Quantifying preserved renal volume and function in patients undergoing standard partial nephrectomy vs. tumor enucleation for localized renal tumors.

INTRODUCTION: Renal parenchymal volume loss from standard partial nephrectomy (SPN) is a significant prognosticator for postoperative renal function. Tumor enucleation (TE) minimizes parenchymal loss compared to SPN. Little is known regarding discrete changes in renal function associated with volume loss. We sought to quantify the differences between SPN and TE in preserving parenchymal volume and estimated glomerular filtration rate (eGFR). METHODS: We identified 420 patients who underwent robotic partial nephrectomy (SPN or TE) at our tertiary care center from 2009 to 2022. Parenchymal volumes were calculated using TeraRecon 3D reconstruction software from axial imaging performed preoperatively and within 6 months postoperatively. Renal volume preserved and renal function were evaluated with multivariable linear and logistic regression models. RESULTS: At 1 year, eGFR was 7% lower in patients undergoing SPN compared to TE (P < 0.01). Across both SPN and TE, only volume of preserved parenchyma was predictive of eGFR and chronic kidney disease (CKD) progression (both P < 0.01). TE preserved more healthy parenchymal volume compared to SPN (median percentage 97.6% vs 89.2%; P < 0.001). Each 1% of volumetric loss corresponded to a 0.35% decrease in eGFR at 1 year postoperatively (P < 0.01). CONCLUSIONS: Volume of preserved renal parenchyma was the strongest factor associated with preserved eGFR and reduced odds of CKD progression. TE preserved more parenchyma than SPN, which translated to higher eGFR preservation at 1 year postoperatively.

Genetic Variation and Regulation of MICA Alters Natural Killer Cell-Mediated Immunosurveillance in Early-Onset Colorectal Cancer.

The incidence of colorectal cancer (CRC) among individuals under age 50, or early-onset CRC (EOCRC), has been rising over the past few decades for unclear reasons, and the etiology of the disease remains largely unknown. Known genetic risk factors do not explain this increase, pointing to possible environmental and as-yet unidentified genetic contributors and their interactions. Previous research linked genetic variation on chromosome 6 to increased CRC risk. This region harbors multiple immune genes, including the gene encoding Major Histocompatibility Complex (MHC) class I polypeptide-related sequence A (MICA). MICA is a polygenic ligand for the Natural Killer Group 2D receptor (NKG2D), a receptor expressed on Natural Killer (NK) cells and other lymphocytes. Given that intra-tumoral NK cell infiltration correlates with favorable CRC outcomes, we hypothesized that germline genetic variation in MICA could influence CRC risk. In a discovery set of 40,125 cases and controls, we show that the minor G allele at Chr6:31373718C>G (hg19) is associated with increased risk for CRC (odds ratio (OR) = 1.09, 95% confidence interval (CI) 1.04 - 1.15, p = 0.0009). The effect is stronger in EOCRC (OR = 1.26, 95% CI 1.08 - 1.44, p = 0.0023) than in those 50 and over (OR = 1.07, 95% CI 1.02 - 1.13; p = 0.012) (Ratio of ORs = 1.32, 95% CI 1.14 - 1.52, p = 0.0002). In an independent validation set of 77,983 cases and controls, the adjusted interaction by age-of-onset was significant at OR = 1.15 (95% CI 1.03 - 1.34, p = 0.0150) with a higher risk in EOCRC. Expression quantitative trait locus analysis in normal colonic epithelia showed that MICA RNA expression decreases linearly with each additional copy of the minor G allele (p = 3.345 × 10e-18). Bulk RNA analysis of the tumor immune microenvironment revealed that tumors from patients with CG or GG genotypes have lower resting and activated NK cell infiltration as compared to tumors from patients with CC genotype. Multiplex immunofluorescence analysis demonstrated that patients with a G allele (i.e. CG or GG genotype, but not CC genotype) have a statistically significant decrease in the number of NK cells in tumor compared to adjacent normal colonic mucosa. Taken together, population-based epidemiologic, molecular, genetic, cellular and immunologic evidence demonstrate that MICA genotype is associated with increased risk of EOCRC and reduced number of NK cells in colorectal tumors, suggesting that patients with a G allele have altered NK cell-mediated immunosurveillance. These novel findings suggest that EOCRC may have a previously unrecognized innate immune-mediated etiology which merits further investigation.

Adjuvant Pembrolizumab versus Observation in Muscle-Invasive Urothelial Carcinoma.

BACKGROUND: Muscle-invasive urothelial carcinoma is an aggressive disease with high rates of relapse. Whether pembrolizumab as adjuvant therapy would be effective in patients with high-risk muscle-invasive urothelial carcinoma after radical surgery is unknown. METHODS: In this phase 3 trial, we randomly assigned patients, in a 1:1 ratio, to receive pembrolizumab at a dose of 200 mg every 3 weeks for 1 year or to undergo observation. Randomization was stratified according to pathological stage, centrally tested programmed death ligand 1 (PD-L1) status, and previous neoadjuvant chemotherapy. The coprimary end points were disease-free survival and overall survival in the intention-to-treat population. We considered the trial to be successful if either disease-free survival or overall survival was significantly longer with pembrolizumab than with observation. RESULTS: A total of 702 patients underwent randomization; 354 were assigned to receive pembrolizumab, and 348 were assigned to observation. As of July 5, 2024, the median duration of follow-up for disease-free survival was 44.8 months. The median disease-free survival was 29.6 months (95% confidence interval [CI], 20.0 to 40.7) with pembrolizumab and 14.2 months (95% CI, 11.0 to 20.2) with observation (hazard ratio for disease progression or death, 0.73; 95% CI, 0.59 to 0.90; two-sided P = 0.003). Grade 3 or higher adverse events (regardless of attribution) occurred in 50.7% of the patients in the pembrolizumab group and in 31.6% of the patients in the observation group. CONCLUSIONS: Among patients with high-risk muscle-invasive urothelial carcinoma after radical surgery, disease-free survival was significantly longer with adjuvant pembrolizumab than with observation. (Funded by the National Cancer Institute of the National Institutes of Health and others; Alliance A031501 AMBASSADOR ClinicalTrials.gov number, NCT03244384.).

Motor control of the palatoglossus and genioglossus during changes in breathing route.

High activity of upper airway dilator muscles is thought to be critical in preventing sleep-related upper airway collapse. To date, most of the research regarding upper airway dilator muscles has focused on the genioglossus muscle, which protrudes the tongue and opens the retroglossal airway. However, collapse commonly occurs in the retropalatal region. We therefore aimed to examine the motor control of the palatoglossus muscle as well as investigate breathing route-related changes in genioglossus and palatoglossus motor units. Single motor unit recordings of the genioglossus and palatoglossus were made simultaneously in healthy individuals during wakefulness while breathing through the nose with the mouth closed (NMC), nose with mouth open (NMO) or orally (OMO). The palatoglossus was found to have all 5 motor unit firing patterns that have been observed in other upper airway dilator muscles, but during nasal breathing had a higher proportion of tonically active but inspiratory modulated motor units as compared to the genioglossus (67% vs 30%). When still breathing nasally but with the mouth open, the units with an expiratory firing pattern in genioglossus, and all firing patterns in palatoglossal, increased their firing rates compared to nasal breathing with the mouth closed (GG: 17.8±4.9 vs 23.1±4.8 Hz, PG: 17.0±4.0 vs 19.3±4.0 Hz). Finally, oral breathing resulted in dramatic reductions in the number of palatoglossal motor units that were firing (35 units vs 92 during nasal breathing). Palatoglossus activity may contribute importantly to airway collapsibility and may provide an alternate pathway for preventing sleep-related airway collapse.

Correlation of Imaging and Hemodynamic Findings with Clinical Outcomes for Diagnosis of Left Renal Vein Compression Syndrome.

PURPOSE: Left renal vein compression syndrome (LRVCS) remains a challenging diagnosis. This study aimed to correlate imaging and hemodynamic findings with clinical outcomes for patients with LRVCS. MATERIALS AND METHODS: A retrospective review of 66 renal venography procedures with or without intravascular ultrasound (IVUS) was performed from 2017 to 2023 at a single institution. Patients with prior LRVCS treatment or other indications were excluded (n = 11). Primary outcome measure was correlation of catheter-based endovascular (CBE) findings with clinical outcomes (n = 55). Secondary outcome measures included correlation of CBE findings and LRV (i.e., beak) angle > 32°, beak sign, aortomesenteric angle (AMA < 41°), and hilar-to-aortomesenteric ratio (HTAMR ≥ 4.9) on cross sectional imaging. Descriptive statistics, chi-square testing, and ROC analyses were used. RESULTS: Of the 55 patients, 52 (94.5%) were females (median age 31, range 14-72) and 56.4% (n = 31) had a diagnosis of LRVCS on CBE evaluation. A renocaval pressure gradient of ≥ 3 mmHg, presence of collaterals, and > 50% area stenosis on IVUS were significantly associated with CBE diagnosis of LRVCS (p < 0.001). Surgical treatment (renal autotransplantation or LRV transposition) was recommended to all patients with CBE diagnosis of LRVCS (n = 31). 81.2% (18/22) of patients who underwent surgery reported symptom resolution or improvement. When the cross sectional imaging measurements were compared with CBE evaluation, AMA was the most sensitive (100%), HTAMR and beak sign were highly specific (93.3%), and beak angle was the most predictive (77.4% sensitivity; 86.7% specificity). CONCLUSION: CBE diagnosis of LRVCS was highly predictive of surgical candidacy and post-surgical symptom resolution. The presence of collaterals, > 50% area stenosis on IVUS, or a renocaval pressure gradient ≥ 3 mmHg had a significant association with a CBE diagnosis of LRVCS.

Elucidating the Transition of 3D Morphological Evolution of Binary Alloys in Molten Salts with Metal Ion Additives.

Molten salts serve as effective high-temperature heat transfer fluids and thermal storage media used in a wide range of energy generation and storage facilities, including concentrated solar power plants, molten salt reactors and high-temperature batteries. However, at the salt-metal interfaces, a complex interplay of charge-transfer reactions involving various metal ions, generated either as fission products or through corrosion of structural materials, takes place. Simultaneously, there is a mass transport of ions or atoms within the molten salt and the parent alloys. The precise physical and chemical mechanisms leading to the diverse morphological changes in these materials remain unclear. To address this knowledge gap, this work employed a combination of synchrotron X-ray nanotomography and electron microscopy to study the morphological and chemical evolution of Ni-20Cr in molten KCl-MgCl2, while considering the influence of metal ions (Ni2+, Ce3+, and Eu3+) and variations in salt composition. Our research suggests that the interplay between interfacial diffusivity and reactivity determines the morphological evolution. The summary of the associated mass transport and reaction processes presented in this work is a step forward toward achieving a fundamental comprehension of the interactions between molten salts and alloys. Overall, the findings offer valuable insights for predicting the diverse chemical and structural alterations experienced by alloys in molten salt environments, thus aiding in the development of protective strategies for future applications involving molten salts.

Global hypokinesis in resting transthoracic echocardiography diagnosis of heart failure and coronary artery disease.

Objectives: Although coronary artery disease (CAD) and heart failure (HF) are separate entities, HF is a common complication of CAD, and both CAD and HF are known causes of wall motion abnormalities (WMA) of transthoracic echocardiography (TTE). Specifically, global hypokinesis on TTE could logically be due to multivessel CAD or non-ischemic cardiomyopathy. The purpose of this study was to investigate the relationship between CAD, HF, and WMA on TTE. Methods: A single-center retrospective chart review was conducted of adults who had a resting TTE and cardiac catheterization within 30 days. We analysed the association between global hypokinesis, triple-vessel CAD, and HF diagnosis. Results: Across 754 included patients, there was a positive association between global hypokinesis on TTE and HF diagnosis (P < .001). There was no association between global hypokinesis on TTE and triple-vessel CAD (P = .341), possibly an inverse correlation. The sensitivity of regional (R) WMAs on TTE for diagnosing CAD was generally lower in patients without heart failure (44%), while specificity was higher in these same patients (89%). Conclusions: There was a positive association between global hypokinesis and HF, and a possible inverse correlation between global hypokinesis and triple-vessel CAD. This could be explained by heart failure diagnosis and other diagnoses having a stronger effect on global hypokinesis than any potential effect from triple-vessel CAD. These sensitivity and specificity results for RWMA on CAD, stratified by HF diagnosis and/or global hypokinesis, can be used to inform clinical decision-making in an acute coronary syndrome case with borderline electrocardiography and/or troponin findings.

MRI at diagnostic versus confirmatory biopsy during MRI-based active surveillance of prostate cancer.

OBJECTIVES: Active surveillance (AS) is a management strategy for patients with favorable risk prostate cancer. Multi-parametric magnetic resonance imaging (mpMRI) may impact upgrading rates, but there is mixed evidence on the appropriate timing to introduce mpMRI. We evaluated timing of initial mpMRI use for patients on AS and compared upgrading and intervention rates for AS candidates who received initial mpMRI before diagnostic biopsy vs. confirmatory biopsy. SUBJECTS AND METHODS: Patients enrolled in AS captured by the Prospective Loyola Urology mpMRI (PLUM) Prostate Biopsy Cohort which captures men undergoing MRI-fusion prostate biopsy. We included patients enrolled in AS between January 2014 and October 2022. We conducted a retrospective analysis of patients who underwent MRI-fusion prostate biopsy while on AS at our institution. The cohort was stratified by men who underwent first mpMRI prior to diagnostic biopsy (MRI-DBx), confirmatory biopsy (MRI-CBx), or a subsequent surveillance biopsy. Oncologic outcomes including pathologic reclassification, intervention-free survival, progression-free survival, and overall survival were evaluated. RESULTS: Of 346 patients identified on AS, 94 (27.2%) received mpMRI at the time of diagnostic biopsy, 182 (52.6%) at confirmatory biopsy, and 70 (20.2%) at a later biopsy. At confirmatory biopsy (median 14 months), there was no difference in upgrading (HR 0.95, P = 0.78) or intervention rates (HR 0.97, P = 0.88) between MRI-DBx and MRI-CBx. PI-RADS score on initial mpMRI was associated with upgrading during AS follow-up relative to men with negative mpMRI (HR 4.20 (P = 0.04), 3.24 (P < 0.001), and 1.99 (P < 0.001) for PI-RADS 5, 4, and 3, respectively), and PSA density was associated with intervention (HR 1.52, P = 0.03). CONCLUSION: mpMRI can serve as a prognostic tool to select and monitor AS patients, but there was no difference in upgrading or intervention rates based on initial timing of MRI.

Regional wall motion abnormalities in transthoracic echocardiography in patients with significant coronary artery disease and coronary collateral circulation in adults.

BACKGROUND: Coronary collateral circulation is a common finding in patients with chronic total occlusions (CTOs) resulting from chronic coronary artery disease (CAD). Regional wall motion abnormalities (RWMA) on transthoracic echocardiography (TTE) can be used for the diagnosis of CAD. However, little work has been done to investigate the impact of collateral vessels on the diagnostic accuracy of resting TTE for CAD. METHODS: A retrospective chart review was conducted of adults who received a resting TTE and cardiac catheterization within 30 days over a 4-year period at the Temple Baylor Scott & White echocardiography laboratory. Exclusion criteria included catheterization without coronary angiography and prior history of CAD, percutaneous coronary intervention (PCI), or coronary artery bypass graft (CABG). We analyzed RWMA on TTE in patients with CAD and coronary collateral circulation on cardiac catheterization to assess for correlation. RESULTS: Of the 753 patients were included in this study, 453 had CAD, 272 had both CAD and RWMA, 111 had collateral circulation, and 73 had collateral circulation and RWMA. There was no significant difference in RWMA in patients with CAD with and without collateral circulation. There was no significant difference in the sensitivity (60.0 % vs 59.2 %) and specificity (78.4 % vs 73.9 %) after collateral-adjusted interpretation of RWMA and CAD (p = 0.3). DISCUSSION: Our results suggest the average coronary collateral system is of insufficient clinical significance to prevent the development of RWMA on resting TTE.

Efficacy of Intravesical Nadofaragene Firadenovec for Patients With Bacillus Calmette-Guérin-Unresponsive Nonmuscle-Invasive Bladder Cancer: 5-Year Follow-Up From a Phase 3 Trial.

PURPOSE: Nadofaragene firadenovec-vncg is a nonreplicating adenoviral vector-based gene therapy for bacillus Calmette-Guérin (BCG)-unresponsive carcinoma in situ (CIS) with/without high-grade Ta/T1. We report outcomes following 5 years of planned follow-up. MATERIALS AND METHODS: This open-label phase 3 trial (NCT02773849) enrolled patients with BCG-unresponsive nonmuscle-invasive bladder cancer in 2 cohorts: CIS ± Ta/T1 (CIS; n = 107) and Ta/T1 without CIS (Ta/T1 cohort; n = 50). Patients received 75 mL (3 × 1011 vp/mL) nadofaragene firadenovec intravesically once every 3 months with cystoscopy and cytology assessments, with continued treatment offered to those remaining high grade recurrence-free (HGRF). RESULTS: One hundred fifty-seven patients were enrolled from 33 US sites (n = 151 included in efficacy analyses). Median follow-up was 50.8 months (interquartile range 39.1-60.0), with 27% receiving ≥ 5 instillations and 7.6% receiving treatment for ≥ 57 months. Of patients with CIS 5.8% (95% CI 2.2-12.2) were HGRF at month 57, and 15% (95% CI 6.1-27.8) of patients with high-grade Ta/T1 were HGRF at month 57. Kaplan-Meier-estimated HGRF survival at 57 months was 13% (95% CI 6.9-21.5) and 33% (95% CI 19.5-46.6) in the CIS and Ta/T1 cohorts, respectively. Cystectomy-free survival at month 60 was 49% (95% CI 40.0-57.1): 43% (95% CI 32.2-53.7) in the CIS cohort and 59% (95% CI 43.1-71.4) in the Ta/T1 cohort. Overall survival at 60 months was 80% (71.0, 86.0): 76% (64.6-84.5) and 86% (70.9-93.5) in the CIS and Ta/T1 cohorts, respectively. Only 5 patients (4 with CIS and 1 with Ta/T1) experienced clinical progression to muscle-invasive disease. CONCLUSIONS: At 60 months, nadofaragene firadenovec-vncg allowed bladder preservation in nearly half of the patients and proved to be a safe option for BCG-unresponsive nonmuscle-invasive bladder cancer.

Natural compounds from freshwater mussels disrupt fungal virulence determinants and influence fluconazole susceptibility in the presence of macrophages in Cryptococcus neoformans.

Cryptococcus neoformans is a human fungal pathogen responsible for fatal infections, especially in patients with a depressed immune system. Overexposure to antifungal drugs due to prolonged treatment regimens and structure-similar applications in agriculture have weakened the efficacy of current antifungals in the clinic. The rapid evolution of antifungal resistance urges the discovery of new compounds that inhibit fungal virulence determinants, rather than directly killing the pathogen, as alternative strategies to overcome disease and reduce selective pressure toward resistance. Here, we evaluated the efficacy of freshwater mussel extracts (crude and clarified) against the production of well-defined virulence determinants (i.e., thermotolerance, melanin, capsule, and biofilm) and fluconazole resistance in C. neoformans. We demonstrated the extracts' influence on fungal thermotolerance, capsule production, and biofilm formation, as well as susceptibility to fluconazole in the presence of macrophages. Additionally, we measured the inhibitory activity of extracts against commercial peptidases (family representatives of cryptococcal orthologs) related to fungal virulence determinants and fluconazole resistance, and integrated these phenotypic findings with quantitative proteomics profiling. Our approach defined distinct signatures of each treatment and validated a new mechanism of anti-virulence action toward the polysaccharide capsule from a selected extract following fractionation. By understanding the mechanisms driving the antifungal activity of mussels, we may develop innovative treatment options to overcome fungal infections and promote susceptibility to fluconazole in resistant strains. IMPORTANCE: As the prevalence and severity of global fungal infections rise, along with an increasing incidence of antifungal resistance, new strategies to combat fungal pathogens and overcome resistance are urgently needed. Critically, our current methods to overcome fungal infections are limited and drive the evolution of resistance forward; however, an anti-virulence approach to disarm virulence factors of the pathogen and promote host cell clearance is promising. Here, we explore the efficacy of natural compounds derived from freshwater mussels against classical fungal virulence determinants, including thermotolerance, capsule production, stress response, and biofilm formation. We integrate our phenotypic discoveries with state-of-the-art mass spectrometry-based proteomics to identify mechanistic drivers of these antifungal properties and propose innovative avenues to reduce infection and support the treatment of resistant strains.

Robotic versus open radical cystectomy for bladder cancer: evaluation of complications, survival, and opioid prescribing patterns.

We aim to compare complications, readmission, survival, and prescribing patterns of opioids for post-operative pain management for Robotic-assisted laparoscopic radical cystectomy (RARC) as compared to open radical cystectomy (ORC). Patients that underwent RARC or ORC for bladder cancer at a tertiary care center from 2005 to 2021 were included. Recurrence-free survival (RFS) and overall survival (OS) were evaluated with Kaplan-Meier curves and multivariable Cox proportional hazards regression models. Comparisons of narcotic usage were completed with oral morphine equivalents (OMEQ). Multivariable linear regression was used to assess predictors of OMEQ utilization. A total of 128 RARC and 461 ORC patients were included. There was no difference in rates of Clavien-Dindo grade ≥ 3 complications between RARC and ORC (36.7 vs 30.1%, p = 0.16). After a mean follow up of 3.4 years, RFS (HR 0.96, 95%CI 0.58-1.56) and OS (HR 0.69, 95%CI 0.46-1.05) were comparable between RARC and ORC. There was no difference in the narcotic usage between patients in the RARC and ORC groups during the last 24 h of hospitalization (median OMEQ: 0 vs 0, p = 0.33) and upon discharge (median OMEQ: 178 vs 210, p = 0.36). Predictors of higher OMEQ discharge prescriptions included younger age [(- )3.46, 95%CI (-)5.5-(-)0.34], no epidural during hospitalization [- 95.85, 95%CI (- )144.95-(- )107.36], and early time-period of surgery [(- )151.04, 95%CI (- )194.72-(- )107.36]. RARC has comparable 90-day complication rates and early survival outcomes to ORC and remains a viable option for bladder cancer. RARC results in comparable levels of opioid utilization for pain management as ORC.

Neoadjuvant Chemotherapy Before Radical Cystectomy for Muscle-Invasive Bladder Cancer: Elective and Eligibility Factors Impacting Utilization.

INTRODUCTION: We aimed to assess utilization of neoadjuvant chemotherapy (NAC) and etiologies for lack of NAC receipt among patients with muscle-invasive bladder cancer (MIBC). METHODS: Patients diagnosed with MIBC undergoing radical cystectomy at a single institution (2005-2021) were included. Patients were categorized by receipt of NAC, and reasons for no NAC were categorized into eligibility and elective factors. Overall survival was analyzed using univariable and multivariable Cox proportional hazards regression models and modeled with Kaplan-Meier curves. RESULTS: Three hundred eighty patients with MIBC were included; 154 (40.5%) received NAC. Patients were not candidates for NAC due to renal dysfunction (16.6%), clinical contraindications (4.7%), salvage setting (2.1%), and histology (5.3%; total N = 109). Among 271 (71.3%) who were eligible, utilization increased from early (2005-2016) to recent (2016-2021) time periods (34.2% to 85.7% among NAC-eligible, P < .001; 22.8% vs 67.1% among all MIBC, P < .001). Elective factors for not receiving NAC included patient symptoms (7.8%), disease progression concern (7.0%), patient preference/refusal (20.3%) and provider discretion (8.1%) among 271 NAC-eligible patients. Notably, patient preference/refusal decreased from 33.6% to 3.4% in recent years (P < .001). On multivariable analysis, lack of NAC utilization due to renal dysfunction (HR 2.18, P = .002), clinical contraindications (HR 2.62, P = .01), and elective factors (HR 1.88, P = .01) were associated with worse overall survival. CONCLUSIONS: NAC utilization increased over time with 85.7% of eligible patients with MIBC receiving NAC in recent years. Renal dysfunction, patient preference, and clinical contraindications were primary etiologies for lack of NAC. Fewer patients refused NAC in recent years leading to a potential ceiling for NAC utilization.

Novel insights into genetic susceptibility for colorectal cancer from transcriptome-wide association and functional investigation.

BACKGROUND: Transcriptome-wide association studies have been successful in identifying candidate susceptibility genes for colorectal cancer (CRC). To strengthen susceptibility gene discovery, we conducted a large transcriptome-wide association study and an alternative splicing transcriptome-wide association study in CRC using improved genetic prediction models and performed in-depth functional investigations. METHODS: We analyzed RNA-sequencing data from normal colon tissues and genotype data from 423 European descendants to build genetic prediction models of gene expression and alternative splicing and evaluated model performance using independent RNA-sequencing data from normal colon tissues of the Genotype-Tissue Expression Project. We applied the verified models to genome-wide association studies (GWAS) summary statistics among 58 131 CRC cases and 67 347 controls of European ancestry to evaluate associations of genetically predicted gene expression and alternative splicing with CRC risk. We performed in vitro functional assays for 3 selected genes in multiple CRC cell lines. RESULTS: We identified 57 putative CRC susceptibility genes, which included the 48 genes from transcriptome-wide association studies and 15 genes from splicing transcriptome-wide association studies, at a Bonferroni-corrected P value less than .05. Of these, 16 genes were not previously implicated in CRC susceptibility, including a gene PDE7B (6q23.3) at locus previously not reported by CRC GWAS. Gene knockdown experiments confirmed the oncogenic roles for 2 unreported genes, TRPS1 and METRNL, and a recently reported gene, C14orf166. CONCLUSION: This study discovered new putative susceptibility genes of CRC and provided novel insights into the biological mechanisms underlying CRC development.

Laparoscopic cholecystectomy critical view of safety (LC-CVS): a multi-national validation study of an objective, procedure-specific assessment using video-based assessment (VBA).

BACKGROUND: A novel 6-item objective, procedure-specific assessment for laparoscopic cholecystectomy incorporating the critical view of safety (LC-CVS OPSA) was developed to support trainee formative and summative assessments. The LC-CVS OPSA included two retraction items (fundus and infundibulum retraction) and four CVS items (hepatocystic triangle visualization, gallbladder-liver separation, cystic artery identification, and cystic duct identification). The scoring rubric for retraction consisted of poor (frequently outside of defined range), adequate (minimally outside of defined range) and excellent (consistently inside defined range) and for CVS items were "poor-unsafe", "adequate-safe", or "excellent-safe". METHODS: A multi-national consortium of 12 expert LC surgeons applied the OPSA-LC CVS to 35 unique LC videos and one duplicate video. Primary outcome measure was inter-rater reliability as measured by Gwet's AC2, a weighted measure that adjusts for scales with high probability of random agreement. Analysis of the inter-rater reliability was conducted on a collapsed dichotomous scoring rubric of "poor-unsafe" vs. "adequate/excellent-safe". RESULTS: Inter-rater reliability was high for all six items ranging from 0.76 (hepatocystic triangle visualization) to 0.86 (cystic duct identification). Intra-rater reliability for the single duplicate video was substantially higher across the six items ranging from 0.91 to 1.00. CONCLUSIONS: The novel 6-item OPSA LC CVS demonstrated high inter-rater reliability when tested with a multi-national consortium of LC expert surgeons. This brief instrument focused on safe surgical practice was designed to support the implementation of entrustable professional activities into busy surgical training programs. Instrument use coupled with video-based assessments creates novel datasets with the potential for artificial intelligence development including computer vision to drive assessment automation.

A multi-national, video-based qualitative study to refine training guidelines for assigning an "unsafe" score in laparoscopic cholecystectomy critical view of safety.

BACKGROUND: The critical view of safety (CVS) was incorporated into a novel 6-item objective procedure-specific assessment for laparoscopic cholecystectomy (LC-CVS OPSA) to enhance focus on safe completion of surgical tasks and advance the American Board of Surgery's entrustable professional activities (EPAs) initiative. To enhance instrument development, a feasibility study was performed to elucidate expert surgeon perspectives regarding "safe" vs. "unsafe" practice. METHODS: A multi-national consortium of 11 expert LC surgeons were asked to apply the LC-CVS OPSA to ten LC videos of varying surgical difficulty using a "safe" vs. "unsafe" scale. Raters were asked to provide written rationale for all "unsafe" ratings and invited to provide additional feedback regarding instrument clarity. A qualitative analysis was performed on written responses to extract major themes. RESULTS: Of the 660 ratings, 238 were scored as "unsafe" with substantial variation in distribution across tasks and raters. Analysis of the comments revealed three major categories of "unsafe" ratings: (a) inability to achieve the critical view of safety (intended outcome), (b) safe task completion but less than optimal surgical technique, and (c) safe task completion but risk for potential future complication. Analysis of reviewer comments also identified the potential for safe surgical practice even when CVS was not achieved, either due to unusual anatomy or severe pathology preventing safe visualization. Based upon findings, modifications to the instructions to raters for the LC-CVS OPSA were incorporated to enhance instrument reliability. CONCLUSIONS: A safety-based LC-CVS OPSA has the potential to significantly improve surgical training by incorporating CVS formally into learner assessment. This study documents the perspectives of expert biliary tract surgeons regarding clear identification and documentation of unsafe surgical practice for LC-CVS and enables the development of training materials to improve instrument reliability. Learnings from the study have been incorporated into rater instructions to enhance instrument reliability.

CT Navigation for Percutaneous Needle Placement: How I Do It.

CT navigation (CTN) has recently been developed to combine many of the advantages of conventional CT and CT-fluoroscopic guidance for needle placement. CTN systems display real-time needle position superimposed on a CT dataset. This is accomplished by placing electromagnetic (EM) or optical transmitters/sensors on the patient and needle, combined with fiducials placed within the scan field to superimpose a known needle location onto a CT dataset. Advantages of CTN include real-time needle tracking using a contemporaneous CT dataset with the patient in the treatment position, reduced radiation to the physician, facilitation of procedures outside the gantry plane, fewer helical scans during needle placement, and needle guidance based on diagnostic-quality CT datasets. Limitations include the display of a virtual (vs actual) needle position, which can be inaccurate if the needle bends, the fiducial moves, or patient movement occurs between scans, and limitations in anatomical regions with a high degree of motion such as the lung bases. This review summarizes recently introduced CTN technologies in comparison to historical methods of CT needle guidance. A "How I do it" section follows, which describes how CT navigation has been integrated into the study center for both routine and challenging procedures, and includes step-by-step explanations, technical tips, and pitfalls.

Percutaneous treatment of symptomatic deep vein thrombosis in adolescents using large-bore thrombectomy systems.

BACKGROUND: While large-bore mechanical thrombectomy provides effective venous thrombus removal, often with avoidance of thrombolytics, literature surrounding the application of these devices in pediatric patients is sparse. OBJECTIVE: To report technical success and outcomes following large-bore thrombectomy systems in adolescent patients with deep venous thrombosis. MATERIALS AND METHODS: A retrospective review identified all patients less than 18 years of age undergoing mechanical venous thrombectomy at a single institution between 2018 and 2022. No patients were excluded. Technical success was defined as extraction of thrombus sufficient to restore unimpeded flow in affected segments. Clinical success was defined as resolution of presenting symptoms. RESULTS: Nine consecutive patients (6 females, 3 males; age range 15-17 years) underwent 10 thrombectomy procedures using ClotTriever (n=6; 60%), FlowTriever (n=2; 20%), or both (n=2; 20%). Chronicity of thrombus was categorized as acute (<2 weeks) in 6 (60%), subacute (2-6 weeks) in 1 (10%), and chronic (>6 weeks) in 3 (30%). Distribution of thrombus was lower extremity and/or inferior vena cava (IVC) in 9 (90%) and unilateral axillo-subclavian in 1 (10%). Technical success was achieved in 9 interventions (90%). Clinical success was achieved in 8 patients (88.9%). No patients received thrombolytics. There were no intraprocedural adverse events (AE). Minor complications (Society of Interventional Radiology mild adverse events) were observed in a delayed fashion following 2 interventions (20%). CONCLUSIONS: This preliminary experience demonstrated high rates of technical and clinical success with large-bore deep venous thrombectomy in adolescent patients across a range of thrombus chronicity and locations.