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Unscheduled treatment interruptions may lead to reduced quality of care in radiation therapy (RT). Identifying the RT prescription dose effects on the outcome of treatment interruptions, mediated through doses distributed into different organs at risk (OARs), can inform future treatment planning. The radiation exposure to OARs can be summarized by a matrix of dose-volume histograms (DVH) for each patient. Although various methods for high-dimensional mediation analysis have been proposed recently, few studies investigated how matrix-valued data can be treated as mediators. In this paper, we propose a novel Bayesian joint mediation model for high-dimensional matrix-valued mediators. In this joint model, latent features are extracted from the matrix-valued data through an adaptation of probabilistic multilinear principal components analysis (MPCA), retaining the inherent matrix structure. We derive and implement a Gibbs sampling algorithm to jointly estimate all model parameters, and introduce a Varimax rotation method to identify active indicators of mediation among the matrix-valued data. Our simulation study finds that the proposed joint model has higher efficiency in estimating causal decomposition effects compared to an alternative two-step method, and demonstrates that the mediation effects can be identified and visualized in the matrix form. We apply the method to study the effect of prescription dose on treatment interruptions in anal canal cancer patients., (© The Author(s) 2024. Published by Oxford University Press on behalf of The International Biometric Society.)

Background: The unprecedented COVID-19 pandemic has highlighted the strategic value of wastewater-based surveillance (WBS) of SARS-CoV-2. This multisite 28-month-long study focused on WBS for older residents in 12 long-term care facilities (LTCFs) in Edmonton (AB, Canada) by assessing relationships between COVID-19, WBS, and serostatus during the pandemic., Methods: Wastewater samples collected two to three times per week were tested for SARS-CoV-2 using RT-quantitative PCR. The serostatus of antibodies was examined using immunoassays. The data of clinical COVID-19 outbreaks based on extensive testing were obtained from local public health officials. Analyses included calculating correlations between 7-day rolling averages for WBS and COVID-19 cases and investigating whether WBS led or lagged confirmed outbreaks using a multinomial test., Findings: Wastewater results correlated well with clinical COVID-19 infections and outbreaks at participating LTCFs. 1058 (36·0%) of 2936 collected wastewater samples were SARS-CoV-2 positive, compared with 1247 people (resident n=671, staff n=572, and unknown n=4) reporting positive test results of 21 673 clinical samples assessed (5·8%). WBS led clinical testing in 32 (60·4%) confirmed outbreaks, which was significantly different from WBS lagged (12 outbreaks [22·6%, 95% CI 11·3-33·7]). Non-detection of WBS SARS-CoV-2 served as a negative predictor for outbreaks. WBS results attested protective immunity in vaccinated individuals before the omicron wave. A parallel increase in the proportions of positive WBS SARS-CoV-2 and anti-nucleocapsid antibodies underlined that omicron was an immunity-evading variant despite high seropositivity of neutralising antibodies after multiple doses of vaccine., Interpretation: Implementation of WBS could enable targeted clinical investigations and improve cost-effectiveness of COVID-19 outbreak management in LTCFs. WBS and serostatus provided informed dynamic changes of infections and immunity. Critical evidence was that LTCF WBS is an effective early warning system to support rapid public health outbreak management and protect vulnerable older populations., Funding: Canadian Immunity Task Force for COVID-19 and Alberta Health., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background and Purpose: Currently, there is a lack of research directly comparing photon-counting detector CT (PCD-CT) and energy-integrating detector CT (EID-CT) in pediatric temporal bone CT imaging. The purpose of this study was to compare the image quality and radiation dose of temporal bone CT scans in pediatric patients acquired with PCD-CT and EID-CT., Materials and Methods: The retrospective study included a total of 110 pediatric temporal bone CT scans (PCD-CT, n = 52; EID-CT, n = 58). Two independent readers evaluated the spatial resolution of 4 anatomic structures (tympanic membrane, incudostapedial joint, stapedial crura, and cochlear modiolus) and overall image quality by using a 4-point scale. Interreader agreement was assessed. Dose-length product for each CT was compared, and subgroup analyses were performed based on age (younger than 3 years, 3-5 years, 6-11 years, and 12 years and above)., Results: PCD-CT demonstrated statistically significantly higher scores than EID-CT for all items (tympanic membrane, 2.9 versus 2.4; incudostapedial joint, 3.6 versus 2.6; stapedial crura, 3.2 versus 2.4; cochlear modiolus, 3.4 versus 2.8; overall image quality, 3.6 versus 2.8; P  < .05). Interreader agreement ranged from good to excellent (interclass correlation coefficients, 0.6-0.81). PCD-CT exhibited a 43% dose reduction compared with EID-CT, with a particularly substantial reduction of over 70% in the subgroups of children younger than 6 years., Conclusions: PCD temporal bone CT achieves significantly superior imaging quality at a lower radiation dose compared with EID-CT., (© 2024 by American Journal of Neuroradiology.)

Background: The causes for delays during the COVID19 pandemic and their impact on head and neck cancer (HNC) diagnosis and staging are not well described., Methods: Two cohorts were defined a priori for review and analysis-a Pre-Pandemic cohort (June 1 to December 31, 2019) and a Pandemic cohort (June 1 to December 31, 2020). Delays were categorized as COVID-19 related or not, and as clinician, patient, or policy related., Results: A total of 638 HNC patients were identified including 327 in the Pre-Pandemic Cohort and 311 in the Pandemic Cohort. Patients in the Pandemic cohort had more N2-N3 category (41% vs. 33%, p = 0.03), T3-T4 category (63% vs. 50%, p = 0.002), and stage III-IV (71% vs. 58%, p < 0.001) disease. Several intervals in the diagnosis to treatment pathway were significantly longer in the pandemic cohort as compared to the Pre-Pandemic cohort. Among the pandemic cohort, 146 (47%) experienced a delay, with 112 related to the COVID-19 pandemic; 80 (71%) were clinician related, 15 (13%) were patient related, and 17 (15%) were policy related., Conclusions: Patients in the Pandemic cohort had higher stage disease at diagnosis and longer intervals along the diagnostic pathway, with COVID-19 related clinician factors being the most common cause of delay., (© 2024 The Authors. Head & Neck published by Wiley Periodicals LLC.)

Objective: Children and youth with special health care needs (CYSHCN) require additional considerations for staying safe in emergencies. Our team of clinicians and preparedness professionals developed and tested a virtual home preparedness intervention (VHPI) in families with CYSHCN receiving care in a statewide medical home network., Methods: The VHPI comprised 1) a pre/post interview covering fire safety, emergency evacuation, sheltering in place, and informing emergency responders of the child/youth's care needs; 2) a resource packet containing emergency planning templates and information on local supports; and 3) individualized referrals coordinated through the medical home/community partners. Eligible CYSHCN had medical technology reliance, physical/mobility needs, communication/intellectual challenges, and/or vision/hearing loss. Preparedness was measured as pre/post affirmed rates of 19 items from the interview and as mean composite scores of these items; associations were evaluated using generalized estimating equations-based regression for repeated measures., Results: The pre and post-VHPI interviews were completed by 170 and 148 participants, respectively. Significant individual-item gains included having a current Emergency Information Form for the child/youth (31% [pre] to 47% [post] affirmed) and assembling an evacuation kit (50% to 68%). The mean preparedness score was 13.33/19 items affirmed at baseline and increased to 14.96 post-VHPI (P < .01). In the adjusted regression model, the post-intervention preparedness score remained significantly higher than pre-VHPI, with mean increases of 1.22 preparedness steps affirmed for homeowners and 1.85 for renters., Conclusions: Preparedness scores improved post-VHPI in families with CYSHCN. Future work should address incorporating the VHPI into care visits in the medical home., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: R Turchi: Centers for Disease Control and Prevention (CDC) funding and contract for this study, continuing medical education (CME) funding from St. Christopher's Hospital for Children to attend academic meetings, and leadership roles in the American Academy of Pediatrics, Health Resources & Services Administration Maternal and Child Health Bureau (HRSA MCHB), and Academic Pediatric Association. All other authors have no disclosure to share., (Copyright © 2024 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.)

Mitochondria require the constant import of nuclear-encoded proteins for proper functioning. Impaired protein import not only depletes mitochondria of essential factors but also leads to toxic accumulation of un-imported proteins outside the organelle. Here, we investigate the consequences of impaired mitochondrial protein import in human cells. We demonstrate that un-imported proteins can clog the mitochondrial translocase of the outer membrane (TOM). ATAD1, a mitochondrial ATPase, removes clogged proteins from TOM to clear the entry gate into the mitochondria. ATAD1 interacts with both TOM and stalled proteins, and its knockout results in extensive accumulation of mitochondrial precursors as well as decreased protein import. Increased ATAD1 expression contributes to improved fitness of cells with inefficient mitochondrial protein import. Overall, we demonstrate the importance of the ATAD1 quality control pathway in surveilling protein import and its contribution to cellular health., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective. To develop and validate a dose-of-the-day (DOTD) treatment plan verification procedure for liver and pancreas cancer patients treated with an magnetic resonance (MR)-Linac system. Approach. DOTD was implemented as an automated process that uses 3D datasets collected during treatment delivery. Particularly, the DOTD pipeline's input included the adapt-to-shape (ATS) plan-i.e. 3D-MR dataset acquired at beginning of online session, anatomical contours, dose distribution-and 3D-MR dataset acquired during beam-on (BON). The DOTD automated analysis included (a) ATS-to-BON image intensity-based deformable image registration (DIR), (b) ATS-to-BON contours mapping via DIR, (c) BON-to-ATS contours copying through rigid registration, (d) determining ATS-to-BON dosimetric differences, and (e) PDF report generation. The DIR process was validated by two expert reviewers. ATS-plans were recomputed on BON datasets to assess dose differences. DOTD analysis was performed retrospectively for 75 treatment fractions (12-liver and 5-pancreas patients). Main results. The accuracy of DOTD process relied on DIR and mapped contours quality. Most DIR-generated contours (99.6%) were clinically acceptable. DICE correlated with depreciation of DIR-based region of interest mapping process. The ATS-BON plan difference was found negligible (<1%). The duodenum and large bowel exhibited highest variations, 24% and 39% from fractional values, for 5-fraction liver and pancreas. For liver 1-fraction, a 62% variation was observed for duodenum. Significance. The DOTD methodology provides an automated approach to quantify 3D dosimetric differences between online plans and their delivery. This analysis offers promise as a valuable tool for plan quality assessment and decision-making in the verification stage of the online workflow., (© 2024 Institute of Physics and Engineering in Medicine.)

Tuberculosis (TB) continues to be a major global health burden and kills over a million people annually. New immunization strategies are required for the development of an efficacious TB vaccine that can potentially induce sterilizing immunity. In this study, we first confirmed that a live vaccine strain of Mycobacterium smegmatis , previously designated as IKEPLUS, conferred a higher survival benefit than the Bacillus Calmette-Guerin (BCG) in a murine model of intravenous Mycobacterium tuberculosis (Mtb) infection. We have shown that there was a significant increase in the expression of the Rv0282 gene, which is encoded in the esx-3 locus, which played an important role in iron uptake when IKEPLUS was grown in both low zinc and iron-containing Sauton medium. We then confirmed using in vitro assays of biofilm formation that zinc plays a vital role in the growth and formation of M. smegmatis biofilms. IKEPLUS grown in low zinc media led to the better protection of mice after intravenous challenge with a very high dosage of Mtb. We also showed that various variants of IKEPLUS induced apoptotic cell-death of infected macrophages at a higher rate than wild-type M. smegmatis . We next attempted to determine if zinc containing ribosomal proteins such as rpmb2 could contribute to protective efficacy against Mtb infection. Since BCG has an established role in anti-mycobacterial efficacy, we boosted BCG vaccinated mice with rmpb2, but this did not lead to an increment in the protection mediated by BCG.

The goal of radiation therapy for cancer is to deliver prescribed radiation dose to the tumor while minimizing dose to the surrounding healthy tissues. To evaluate treatment plans, the dose distribution to healthy organs is commonly summarized as dose-volume histograms (DVHs). Normal tissue complication probability (NTCP) modeling has centered around making patient-level risk predictions with features extracted from the DVHs, but few have considered adapting a causal framework to evaluate the safety of alternative treatment plans. We propose causal estimands for NTCP based on deterministic and stochastic interventions, as well as propose estimators based on marginal structural models that impose bivariable monotonicity between dose, volume, and toxicity risk. The properties of these estimators are studied through simulations, and their use is illustrated in the context of radiotherapy treatment of anal canal cancer patients., (© The Author(s) 2024. Published by Oxford University Press.)

Introduction: Zastaprazan is a potent potassium-competitive acid blocker developed to treat gastroesophageal reflux disease. The aim of this study was to evaluate the efficacy and safety of zastaprazan compared with esomeprazole in patient with erosive esophagitis (EE)., Methods: A phase III, multicenter, randomized, double-blind, noninferiority clinical study was conducted with 300 subjects with confirmed EE. Subjects were randomized to receive zastaprazan 20 mg or esomeprazole 40 mg once daily up to 8 weeks. The primary end point was the cumulative proportion of subject with healed EE confirmed by endoscopy at week 8. The secondary end points included the healing rate at week 4, symptom response, and quality of life assessment. Safety profiles and serum gastrin levels were also assessed., Results: In the full analysis set, the cumulative healing rate at week 8 were 97.92% (141/144) for zastaprazan and 94.93% (131/138) ( P = 0.178) for esomeprazole. The healing rate at week 4 in the zastaprazan group was higher than the esomeprazole group (95.14% [137/144] vs 87.68% [121/138]; P = 0.026). There was no significant difference between groups in healing rates (the per-protocol set) at week 8 and week 4, symptom responses, quality of life assessments, and safety profiles. In addition, serum gastrin levels increased during treatment in both groups, with a significant difference between the 2 groups ( P = 0.047), but both decreased after treatment., Discussion: An 8-week therapy of zastaprazan 20 mg is noninferior to esomeprazole 40 mg in subjects with predominantly low-grade EE. The healing rate at week 4 appears to be higher for zastaprazan than esomeprazole., (Copyright © 2024 by The American College of Gastroenterology.)

Objective: To determine how serologic responses to coronavirus disease 2019 (COVID-19) vaccination and infection in immune-mediated inflammatory disease (IMID) are affected by time since last vaccination and other factors., Methods: Post-COVID-19 vaccination, data, and dried blood spots or sera were collected from adults with rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, ankylosing spondylitis and spondylarthritis, and psoriasis and psoriatic arthritis. The first sample was collected at enrollment, then at 2 to 4 weeks and 3, 6, and 12 months after the latest vaccine dose. Multivariate generalized estimating equation regressions (including medications, demographics, and vaccination history) evaluated serologic response, based on log-transformed anti-receptor-binding domain (RBD) IgG titers; we also measured antinucleocapsid (anti-N) IgG., Results: Positive associations for log-transformed anti-RBD titers were seen with female sex, number of doses, and self-reported COVID-19 infections in 2021 to 2023. Negative associations were seen with prednisone, anti-tumor necrosis factor agents, and rituximab. Over the 2021-2023 period, most (94%) of anti-N positivity was associated with a self-reported infection in the 3 months prior to testing. From March 2021 to February 2022, anti-N positivity was present in 5% to 15% of samples and was highest in the post-Omicron era, with antinucleocapsid positivity trending to 30% to 35% or higher as of March 2023. Anti-N positivity in IMID remained lower than Canada's general population seroprevalence (> 50% in 2022 and > 75% in 2023). Time since last vaccination was negatively associated with log-transformed anti-RBD titers, particularly after 210 days., Conclusion: Ours is the first pan-Canadian IMID assessment of how vaccine history and other factors affect serologic COVID-19 vaccine responses. These findings may help individuals personalize vaccination decisions, including consideration of additional vaccination when > 6 months has elapsed since last COVID-19 vaccination/infection., (Copyright © 2024 by the Journal of Rheumatology.)

Testing for human immunodeficiency virus (HIV) and hepatitis C virus (HCV) using dried blood spot (DBS) specimens has been an integral part of bio-behavioural surveillance in Canada for almost two decades, though less is known regarding the use of DBS in surveillance of other sexually transmitted and blood-borne infections (STBBI). A systematic review was conducted using a peer-reviewed search strategy to assess the current evidence regarding the validity of STBBI testing using DBS specimens. Eligibility criteria included studies reporting use of DBS specimens for STBBI testing with either commercially available or "in-house" tests in populations 15 years of age or older. Studies reporting a measure of validity such as sensitivity, specificity, positive and negative predictive values were eligible for inclusion. Quality of studies and risk of bias were assessed using the QUADAS-2 tool. A total of 7,132 records were identified. Of these, 174 met the criteria for inclusion. Among the studies that reported validity measures, a substantial proportion demonstrated high sensitivity (≥90%) in 62.5% of cases (N = 334/534 sensitivity measurements), and high specificity (≥90%) was observed in 84.9% of instances (N = 383/451 specificity measurements). However, the quality of the studies varied greatly. Our findings support the validity of the use of DBS specimens in STBBI testing where sufficient evidence was available, but validity is highly dependent on thorough method development and validation., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Cholette et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Zastaprazan (JP-1366), a novel potassium-competitive acid blocker, is a new drug for the treatment of erosive esophagitis. JP-1366 is highly metabolized in human, mouse, and dog hepatocytes but moderately metabolized in rat and monkey hepatocytes when estimated from the metabolic stability of this compound in hepatocyte suspension and when 18 phase I metabolites and 5 phase II metabolites [i.e., N -dearylation (M6), hydroxylation (M1, M19, M21), dihydroxylation (M7, M8, M14, M22), trihydroxylation (M13, M18), hydroxylation and reduction (M20), dihydroxylation and reduction (M9, M16), hydrolysis (M23), hydroxylation and glucuronidation (M11, M15), hydroxylation and sulfation (M17), dihydroxylation and sulfation (M10, M12), N -dearylation and hydroxylation (M3, M4), N -dearylation and dihydroxylation (M5), and N -dearylation and trihydroxylation (M2)] were identified from JP-1366 incubation with the hepatocytes from humans, mice, rats, dogs, and monkeys. Based on the cytochrome P450 (CYP) screening test and immune-inhibition analysis with CYP antibodies, CYP3A4 and CYP3A5 played major roles in the metabolism of JP-1366 to M1, M3, M4, M6, M8, M9, M13, M14, M16, M18, M19, M21, and M22. CYP1A2, 2C8, 2C9, 2C19, and 2D6 played minor roles in the metabolism of JP-1366. UDP-glucuronosyltransferase (UGT) 2B7 and UGT2B17 were responsible for the glucuronidation of M1 to M15. However, JP-1366 and active metabolite M1 were not substrates for drug transporters such as organic cation transporter (OCT) 1/2, organic anion transporter (OAT) 1/3, organic anion transporting polypeptide (OATP)1B1/1B3, multidrug and toxic compound extrusion (MATE)1/2K, P-glycoprotein (P-gp), and breast cancer-resistant protein (BCRP). Only M1 showed substrate specificity for P-gp. The findings indicated that drug-metabolizing enzymes, particularly CYP3A4/3A5, may have a significant role in determining the pharmacokinetics of zastaprazan while drug transporters may only have a small impact on the absorption, distribution, and excretion of this compound.

Cytokines are small secreted proteins that have specific effects on cellular interactions and are crucial for functioning of the immune system. Cytokines are involved in almost all diseases, but as microscopic chemical compounds they cannot be visualized at imaging for obvious reasons. Several imaging manifestations have been well recognized owing to the development of cytokine therapies such as those with bevacizumab (antibody against vascular endothelial growth factor) and chimeric antigen receptor (CAR) T cells and the establishment of new disease concepts such as interferonopathy and cytokine release syndrome. For example, immune effector cell-associated neurotoxicity is the second most common form of toxicity after CAR T-cell therapy toxicity, and imaging is recommended to evaluate the severity. The emergence of COVID-19, which causes a cytokine storm, has profoundly impacted neuroimaging. The central nervous system is one of the systems that is most susceptible to cytokine storms, which are induced by the positive feedback of inflammatory cytokines. Cytokine storms cause several neurologic complications, including acute infarction, acute leukoencephalopathy, and catastrophic hemorrhage, leading to devastating neurologic outcomes. Imaging can be used to detect these abnormalities and describe their severity, and it may help distinguish mimics such as metabolic encephalopathy and cerebrovascular disease. Familiarity with the neuroimaging abnormalities caused by cytokine storms is beneficial for diagnosing such diseases and subsequently planning and initiating early treatment strategies. The authors outline the neuroimaging features of cytokine-related diseases, focusing on cytokine storms, neuroinflammatory and neurodegenerative diseases, cytokine-related tumors, and cytokine-related therapies, and describe an approach to diagnosing cytokine-related disease processes and their differentials. © RSNA, 2024 Supplemental material is available for this article.

Importance: Patients with unknown primary squamous cell carcinoma (CUP) with cervical metastases typically receive comprehensive radiotherapy (RT) of the pharynx and bilateral neck. Typically, these patients receive comprehensive RT of the pharynx and bilateral neck that may produce treatment-related toxic effects., Objective: To determine whether localization of occult oropharyngeal cancers with transoral robotic surgery (TORS) combined with reduced pharyngeal and neck RT volumes provides acceptable disease control., Design, Setting, and Participants: This phase 2, single-group nonrandomized controlled trial at a single institution accrued 32 prospective participants with p16-positive CUP without a primary squamous cell carcinoma on examination and imaging from 2017 to 2019, and 24-month follow-up. The data analysis was conducted from January 2021 to June 2022., Intervention: Diagnostic- (n = 13) or therapeutic-intent (n = 9) TORS, with pharyngeal-sparing radiotherapy (PSRT) prescribed for negative margins or pT0, and unilateral neck RT (UNRT) prescribed for unilateral lymphadenopathy with lateralized primary tumor or pT0., Main Outcomes and Measures: Out-of-radiation treatment volume failure (<15% was hypothesized to be acceptable) and reports of local and regional recurrence, overall survival, toxic effects, swallowing outcomes (per the MD Anderson Dysphagia Inventory), and videofluoroscopic swallow (per Dynamic Imaging Grade of Swallowing Toxic Effects [DIGEST]) ratings., Results: The study sample comprised 22 patients (mean [SD] age, 59.1 [5.7] years; 3 [14%] females and 19 [86%] male) with CUP. Of these, 19 patients (86%) had tumor stage cN1; 2 (9%), cN2; and 1 (5%), cN3. Five patients (23%), 14 patients (64%), and 3 patients (13%) had 0, 1, or 2 primary tumors, respectively. Twenty patients received RT; of these, 9 patients (45%) underwent PSRT and 10 patients (50%), UNRT. In the diagnostic-intent group, 8 patients (62%) and 5 patients (38%) underwent RT and RT-concurrent chemotherapy, respectively. In the therapeutic-intent group, 6 patients (67%) and 1 patient (11%) received adjuvant RT-concurrent chemotherapy, respectively; 2 patients declined RT. Two-year out-of-radiation treatment volume failure, locoregional control, distant metastasis control, and overall survival were 0%, 100%, 95%, and 100%, respectively. Grade 3 or 4 surgical, acute, and late toxic effects occurred in 2 (9%), 5 (23%), and 1 (5%) patients, respectively. PSRT was associated with lower RT dose to superior constrictors (37 vs 53 Gy; mean difference, 16 Gy; 95% CI, 6.4, 24.9), smaller decline in swallowing scores during treatment (19.3 vs 39.7; mean difference, -20.4; 95% CI, -34.1 to -6.1), and fewer patients with worsening DIGEST grade on findings of videofluoroscopic swallow studies at 2 years (0% vs 60%; difference, 60%; 95% CI, 30% to 90%)., Conclusions and Relevance: These findings indicate that TORS for p16-positive CUP allows RT volume deintensification with excellent outcomes and support future investigation in randomized clinical trials., Trial Registration: ClinicalTrials.gov Identifier: NCT03281499.

Protein phosphatase, Mg 2+ /Mn 2+ dependent 1D (PPM1D), is a serine/threonine phosphatase that is recurrently activated in cancer, regulates the DNA damage response (DDR), and suppresses the activation of p53. Consistent with its oncogenic properties, genetic loss or pharmacologic inhibition of PPM1D impairs tumor growth and sensitizes cancer cells to cytotoxic therapies in a wide range of preclinical models. Given the therapeutic potential of targeting PPM1D specifically and the DDR and p53 pathway more generally, we sought to deepen our biological understanding of PPM1D as a drug target and determine how PPM1D inhibition differs from other therapeutic approaches to activate the DDR. We performed a high throughput screen to identify new allosteric inhibitors of PPM1D, then generated and optimized a suite of enzymatic, cell-based, and in vivo pharmacokinetic and pharmacodynamic assays to drive medicinal chemistry efforts and to further interrogate the biology of PPM1D. Importantly, this drug discovery platform can be readily adapted to broadly study the DDR and p53. We identified compounds distinct from previously reported allosteric inhibitors and showed in vivo on-target activity. Our data suggest that the biological effects of inhibiting PPM1D are distinct from inhibitors of the MDM2-p53 interaction and standard cytotoxic chemotherapies. These differences also highlight the potential therapeutic contexts in which targeting PPM1D would be most valuable. Therefore, our studies have identified a series of new PPM1D inhibitors, generated a suite of in vitro and in vivo assays that can be broadly used to interrogate the DDR, and provided important new insights into PPM1D as a drug target.

Background: Pancreatic ductal adenocarcinoma (PDAC) presents significant challenges in diagnosis, staging, and appropriate treatment. Furthermore, patients with PDAC often experience complex symptomatology and psychosocial implications that require multi-disciplinary and inter-professional supportive care management from health professionals. Despite these hurdles, the implementation of inter-professional clinic approaches showed promise in enhancing clinical outcomes. To assess the effectiveness of such an approach, we examined the impact of the Wallace McCain Centre for Pancreatic Cancer (WMCPC), an inter-professional clinic for patients with PDAC at the Princess Margaret Cancer Centre (PM). Methods: This retrospective cohort study included all patients diagnosed with PDAC who were seen at the PM before (July 2012-June 2014) and after (July 2014-June 2016) the establishment of the WMCPC. Standard therapies such as surgery, chemotherapy, and radiation therapy remained consistent across both time periods. The cohorts were compared in terms of survival rates, disease stage, referral patterns, time to treatment, symptoms, and the proportion of patients assessed and supported by nursing and allied health professionals. Results: A total of 993 patients were included in the review, comprising 482 patients pre-WMCPC and 511 patients post-WMCPC. In the multivariate analysis, adjusting for ECOG (Eastern Cooperative Oncology Group) and stage, it was found that post-WMCPC patients experienced longer median overall survival (mOS, HR 0.84, 95% CI 0.72-0.98, p = 0.023). Furthermore, the time from referral to initial consultation date decreased significantly from 13.4 to 8.8 days in the post-WMCPC cohort ( p < 0.001), along with a reduction in the time from the first clinic appointment to biopsy (14 vs. 8 days, p = 0.022). Additionally, patient-reported well-being scores showed improvement in the post-WMCPC cohort ( p = 0.02), and these patients were more frequently attended to by nursing and allied health professionals ( p < 0.001). Conclusions: The implementation of an inter-professional clinic for patients diagnosed with PDAC led to improvements in overall survival, patient-reported well-being, time to initial assessment visit and pathological diagnosis, and symptom management. These findings advocate for the adoption of an inter-professional clinic model in the treatment of patients with PDAC.

Polypharmacy remains an important challenge for patients with extensive medical complexity. Given the primary care shortage and the increasing aging population, effective polypharmacy management is crucial to manage the increasing burden of care. The capacity of large language model (LLM)-based artificial intelligence to aid in polypharmacy management has yet to be evaluated. Here, we evaluate ChatGPT's performance in polypharmacy management via its deprescribing decisions in standardized clinical vignettes. We inputted several clinical vignettes originally from a study of general practicioners' deprescribing decisions into ChatGPT 3.5, a publicly available LLM, and evaluated its capacity for yes/no binary deprescribing decisions as well as list-based prompts in which the model was prompted to choose which of several medications to deprescribe. We recorded ChatGPT responses to yes/no binary deprescribing prompts and the number and types of medications deprescribed. In yes/no binary deprescribing decisions, ChatGPT universally recommended deprescribing medications regardless of ADL status in patients with no overlying CVD history; in patients with CVD history, ChatGPT's answers varied by technical replicate. Total number of medications deprescribed ranged from 2.67 to 3.67 (out of 7) and did not vary with CVD status, but increased linearly with severity of ADL impairment. Among medication types, ChatGPT preferentially deprescribed pain medications. ChatGPT's deprescribing decisions vary along the axes of ADL status, CVD history, and medication type, indicating some concordance of internal logic between general practitioners and the model. These results indicate that specifically trained LLMs may provide useful clinical support in polypharmacy management for primary care physicians., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Parent engagement and involvement is essential for the successful implementation of augmentative and alternative communication (AAC) systems in the home. The purpose of the current study is to gain a deeper understanding of caregivers' experiences with AAC systems and their collaboration with school professionals during the implementation of AAC, which may have led to subsequent abandonment., Method: This review intentionally included qualitative studies that employed semistructured interviews, focus groups, and ethnographic investigations that documented the experiences and perceptions of families implementing AAC at home. Electronic database search, ancestral search, and forward search procedures resulted in a total of 27 peer-reviewed studies portraying the voices of 319 caregivers., Results: An inductive analysis was conducted to record recurring themes into codes. The codes were thematically synthesized into three main themes: (a) the family unit, (b) the service providers, and (c) the AAC system., Conclusions: The results emphasized the need for participatory practices of family involvement in co-constructing a collaborative AAC service provision. Future research directions should implement this practice and explore the outcomes of this process to validate its efficacy.

Background: Patient-reported outcomes measures (PROM) are self-reflections of an individual's physical functioning and emotional well-being. The Edmonton Symptom Assessment Scale (ESAS) is a simple and validated PRO tool of 10 common symptoms and a patient-reported functional status (PRFS) measure. The prognostic value of this tool is unknown in patients with gastroesophageal cancer (GEC). In this study, we examined the association between the ESAS score and overall survival (OS) in patients with GEC, the prognostication difference between ESAS and Eastern Cooperative Oncology Group (ECOG), and assessed the correlation between PRFS and the physician-reported ECOG performance status (PS)., Methods: The study was a retrospective cohort study of 211 patients with GEC with localized (stages I-III) and metastatic disease who completed at least one baseline ESAS prior to treatment. Patients were grouped into 3 cohorts based on ESAS score. OS was assessed using the Kaplan-Meier method, and the concordance index (c-index) was calculated for ESAS and physician-reported ECOG. The agreement between PRFS and physician-ECOG was also assessed., Results: In total, 211 patients were included. The median age was 60.8 years; 90% of patients were ECOG PS 0-1; 38% of patients were stages I-III, while 62% were de novo metastatic patients. Median OS in low, moderate, high symptom burden (SB) patients' cohorts was 19.17 m, 16.39 mm, and 12.68 m, respectively (P < .04). The ability to predict death was similar between physician-ECOG and ESAS (c-index 0.56 and 0.5753, respectively) and PRFS and physician-ECOG (c-index of 0.5615 and 0.5545, respectively). The PS agreement between patients and physicians was 50% with a weighted Kappa of 0.27 (95% CI: 0.17-0.38)., Conclusion: Patient's SB seems to carry a prognostic significance. ESAS and physician-reported ECOG exhibit comparable prognostic values. Physicians and patients can frequently have divergent opinions on PS. ESAS takes a patient-centered approach and should be encouraged in practice among patients with GEC as an additional tool for prognostication., (© The Author(s) 2024. Published by Oxford University Press.)

Diffuse large B-cell lymphoma (DLBCL) relapses in approximately 40% of patients following frontline therapy. We reported that STAT6 D419  mutations are enriched in relapsed/refractory DLBCL (rrDLBCL) samples, suggesting that JAK/STAT signaling plays a role in therapeutic resistance. We hypothesized that STAT6 D419 mutations can improve DLBCL cell survival by reprogramming the microenvironment to sustain STAT6 activation. Thus, we investigated the role of STAT6 D419 mutations on DLBCL cell growth and its microenvironment. We found that phospho-STAT6 D419N was retained in the nucleus longer than phospho-STAT6 WT following IL-4 stimulation, and STAT6 D419N recognized a more restricted DNA-consensus sequence than STAT6 WT. Upon IL-4 induction, STAT6 D419N expression led to a higher magnitude of gene expression changes, but in a more selective list of gene targets compared with STAT WT . The most significantly expressed genes induced by STAT6 D419N were those implicated in survival, proliferation, migration, and chemotaxis, in particular CCL17. This chemokine, also known as TARC, attracts helper T-cells to the tumor microenvironment, especially in Hodgkin's lymphoma. To this end, in DLBCL, phospho-STAT6 + rrDLBCL cells had a greater proportion of infiltrating CD4 + T-cells than phospho-STAT6 - tumors. Our findings suggest that STAT6 D419 mutations in DLBCL lead to cell autonomous changes, enhanced signaling, and altered composition of the tumor microenvironment., (© 2024. The Author(s).)

Systemic inhibition of the mammalian target of rapamycin (mTOR) delays aging and many age-related conditions including arterial and metabolic dysfunction. However, the mechanisms and tissues involved in these beneficial effects remain largely unknown. Here, we demonstrate that activation of S6K, a downstream target of mTOR, is increased in arteries with advancing age, and that this occurs preferentially in the endothelium compared with the vascular smooth muscle. Induced endothelial cell-specific deletion of mTOR reduced protein expression by 60-70%. Although this did not significantly alter arterial and metabolic function in young mice, endothelial mTOR reduction reversed arterial stiffening and improved endothelium-dependent dilation (EDD) in old mice, indicating an improvement in age-related arterial dysfunction. Improvement in arterial function in old mice was concomitant with reductions in arterial cellular senescence, inflammation, and oxidative stress. The reduction in endothelial mTOR also improved glucose tolerance in old mice, and this was associated with attenuated hepatic gluconeogenesis and improved lipid tolerance, but was independent of alterations in peripheral insulin sensitivity, pancreatic beta cell function, or fasted plasma lipids in old mice. Lastly, we found that endothelial mTOR reduction suppressed gene expression of senescence and inflammatory markers in endothelial-rich (i.e., lung) and metabolically active organs (i.e., liver and adipose tissue), which may have contributed to the improvement in metabolic function in old mice. This is the first evidence demonstrating that reducing endothelial mTOR in old age improves arterial and metabolic function. These findings have implications for future drug development., (© 2023 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Background and Objective: Optimizing the extent of resection (EOR) and facial nerve outcomes (FNO) remain a challenge in medium to large vestibular schwannomas (VS). Currently, tumor size has been the only consistently reported factor predicting FNO and EOR. Here, we sought to evaluate whether the degree of the tumor's compression on the middle cerebellar peduncle (PC) influences FNO and EOR in medium to large VS., Methods: This retrospective case series included 99 patients who underwent surgical resection of their VSs from 2014 to 2022. Preoperative MR imaging was used to measure the degree of PC. Patient medical records were queried to determine the EOR and FNO., Results: Patients with unfavorable FNO (HB 3 +) immediately post-op had significantly greater PC than those with favorable FNO (19.9 vs. 15.4 mm, P = .047). This significance was not observed at the last follow-up but there was a trend. When medium-sized tumors (15-30 mm) were analyzed separately, patients with unfavorable FNO immediate post-op and at last follow-up had significantly greater PC than their favorable counterparts (14.1 vs 8.7 mm). Significantly greater PC was also observed in patients who underwent subtotal resection (20.7 mm) compared to near (14.3 mm) and gross total resection (10.8 mm). Multivariate analyses confirmed these findings in medium-sized tumors, but not large-sized tumors., Conclusion: The degree of PC as measured on preoperative imaging can predict FNO and EOR in medium-sized vestibular schwannomas. Medium-sized tumors with > 15 mm of PC likely will have worse FNO and lower EOR., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Targeted screening programs for patients at high risk for anal squamous-cell carcinoma have been proposed; however, the evidence in support of screening remains unclear., Objective: This study aimed to determine whether screening high-risk patients (predominantly those living with HIV) detected squamous-cell carcinoma at an earlier stage compared to the routine practice of not screening., Design: This is a cohort study., Settings: This study was conducted at a quaternary care center in Canada., Patients: Included patients were at least 18 years old with a pathologic diagnosis of invasive anal squamous-cell carcinoma between 2002 and 2022., Interventions: Patients diagnosed through a high-risk screening program were compared to those who did not undergo screening., Main Outcome Measures: The primary outcome was clinical stage at presentation, categorized as T1N0M0 vs other. Secondary outcomes included treatments received, treatment failure, and overall survival., Results: A total of 612 patients with anal squamous-cell carcinoma were included, with 26 of those patients diagnosed through a screening program. Patients with screen-detected cancers had greater odds of presenting with T1N0M0 tumors compared to unscreened patients (18 [69.2%] vs 84 [14.3%]; adjusted OR 9.95; 95% CI, 3.95-25.08). A propensity score-matched sensitivity analysis found similar results (OR 11.13; 95% CI, 4.67-26.52). Screened patients had greater odds of treatment with wide local excision alone, as opposed to any combination of chemotherapy, radiation therapy, and surgery (3 [12.5%] vs 18 [3.2%]; OR 4.38; 95% CI, 1.20-16.04). There were no statistically significant differences in treatment failure or overall survival between groups., Limitations: The small number of screened patients limits the power of the analysis., Conclusions: Screening for anal squamous-cell carcinoma among high-risk populations detects cancers at an earlier stage. Patients with screen-detected cancers also had a greater likelihood of being candidates for wide local excision alone, which may have spared them the morbidity associated with chemoradiotherapy or abdominoperineal resection. See Video Abstract., Cnceres De Ano En Pacientes Previamente Detectados Por Cribado Versus No Detectados Estadio Del Tumor Y Resultados Del Tratamiento: ANTECEDENTES:Se han propuesto programas de cribado dirigidos a pacientes con alto riesgo de carcinoma anal de células escamosas; sin embargo, la evidencia a favor de la detección sigue sin estar clara.OBJETIVO:Este estudio tuvo como objetivo determinar si el cribado de pacientes de alto riesgo (predominantemente aquellos que viven con el VIH) detectó el carcinoma de células escamosas en una etapa más temprana en comparación con la práctica habitual de no cribado.DISEÑO:Este es un estudio de cohortes.CONFIGURACIÓN:Este estudio se realizó en un centro de atención cuaternaria en Canadá.PACIENTES:Los pacientes incluidos tenían al menos 18 años con un diagnóstico patológico de carcinoma de células escamosas anal invasivo entre 2002 y 2022.INTERVENCIONES:Los pacientes diagnosticados mediante un programa de cribado de alto riesgo se compararon con aquellos que no se sometieron a cribado.PRINCIPALES MEDIDAS DE RESULTADO:El resultado primario fue el estadio clínico en la presentación, categorizado como T1N0M0 versus otro. Los resultados secundarios incluyeron los tratamientos recibidos, el fracaso del tratamiento y la supervivencia general.RESULTADOS:Se incluyeron un total de 612 pacientes con carcinoma anal de células escamosas, con 26 de esos pacientes diagnosticados a través de un programa de cribado. Los pacientes con cánceres detectados mediante cribado tenían mayores probabilidades de presentar tumores T1N0M0 en comparación con los pacientes no cribados (18 [69.2%] frente a 84 [14.3%]; razón de probabilidad ajustada 9.95; intervalo de confianza del 95 % 3.95 -25.08). Un análisis de sensibilidad emparejado por puntaje de propensión encontró resultados similares (odds ratio 11.13; intervalo de confianza del 95% 4.67 -26.52; p < 0.001). Los pacientes examinados tenían mayores probabilidades de recibir tratamiento con escisión local amplia sola, en comparación con cualquier combinación de quimioterapia, radiación y cirugía (3 [12.5%] frente a 18 [3.2%]; razón de probabilidad 4.38; intervalo de confianza del 95 % 1.20 -16.04). No hubo diferencias estadísticamente significativas en el fracaso del tratamiento o la supervivencia global entre los grupos.LIMITACIONES:El pequeño número de pacientes evaluados limita el poder del análisis.CONCLUSIONES:La detección del carcinoma anal de células escamosas entre las poblaciones de alto riesgo detecta los cánceres en una etapa más temprana. Los pacientes con cánceres detectados mediante cribado también tenían una mayor probabilidad de ser candidatos para una escisión local amplia sola, lo que puede haberles evitado la morbilidad asociada con la quimiorradioterapia o la resección abdominoperineal. (Traducción --Dr. Aurian Garcia Gonzalez )., (Copyright © The ASCRS 2023.)

Tuberculous meningitis (TB meningitis) is the most devastating form of tuberculosis (TB) and there is a critical need to optimize treatment. Linezolid is approved for multidrug resistant TB and has shown encouraging results in retrospective TB meningitis studies, with several clinical trials underway assessing its additive effects on high-dose (35 mg/kg/day) or standard-dose (10 mg/kg/day) rifampin-containing regimens. However, the efficacy of adjunctive linezolid to rifampin-containing first-line TB meningitis regimens and the tissue pharmacokinetics (PK) in the central nervous system (CNS) are not known. We therefore conducted cross-species studies in two mammalian (rabbits and mice) models of TB meningitis to test the efficacy of linezolid when added to the first-line TB regimen and measure detailed tissue PK (multicompartmental positron emission tomography [PET] imaging and mass spectrometry). Addition of linezolid did not improve the bactericidal activity of the high-dose rifampin-containing regimen in either animal model. Moreover, the addition of linezolid to standard-dose rifampin in mice also did not improve its efficacy. Linezolid penetration (tissue/plasma) into the CNS was compartmentalized with lower than previously reported brain and cerebrospinal fluid (CSF) penetration, which decreased further two weeks after initiation of treatment. These results provide important data regarding the addition of linezolid for the treatment of TB meningitis., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: To develop effective public health policies, programs, and services tailored to the unique sexual health needs of migrant populations, it is essential to understand the myriad socio-ecological factors that influence their sexual health. This qualitative community-based participatory study aimed to explore factors influencing migrants' sexual health at different socio-ecological levels in a Canadian setting., Methods: Participants (n = 34) from African, Caribbean, Black; Latin American; South Asian; Middle Eastern, as well as East and Southeast Asian communities were recruited across Manitoba using printed flyers, community organizations, and social media. Individual interviews, conducted in English, French, Mandarin, Cantonese, Tagalog, Arabic, Swahili, and Tigrinya languages, explored questions relating to sexual health and experiences with service providers. Data were analyzed using reflexive thematic analysis and socio-ecological systems theory., Results: The study uncovered a range of individual, interpersonal, institutional, and socio-structural factors that affect the sexual health of migrants in Manitoba. Individual factors such as sexual health knowledge and testing practices, interpersonal factors like the type of sexual partnerships, institutional factors such as sexual health information needs, language, and service access barriers, and structural-level factors like gender norms and HIV stigma exerted a significant influence on the sexual health practices of study respondents. Sexual health awareness was influenced by various factors including length of time in Canada and involvement in community-based services. Study respondents identified issues related to access to HIV testing and sexual health information, as well as language barriers, racism in healthcare, and HIV stigma. Gender and social norms played a significant role in discouraging communication about sex and safer sex practices., Conclusions: The study highlights the complex interplay of factors that influence the sexual health of migrants, and the need for targeted sexual health awareness campaigns and provision of sexual health information in languages spoken by migrants. Public health interventions focused on improving the sexual health outcomes for migrants should consider the socio-ecological elements identified in this study. These findings can inform public health campaigns to increase access to services and address sexual health inequities among migrant communities in Canada., (© 2023. The Author(s).)

Single-cell RNA sequencing (scRNA-seq) is the state-of-the-art approach to study transcriptomic signatures in individual cells in respiratory health and disease. However, classical scRNA-seq approaches provide no spatial information and are performed using either bronchoalveolar lavage fluid (BAL) or lung single cell suspensions to assess transcript levels in airway and tissue immune cells, respectively. Herein we describe a simple method to simultaneously characterize transcriptomic features of airway, lung parenchymal and intravascular immune cells based on differential in vivo labeling with barcoded antibodies. In addition to gaining basic spatial information, this approach allows for direct comparison of cells within different anatomical compartments. Furthermore, this method provides a time- and cost-effective alternative to classical scRNA-seq where lung and BAL samples are processed individually, reducing animal and reagent use. We demonstrate the feasibility of this approach in a preclinical mouse model of bacterial lung infection comparing airway, parenchymal and vasculature neutrophils early after infection., Competing Interests: Authors BM, JK, YS, TW, and AD were employed by the company AstraZeneca. The authors declare that this study received funding from AstraZeneca. The funder had the following involvement in the study: all authors are employed by the funder., (Copyright © 2023 Mindt, Kim, Warren, Song and DiGiandomenico.)

Conventional water treatment practices utilizing chemical disinfection, especially chlorination, are considered generally effective in producing microbiologically safe drinking water. However, protozoan pathogens such as oocysts of Cryptosporidium parvum are very resistant to chlorine, which has led to consideration of alternative disinfectants for their control. Free bromine, HOBr, has not been evaluated extensively as an alternative halogen disinfectant for inactivation of Cryptosporidium parvum in drinking water or reclaimed water for non-potable uses. Bromine is a versatile disinfectant consisting of different chemical forms with persistent microbicidal efficacy under varied water quality conditions and is effective against a range of waterborne microbes of health concern. The objectives of this study are to (1) compare the efficacy of free bromine to free chlorine at similar concentrations (as milligrams per liter) for disinfection of Cryptosporidium parvum oocysts, Bacillus atrophaeus spores, and MS2 coliphage in a model buffered water and (2) evaluate the kinetics of inactivation of these microorganisms using appropriate disinfection models. Overall, at a target concentration of ∼5 mg/L, bromine averaged 0.6 log (73.8%) reductions of C. parvum oocyst infectivity after 300 min (CT: 1166 min·mg/L) and produced up to a 0.8 log reduction disinfectant activity. An ∼5.0 mg/L chlorine dose increased oocyst infectivity by only 0.4 log (64%) after 300 min (CT: 895 min·mg/L). Bacillus atrophaeus spores and MS2 coliphage treated with bromine and chlorine were reduced by 4 log 10 (99.99%) for both disinfectants over the duration of the experiments.

Oral toxicities such as osteoradionecrosis can be minimized by dental screening and prophylactic dental care prior to head and neck (HN) radiation therapy (RT). However, limited information is available about how dental insurance interacts with prophylactic dental care and osteoradionecrosis. To address this gap in knowledge, we conducted a cohort study of 2743 consecutive adult patients treated with curative radiation for HN malignancy who underwent pre-radiation dental assessment and where required, prophylactic dental treatment. Charts were reviewed to determine patient demographics, dental findings, dental treatment and development of osteoradionecrosis following radiation. Three insurance cohorts were identified: private-insured (50.4 %), public-insured (7.3 %), being patients with coverage through government-funded disability and welfare programs, and self-pay (42.4 %). More than half the public-insured patients underwent prophylactic pre-radiation dental extractions, followed by self-pay patients (44 %) and private-insured patients (26.6 %). After a median follow-up time of 4.23 years, 6.5 % of patients developed osteoradionecrosis. The actuarial rate of osteoradionecrosis in the public-insured patients was 14.7 % at 5-years post-RT, compared to 7.5 % in private-insured patients and 6.7 % in self-pay patients. On multivariable analysis, dental insurance status, DMFS160, age at diagnosis, sex, tumor site, nodal involvement, years smoked and gross income were all significant risk factors for tooth removal prior to HN radiation. However, only public-insured status, tumor site and years smoked were significant risk factors for development of osteoradionecrosis. Our findings demonstrate that lack of comprehensive dental coverage (patients who self-pay or who have limited coverage under public-insured programs) associates strongly with having teeth removed prior to HN RT. Nearly 1 in 6 patients covered under public-insurance developed osteoradionecrosis within 5 years of completing their treatment. Well-funded dental insurance programs for HN cancer patients might reduce the number of pre-RT extractions performed in these patients, improving quality of life post-RT., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: Despite rising popularity and performance, studies evaluating the use of large language models for clinical decision support are lacking. Here, we evaluate ChatGPT (Generative Pre-trained Transformer)-3.5 and GPT-4's (OpenAI, San Francisco, California) capacity for clinical decision support in radiology via the identification of appropriate imaging services for two important clinical presentations: breast cancer screening and breast pain., Methods: We compared ChatGPT's responses to the ACR Appropriateness Criteria for breast pain and breast cancer screening. Our prompt formats included an open-ended (OE) and a select all that apply (SATA) format. Scoring criteria evaluated whether proposed imaging modalities were in accordance with ACR guidelines. Three replicate entries were conducted for each prompt, and the average of these was used to determine final scores., Results: Both ChatGPT-3.5 and ChatGPT-4 achieved an average OE score of 1.830 (out of 2) for breast cancer screening prompts. ChatGPT-3.5 achieved a SATA average percentage correct of 88.9%, compared with ChatGPT-4's average percentage correct of 98.4% for breast cancer screening prompts. For breast pain, ChatGPT-3.5 achieved an average OE score of 1.125 (out of 2) and a SATA average percentage correct of 58.3%, as compared with an average OE score of 1.666 (out of 2) and a SATA average percentage correct of 77.7%., Discussion: Our results demonstrate the eventual feasibility of using large language models like ChatGPT for radiologic decision making, with the potential to improve clinical workflow and responsible use of radiology services. More use cases and greater accuracy are necessary to evaluate and implement such tools., (Copyright © 2023 American College of Radiology. Published by Elsevier Inc. All rights reserved.)

Aim: Extracorporeal membrane oxygenation (ECMO) may be beneficial in treatment of massive pulmonary embolus (PE), however the current evidence to guide its use is limited. We aimed to compare the incidence, characteristics, treatments, and outcomes of patients with massive PE by mode of ECMO from a large international registry., Methods: Retrospective observational study of the Extracorporeal Life Support Organization (ELSO) database., Results: A total of 821 patients underwent 833 ECMO episodes for PE. Mean age was 49 (±15) years, 408 (50.1%) were female, and 450 (54.7%) had a cardiac arrest prior to ECMO initiation. Venoarterial (VA) ECMO was the most common mode in 489 (58.7%), followed by extracorporeal cardiopulmonary resuscitation (ECPR) in 229 (27.4%) and venovenous (VV) ECMO in 85 (10.2%). The number of episodes per year increased over the study period, predominantly driven by an increase in ECPR. In-hospital mortality was the highest for ECPR 156/229 (68.1%), followed by VA ECMO 209/498 (42.7%) and VV ECMO 24/85 (28.2%) P < 0.001. After controlling for univariate and clinically significant variables at the time of ECMO initiation, increasing age (OR 1.02 (1.00-1.03), lower pH (OR 0.18 (0.03-0.44), lower diastolic blood pressure (OR 0.99 (0.97-1.00) and ECPR mode (OR 3.67 (1.46-9.230) were independently associated with in-hospital mortality., Conclusion: ECMO use for massive PE is increasing globally, and overall mortality rates compare favorably with other indications of ECMO. The use of ECPR and worsening metabolic status at initiation were associated with higher in-hospital mortality, suggesting delays in initiating ECMO should be avoided., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Study Design: Systematic review and meta-analysis., Objectives: To evaluate outcomes of surgical treatment for nephrolithiasis in individuals with spinal cord injury (SCI)., Methods: We systematically reviewed the Ovid MEDLINE, Embase, CENTRAL, and Web of Science databases for studies examining outcomes of kidney stone procedures in individuals with SCI. Our primary outcomes were stone-free rate (SFR) and complications as categorized by Clavien-Dindo classification. A meta-analysis of comparative studies was performed to assess differences in SFR and complication rate between individuals with and without SCI following PCNL., Results: A total of 27 retrospective and observational articles were included. Interventions for kidney stones included PCNL, shockwave lithotripsy (SWL), and ureteroscopy. Pooled SFR in individuals with SCI was 54%, for SWL, 74% for PCNL, and 36% for ureteroscopy. Meta-analyses found that there was higher rate of grades I (OR 9.54; 95% CI, 3.06 to 29.79), II (OR 3.38; 95% CI, 1.85 to 6.18), and III-V (OR 2.38; 95% CI, 1.35 to 4.19) complications in individuals with SCI compared to non-SCI individuals following PCNL. The rate of infectious complications was also higher in individuals with SCI (OR 6.15; 95% CI, 1.86 to 20.39). However, there was no difference in SFR (OR 0.64; 95% CI, 0.15 to 2.64) between groups., Conclusions: Individuals with SCI are at higher risk of minor, major, and infectious complications following PCNL compared to non-SCI individuals. There was no significant difference between groups in SFR following PCNL, suggesting that PCNL is an effective surgery for kidney stones in individuals with SCI., (© 2023. The Author(s), under exclusive licence to International Spinal Cord Society.)

Background: Large language model (LLM)-based artificial intelligence chatbots direct the power of large training data sets toward successive, related tasks as opposed to single-ask tasks, for which artificial intelligence already achieves impressive performance. The capacity of LLMs to assist in the full scope of iterative clinical reasoning via successive prompting, in effect acting as artificial physicians, has not yet been evaluated., Objective: This study aimed to evaluate ChatGPT's capacity for ongoing clinical decision support via its performance on standardized clinical vignettes., Methods: We inputted all 36 published clinical vignettes from the Merck Sharpe & Dohme (MSD) Clinical Manual into ChatGPT and compared its accuracy on differential diagnoses, diagnostic testing, final diagnosis, and management based on patient age, gender, and case acuity. Accuracy was measured by the proportion of correct responses to the questions posed within the clinical vignettes tested, as calculated by human scorers. We further conducted linear regression to assess the contributing factors toward ChatGPT's performance on clinical tasks., Results: ChatGPT achieved an overall accuracy of 71.7% (95% CI 69.3%-74.1%) across all 36 clinical vignettes. The LLM demonstrated the highest performance in making a final diagnosis with an accuracy of 76.9% (95% CI 67.8%-86.1%) and the lowest performance in generating an initial differential diagnosis with an accuracy of 60.3% (95% CI 54.2%-66.6%). Compared to answering questions about general medical knowledge, ChatGPT demonstrated inferior performance on differential diagnosis (β=-15.8%; P<.001) and clinical management (β=-7.4%; P=.02) question types., Conclusions: ChatGPT achieves impressive accuracy in clinical decision-making, with increasing strength as it gains more clinical information at its disposal. In particular, ChatGPT demonstrates the greatest accuracy in tasks of final diagnosis as compared to initial diagnosis. Limitations include possible model hallucinations and the unclear composition of ChatGPT's training data set., (©Arya Rao, Michael Pang, John Kim, Meghana Kamineni, Winston Lie, Anoop K Prasad, Adam Landman, Keith Dreyer, Marc D Succi. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 22.08.2023.)

A promising new field of genetically encoded ultrasound contrast agents in the form of gas vesicles has recently emerged, which could extend the specificity of medical ultrasound imaging. However, given the delicate genetic nature of how these genes are integrated and expressed, current methods of producing gas vesicle-expressing mammalian cell lines requires significant cell processing time to establish a clonal/polyclonal line that robustly expresses the gas vesicles sufficiently enough for ultrasound contrast. Here, we describe an inducible and drug-selectable acoustic reporter gene system that can enable gas vesicle expression in mammalian cell lines, which we demonstrate using HEK293T cells. Our drug-selectable construct design increases the stability and proportion of cells that successfully integrate all plasmids into their genome, thus reducing the amount of cell processing time required. Additionally, we demonstrate that our drug-selectable strategy forgoes the need for single-cell cloning and fluorescence-activated cell sorting, and that a drug-selected mixed population is sufficient to generate robust ultrasound contrast. Successful gas vesicle expression was optically and ultrasonically verified, with cells expressing gas vesicles exhibiting an 80% greater signal-to-noise ratio compared to negative controls and a 500% greater signal-to-noise ratio compared to wild-type HEK293T cells. This technology presents a new reporter gene paradigm by which ultrasound can be harnessed to visualize specific cell types for applications including cellular reporting and cell therapies., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors. Bioengineering & Translational Medicine published by Wiley Periodicals LLC on behalf of American Institute of Chemical Engineers.)

Meningeal lesions can be caused by various conditions and pose diagnostic challenges. The authors review the anatomy of the meninges in the brain and spinal cord to provide a better understanding of the localization and extension of these diseases and summarize the clinical and imaging features of various conditions that cause dural and/or leptomeningeal enhancing lesions. These conditions include infectious meningitis (bacterial, tuberculous, viral, and fungal), autoimmune diseases (vasculitis, connective tissue diseases, autoimmune meningoencephalitis, Vogt-Koyanagi-Harada disease, neuro-Behçet syndrome, Susac syndrome, and sarcoidosis), primary and secondary tumors (meningioma, diffuse leptomeningeal glioneuronal tumor, melanocytic tumors, and lymphoma), tumorlike diseases (histiocytosis and immunoglobulin G4-related diseases), medication-induced diseases (immune-related adverse effects and posterior reversible encephalopathy syndrome), and other conditions (spontaneous intracranial hypotension, amyloidosis, and moyamoya disease). Although meningeal lesions may manifest with nonspecific imaging findings, correct diagnosis is important because the treatment strategy varies among these diseases. © RSNA, 2023 Online supplemental material and the slide presentation from the RSNA Annual Meeting are available for this article. Quiz questions for this article are available through the Online Learning Center.

Acute infections of the oral cavity and suprahyoid neck range from simple superficial conditions that can be treated as an outpatient to complex multispatial processes that require surgical intervention and inpatient admission. This article provides an imaging overview of the range of infections in this region that may be encountered by oral and maxillofacial surgeons, emergency physicians, and primary care providers., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: This study compared the dynamic susceptibility contrast (DSC) magnetic resonance imaging parameters and apparent diffusion coefficient (ADC) between pilocytic astrocytoma (PA) and diffuse midline glioma, H3K27-altered (DMG) variants., Methods: The normalized relative cerebral blood volume (nrCBV), normalized relative flow (nrCBF), percentile signal recovery (PSR), and normalized mean ADC (nADCmean) of 23 patients with midline PAs (median age, 13 years [range, 1-71 years]; 13 female patients) and 40 patients with DMG (8.5 years [1-35 years]; 19 female patients), including 35 patients with H3.3- and five patients with H3.1-mutant tumors, treated between January 2016 and May 2022 were statistically compared., Results: DMG had a significantly lower nADCmean (median: 1.48 vs. 1.96; p = 0.00075) and lower PSR (0.97 vs. 1.23, p = 0.13) but higher nrCBV and nrCBF (1.66 vs. 1.17, p = 0.058, respectively, and 1.87 vs. 1.19, p = 0.028, respectively) than PA. The H3.3 variant had a lower nADCmean than the H3.1 variant (1.46 vs. 1.80, p = 0.10)., Conclusion: DMG had lower ADC and PSR and higher rCBV and rCBF than PA. The H3.3 variant had a lower ADC than the H3.1 variant. Recognizing the differences and similarities in the DSC parameters and ADC between these tumors may help presurgical diagnosis., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Kurokawa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The global prevalence of GERD is substantially increasing each year, and GERD is a chronic disease that reduces the quality of life of patients. The efficacy of conventional drugs is diverse, and most require long-term or lifetime administration; thus, the development of more effective therapeutic agents is needed. Herein, a more effective treatment for GERD was tested. We investigated whether JP-1366 affected gastric H+/K+-ATPase activity and used the Na+/K+-ATPase assay to confirm the selectivity of H+/K+-ATPase inhibition. To clarify the mechanism of enzyme inhibition, JP-1366 and TAK-438 were analyzed by Lineweaver-Burk. Also, we investigated the effects of JP-1366 in various models involving reflux esophagitis. We found that JP-1366 mediates strong, selective, and dose-dependent inhibition of H+/K+-ATPase. We found that JP-1366 significantly suppressed gastric acid secretion in histamine-treated pylorus-ligated rats in a dose-dependent manner. Additionally, we confirmed that JP-1366 inhibited histamine-stimulated gastric acid secretion in the HPD model. JP-1366 exhibited a more than 2-fold higher inhibitory effect on esophageal injury than TAK-438 in GERD lesions and had a more potent inhibitory effect in indomethacin- or aspirin-induced gastric ulcer rat models than TAK-438. Additionally, JP-1366 inhibited gastric ulcers. These results support the possibility that JP-1366 is a good candidate drug for treating acid-related diseases., (© 2023 Onconic Therapeutics. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

Importance: The long-term outcomes associated with adding bevacizumab, a vascular endothelial growth factor inhibitor, to standard chemoradiation have continued to be favorable for a group of patients with locoregionally advanced nasopharyngeal carcinoma (NPC)., Objective: To assess long-term toxic effects and clinical outcomes associated with chemotherapy, radiation therapy (RT), and bevacizumab for NPC., Design, Setting, and Participants: This single-arm phase II nonrandomized controlled trial was conducted by the National Cancer Trials Network group and NRG Oncology (formerly Radiation Therapy Oncology Group), with accrual from December 13, 2006, to February 5, 2009, and data analysis from June 26 to July 1, 2019. The study was conducted at 19 cancer centers with a median (IQR) follow-up of 9.0 (7.7-9.3) years. Included patients were adults (aged ≥18 years) with NPC that was World Health Organization (WHO) histologic grade I to IIb or III, American Joint Committee on Cancer stage IIB or greater, and with or without lymph node involvement., Interventions: Patients received 3 cycles of bevacizumab (15 mg/kg) concurrently with standard cisplatin (100 mg/m2) and RT (69.96 Gy) followed by 3 cycles of adjuvant bevacizumab (15 mg/kg) given concurrently with cisplatin (80 mg/m2) and fluorouracil (1000 mg/m2/d)., Main Outcomes and Measures: The primary end point was grade 4 hemorrhage or grade 5 adverse events in the first year. Secondary end points were locoregional progression-free (LRPF) interval, distant metastasis-free (DMF) interval, progression-free survival (PFS), overall survival (OS), and other adverse events. Long-term toxic effects and clinical outcomes were reported due to the limited follow-up in the initial report for this trial and the importance of long-term outcomes when combining bevacizumab with chemoradiation., Results: Among 46 patients with NPC who were enrolled, 44 patients were analyzed (29 males [65.9%]; 23 Asian [52.3%], 2 Black [4.5%], and 16 White [36.4%]; 38 not Hispanic [86.4%]; median [IQR] age, 48.5 [39.0-56.0] years). There were 33 patients with a Zubrod performance status of 0, indicating that they were fully functional and asymptomatic (75.0%); 32 patients with a WHO histologic grade of IIb or III (72.7%); and 39 patients with stage III or IVB disease (88.6%). Among analyzed patients, 42 individuals received radiation therapy of 69.96 Gy or greater (95.5%; dose range, 65.72-70.00 Gy); 30 patients received 3 cycles of cisplatin (68.2%) with RT, and 31 patients received 3 cycles of bevacizumab with RT (70.5%); this was followed by 3 cycles of adjuvant cisplatin in 21 patients (47.7%), fluorouracil in 24 patients (54.5%), and bevacizumab in 23 patients (52.3%). No grade 4 hemorrhage or grade 5 AEs were reported in the first year or thereafter. Late grade 3 AEs occurred in 16 patients (36.4%), including 7 patients with dysphagia (15.9%), 6 patients with hearing impairment (13.6%), and 2 patients with dry mouth (4.5%). The 1- and 5-year rates of feeding tube use were 5 of 41 patients (12.2%) and 0 of 27 patients, respectively. There were 19 patients (43.2%) who progressed or died without disease progression (6 patients with locoregional progression [13.6%], 8 patients with distant progression [18.2%], and 5 patients who died without progression [11.4%]). The 5- and 7-year rates were 79.5% (95% CI, 67.6%-91.5%) and 69.7% (95% CI, 55.9%-83.5%) for OS, 61.2% (95% CI, 46.8%-75.6%) and 56.3% (95% CI, 41.5%-71.1%) for PFS, 74.9% (95% CI, 61.4%-86.6%) and 72.3% (95% CI, 58.4%-84.7%) for LRPF interval, and 79.5% (95% CI,66.4%-90.0%) for both times for DMF interval. Among 13 patients who died, death was due to disease in 8 patients (61.5%)., Conclusions and Relevance: In this nonrandomized controlled trial, no grade 4 hemorrhage or grade 5 AEs were reported in the first year or thereafter among patients with NPC receiving bevacizumab combined with chemoradiation. The rate of distant metastasis was low although 89% of patients had stage III to IVB disease, suggesting that further investigation may be warranted., Trial Registration: ClinicalTrials.gov Identifier: NCT00408694.

Ectopic tissue is an anatomic abnormality in which tissue develops in an area outside its normal location. It is primarily caused by abnormalities during the process of embryologic development. Although the majority of individuals with ectopic tissues remain asymptomatic, various symptoms and associated complications can occur. Failure in normal embryologic development leads to loss of normal physiologic function or may result in harmful functions such as ectopic hormonal secretion in the ectopic pituitary adenoma. Ectopic tissues may also frequently mimic tumors. For example, developmental abnormalities in the pharyngeal pouches may result in an ectopic parathyroid gland and ectopic thymus, both of which are frequently misdiagnosed as tumors. Adequate knowledge of embryology is essential for understanding the differential diagnoses of ectopic tissues and facilitating appropriate management. The authors summarize the embryologic development and pathogenesis of ectopic tissues by using illustrations to facilitate a deeper understanding of embryologic development and anatomy. Characteristic imaging findings (US, CT, MRI, and scintigraphy) are described for ectopic tissues of the brain, head, neck, thorax, abdomen, and pelvis by focusing on common conditions that radiologists may encounter in daily practice and their differential diagnoses. © RSNA, 2023 Quiz questions for this article are available through the Online Learning Center.

Introduction: Tranexamic acid (TXA) is an antifibrinolytic agent widely used in surgery to decrease bleeding and reduce the need for blood product transfusion. The role of TXA in urology is not well-summarized. We conducted a systematic review of studies reporting outcomes of TXA use in urological surgery., Methods: A comprehensive search was conducted from the following databases: PubMed, Embase, Cochrane Library, and Web of Science. Two reviewers performed title and abstract screening, full-text review, and data collection. Primary outcomes included estimated blood loss (EBL), decrease in hemoglobin, decrease in hematocrit, and blood transfusion rates. Secondary outcomes included TXA administration characteristics, length of stay, operative time, and postoperative thromboembolic events., Results: A total of 26 studies consisting of 3261 patients were included in the final analysis. These included 11 studies on percutaneous nephrolithotomy, 10 on transurethral resection of prostate, three on prostatectomy, and one on cystectomy. EBL, transfusion rate, hemoglobin drop, operative time, and length of stay were significantly improved with TXA administration. In addition, the use of TXA was not associated with an increased risk of venous thromboembolism (VTE ). The route, dosage, and timing of TXA administration varied considerably between included studies., Conclusions: TXA use may improve blood loss, transfusion rates, and perioperative parameters in urological procedures. In addition, there is no increased risk of VTE associated with TXA use in urological surgery; however, there is still a need to determine the most effective TXA administration route and dose. This review provides evidence-based data for decision-making in urological surgery.

Objective: Among persons with immune-mediated inflammatory diseases (IMIDs) who received SARS - CoV-2 vaccines, we compared postvaccine antibody responses and IMID disease activity/states., Design: Single-centre prospective cohort study., Setting: Specialty ambulatory clinics in central Canada., Participants: People with inflammatory arthritis (n=78; 77% rheumatoid arthritis), systemic autoimmune rheumatic diseases (n=84; 57% lupus), inflammatory bowel disease (n=93; 43% Crohn's) and multiple sclerosis (n=72; 71% relapsing-remitting) (female 79.4%, white 84.7%, mean (SD) age 56.0 (14.3) years) received COVID-19 vaccinations between March 2021 and September 2022., Primary Outcome: Postvaccination anti-spike, anti-receptor binding domain (anti-RBD) and anti-nucleocapsid (anti-NC) IgG antibodies tested by multiplex immunoassays compared across vaccine regimens and with responses in 370 age-matched and sex-matched vaccinated controls., Secondary Outcomes: COVID-19 infection and self-reported IMID disease activity/state., Results: Most (216/327, 66.1%) received homologous messenger RNA (mRNA) (BNT162b2 or mRNA1273) vaccines, 2.4% received homologous ChAdOx1 and 30.6% received heterologous vaccines (23.9% ChAdOx1/mRNA, 6.4% heterologous mRNA) for their first two vaccines (V1, V2). Seroconversion rates were 52.0% (91/175) for post-V1 anti-spike and 58.9% (103/175) for anti-RBD; 91.5% (214/234) for post-V2 anti-spike and 90.2% (211/234) for anti-RBD; and were lower than controls (post-V2 anti-spike 98.1% (360/370), p<0.0001). Antibody titres decreased 3 months after V2 but increased 1 month after the third vaccine (V3) and 1 month after the fourth vaccine (V4) (BAU/mL median (IQR), anti-spike 1835 (2448) 1 month post-V2, 629.1 (883.4) 3 months post-V2, 4757.5 (7033.1) 1 month post-V3 and 4356.0 (9393.4) 1 month post-V4; anti-RBD 1686.8 (2199.44) 1 month post-V2, 555.8 (809.3) 3 months post-V2, 4280.3 (6380.6) 1 month post-V3 and 4792.2 (11 673.78) 1 month post-V4). If primed with a vector vaccine, an mRNA vaccine increased antibody titres to those comparable to homologous mRNA vaccines. Anti-RBD and anti-spike titres were higher in anti-NC seropositive (n=31; 25 participants) versus seronegative samples (BAU/mL median (IQR) anti-RBD 11 755.3 (20 373.1) vs 1248.0 (53 278.7); anti-spike 11 254.4 (15 352.6) vs 1313.1 (3106.6); both p<0.001). IMID disease activity/state and rates of self-reported moderate or severe IMID flare were similar across vaccinations., Conclusion: Heterologous COVID-19 vaccination improves seroconversion rates following a vector vaccine and does not lead to IMID disease flare. IMIDs benefit from at least three vaccines., Competing Interests: Competing interests: CAH: unrelated grant funding from Pfizer; advisory board for AstraZeneca Canada for unrelated product; unrelated research funds from Research Manitoba, Health Science Center Foundation and International League of Associations for Rheumatology; and unrelated educational funds from the Royal College of Physicians and Surgeons of Canada. RAM: receives research funding from CIHR, Research Manitoba, Multiple Sclerosis Society of Canada, Multiple Sclerosis Scientific Foundation, Crohn’s and Colitis Canada, National Multiple Sclerosis Society, CMSC, Arthritis Society, Brain Canada, and US Department of Defense; coinvestigator on a study funded in part by Biogen Idec and Roche Canada; and supported by the Waugh Family Chair in Multiple Sclerosis. CNB: supported by the Bingham Chair in Gastroenterology; has served on advisory boards for AbbVie Canada, Amgen Canada, Bristol Myers Squibb Canada, Roche Canada, Janssen Canada, Sandoz Canada, Takeda Canada and Pfizer Canada; consultant for Mylan Pharmaceuticals and Takeda; educational grants from AbbVie Canada, Pfizer Canada, Takeda Canada and Janssen Canada; speaker’s panel for AbbVie Canada, Janssen Canada, Pfizer Canada and Takeda Canada; and received research funding from AbbVie Canada, Bristol Myers Squibb Canada, Sandoz Canada and Pfizer Canada. CC: receives grant funding from PHAC and CITF through internal research funding streams at PHAC. JK: receives grant funding from PHAC through internal research funding streams at PHAC., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: To retrospectively review the clinical outcomes of patients with metastatic breast cancer (MBCa) following liver directed ablative intent radiotherapy (RT)., Methods: Demographics, disease and treatment characteristics of patients with MBCa who received liver metastasis (LM) directed ablative RT between 2004-2020 were analysed. The primary outcome was local control (LC), secondary outcomes included overall survival (OS) and progression-free survival (PFS) analyzed by univariate (UVA) and multi-variable analysis (MVA)., Results: Thirty MBCa patients with 50 LM treated with 5-10 fraction RT were identified. Median follow-up was 14.6 (range 0.9-156.2) months. Class of metastatic disease was described as induced (12 patients, 40%), repeat (15 patients, 50%) and de novo (three patients, 10%). Median size of treated LM was 3.1 cm (range 1-8.8 cm) and median biologically effective dose delivered was 122 (Q1-Q3; 98-174) Gy 3 . One-year LC rate was 100%. One year and two-year survival was 89% and 63%, respectively, with size of treated LM predictive of OS (HR 1.35, p = 0.023) on UVA. Patients with induced OMD had a significantly higher rate of progression (HR 4.77, p = 0.01) on UVA, trending to significance on MVA (HR 3.23, p = 0.051)., Conclusions: Hypo-fractionated ablative liver RT in patients with MBCa provides safe, tolerable treatment with excellent LC.

Background and Purpose: CNS neuroblastoma, FOXR2-activated (CNS NB-FOXR2) is a newly recognized tumor type in the 2021 World Health Organization classification of central nervous system (CNS) tumors. We aimed to investigate the clinical and neuroimaging findings of CNS NB-FOXR2 and systematically review previous publications and three new cases., Methods: We searched PubMed, SCOPUS, and Embase databases for patients with pathologically proven CNS NB-FOXR2 with sufficient information for preoperative CT and MRI findings. Two board-certified radiologists reviewed the studies and imaging data., Results: Thirty-one patients from six previous publications and 3 patients from our hospital comprised the study population (median age, 4.2 [range: 1.4-16] years; 19 girls). Clinically, CNS NB-FOXR2 mainly affected children between 2 and 6 years (24/34, 67.6%). Nausea/vomiting and seizures were reported as the main presenting symptoms (100% in total). The tumors frequently showed hyperdensity compared to the cortex on nonenhanced CT (4/5, 80%) with calcification along the inner rim of the tumor (4/5, 80%). More than half of patients showed susceptibility artifacts indicating intratumoral hemorrhage and/or calcification (15/28, 53.6%) on T2*- and/or susceptibility-weighted imaging. Elevated relative cerebral blood volume and flow and percentile signal recovery were observed in one case with dynamic susceptibility contrast MRI., Conclusions: Characteristic imaging features including hyperdense attenuation of the solid components and calcification along the inner rim on CT and susceptibility-weighted imaging may assist with preoperative diagnosis of CNS NB-FOXR2 in pediatric patients., (© 2023 The Authors. Journal of Neuroimaging published by Wiley Periodicals LLC on behalf of American Society of Neuroimaging.)

Background: Zastaprazan (JP-1366) is a novel potassium-competitive acid blocker with favourable preclinical safety and efficacy profile being developed for the treatment of acid-related diseases., Aims: To investigate the safety, tolerability, pharmacodynamics and pharmacokinetics of zastaprazan., Methods: A randomised, open-label, placebo- and active-controlled, single and multiple ascending dose clinical trial was conducted in healthy Korean male subjects. Intragatric pH and serum gastrin were measured to assess the pharmacodynamics, while serial blood and urine samples were collected to assess the pharmacokinetics. Pharmacogenomic evaluation was conducted to explore genetic variants, which can affect the pharmacodynamics and pharmacokinetics. Safety and tolerability including hepatotoxicity were evaluated., Results: Suppression of gastric acid secretion increased as the dose of zastaprazan increased. The percentage of time that gastric pH was over 4 (%Time pH >4) with zastaprazan 20 mg (85.19%) and 40 mg (91.84%) were similar to or greater than that with esomeprazole 40 mg (72.06%). Zastaprazan was rapidly absorbed within 2 h and eliminated with a half-life of 6-10 h. Pharmacogenomic analysis found no genetic variant of drug metabolising enzymes including CYP2C19 or drug transporters associated with the exposure of zastaprazan. Zastaprazan was well tolerated with no clinically significant changes in safety and tolerability assessments., Conclusions: Zastaprazan was safe and well tolerated after a single oral dose up to 60 mg and multiple oral doses up to 40 mg. It also showed rapid, potent suppression of gastric acid secretion. Pharmacodynamic and pharmacokinetic profile of zastaprazan was suitable for treatment of patients with acid-related diseases., (© 2023 John Wiley & Sons Ltd.)