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Abstract Anti-PD(L)-1 inhibition combined with platinum doublet chemotherapy (Chemo-IO) has become the most frequently used standard of care regimen in patients with non-small cell lung cancer (NSCLC). The negative impact of antibiotics on clinical outcomes prior to anti-PD(L)-1 inhibition monotherapy (IO) has been demonstrated in multiple studies, but the impact of antibiotic exposure prior to initiation of Chemo-IO is controversial. We assessed antibiotic exposures at two time windows: within 60 days prior to therapy (-60 d window) and within 60 days prior to therapy and 42 days after therapy (-60 + 42d window) in 2028 patients with advanced NSCLC treated with Chemo-IO and IO monotherapy focusing on objective response rate (ORR: rate of partial response and complete response), progression-free survival (PFS), and overall survival (OS). We also assessed impact of antibiotic exposure in an independent cohort of 53 patients. Univariable and multivariable analyses were conducted along with a meta-analysis from similar studies. For the -60 d window, in the Chemo-IO group (N = 769), 183 (24%) patients received antibiotics. Antibiotic exposure was associated with worse ORR (27% vs 40%, p = 0.001), shorter PFS (3.9 months vs. 5.9 months, hazard ratio [HR] 1.35, 95%CI 1.1,1.6, p = 0.0012), as well as shorter OS (10 months vs. 15 months, HR 1.50, 95%CI 1.2,1.8, p = 0.00014). After adjusting for known prognostic factors in NSCLC, antibiotic exposure was independently associated with worse PFS (HR 1.39, 95%CI 1.35,1.7, p = 0.002) and OS (HR 1.61, 95%CI 1.28,2.03, p

Abstract The ROS1 proto‐oncogene encodes a receptor tyrosine kinase with structural homology to other oncogenic drivers, including ALK and TRKA‐B‐C. The FDA‐approved tyrosine kinase inhibitors (TKIs) crizotinib and entrectinib have demonstrated efficacy in treating ROS1 fusion‐positive NSCLC. However, limitations such as poor blood‐brain barrier penetration and acquired resistance, particularly the ROS1 G2032R solvent‐front mutation, hinder treatment durability. Repotrectinib, a next‐generation macrocyclic TKI, was rationally designed to overcome on‐target resistance mutations and improve brain distribution through its low molecular weight. In the TRIDENT‐1 clinical trial, repotrectinib demonstrated significant efficacy in both TKI‐naïve and TKI‐pretreated patients with ROS1‐rearranged NSCLC, including those with CNS metastases and G2032R resistance mutations. In the TKI‐naïve cohort (n = 71), 79% of patients achieved an objective response, with a median progression‐free survival (PFS) of 35.7 months, surpassing all previously approved ROS1 TKIs. In patients who had received one prior ROS1 TKI but were chemotherapy‐naïve (n = 56), objective responses were observed in 38%, and median PFS was 9.0 months. The safety profile of repotrectinib was consistent with earlier‐generation ROS1 TKIs and common adverse events included anemia, neurotoxicity, increased creatine kinase levels, and weight gain. These findings underscore the potential of repotrectinib to address unmet needs in ROS1‐rearranged NSCLC, offering durable responses and improved intracranial activity. Future research should prioritize developing next‐generation, selective ROS1 inhibitors to reduce Trk‐mediated toxicities and improve treatment tolerance.

Introduction: NSCLC is the leading cause of cancer-related mortality. Although immune-checkpoint inhibitors (ICIs) have improved survival in patients with advanced NSCLC, treatment resistance remains a challenge. Cryoactivation, a technique inducing cell death by cycles of freezing and thawing, has the potential to augment tumor responses when combined with ICIs. Methods: This single-arm phase 1 clinical trial enrolled patients with previously untreated advanced NSCLC and 50% or higher programmed cell death ligand-1 (PD-L1). Patients underwent cryoactivation followed by ICI monotherapy initiated 5 days later. The primary end point was the objective response rate. Co-secondary end points included the safety and feasibility of the procedure and overall survival. Immune cell infiltration by immunohistochemistry was performed on paired pre- and post-treatment samples, with patients dichotomized according to clinical benefit (CB) rate (CB versus no CB [NCB]). Results: Eight patients were enrolled. Two patients achieved a partial response, yielding an objective response rate of 25%. Median progression-free survival and overall survival were 3.8 and 13.0 months, respectively. The cryoactivation procedure was well tolerated, without grade 3 to 4 adverse events. Post-hoc analysis reported a CB rate of 50%. Immunohistochemistry analysis reported a numerical difference in the cluster of differentiation 8–positive (CD8+) T cell infiltration in CB versus NCB in the pre- and post-treatment biopsies (p = 0.09) and an increase in CD8+ T cells in the post-treatment biopsies of CB versus NCB (p = 0.03). Conclusions: Although cryoactivation combined with pembrolizumab was safe and well tolerated in patients with NSCLC, therapeutic benefits were not evident compared with historical cohorts of ICI monotherapy. Correlative analyses validated CD8+ T cell recruitment in patients deriving CB.

Background: The recurrence of common bile duct stones and other biliary events after endoscopic retrograde cholangiopancreatography (ERCP) is frequent. Despite recommendations for early cholecystectomy intervention during the same admission is carried out inconsistently. Methods: We reviewed the records of patients who underwent ERCP for gallstone disease and common bile duct clearance followed by cholecystectomy between July 2012 and June 2022. Patients were divided into 2 groups: the index group underwent cholecystectomy during the same admission and the delayed group was discharged and had their cholecystectomy postponed. Data on demographics and prognosis factors were collected and analyzed. Results: The study population was composed of 268 patients, with 71 (26.6%) having undergone cholecystectomy during the same admission after common bile duct clearance with ERCP. A greater proportion of patients aged 80 years and older were in the index group than in the delayed group. The American Society of Anesthesiologists score was significantly higher in the index group. There was no significant difference between groups regarding surgical complications, open cholecystectomy and death. The operative time was significantly longer in the delayed group. Among patients with delayed cholecystectomy, 18.3% had at least 1 recurrence of common bile duct stones (CBDS) and 38.6% had recurrence of any gallstone-related events before cholecystectomy. None of these events occurred in the the index group. There was no difference in the recurrence of CBDS and other biliary events after initial diagnosis associated with stone disease. Conclusion: Cholecystectomy during the same admission after common bile duct clearance is safe, even in older adults with comorbidities. Compared with delayed cholecystectomy, it was not associated with adverse outcomes and may have prevented recurrence of biliary events. Contexte : La récurrence de la cholédocholithiase et d'autres lithiases biliaires est fréquente après la cholangiopancréatographie rétrograde endoscopique (CPRE). Même s'il est recommandé de procéder à une cholécystectomie hâtive, l'intervention n'est pas systématiquement effectuée lors d'une même admission pour CPRE. Méthodes : Nous avons passé en revue les dossiers de personnes ayant subi une CPRE pour extraction de calculs biliaires et de cholédocolithiase suivie de cholécystectomie entre juillet 2012 et juin 2022. Les cas ont été répartis en 2 groupes : le groupe index réunissait les cas ayant subi la cholécystectomie lors de la même admission, et l'autre groupe réunissait ceux dont la cholécystectomie a été faite ultérieurement. Les caractéristiques démographiques et les pronostics ont été recueillis et analysés. Résultats : La population étudiée comptait 268 personnes, dont 71 (26,6%) ont subi leur cholécystectomie lors de la même admission après la CPRE pour extraction de cholédocholithiase. Le groupe index comportait un plus grand nombre d'individus de 80 ans et plus que l'autre groupe. Le score ASA (Société américaine des anesthésiologistes) était significativement plus élevé dans le groupe index. On n'a noté aucune différence significative entre les 2 groupes aux plans des complications chirurgicales, de la cholécystectomie ouverte et de la mortalité. Le temps opératoire a été significativement plus long dans le groupe opéré ultérieurement; et chez les patients de ce groupe, 18,3% ont eu au moins 1 récurrence de cholédocolithiase (CL) et 38,6% ont eu une récurrence de lithiase biliaire avant de subir leur cholécystectomie. Aucun de ces incidents n'est survenu dans le groupe index. Il n'y a eu aucune différence quant à la récurrence des cholédocholithiases et autres lithiases biliaires après le diagnostic initial de lithiase. Conclusion : La cholécystectomie effectuée dans la foulée de l'extraction d'une cholédocholithisase est sécuritaire, même chez les patients âgés présentant des comorbidités. Comparativement à la cholécystectomie effectuée ultérieurement, elle n'a été associée à aucune complication et peut avoir contribué à prévenir une récurrence des lithiases biliaires., The presence of common bile duct stones (CBDS) in patients with gallstones is estimated to be 5%-30%. (1-6) In the era of laparoscopic cholecystectomy, endoscopic retrograde cholangiopancreatography (ERCP) and stone [...]

This article examines the use of non-English resources in academic libraries, with a focus on reference and instruction. Academic librarians from the United States and Canada were surveyed about their perceptions regarding the use of non-English resources during reference and instruction duties and the results are considered through a diversity, equity, and inclusion lens. The authors explore literature regarding the dominance of the English language in higher education, scholarly communication, and academic publishing. Library literature is also reviewed, emphasizing reference and instruction services viewed through a critical librarianship or "critlib" lens. These perspectives are applied to the survey results with a discussion of the implications for academic reference and instruction librarians. The article concludes with suggestions for areas of future research. [ABSTRACT FROM AUTHOR]

BackgroundThere is growing interest in developing impedance planimetry as a tool to enhance the clinical outcomes for endoscopic and surgical management of achalasia. The primary aim of this study was to determine whether impedance planimetry measurements can predict clinical response and reflux following peroral endoscopic myotomy (POEM).MethodsA multicenter cohort study of patients with achalasia undergoing POEM was established from prospective databases and retrospective chart reviews. Patients who underwent impedance planimetry before and after POEM were included. Clinical response was defined as an Eckardt score of ≤ 3. Tenfold cross-validated area under curve (AUC) values were established for the different impedance planimetry measurements associated with clinical response and reflux development.ResultsOf the 290 patients included, 91.7 % (266/290) had a clinical response and 39.4 % (108/274) developed reflux following POEM. The most predictive impedance planimetry measurements for a clinical response were: percent change in cross-sectional area (%ΔCSA) and percent change in distensibility index (%ΔDI), with AUCs of 0.75 and 0.73, respectively. Optimal cutoff values for %ΔCSA and %ΔDI to determine a clinical response were a change of 360 % and 272 %, respectively. Impedance planimetry values were much poorer at predicting post-POEM reflux, with AUCs ranging from 0.40 to 0.62.ConclusionPercent change in CSA and distensibility index were the most predictive measures of a clinical response, with a moderate predictive ability. Impedance planimetry values for predicting reflux following POEM showed weak predictive capacity.

Purpose: While corneal transplantation is known to have a potential risk of transmission of variant Creutzfeldt-Jacob Disease (vCJD), the magnitude of this risk has not been quantified. Observations: A case report is presented of a 73 year-old man with a penetrating keratoplasty graft from corneal tissue that was recalled after transplantation due to risk of vCJD because it was later discovered that the donor had traveled to the United Kingdom (UK). Probabilities of vCJD transmission were extrapolated using Creutzfeldt-Jacob Disease (CJD) mortality (incidence) rate, all-cause death rate, and rate of recovery for intended transplantation. Conclusions: An overestimate of the risk of transplanting a cornea infected with vCJD in 2018 was 1 in 940,000. The true risk of vCJD transmission would be even lower due to an incomplete infectivity rate. We conclude that the risk of transmission of latent vCJD by corneal transplantation from a donor who traveled to the UK from 1980 to 1996 is exceedingly low.

Understanding soil moisture dynamics at the sub-kilometre scale is increasingly important, especially with the continuous development of hyper-resolution land surface and hydrological models. Cosmic-ray neutron sensors (CRNSs) are able to provide estimates of soil moisture at this elusive scale, and networks of these sensors have been expanding across the world over the previous decade. However, each network currently implements its own protocol when processing raw data into soil moisture estimates. As a consequence, this lack of a harmonised global data set can ultimately lead to limitations in the global assessment of the CRNS technology from multiple networks. Here, we present crspy, an open-source Python tool that is designed to facilitate the processing of raw CRNS data into soil moisture estimates in an easy and harmonised way. We outline the basic structure of this tool, discussing the correction methods used as well as the metadata that crspy can create about each site. Metadata can add value to global-scale studies of field-scale soil moisture estimates by providing additional routes to understanding catchment similarities and differences. We demonstrate that current differences in processing methodologies can lead to misinterpretations when comparing sites from different networks and that having a tool to provide a harmonised data set can help to mitigate these issues. By being open source, crspy can also serve as a development and testing tool for new understanding of the CRNS technology as well as being used as a teaching tool for the community.

Monitoring the snow water equivalent (SWE) in the harsh environments of high mountain regions is a challenge. Here, we explore the use of muon counts to infer SWE. We deployed a muonic cosmic ray snow gauge (μ-CRSG) on a Swiss glacier during the snow-rich winter season 2020/21 (almost 2000 mm w.e.). The μ-CRSG measurements agree well with measurements by a neutronic cosmic ray snow gauge (n-CRSG), and they lie within the uncertainty of manual observations. We conclude that the μ-CRSG is a highly promising method to monitor SWE in remote high mountain environments with several advantages over the n-CRSG.

Background Methods Results Conclusions Intravenous immunoglobulin (IVIG) shortage represents an emerging issue in transfusion medicine. Limited data are available to determine effective strategies for optimal use. The objective of this retrospective observational study was to determine the impact of institutional measures on IVIG use at a large academic center.IVIG infusions from November 26, 2018 to September 25, 2022 were categorized according to their appropriateness (Recommended, Option of treatment, or Unrecommended), based on provincial guidelines, and separated into three phases: Reference, Transition, and Post‐Implementation phases, the latter following the adoption of restrictive measures, including mandatory standardized order forms, a blood bank gatekeeping strategy, and the creation of a stewardship committee.A total of 5431 IVIG infusions were administered to 544 patients, accounting for 295,033 g. The most common indication categories were neurology (30.4%), immunology (29.0%), and hematology (17.4%). From Reference to Post‐Implementation phase, IVIG infusions decreased from 2275 to 2000 with unrecommended indications dropping from 9.5% to 7.4% (p = 0.01), and a global reduction of 23.0% (from 131,163 g to 100,936 g of IVIG). Decrease in chronic immunomodulation accounted for 48.3% of total reduction (14,610 g of 30,227 g), whereas single‐use immunomodulation, 40.5% (12,237 g of 30,227 g). Moreover, an absolute reduction of 16.9% was observed in orders exceeding the recommended doses (20.8% to 3.9%; p < 0.0001). Together, the unrecommended and excessive IVIG doses decreased from 19,975 g (15.2%) to 6670 g (6.6%).A global reduction in IVIG use and a preferential decrease in the unrecommended orders were observed, most likely attributable to the bundle of restrictive strategies implemented. [ABSTRACT FROM AUTHOR]

The ROS1 proto‐oncogene encodes a receptor tyrosine kinase with structural homology to other oncogenic drivers, including ALK and TRKA‐B‐C. The FDA‐approved tyrosine kinase inhibitors (TKIs) crizotinib and entrectinib have demonstrated efficacy in treating ROS1 fusion‐positive NSCLC. However, limitations such as poor blood‐brain barrier penetration and acquired resistance, particularly the ROS1 G2032R solvent‐front mutation, hinder treatment durability. Repotrectinib, a next‐generation macrocyclic TKI, was rationally designed to overcome on‐target resistance mutations and improve brain distribution through its low molecular weight. In the TRIDENT‐1 clinical trial, repotrectinib demonstrated significant efficacy in both TKI‐naïve and TKI‐pretreated patients with ROS1‐rearranged NSCLC, including those with CNS metastases and G2032R resistance mutations. In the TKI‐naïve cohort (n = 71), 79% of patients achieved an objective response, with a median progression‐free survival (PFS) of 35.7 months, surpassing all previously approved ROS1 TKIs. In patients who had received one prior ROS1 TKI but were chemotherapy‐naïve (n = 56), objective responses were observed in 38%, and median PFS was 9.0 months. The safety profile of repotrectinib was consistent with earlier‐generation ROS1 TKIs and common adverse events included anemia, neurotoxicity, increased creatine kinase levels, and weight gain. These findings underscore the potential of repotrectinib to address unmet needs in ROS1‐rearranged NSCLC, offering durable responses and improved intracranial activity. Future research should prioritize developing next‐generation, selective ROS1 inhibitors to reduce Trk‐mediated toxicities and improve treatment tolerance. [ABSTRACT FROM AUTHOR]

Background: 5-FU-based chemoradiotherapy (CRT) could be associated with severe treatment-related toxicities in patients harboring at-risk DPYD polymorphisms. Methods: The studied population included consecutive patients with locoregionally advanced oropharyngeal carcinoma treated with carboplatin and 5-FU-based CRT one year before and after the implementation of upfront DPYD*2A genotyping. We aimed to determine the effect of DPYD genotyping on grade ≥3 toxicities. Results: 181 patients were analyzed (87 patients before and 94 patients following DPYD*2A screening). Of the patients, 91% (n = 86) were prospectively genotyped for the DPYD*2A allele. Of those screened, 2% (n = 2/87) demonstrated a heterozygous DPYD*2A mutation. Extended genotyping of DPYD*2A-negative patients later allowed for the retrospective identification of six additional patients with alternative DPYD variants (two c.2846A>T and four c.1236G>A mutations). Grade ≥3 toxicities occurred in 71% of the patients before DPYD*2A screening versus 62% following upfront genotyping (p = 0.18). When retrospectively analyzing additional non-DPYD*2A variants, the relative risks for mucositis (RR 2.36 [1.39–2.13], p = 0.0063), dysphagia (RR 2.89 [1.20–5.11], p = 0.019), and aspiration pneumonia (RR 13 [2.42–61.5)], p = 0.00065) were all significantly increased. Conclusion: The DPYD*2A, c.2846A>T, and c.1236G>A polymorphisms are associated with an increased risk of grade ≥3 toxicity to 5-FU. Upfront DPYD genotyping can identify patients in whom 5-FU-related toxicity should be avoided.

Grounded in situ, or invasive, cosmic ray neutron sensors (CRNSs) may allow for continuous, unattended measurements of snow water equivalent (SWE) over complete winter seasons and allow for measurements that are representative of spatially variable Arctic snow covers, but few studies have tested these types of sensors or considered their applicability at remote sites in the Arctic. During the winters of 2016/2017 and 2017/2018 we tested a grounded in situ CRNS system at two locations in Canada: a cold, low- to high-SWE environment in the Canadian Arctic and at a warm, low-SWE landscape in southern Ontario that allowed easier access for validation purposes. Five CRNS units were applied in a transect to obtain continuous data for a single significant snow feature; CRNS-moderated neutron counts were compared to manual snow survey SWE values obtained during both winter seasons. The data indicate that grounded in situ CRNS instruments appear able to continuously measure SWE with sufficient accuracy utilizing both a linear regression and nonlinear formulation. These sensors can provide important SWE data for testing snow and hydrological models, water resource management applications, and the validation of remote sensing applications.