluation was based on accuracy and the area under the receiver operating characteristic curve (AUC). Results.— The developed model data set yielded generalizable performance, with a 5-fold average testing accuracy of 84% (AUC = 0.78), and a closely aligning accuracy of 83% (AUC = 0.92) on the independent holdout data set. Conclusions.— The proposed artificial intelligence approach contributes toward a comprehensive solution for addressing commonly encountered renal oncocytic neoplasms, encompassing well-established entities like RO along with the challenging “gray zone” LOT, thereby proving applicable in clinical practice.

Multiple cell death and inflammatory signaling pathways converge on two critical factors: receptor-interacting serine/threonine kinase 1 (RIPK1) and caspase-8. Careful regulation of these molecules is critical to control apoptosis, pyroptosis, and inflammation. Here, we found a pivotal role of Raver1 as an essential regulator of Ripk1 pre-mRNA splicing, expression, and functionality and the subsequent caspase-8-dependent inflammatory cell death. We show that Raver1 influences mRNA diversity primarily by repressing alternative exon inclusion. Macrophages from Raver1 -deficient mice exhibit altered splicing of Ripk1 . As a result, Raver1 -deficient primary macrophages display diminished cell death and decreased interleukin-18 and interleukin-1ß production, when infected with Yersinia bacteria, or by restraining TGF-ß-activated kinase 1 or IKKβ in the presence of lipopolysaccharide, tumor necrosis factor family members, or interferon-γ. These responses are accompanied by reduced activation of caspase-8, Gasdermin D and E, and caspase-1 in the absence of Raver1 . Consequently, Raver1 -deficient mice showed heightened susceptibility to Yersinia infection. Raver1 and RIPK1 also controlled the expression and function of the C-type lectin receptor Mincle. Our study underscores the critical regulatory role of Raver1 in modulating innate immune responses and highlights its significance in directing in vivo and in vitro inflammatory processes.

BACKGROUND: Although most transplant centers preferentially offer minimally invasive approaches to donor nephrectomies, there remains less standardization specific to the kidney extraction site. This study aimed to evaluate incisional hernia occurrence in living kidney donors based on kidney extraction site location. STUDY DESIGN: This was a retrospective study of all donors who underwent minimally invasive living donor nephrectomies at the Mayo Clinic Arizona between 2011 and 2023 with a 2-year external validation cohort from Mayo Clinic Florida and Mayo Clinic Minnesota. The cohort was divided into 2 groups based on the kidney extraction site type: midline infraumbilical and Pfannenstiel. RESULTS: In the primary cohort, incisional hernia occurrence was observed in 1.2% of donors with an infraumbilical midline kidney extraction site compared with 0.1% with a Pfannenstiel extraction site (p = 0.04). Donors with an infraumbilical midline kidney extraction site were more likely to be men (50.8% vs 23.3%, p < 0.0001), have a higher BMI (mean 27.2 vs 26 kg/m2, p < 0.0001), and have current or former tobacco use (p = 0.002). There were no differences in incisional hernia occurrence when comparing minimally invasive surgical techniques (p = 0.52). In the external validation cohort, hernia occurrence was observed in 4.5% of donors with a midline incision compared with 0.0% with a Pfannenstiel incision (p = 0.09). Using combined data from the 3 sites, the use of a Pfannenstiel incision as the extraction site was associated with significantly lower odds of developing a hernia compared with the infraumbilical midline incision (odds ratio 0.06, 95% CI 0.008 to 0.456). CONCLUSIONS: Although the risk of hernia in living kidney donors is generally low, the use of a Pfannenstiel incision for kidney extraction appears to offer an additional incremental reduction in risk.

OBJECTIVE Sepsis is associated with significant morbidity and mortality in pediatric hematology, oncology, and transplant (PHOT) patients. This study characterized PHOT patients who developed hospital-onset sepsis more than 12 hours after admission and identified risk factors for 30-day sepsis-attributable (SA) mortality. PATIENTS AND METHODS We analyzed an existing multicenter database of sepsis collected prospectively over 5 years (2017–2021) as part of the Improving Pediatric Sepsis Outcomes Collaborative. Sepsis was defined using operational elements documented in the health records based on International Classification of Diseases, Tenth Revision codes, treatment, diagnostic tests, and sepsis screen, huddle, or order set use. RESULTS A total of 9604 sepsis episodes in PHOT patients from 49 hospitals were analyzed: 70.5% were identified in the emergency department (ED), 10.9% in inpatient settings less than or equal to 12 hours from admission, and 18.6% were hospital onset. Only 52.5% of patients with hospital-onset sepsis were identified using a sepsis recognition method compared with 87.2% in the ED (P &lt; .001). The overall 30-day SA mortality was 2.2%, with a higher rate (6.9%) among those with hospital-onset sepsis compared with those who developed sepsis at presentation or less than or equal to 12 hours (1.1%, P &lt; .001). CONCLUSIONS Although the difference in SA mortality between hospitalized and nonhospitalized patients may be impacted by nonmeasurable confounders inherent to the type of patients presenting in the different care settings, we reported system-based improvements that may reduce mortality. The 30-day SA mortality was lower in hospitalized PHOT patients when sepsis was detected by early recognition methods, supporting the need for efforts to implement sepsis recognition tools in the inpatient setting.

BACKGROUND AND OBJECTIVES: Aggressive resection for primary tumors of the spine are associated with a high rate of adverse events (AEs), but the impact of AEs on patient-reported outcomes (PROs) remains unknown and is critical to the shared decision-making. Our primary objective was to assess the impact of surgical AEs on PROs using an international registry. Assessing the impact on clinical outcomes and identifying risk factors for AEs were our secondary objectives. METHODS: Patients who underwent surgery for a primary spinal tumor were selected through the Primary Tumor Research and Outcomes Network. Our primary outcome was the impact of AEs on PROs at 3 and 12 months after surgery (measured with Spinal Oncology Study Group Outcomes Questionnaire, Short-Form 36, and EuroQol 5 Dimension). We also assessed the impact on clinical outcomes (local control, surgical margins, readmission, reoperation, and mortality). We stratified our results according to severity of AEs, histology, and type of resection. RESULTS: 374 patients met inclusion criteria (219 males/155 females). The mean age of the cohort was 48.7 years. The most frequent histology was chordoma (37.3%) followed by chondrosarcoma (8.8%). Sixty-seven patients (17.9%) experienced at least 1 intraoperative AE and 117 patients (31.3%) had at least 1 postoperative AE within 3 months. Overall, 159 patients (42.5%) experienced AEs. The readmission rate was significantly higher in patients who experienced AEs (Any AE: 10.1% vs no AE: 1.9% within 3 months; P = <0.001). PROs were not significantly affected by AEs in most questionnaires. Local control, risk of reoperation, mortality, and achieving preplanned margins were similar between AE groups. CONCLUSION: The rate of surgical AEs is considerable in this population. Surgical AEs seem to be associated with a higher number of readmissions, but do not seem to result in significant differences in PROs or in a higher risk of reoperation, mortality, and failure to achieve preplanned margins.

Abstract We present a comprehensive global analysis of genetic variants associated with autosomal-dominant Alzheimer’s disease (ADAD). A total of 550 variants in the APP, PSEN1 and PSEN2 genes were identified, of which 279 were classified as pathogenic or likely pathogenic based on American College of Medical Genetics and Genomics and the Association for Molecular Pathology criteria, utilizing data from the Dominantly Inherited Alzheimer Network (DIAN), literature and public databases. Symptomatic age at onset (AAO) data were estimated for 227 of these variants, allowing detailed characterization of their frequency, pathogenicity and AAO. Importantly, 226 variants met eligibility criteria for inclusion in disease-modifying clinical trials. Furthermore, we demonstrated the predictive value of mean variant AAO and parental AAO in predicting symptomatic AAO, validated against converters who became symptomatic during follow-up in the DIAN Observational Study. This dataset provides critical insights into the global landscape of ADAD and reveals the genetic and AAO heterogeneity of ADAD variants while refining variant trial eligibility criteria.

ObjectiveThe objective was to determine the mortality rate as well as the causes and predictors of death in antiphospholipid antibody (aPL)–positive patients with and without antiphospholipid syndrome (APS) classification.MethodsThe inclusion criterion for the multicenter international Antiphospholipid Syndrome Alliance for Clinical Trials and International Networking (APS ACTION) registry is positive aPLs according to the Revised Sapporo Classification Criteria tested within one year before enrollment. Patients are observed every 12 ± 3 months with clinical data and blood collection. For this prospective analysis, we first analyzed the causes of death for patients reported as “deceased.” Secondly, we analyzed risk factors for death using the adjusted Cox proportional hazards model and calculated survival probability using the Kaplan‐Meier model based on different age groups.ResultsOf 967 patients, 43 (5%) were deceased after a median follow‐up of 5.3 years. Based on the univariate analysis, deceased patients, compared to living patients, were more likely to be older and have a history of arterial thrombosis, catastrophic APS, concomitant systemic autoimmune diseases (SAIDs), and baseline cardiovascular disease (CVD) risk factors. Based on the Cox proportional hazards model adjusted for age and for each of the strongest predictors of death, arterial thrombosis (hazard ratio [HR] 2.94, 95% confidence interval [CI] 1.50–5.76), concomitant SAIDs (HR 2.97, 95% 1.56–5.63), and baseline any CVD risk factor (HR 2.43, 95% CI 1.05–5.71) were significantly associated with mortality.ConclusionIn our cohort of persistently aPL‐positive patients, the mortality rate was 5% after a median follow‐up of five years and was highest for patients ≥60 years old at registry entry. History of arterial thrombosis, concomitant SAIDs, and baseline any CVD risk factor independently predicted future death.

Introduction: Cerebral Amyloid Angiopathy (CAA) is caused by the progressive deposition of β-amyloid in the walls of small to medium-sized cerebral vessels. Although seizures represent a debilitating manifestation of CAA, little is known about their prevalence or associated factors. We aim to fill this gap by determining the prevalence of seizures in CAA and identify factors associated with an increased risk of seizures. Methods: We identified consecutive patients with CAA, evaluated within the Mayo Clinic health system between January 2010 and December 2023 using the ICD-10 code. Data on demographics and comorbidities were compared between those with and without seizures using the chi-square test for categorical variables and independent samples t-test for continuous variables. Odds ratios (OR) were estimated after adjusting for age, sex, and race in multivariable logistic regression. Results: We included 1,914 patients with CAA with a mean age of 75.4 ± 8.6 years, of whom 52.3% were female and 87.5% were white. Seizures were observed in 347 patients (18.1%). Individuals with seizures were significantly younger (mean age 67.7 ± 9.1 vs. 77.2 ± 7.5 years, p < 0.001). Multivariable modeling identified alcohol abuse (OR 1.92, 95% CI 1.03-3.56, p=0.04), diabetes mellitus (OR 2.14, 95% CI 1.13-4.06, p=0.02), hypertension (OR 1.79, 95% CI 1.33 - 2.41, p= <0.001), liver disease (OR 1.75, 95% CI 1.14-2.69, p=0.01), and ischemic stroke (OR 1.33, 95% CI 1.01-1.74, p=0.04) as independently associated with an increased risk of seizures. Conclusion: We found that seizures affect nearly one in five patients with CAA. Also, comorbidities such as alcohol abuse, diabetes mellitus, hypertension, liver disease, and ischemic stroke were found to be significantly associated with an increased risk of seizures. Longitudinal studies are warranted to confirm these risk factors, some of which may be modifiable.