Umbravirus-like RNA viruses are capable of independent systemic plant infection in the absence of encoded movement proteins.

The signature feature of all plant viruses is the encoding of movement proteins (MPs) that supports the movement of the viral genome into adjacent cells and through the vascular system. The recent discovery of umbravirus-like viruses (ULVs), some of which only encode replication-associated proteins, suggested that they, as with umbraviruses that lack encoded capsid proteins (CPs) and silencing suppressors, would require association with a helper virus to complete an infection cycle. We examined the infection properties of 2 ULVs: citrus yellow vein associated virus 1 (CY1), which only encodes replication proteins, and closely related CY2 from hemp, which encodes an additional protein (ORF5CY2) that was assumed to be an MP. We report that both CY1 and CY2 can independently infect the model plant Nicotiana benthamiana in a phloem-limited fashion when delivered by agroinfiltration. Unlike encoded MPs, ORF5CY2 was dispensable for infection of CY2, but was associated with faster symptom development. Examination of ORF5CY2 revealed features more similar to luteoviruses/poleroviruses/sobemovirus CPs than to 30K class MPs, which all share a similar single jelly-roll domain. In addition, only CY2-infected plants contained virus-like particles (VLPs) associated with CY2 RNA and ORF5CY2. CY1 RNA and a defective (D)-RNA that arises during infection interacted with host protein phloem protein 2 (PP2) in vitro and in vivo, and formed a high molecular weight complex with sap proteins in vitro that was partially resistant to RNase treatment. When CY1 was used as a virus-induced gene silencing (VIGS) vector to target PP2 transcripts, CY1 accumulation was reduced in systemic leaves, supporting the usage of PP2 for systemic movement. ULVs are therefore the first plant viruses encoding replication and CPs but no MPs, and whose systemic movement relies on a host MP. This explains the lack of discernable helper viruses in many ULV-infected plants and evokes comparisons with the initial viruses transferred into plants that must have similarly required host proteins for movement.

Surgery and Surgical Training Prior to Graduate Medical Education: A Blue Ribbon Committee II, Medical Student Education Subcommittee Report.

OBJECTIVE: To update and add to the first report commissioned by the Blue Ribbon Committee about 20 years prior. SUMMARY OF BACKGROUND DATA: Following a summit in late 2022 commissioned by the American Board of Surgery regarding competency-based reforms in surgical education and via a partnership with the American College of Surgeons (ACS) and other stakeholders, a Blue Ribbon Committee (BRC-II) on surgical education was formed. The BRC-II would have seven subcommittees. This paper details the work of the Medical Student Subcommittee within the BRC- II. METHODS: The subcommittee's work, supported by staff from the ACS, entailed a thorough literature review, which involved collating and aggregating the findings, identifying key challenges and opportunities, and committing to draft recommendations. These recommendations were then presented and refined via discussions with the Blue Ribbon Committee at large in multiple virtual and in-person settings. RESULTS: The subcommittee's work is detailed below and further summarized in table format. The section below elucidates the medical student education continuum and discusses the pertinent topics of recruitment, surgical engagement in medical student training and the surgical image, training for the current surgical practice model, trainee selection for graduate medical education (GME), and optimizing the transition from undergraduate medical education (UME) to GME. CONCLUSIONS: The last two decades have shown significant changes and shifts in medical education and surgical practice. The findings of BRC-II in this manuscript help to structure the current and future necessary improvements, focusing on different aspects of medical student education.

Role of Phenylethanolamine-N-methyltransferase on Nicotine-Induced Vasodilation in Rat Cerebral Arteries.

OBJECTIVE: The sympathetic-parasympathetic (or axo-axonal) interaction mechanism mediated that neurogenic relaxation, which was dependent on norepinephrine (NE) releases from sympathetic nerve terminal and acts on ß2-adrenoceptor of parasympathetic nerve terminal, has been reported. As NE is a weak ß2-adrenoceptor agonist, there is a possibility that synaptic NE is converted to epinephrine by phenylethanolamine-N-methyltransferase (PNMT) and then acts on the ß2-adrenoceptors to induce neurogenic vasodilation. METHODS: Blood vessel myography technique was used to measure relaxation and contraction responses of isolated basilar arterial rings of rats. RESULTS: Nicotine-induced relaxation was sensitive to propranolol, guanethidine (an adrenergic neuronal blocker), and Nω-nitro-l-arginine. Nicotine- and exogenous NE-induced vasorelaxation was partially inhibited by LY-78335 (a PNMT inhibitor), and transmural nerve stimulation depolarized the nitrergic nerve terminal directly and was not inhibited by LY-78335; it then induced the release of nitric oxide (NO). Epinephrine-induced vasorelaxation was not affected by LY-78335. However, these vasorelaxations were completely inhibited by atenolol (a ß1-adrenoceptor antagonist) combined with ICI-118,551 (a ß2-adrenoceptor antagonist). CONCLUSIONS: These results suggest that NE may be methylated by PNMT to form epinephrine and cause the release of NO and vasodilation. These results provide further evidence supporting the physiological significance of the axo-axonal interaction mechanism in regulating brainstem vascular tone.

Non-Small Cell Lung Cancer, Version 4.2024, NCCN Clinical Practice Guidelines in Oncology

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer (NSCLC) provide recommendations for the treatment of patients with NSCLC, including diagnosis, primary disease management, surveillance for relapse, and subsequent treatment. The panel has updated the list of recommended targeted therapies based on recent FDA approvals and clinical data. This selection from the NCCN Guidelines for NSCLC focuses on treatment recommendations for advanced or metastatic NSCLC with actionable molecular biomarkers.

NCCN Guidelines® Insights: Mesothelioma: Pleural, Version 1.2024.

Mesothelioma is a rare cancer that originates from the mesothelial surfaces of the pleura and other sites, and is estimated to occur in approximately 3,500 people in the United States annually. Pleural mesothelioma is the most common type and represents approximately 85% of these cases. The NCCN Guidelines for Mesothelioma: Pleural provide recommendations for the diagnosis, evaluation, treatment, and follow-up for patients with pleural mesothelioma. These NCCN Guidelines Insights highlight significant updates to the NCCN Guidelines for Mesothelioma: Pleural, including revised guidance on disease classification and systemic therapy options.

Maryland's Global Budget Revenue Program and Equitable Access to Esophagectomy for Esophageal Cancer.

INTRODUCTION: We evaluated equity in access to esophagectomy after Maryland's 2014 "Global Budget Revenue" (GBR) implementation, which equalizes reimbursement rates irrespective of patient insurance and employs an annual hospital revenue ceiling to incentivize reductions in unnecessary resource utilization. We hypothesized that more traditionally underserved patients would undergo surgical treatment for esophageal cancers after GBR. METHODS: Using Maryland's Health Services Cost Review Commission database, we retrospectively analyzed patient demographics, insurance statuses, inflation-adjusted hospital charges, postoperative outcomes, and discharge dispositions for esophagectomies for neoplasms between 2012 and 2018. RESULTS: Four hundred eighty six patients were included: 22.0% (107) pre-GBR and 78.0% (379) post-GBR. The proportion of African-American patients increased post-GBR (5.6% versus 12.9%, P = 0.035) and subsequently exhibited year-over-year increases. While not statistically significant, the proportion of Medicaid patients increased from 4.7% to 10.0% (P = 0.085). The post-GBR era also saw patients from 10 new counties, six of which were in Maryland's bottom half of counties ranked by median household income, receive operative esophageal cancer treatment without losing representation from pre-GBR counties. Patient age and sex were comparable between the two groups, and there were no significant differences in mortality or 30-day readmissions. Inflation-adjusted hospital charges and length of hospital stay did not appreciably change post-GBR, including after adjusting for age, comorbidities, and surgical approach. CONCLUSIONS: GBR increased access to esophagectomy for African-Americans, those insured by Medicaid, and those from lower socioeconomic status counties. Contrary to prior studies of outpatient and emergency room settings, we found the GBR program's goal of reduction of resource utilization and cost were not apparent in this complex surgical population.

Superficial parasternal intercostal plane blocks in cardiac surgery: a systematic review and meta-analysis.

PURPOSE: Traditional multimodal analgesic strategies have several contraindications in cardiac surgery patients, forcing clinicians to use alternative options. Superficial parasternal intercostal plane blocks, anesthetizing the anterior cutaneous branches of the thoracic intercostal nerves, are being explored as a straightforward method to treat pain after sternotomy. We sought to evaluate the literature on the effects of superficial parasternal blocks on pain control after cardiac surgery. METHODS: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs). We searched MEDLINE, Embase, CENTRAL, and Web of Science databases for RCTs evaluating superficial parasternal intercostal plane blocks in adult patients undergoing cardiac surgery via midline sternotomy published from inception to 11 March 2022. The prespecified primary outcome was opioid consumption at 12 hr. The risk of bias was assessed with the Cochrane Collaboration Risk of Bias Tool, and the quality of evidence was evaluated using the grading of recommendations, assessments, development, and evaluations. Outcomes were analyzed with a random-effects model. All subgroups were prespecified. RESULTS: We reviewed 1,275 citations. Eleven RCTs, comprising 756 patients, fulfilled the inclusion criteria. Only one study reported the prespecified primary outcome, precluding the possibility of meta-analysis. This study reported a reduction in opioid consumption (-11.2 mg iv morphine equivalents; 95% confidence interval [CI], -8.2 to -14.1) There was a reduction in opioid consumption at 24 hr (-7.2 mg iv morphine equivalents; 95% CI, -5.6 to -8.7; five trials; 436 participants; moderate certainty evidence). All five studies measuring complications reported that none were detected, which included a sample of 196 blocks. CONCLUSION: The literature suggests a potential benefit of using superficial parasternal blocks to improve acute postoperative pain control after cardiac surgery via midline sternotomy. Future studies specifying dosing regimens and adjuncts are required. STUDY REGISTRATION: PROSPERO (CRD42022306914); first submitted 22 March 2022.

RéSUMé: OBJECTIF: Il existe plusieurs contre-indications aux stratégies analgésiques multimodales traditionnelles chez la patientèle de chirurgie cardiaque, ce qui oblige les clinicien·nes à se tourner vers d'autres options. Les blocs des plans intercostaux parasternaux superficiels, anesthésiant les branches cutanées antérieures des nerfs intercostaux thoraciques, sont l'une des méthodes simples actuellement explorées pour traiter la douleur après une sternotomie. Nous avons cherché à évaluer la littérature sur les effets des blocs parasternaux superficiels sur le contrôle de la douleur après une chirurgie cardiaque. MéTHODE: Nous avons réalisé une revue systématique et une méta-analyse des études randomisées contrôlées (ERC). Nous avons fait des recherches dans les bases de données MEDLINE, Embase, CENTRAL et Web of Science pour en tirer les ERC évaluant les blocs des plans intercostaux parasternaux superficiels chez les patient·es adultes bénéficiant d'une chirurgie cardiaque par sternotomie médiane publiées depuis leur création jusqu'au 11 mars 2022. Le critère d'évaluation principal préspécifié était la consommation d'opioïdes à 12 heures. Le risque de biais a été évalué à l'aide de l'outil Cochrane Collaboration Risk of Bias, et la qualité des données probantes à l'aide de l'outil GRADE. Les résultats ont été analysés à l'aide d'un modèle à effets aléatoires. Tous les sous-groupes étaient préspécifiés. RéSULTATS: Nous avons examiné 1275 citations. Onze ERC, comprenant 756 patient·es, remplissaient les critères d'inclusion. Une seule étude a rapporté le critère d'évaluation principal préspécifié, ce qui a exclu la possibilité d'une méta-analyse. Cette étude a rapporté une réduction de la consommation d'opioïdes (−11,2 mg équivalents de morphine iv; intervalle de confiance [IC] à 95 %, −8,2 à −14,1). Il y a eu une réduction de la consommation d'opioïdes à 24 heures (−7,2 mg équivalents de morphine iv; IC 95 %, −5,6 à −8,7; cinq études; 436 participant·es; données probantes de certitude modérée). Les cinq études mesurant les complications ont rapporté qu'aucune complication n'avait été détectée, en incluant un échantillon de 196 blocs. CONCLUSION: La littérature suggère un avantage potentiel de l'utilisation de blocs parasternaux superficiels pour améliorer le contrôle de la douleur postopératoire aiguë après une chirurgie cardiaque par sternotomie médiane. Des études futures précisant les schémas posologiques et les adjuvants sont nécessaires. ENREGISTREMENT DE L'éTUDE: PROSPERO (CRD42022306914); soumis pour la première fois le 22 mars 2022.

Pragmatic Emergency Department Intervention Reducing Default Quantity of Opioid Tablets Prescribed.

Introduction: The opioid epidemic is a major cause of morbidity and mortality in the United States. Prior work has shown that emergency department (ED) opioid prescribing can increase the incidence of opioid use disorder in a dose-dependent manner, and systemic changes that decrease default quantity of discharge opioid tablets in the electronic health record (EHR) can impact prescribing practices. However, ED leadership may be interested in the impact of communication around the intervention as well as whether the intervention may differentially impact different types of clinicians (physicians, physician assistants [PA], and nurse practitioners). We implemented and evaluated a quality improvement intervention of an announced decrease in EHR default quantities of commonly prescribed opioids at a large, academic, urban, tertiary-care ED. Methods: We gathered EHR data on all ED discharges with opioid prescriptions from January 1, 2019-December 6, 2021, including chief complaint, clinician, and opioid prescription details. Data was captured and analyzed on a monthly basis throughout this time period. On March 29, 2021, we implemented an announced decrease in EHR default dispense quantities from 20 tablets to 12 tablets for commonly prescribed opioids. We measured pre- and post-intervention quantities of opioid tablets prescribed per discharge receiving opioids, distribution by patient demographics, and inter-clinician variability in prescribing behavior. Results: The EHR change was associated with a 14% decrease in quantity of opioid tablets per discharge receiving opioids, from 14 to 12 tablets (P = <.001). We found no statistically significant disparities in prescriptions based on self-reported patient race (P = 0.68) or gender (P = 0.65). Nurse practitioners and PAs prescribed more opioids per encounter than physicians on average and had a statistically significant decrease in opioid prescriptions associated with the EHR change. Physicians had a lesser but still significant drop in opioid prescribing in the post-intervention period. Conclusion: Decreasing EHR defaults is a robust, simple tool for decreasing opioid prescriptions, with potential for implementation in the 42% of EDs nationwide that have defaults exceeding the recommended 12-tablet supply. Considering significant inter-clinician variability, future interventions to decrease opioid prescriptions should examine the effects of combining EHR default changes with targeted interventions for clinician groups or individual clinicians.

Robotic Surgery in Thoracic Training Programs: A National Needs Assessment.

BACKGROUND: The cardiothoracic surgical trainees perceive a need for more instruction and exposure to robotic-assisted thoracoscopic surgery (RATS) during their training. We sought to assess utilization and trainee exposure to robotic surgery in thoracic residency programs to identify areas for improvement. METHODS: A voluntary electronic survey of 10 questions was distributed to surgeons working in all thoracic surgery residency programs in the United States. The survey asked to provide the size of the residency, the availability and utilization of robots, and the trainee's adoption of robotic surgery in their practice after graduation. Multivariable logistic regression was performed with Stata MP version 17.0 (College Station, TX). RESULTS: Of a total of 76 cardiothoracic surgery training programs, surgeons from 69 training programs completed the survey (90.8%). The majority of pulmonary lobectomy was performed using robotic surgery (55%). About half of the training programs (35/69) have a formal robotic curriculum for the residents. Of 121 thoracic-track trainees, 118 trainees (97.5%) performed robotic surgery as part of their practice, while 62 of 110 (56.4%) cardiothoracic (CT) track and 16 of 158 (10.1%) cardiac-track trainees performed robotic surgery. In a multivariate analysis, the adoption of robotic surgery was associated with having an established robotic training curriculum (OR 5.82, 95% CI 1.32 - 35.7), and a larger training program (OR 3.78, 95% CI 1.34 - 10.6). CONCLUSIONS: A disparity exists in robotic surgical training among the training programs. A standardized curriculum and formal case requirements may be needed to ensure optimal preparation for future graduates.

Learning pathways composed of core subjects with features of reducing cognitive load have better learning outcomes.

BACKGROUND: Changing the course duration or timing of subjects in learning pathways would influence medical students' learning outcomes. Curriculum designers need to consider the strategy of reducing cognitive load and evaluate it continuously. Our institution underwent gradual curricular changes characterized by reducing cognitive load since 2000. Therefore, we wanted to explore the impact of this strategy on our previous cohorts. METHODS: This cohort study explored learning pathways across academic years of more than a decade since 2000. Eight hundred eighty-two medical students between 2006 and 2012 were included eventually. Learning outcomes included an average and individual scores of subjects in different stages. Core subjects were identified as those where changes in duration or timing would influence learning outcomes and constitute different learning pathways. We examined whether the promising learning pathway defined as the pathway with the most features of reducing cognitive load has higher learning outcomes than other learning pathways in the exploring dataset. The relationship between features and learning outcomes was validated by learning pathways selected in the remaining dataset. RESULTS: We found nine core subjects, constituting four different learning pathways. Two features of extended course duration and increased proximity between core subjects of basic science and clinical medicine were identified in the promising learning pathway 2012, which also had the highest learning outcomes. Other pathways had some of the features, and pathway 2006 without such features had the lowest learning outcomes. The relationship between higher learning outcomes and cognitive load-reducing features was validated by comparing learning outcomes in two pathways with and without similar features of the promising learning pathway. CONCLUSION: An approach to finding a promising learning pathway facilitating students' learning outcomes was validated. Curricular designers may implement similar design to explore the promising learning pathway while considering potential confounding factors, including students, medical educators, and learning design of the course.

Using machine learning to identify key subject categories predicting the pre-clerkship and clerkship performance: 8-year cohort study.

BACKGROUND: Medical students need to build a solid foundation of knowledge to become physicians. Clerkship is often considered the first transition point, and clerkship performance is essential for their development. We hope to identify subjects that could predict the clerkship performance, thus helping medical students learn more efficiently to achieve high clerkship performance. METHODS: This cohort study collected background and academic data from medical students who graduated between 2011 and 2019. Prediction models were developed by machine learning techniques to identify the affecting features in predicting the pre-clerkship performance and clerkship performance. Following serial processes of data collection, data preprocessing before machine learning, and techniques and performance of machine learning, different machine learning models were trained and validated using the 10-fold cross-validation method. RESULTS: Thirteen subjects from the pre-med stage and 10 subjects from the basic medical science stage with an area under the ROC curve (AUC) >0.7 for either pre-clerkship performance or clerkship performance were found. In each subject category, medical humanities and sociology in social science, chemistry, and physician scientist-related training in basic science, and pharmacology, immunology-microbiology, and histology in basic medical science have predictive abilities for clerkship performance above the top tertile. Using a machine learning technique based on random forest, the prediction model predicted clerkship performance with 95% accuracy and 88% AUC. CONCLUSION: Clerkship performance was predicted by selected subjects or combination of different subject categories in the pre-med and basic medical science stages. The demonstrated predictive ability of subjects or categories in the medical program may facilitate students' understanding of how these subjects or categories of the medical program relate to their performance in the clerkship to enhance their preparedness for the clerkship.

Multi-institutional beta testing of a novel cervical esophagogastric anastomosis simulator.

Objective: A novel simulator developed to offer hands-on practice for the stapled side-to-side cervical esophagogastric anastomosis was tested previously in a single-center study that supported its value in surgical education. This multi-institutional trial was undertaken to evaluate validity evidence from 6 independent thoracic surgery residency programs. Methods: After a virtual session for simulation leaders, learners viewed a narrated video of the procedure and then alternated as surgeon or first assistant. Using an online survey, perceived value was measured across fidelity domains: physical attributes, realism of materials, realism of experience, value, and relevance. Objective assessment included time, number of sutures tearing, bubble test, and direct inspection. Comparison across programs was performed using the Kruskal-Wallis test. Results: Surveys were completed by 63 participants as surgeons (17 junior and 20 senior residents, 18 fellows, and 8 faculty). For 3 of 5 tasks, mean ratings of 4.35 to 4.44 correlated with "somewhat easy" to "very easy" to perform. The interrupted outer layer of the anastomosis rated lowest, suggesting this task was the most difficult. The simulator was rated as a highly valuable training tool. For the objective measurements of performance, "direct inspection" rated highest followed by "time." A total of 90.5% of participants rated the simulator as ready for use with only minor improvements. Conclusions: Results from this multi-institutional study suggest the cervical esophagogastric anastomosis simulator is a useful adjunct for training and assessment. Further research is needed to determine its value in assessing competence for independent operating and associations between improved measured performance and clinical outcomes.

Computational pathology: A survey review and the way forward.

Computational Pathology (CPath) is an interdisciplinary science that augments developments of computational approaches to analyze and model medical histopathology images. The main objective for CPath is to develop infrastructure and workflows of digital diagnostics as an assistive CAD system for clinical pathology, facilitating transformational changes in the diagnosis and treatment of cancer that are mainly address by CPath tools. With evergrowing developments in deep learning and computer vision algorithms, and the ease of the data flow from digital pathology, currently CPath is witnessing a paradigm shift. Despite the sheer volume of engineering and scientific works being introduced for cancer image analysis, there is still a considerable gap of adopting and integrating these algorithms in clinical practice. This raises a significant question regarding the direction and trends that are undertaken in CPath. In this article we provide a comprehensive review of more than 800 papers to address the challenges faced in problem design all-the-way to the application and implementation viewpoints. We have catalogued each paper into a model-card by examining the key works and challenges faced to layout the current landscape in CPath. We hope this helps the community to locate relevant works and facilitate understanding of the field's future directions. In a nutshell, we oversee the CPath developments in cycle of stages which are required to be cohesively linked together to address the challenges associated with such multidisciplinary science. We overview this cycle from different perspectives of data-centric, model-centric, and application-centric problems. We finally sketch remaining challenges and provide directions for future technical developments and clinical integration of CPath. For updated information on this survey review paper and accessing to the original model cards repository, please refer to GitHub. Updated version of this draft can also be found from arXiv.

Recurrence of Non-Small Cell Lung Cancer With Visceral Pleural Invasion: A Seconday Analysis of a Randomized Clinical Trial.

Importance: The randomized clinical trial Cancer and Leukemia Group B (CALGB) 140503 showed that for patients with clinically staged T1N0 non-small cell lung cancer (NSCLC; ≤2 cm), sublobar resections were associated with similar oncological outcomes to those after lobar resection. The association of the extent of parenchymal resection with recurrence and survival in patients with tumors pathologically upstaged to T2 based on visceral pleural invasion (VPI) is controversial. Objective: To determine survival and recurrence rates in patients with small peripheral pT2 NSCLC (≤2 cm) that was treated by either lobar or sublobar resection in CALGB 140503. Design, Participants, and Setting: CALGB 140503, a randomized multicenter noninferiority trial, included 697 patients with small peripheral NSCLC that was clinically staged as T1N0. Enrollment was from June 2007 through March 2017 at 83 participating institutions, and after a median follow-up of 7 years, the primary outcome of disease-free survival after sublobar resection was noninferior to that after lobar resection. Intervention: Lobar or sublobar resection. Main Outcomes and Measures: Survival end points were estimated by the Kaplan-Meier estimator. Hazard ratios and 95% CIs were estimated using stratified Cox proportional hazard models. Results: Of 679 participants, 390 (57.4%) were female, and the median (range) age was 67.8 (37.8-89.7) years. Among 697 patients randomized, 566 (81.2%) had pT1 tumors (no VPI) and 113 (16.2%) had pT2 tumors (VPI). Five-year disease-free survival was 65.9% (95% CI, 61.9%-70.2%) in patients with pT1 compared with 53.3% (95% CI, 44.3%-64.1%) in patients with pT2 tumors (stratified log-rank: P = .02). Disease recurrence developed in 27.6% of patients with pT1 (locoregional only: 60 [10.8%]; distant only: 81 [14.6%]) and 41.6% of those with pT2 (locoregional only: 17 [15.0%]; distant only: 27 [23.9%]). Five-year recurrence-free survival was 73.1% (95% CI, 69.2%-77.1%) for pT1 tumors and 58.2% (95% CI, 49.2%-68.8%) for pT2 tumors (stratified log-rank: P = .01). There were no intergroup differences in disease-free or recurrence-free survival based on the extent of parenchymal resection. Conclusions and Relevance: The results of this secondary analysis suggest that compared with patients with tumors without VPI, patients who had tumors with VPI had worse disease-free and recurrence-free survival and a higher rate of local and distant disease recurrence. These high rates of recurrence were independent of the extent of parenchymal resection, and these data support the inclusion of these patients in adjuvant therapy trials. Trial Registration: ClinicalTrials.gov Identifier: NCT0049933.

Neoadjuvant nivolumab or nivolumab plus LAG-3 inhibitor relatlimab in resectable esophageal/gastroesophageal junction cancer: a phase Ib trial and ctDNA analyses.

Gastroesophageal cancer dynamics and drivers of clinical responses with immune checkpoint inhibitors (ICI) remain poorly understood. Potential synergistic activity of dual programmed cell death protein 1 (PD-1) and lymphocyte-activation gene 3 (LAG-3) inhibition may help improve immunotherapy responses for these tumors. We report a phase Ib trial that evaluated neoadjuvant nivolumab (Arm A, n = 16) or nivolumab-relatlimab (Arm B, n = 16) in combination with chemoradiotherapy in 32 patients with resectable stage II/stage III gastroesophageal cancer together with an in-depth evaluation of pathological, molecular and functional immune responses. Primary endpoint was safety; the secondary endpoint was feasibility; exploratory endpoints included pathological complete (pCR) and major pathological response (MPR), recurrence-free survival (RFS) and overall survival (OS). The study met its primary safety endpoint in Arm A, although Arm B required modification to mitigate toxicity. pCR and MPR rates were 40% and 53.5% for Arm A and 21.4% and 57.1% for Arm B. Most common adverse events were fatigue, nausea, thrombocytopenia and dermatitis. Overall, 2-year RFS and OS rates were 72.5% and 82.6%, respectively. Higher baseline programmed cell death ligand 1 (PD-L1) and LAG-3 expression were associated with deeper pathological responses. Exploratory analyses of circulating tumor DNA (ctDNA) showed that patients with undetectable ctDNA post-ICI induction, preoperatively and postoperatively had a significantly longer RFS and OS; ctDNA clearance was reflective of neoantigen-specific T cell responses. Our findings provide insights into the safety profile of combined PD-1 and LAG-3 blockade in gastroesophageal cancer and highlight the potential of ctDNA analysis to dynamically assess systemic tumor burden during neoadjuvant ICI that may open a therapeutic window for future intervention. ClinicalTrials.gov registration: NCT03044613 .

A dedicated robotic bedside physician assistant significantly enhances trainee console operating time in general thoracic surgery.

Objective: As trainees rotate through thoracic subspecialties within their curricula, a crucial portion of their robotic training consists of actual console operating time. The more time spent on the surgeon console, the greater the development will be through the course of their training. Implementing a physician assistant at the bedside may increase the operative console time for the trainee and develop robotic skills in a more expeditious rate. The objective was to evaluate the impact a designated robotic physician assistant can have on trainee console learning opportunity. Methods: Operating room data collected consisted of all robotic general thoracic surgical cases that trainees participated in with and without a physician assistant present. Metrics regarding case efficiency included anesthesia ready-to-incision, incision-to-console, and raw resident console times. By using PRISM software, a nonparametric t test was used to analyze each averaged data group compared between when a physician assistant was present and not present. Results: The mean resident console time without and with a physician assistant assist was 45.8 minutes and 80.9 minutes, respectively (P < .0001). The average portion of a case performed by a trainee similarly without and with a physician assistant present was 28.0% and 77.1%, respectively (P < .0001). Case efficiency metrics between physician assistant presence cohorts showed no difference. Conclusions: Thoracic surgical trainees have increased opportunity for robotic skill development within a fellowship or resident program curriculum when a designated robotic physician assistant is present in the operating room. These findings are significant for the improvement of residency and fellowship robotic training models moving forward by incorporating robotic-specialized physician assistants in academic institutions.

Are uroflowmetry and post - void residual urine tests necessary in children with primary nocturnal enuresis?

ABSTRACT Objectives: To examine the benefits of repetitive uroflowmetry and post void residual urine (PVR) tests in children with primary nocturnal enuresis (PNE). Material and methods: Children aged ≥6 years with PNE who visited our clinics for management of enuresis were included for study. Patients were requested to complete a questionnaire including baseline characteristics and Dysfunctional Voiding Symptom Score (DVSS), 2-day bladder diary, and Rome III criteria for constipation. Two uroflowmetry and PVR tests were requested. Children with congenital or neurogenic genitourinary tract disorders were excluded. All children underwent urotherapy and desmopressin combined with anticholinergics or laxatives if indicated. The definition of abnormal flow patterns (≥1 abnormal), elevated PVR (≥1 abnormal), small maximal voided volume (MVV), nocturnal polyuria (NP) and response to treatment complied with the ICCS standardization document. Kaplan-Meier survival analysis and Cox proportional-hazards regression tests were used to evaluate the predictors of response. Results: In total, 100 children aged 8.5±2.3 years were enrolled for study (M: F=66:34) with 7.3±7.4 months of follow-up. Poor correlation was observed between DVSS/small MVV and PVR (p>0.05). Univariate analysis revealed that elevated PVR is associated with significantly less hazard of complete response to medical treatment (HR: 0.52, p=0.03), while not significantly associated with abnormal flow patterns, NP, constipation or small MVV. Multivariate analysis revealed that only elevated PVR (HR 0.30, 95% CI 0.12-0.80) and NP (HR 2.8, 95% CI 1.10-7.28) were significant predictors for complete response. Conclusions: In managing pediatric enuresis, elevated PVR is a significant predictor for lower chance of complete response to treatment whether they had high DVSS or not.