Citations

The scarcity of liver grafts has prompted developments in living donor liver transplantations (LDLT), with previous literature illustrating similar outcomes in recipients compared to deceased donor transplants. However, significant concerns regarding living donor morbidity and mortality have yet to be examined comprehensively. This study aims to provide estimates of the incidence of various outcomes in living liver donors. In this meta-analysis, Medline and Embase were searched from inception to July 2022 for articles assessing the incidence of outcomes in LDLT donors. Complications in the included studies were classified into respective organ systems. Analysis of incidence was conducted using a generalized linear mixed model with Clopper-Pearson intervals. Eighty-seven articles involving 60,829 living liver donors were included. The overall pooled incidence of complications in LDLT donors was 24.7% (CI: 21.6%–28.1%). The incidence of minor complications was 17.3% (CI: 14.7%–20.3%), while the incidence of major complications was lower at 5.5% (CI: 4.5%–6.7%). The overall incidence of donor mortality was 0.06% (CI: 0.0%–0.1%) in 49,027 individuals. Psychological complications (7.6%, CI: 4.9%–11.5%) were the most common among LDLT donors, followed by wound-related (5.2%, CI: 4.4%–6.2%) and respiratory complications (4.9%, CI: 3.8%–6.3%). Conversely, cardiovascular complications had the lowest incidence among the subgroups at 0.8% (CI: 0.4%–1.3%). This study presents the incidence of post-LDLT outcomes in living liver donors, illustrating significant psychological, wound-related, and respiratory complications. While significant advancements in recent decades have contributed towards decreased morbidity in living donors, our findings call for targeted measures and continued efforts to ensure the safety and quality of life of liver donors post-LDLT.

Abstract There is emerging evidence that the cardiac interatrial septum has an important role as a thromboembolic source for ischemic strokes. There is little consensus on treatment of patients with different cardiac interatrial morphologies or pathologies who have had stroke. In this paper, we summarize the important background, diagnostic, and treatment considerations for this patient population as presented during the Federation of American Societies for Experimental Biology (FASEB) Virtual Catalytic Conference on the Cardiac Interatrial Septum and Stroke Risk, held on December 7, 2022. During this conference, many aspects of the cardiac interatrial septum were discussed. Among these were the embryogenesis of the interatrial septum and development of anatomic variants such as patent foramen ovale and left atrial septal pouch. Also addressed were various mechanisms of injury such as shunting physiologies and the consequences that can result from anatomic variants, as well as imaging considerations in echocardiography, computed tomography, and magnetic resonance imaging. Treatment options including anticoagulation and closure were addressed, as well as an in‐depth discussion on whether the left atrial septal pouch is a stroke risk factor. These issues were discussed and debated by multiple experts from neurology, cardiology, and radiology.

Abstract Importance Chronic kidney disease (CKD) is a genetically complex disease determined by an interplay of monogenic, polygenic, and environmental risks. The most common forms of monogenic kidney disorders include autosomal dominant polycystic kidney disease (ADPKD), caused by mutations in the PKD1 or PKD2 genes, and COL4A-associated nephropathy (COL4A-AN), caused by mutations in COL4A3, COL4A4, or COL4A5 genes. These disorders have incomplete penetrance and variable expressivity. It is presently unknown if some of the variability in penetrance can be attributed to polygenic factors. Objective Our objectives were to investigate the interplay of polygenic and monogenic risk of kidney disease and to test the utility of polygenic risk scores for risk stratification in ADPKD and COL4-AN. Design We combined exome/genome sequencing, SNP micro-array, and electronic health record data from the UK Biobank (N = 469,835 participants) and the All of Us (N = 98,622 participants) datasets to test the effects of the genome-wide polygenic score (GPS) for CKD in ADPKD and COL4-AN variant carriers defined by strict variant classification criteria. We used the eMERGE-III electronic CKD phenotype to define cases (estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m2 or kidney failure) and controls (eGFR > 90 mL/min/1.73m2 in the absence of kidney disease diagnoses). The GPS was tested as a predictor of CKD in qualifying variant carriers and non-carriers using logistic regression after adjustment for age, sex, diabetes, and genetic ancestry. Results The GPS was predictive of CKD in ADPKD variant carriers (ORmeta=2.28 per SD, 95%CI: 1.55–3.37, P = 2.6E-05) as well as non-carriers (ORmeta=1.72 per SD, 95% CI = 1.69–1.76, P < E-300) independent of age, sex, diabetes, and genetic ancestry. Compared to the middle tertile of the GPS distribution for non-carriers, ADPKD variant carriers in the top tertile had a 54-fold increased risk of CKD, while ADPKD variant carriers in the bottom tertile had only a 3-fold increased risk of CKD. Similarly, the GPS was predictive of CKD in both COL4-AN carriers (ORmeta=1.78, 95% CI = 1.22–2.58, P = 2.38E-03) and non-carriers (ORmeta=1.70, 95%CI: 1.68–1.73 P < E-300). The carriers in the top GPS tertile had a 2.5-fold higher risk of CKD while the risk for carriers in the bottom GPS tertile was not different from the average population risk. Conclusions and Relevance Variable penetrance of kidney disease in ADPKD and COL4-AN is partially explained by the differences in polygenic risk profiles. Accounting for polygenic factors improves risk stratification in monogenic kidney disease and may have clinical implications for genetic counseling.

4541 Background: PROSPER is a phase 3 National Clinical Trials Network study that accrued pts with clinical stage ≥T2 or TanyN+ RCC of any histology planned for radical/ partial nephrectomy. Pts were randomized to perioperative nivo followed by primary tumor resection and 9 cycles of nivo postoperatively or standard surgery followed by observation. To address concerns that core kidney bx might 1) not provide accurate diagnosis and 2) delay surgery due to adverse events (AEs) or scheduling, the study was amended from requiring all patients to undergo core bx prior to treatment for confirmation of RCC, to only require bx in patients randomized to the nivo arm. Herein, we report the accuracy and safety of primary tumor core bxs in predicting final histology and nuclear grade by both site and central pathology review as well as time from enrollment to surgery. We also report AEs of preoperative nivo. Methods: Concordance of both core bx and primary tumor by site and central pathology review of histology and grade (1-2 vs 3-4) are reported, along with the Cohen’s Kappa value, which measures the agreement and concordance (kappa=0 is no concordance and 1 is highest). AEs relating to core bxs and preoperative nivo, as well as time from enrollment to surgery for each arm, comparing pre- and post-amendment (dropping bx requirement in surgery alone arm) are also reported. Results: 387/404 pts in the nivo arm and 171/415 pts in the surgery alone arm had core bxs. 632 patients had both central pathology and site review available. 41 of all randomized patients (819) were considered as non-RCC and 26/41 were identified via bx. The median times from enrollment to surgery for nivo and control arms pre-amendment were 32d vs 19 d, and post-amendment were 21 d vs 14 d, respectively. The median (25th-75th percentile) number of days from last preoperative nivo to surgery was 14 d (9-20). AEs related to core bx, generally from bleeding, were reported in 13/558 (2.3%) pts. 2/13 bxs resulted in life-threatening complications. 21/353 (6%) of pts receiving nivo pre-surgery had ≥ grade 3-5 AE attributed to nivo. 181/353 (51%) pts had any grade AE attributed to nivo. Concordance between bxs and primary tumor pathologies for determining histological subtype was Kappa = 0.62. Agreement between central pathology and originating site review of primary tumor for determining nuclear grade was Kappa = 0.56, and concordance of histology was Kappa = 0.78. Conclusions: The PROSPER trial use of core bxs in advance of neoadjuvant therapy was generally safe, largely consistent with primary tumor histology and grade, and did not delay resection of the primary tumor. AEs of preoperative nivo were consistent with nivo AEs in metastatic disease. This approach is valid for future neoadjuvant trials. Clinical trial information: NCT03055013 .

Background: The role of minute ventilation/carbon dioxide production ( / CO2) slope, a ventilation efficiency marker, in predicting short-term and long-term health outcomes for patients with nonsmall-cell lung cancer (NSCLC) undergoing lung resection has not been well investigated. Material and Methods: This prospective cohort study consecutively enrolled NSCLC patients who underwent a presurgical cardiopulmonary exercise test from November 2014 to December 2019. The association of / CO2 slope with relapse-free survival (RFS), overall survival (OS), and perioperative mortality was evaluated using the Cox proportional hazards and logistic models. Covariates were adjusted using propensity score overlap weighting. The optimal cut-off point of the E/ CO2 slope was estimated using the receiver operating characteristics curve. Internal validation was completed through bootstrap resampling. Results: A cohort of 895 patients [median age (interquartile range), 59 (13) years; 62.5% male] was followed for a median of 40 (range, 1–85) months. Throughout the study, there were 247 relapses or deaths and 156 perioperative complications. The incidence rates per 1000 person-years for relapses or deaths were 108.8 and 79.6 among patients with high and low E/ CO2 slopes, respectively [weighted incidence rate difference per 1000 person-years, 29.21 (95% CI, 7.30–51.12)]. A E/ CO2 slope of greater than or equal to 31 was associated with shorter RFS [hazard ratio for relapse or death, 1.38 (95% CI, 1.02–1.88), P=0.04] and poorer OS [hazard ratio for death, 1.69 (1.15–2.48), P=0.02] compared to a lower / CO2 slope. A high E/ CO2 slope increased the risk of perioperative morbidity compared with a low E/ CO2 slope [odds ratio, 2.32 (1.54–3.49), P<0.001]. Conclusions: In patients with operable NSCLC, a high E/ CO2 slope was significantly associated with elevated risks of poorer RFS, OS, and perioperative morbidity.

INTRODUCTION: Intrahepatic cholangiocarcinoma (iCCA) is a primary liver malignancy with poor prognosis. Current prognostic methods are most accurate for patients with surgically resectable disease. However, a significant proportion of patients with iCCA are not surgical candidates. We aimed to develop a generalizable staging system based on clinical variables to determine prognosis of all patients with iCCA. METHODS: The derivation cohort included 436 patients with iCCA seen between 2000 and 2011. For external validation, 249 patients with iCCA seen from 2000 to 2014 were enrolled. Survival analysis was performed to identify prognostic predictors. All-cause mortality was the primary end point. RESULTS: Eastern Cooperative Oncology Group status, tumor number, tumor size, metastasis, albumin, and carbohydrate antigen 19-9 were incorporated into a 4-stage algorithm. Kaplan-Meier estimates for 1-year survival were 87.1% (95% confidence interval [CI] 76.1–99.7), 72.7% (95% CI 63.4–83.4), 48.0% (95% CI 41.2–56.0), and 16% (95% CI 11–23.5), respectively, for stages I, II, III, and IV. Univariate analysis yielded significant differences in risk of death for stages II (hazard ratio [HR] 1.71; 95% CI 1.0–2.8), III (HR 3.32; 95% CI 2.07–5.31), and IV (HR 7.44; 95% CI 4.61–12.01) compared with stage I (reference). Concordance indices showed the new staging system was superior to the TNM staging for predicting mortality in the derivation cohort, P < 0.0001. In the validation cohort, however, the difference between the 2 staging systems was not significant. DISCUSSION: The proposed independently validated staging system uses nonhistopathologic data to successfully stratify patients into 4 stages. This staging system has better prognostic accuracy compared with the TNM staging and can assist physicians and patients in treatment of iCCA.

AbstractObjectiveThe aim of this study was to analyze a publicly available sample of rule-based phenotype definitions to characterize and evaluate the variability of logical constructs used.Materials and MethodsA sample of 33 preexisting phenotype definitions used in research that are represented using Fast Healthcare Interoperability Resources and Clinical Quality Language (CQL) was analyzed using automated analysis of the computable representation of the CQL libraries.ResultsMost of the phenotype definitions include narrative descriptions and flowcharts, while few provide pseudocode or executable artifacts. Most use 4 or fewer medical terminologies. The number of codes used ranges from 5 to 6865, and value sets from 1 to 19. We found that the most common expressions used were literal, data, and logical expressions. Aggregate and arithmetic expressions are the least common. Expression depth ranges from 4 to 27.DiscussionDespite the range of conditions, we found that all of the phenotype definitions consisted of logical criteria, representing both clinical and operational logic, and tabular data, consisting of codes from standard terminologies and keywords for natural language processing. The total number and variety of expressions are low, which may be to simplify implementation, or authors may limit complexity due to data availability constraints.ConclusionsThe phenotype definitions analyzed show significant variation in specific logical, arithmetic, and other operators but are all composed of the same high-level components, namely tabular data and logical expressions. A standard representation for phenotype definitions should support these formats and be modular to support localization and shared logic.

Lung adenocarcinoma (LUAD) is the most prevalent form of non–small cell lung cancer (NSCLC) and a leading cause of cancer death. Immune checkpoint inhibitors (ICIs) of programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) signaling induce tumor regressions in a subset of LUAD, but many LUAD tumors exhibit resistance to ICI therapy. Here, we identified Prkci as a major determinant of response to ICI in a syngeneic mouse model of oncogenic mutant Kras / Trp53 loss (KP)–driven LUAD. Protein kinase Cι (PKCι)–dependent KP tumors exhibited resistance to anti–PD-1 antibody therapy (α-PD-1), whereas KP tumors in which Prkci was genetically deleted (KPI tumors) were highly responsive. Prkci- dependent resistance to α-PD-1 was characterized by enhanced infiltration of myeloid-derived suppressor cells (MDSCs) and decreased infiltration of CD8 + T cells in response to α-PD-1. Mechanistically, Prkci regulated YAP1-dependent expression of Cxcl5 , which served to attract MDSCs to KP tumors. The PKCι inhibitor auranofin inhibited KP tumor growth and sensitized these tumors to α-PD-1, whereas expression of either Prkci or its downstream effector Cxcl5 in KPI tumors induced intratumoral infiltration of MDSCs and resistance to α-PD-1. PRKCI expression in tumors of patients with LUAD correlated with genomic signatures indicative of high YAP1-mediated transcription, elevated MDSC infiltration and low CD8 + T cell infiltration, and with elevated CXCL5 / 6 expression. Last, PKCι-YAP1 signaling was a biomarker associated with poor response to ICI in patients with LUAD. Our data indicate that immunosuppressive PKCι-YAP1-CXCL5 signaling is a key determinant of response to ICI, and pharmacologic inhibition of PKCι may improve therapeutic response to ICI in patients with LUAD.

Background: The American Heart Association recently published an updated algorithm for quantifying cardiovascular health (CVH)—the Life’s Essential 8 score. We quantified US levels of CVH using the new score. Methods: We included individuals ages 2 through 79 years (not pregnant or institutionalized) who were free of cardiovascular disease from the National Health and Nutrition Examination Surveys in 2013 through 2018. For all participants, we calculated the overall CVH score (range, 0 [lowest] to 100 [highest]), as well as the score for each component of diet, physical activity, nicotine exposure, sleep duration, body mass index, blood lipids, blood glucose, and blood pressure, using published American Heart Association definitions. Sample weights and design were incorporated in calculating prevalence estimates and standard errors using standard survey procedures. CVH scores were assessed across strata of age, sex, race and ethnicity, family income, and depression. Results: There were 23 409 participants, representing 201 728 000 adults and 74 435 000 children. The overall mean CVH score was 64.7 (95% CI, 63.9–65.6) among adults using all 8 metrics and 65.5 (95% CI, 64.4–66.6) for the 3 metrics available (diet, physical activity, and body mass index) among children and adolescents ages 2 through 19 years. For adults, there were significant differences in mean overall CVH scores by sex (women, 67.0; men, 62.5), age (range of mean values, 62.2–68.7), and racial and ethnic group (range, 59.7–68.5). Mean scores were lowest for diet, physical activity, and body mass index metrics. There were large differences in mean scores across demographic groups for diet (range, 23.8–47.7), nicotine exposure (range, 63.1–85.0), blood glucose (range, 65.7–88.1), and blood pressure (range, 49.5–84.0). In children, diet scores were low (mean 40.6) and were progressively lower in higher age groups (from 61.1 at ages 2 through 5 to 28.5 at ages 12 through 19); large differences were also noted in mean physical activity (range, 63.1–88.3) and body mass index (range, 74.4–89.4) scores by sociodemographic group. Conclusions: The new Life’s Essential 8 score helps identify large group and individual differences in CVH. Overall CVH in the US population remains well below optimal levels and there are both broad and targeted opportunities to monitor, preserve, and improve CVH across the life course in individuals and the population.