GABA(A) Receptor Activation Drives GABARAP-Nix Mediated Autophagy to Radiation-Sensitize Primary and Brain-Metastatic Lung Adenocarcinoma Tumors.

In non-small cell lung cancer (NSCLC) treatment, radiotherapy responses are not durable and toxicity limits therapy. We find that AM-101, a synthetic benzodiazepine activator of GABA(A) receptor, impairs the viability and clonogenicity of both primary and brain-metastatic NSCLC cells. Employing a human-relevant ex vivo 'chip', AM-101 is as efficacious as docetaxel, a chemotherapeutic used with radiotherapy for advanced-stage NSCLC.

Program Director Attitudes Toward Acceptance of Pediatric Dentistry Entrustable Professional Activities (EPAs).

To acquire comments on pediatric dentistry entrustable professional activities (EPAs) from pediatric dentistry residency program directors (PDs). An electronic survey invited PDs to evaluate 16 previously developed EPAs on whether they were critical to patient safety, resident education, or both. PDs were asked to evaluate a fully developed EPA to assess structure and clarity and describe barriers to EPA.

Prenatal tobacco smoke exposure and risk for cognitive delays in infants born very premature.

Prenatal tobacco smoke exposure (TSE) and prematurity are independent risk factors for abnormal neurodevelopment. The objectives were to compare differences in Bayley-III cognitive, language, and motor scores at 2 years corrected age (CA) in 395 infants born very preterm (≤ 32 weeks gestation) with and without prenatal TSE. We performed multivariable linear regression analyses to examine associations between prenatal TSE and neurodevelopmental outcomes and a mediation analysis to estimate direct effects of prenatal TSE on outcomes and indirect effects through preterm birth.

Prenatal Opioid Exposure and Risk for Adverse Brain and Motor Outcomes in Infants Born Premature.

Objective: To compare brain magnetic resonance imaging (MRI) biomarkers and neurodevelopmental test scores in infants born preterm with and without prenatal opioid exposure (POE).

Study Design: We examined 395 preterm infants (≤32 weeks gestational age) who had term-equivalent brain MRIs, composite scores from the Bayley Scales of Infant and Toddler Development-III at 2 years corrected age, and POE data. MRI parameters included total/regional brain volumes and severe punctate white matter lesions (PWMLs).

Safety and efficacy of sirolimus in hospitalised patients with COVID-19 pneumonia.

Background: There is a critical need to develop novel therapies for COVID-19.

Methods: We conducted a phase 2, multicentre, placebo-controlled, double-blind, randomised trial; hospitalised patients with hypoxemic respiratory failure due to COVID-19 and at least one poor prognostic biomarker, were given sirolimus (6 mg on Day 1 followed by 2 mg daily for 14 days or hospital discharge, whichever happens first) or placebo, in a 2:1 randomization scheme favouring sirolimus. Primary outcome was the proportion of patients alive and free from advanced respiratory support measures at Day 28.

GABA(A) receptor activation drives GABARAP-Nix mediated autophagy to radiation-sensitize primary and brain-metastatic lung adenocarcinoma tumors.

Unlabelled: In non-small cell lung cancer (NSCLC) treatment, targeted therapies benefit only a subset of NSCLC, while radiotherapy responses are not durable and toxicity limits therapy. We find that a GABA(A) receptor activator, AM-101, impairs viability and clonogenicity of NSCLC primary and brain metastatic cells. Employing an 'chip', AM-101 is as efficacious as the chemotherapeutic docetaxel, which is used with radiotherapy for advanced-stage NSCLC.

The Association of Emergency Severity Index Score and Patient and Family Experience in a Pediatric Emergency Department.

The study aim was to determine the relationship between a patient's Emergency Severity Index (ESI) score and their or their family's response to the key performance indicator (KPI) question on the post-visit patient and family experience (PFE) survey. Retrospective review of patients presenting to the Pediatric Emergency Department between July 1, 2021, and June 30, 2022, who completed the KPI question on an associated post-visit survey. We performed univariate analyses on all candidate variables; multivariable linear regression identified independent predictors of KPI on the PFE survey.

A Video-Based Study of Emergency Medical Services Handoffs to a Pediatric Emergency Department.

Background: Emergency medical services (EMS) to emergency department (ED) handoffs are important moments in patient care, but patient information is communicated inconsistently.

Objective: The aim of this study was to describe the duration, completeness, and communication patterns of patient handoffs from EMS to pediatric ED clinicians.

Methods: We conducted a video-based, prospective study in the resuscitation suite of an academic pediatric ED.

Risk of Bacteremia in Febrile Children and Young Adults With Sickle Cell Disease in a Multicenter Emergency Department Cohort.

Importance: Bacteremia is a major cause of morbidity and mortality in children and young adults with sickle cell disease (SCD), but among those presenting to the emergency department (ED) with fever, the absolute risk of, risk factors associated with, and outcomes of bacteremia are poorly defined.

Objective: To obtain contemporary data on the absolute risk of, risk factors associated with, and outcomes associated with bacteremia in children and young adults with SCD presenting to the ED with fever.

Design, Setting, And Participants: A multicenter retrospective cohort study was conducted of individuals with SCD younger than 22 years (young adults) presenting to EDs within the Pediatric Health Information Systems database from January 1, 2016, to December 31, 2021, with fever (identified by diagnostic codes for fever or the collection of blood samples for cultures and intravenous antibiotic administration).

Structured Callouts, the Shared Mental Model, and Teamwork: A Video-Based Study in a Pediatric Emergency Department.

Objectives: The shared mental model is essential to high-quality resuscitations. A structured callout (SCO) is often performed to establish the shared mental model, but the literature on SCOs is limited. The objectives of this study are to describe performance of SCOs during pediatric medical emergencies and to determine whether a SCO is associated with better teamwork.

Dynamic use of historical controls in clinical trials for rare disease research: A re-evaluation of the MILES trial.

Background: Randomized controlled trials offer the best design for eliminating bias in estimating treatment effects but can be slow and costly in rare disease research. Additionally, an equal randomization approach may not be optimal in studies in which prior evidence of superiority of one or more treatments exist. Supplementing prospectively enrolled, concurrent controls with historical controls can reduce recruitment requirements and provide patients a higher likelihood of enrolling in a new and possibly superior treatment arm.

Durvalumab plus Cetuximab in Patients with Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: An Open-label, Nonrandomized, Phase II Clinical Trial.

Purpose: The efficacy of cetuximab is poor in metastatic head and neck squamous cell carcinoma (HNSCC). Cetuximab initiates natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity, with resultant recruitment of immune cells and suppression of antitumor immunity. We hypothesized that adding an immune-checkpoint inhibitor (ICI) could overcome this and lead to an enhanced antitumor response.

Phase II Trial of Adjuvant Nivolumab Following Salvage Resection in Patients with Recurrent Squamous Cell Carcinoma of the Head and Neck.

Purpose: Locoregional relapse in patients with head and neck squamous cell carcinoma (HNSCC) is common, approaching 50% for some subsites despite multimodality therapy. Salvage surgery is the standard of care, but able to achieve durable control in only a minority of patients. While adjuvant radiotherapy or chemo-radiotherapy is offered to select patients, this approach can be prohibitively toxic.

Phase II Clinical Trial of Neoadjuvant and Adjuvant Pembrolizumab in Resectable Local-Regionally Advanced Head and Neck Squamous Cell Carcinoma.

Purpose: Patients with resected, local-regionally advanced, head and neck squamous cell carcinoma (HNSCC) have a one-year disease-free survival (DFS) rate of 65%-69% despite adjuvant (chemo)radiotherapy. Neoadjuvant PD-1 immune-checkpoint blockade (ICB) has demonstrated clinical activity, but biomarkers of response and effect on survival remain unclear.

Patients And Methods: Eligible patients had resectable squamous cell carcinoma of the oral cavity, larynx, hypopharynx, or oropharynx (p16-negative) and clinical stage T3-T4 and/or two or more nodal metastases or clinical extracapsular nodal extension (ENE).

A Bayesian semiparametric method for analyzing length-biased data.

Survival data obtained from prevalent cohort study designs are often subject to length-biased sampling. Frequentist methods including estimating equation approaches, as well as full likelihood methods, are available for assessing covariate effects on survival from such data. Bayesian methods allow a perspective of probability interpretation for the parameters of interest, and may easily provide the predictive distribution for future observations while incorporating weak prior knowledge on the baseline hazard function.

Critical appraisal of Bayesian dynamic borrowing from an imperfectly commensurate historical control.

Bayesian dynamic borrowing designs facilitate borrowing information from historical studies. Historical data, when perfectly commensurate with current data, have been shown to reduce the trial duration and the sample size, while inflation in the type I error and reduction in the power have been reported, when imperfectly commensurate. These results, however, were obtained without considering that Bayesian designs are calibrated to meet regulatory requirements in practice and even no-borrowing designs may use information from historical data in the calibration.

Residual tumor volume discriminates prognosis after surgery for neuroendocrine liver metastasis.

Background And Objectives: We developed objective measurements of preoperative and residual tumor volume, and debulking rate, to evaluate their prognostic value for neuroendocrine liver metastasis (NELM).

Methods: Seventy-three patients who underwent surgery for NELM were analyzed retrospectively. Indices of preoperative and postoperative residual tumor volume (pre-volume index [VI] and post-VI) were calculated as the sum of the cubes of individual tumor diameters on preoperative and postoperative imaging, respectively.

PI3-kinase pathway biomarkers in oral cancer and tumor immune cells.

Background: This study investigated the hypothesis that phosphoinositide 3-kinase (PI3-kinase) pathway dysregulation in either head and neck cancer cells and/or tumor infiltrating immune cells would influence outcomes of patients with surgically treated oral tongue squamous cell carcinomas (SCC).

Methods: We constructed tissue microarrays containing 123 oral tongue SCC samples and performed immunohistochemistry using antibodies against 7 PI3-kinase pathway markers: phosphatase and tensin homolog (PTEN), Akt, p-Akt, mammalian target of rapamycin (mTOR), phosphorylated-mammalian target of rapamycin (p-mTOR), survivin, and Ki-67). Expression levels in cancer cells or tumor infiltrating immune cells were correlated with outcomes.

Randomized phase II trial of cixutumumab alone or with cetuximab for refractory recurrent/metastatic head and neck squamous cell carcinoma.

Objectives: Cixutumumab (CIX) and cetuximab (CET) monoclonal antibodies block ligand-binding to insulin-like growth factor-1 receptor (IGF-1R) and epidermal growth factor receptor (EGFR) respectively. The objective of this study was to assess the efficacy of CIX alone or combined with CET in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) patients.

Methods: In this open-label phase II trial, 91 R/M HNSCC patients who progressed within 90 days of platinum-based chemotherapy, were randomized to CIX 10 mg/kg alone or with CET 500 mg/m every 2 weeks.

Bayesian selective response-adaptive design using the historical control.

High quality historical control data, if incorporated, may reduce sample size, trial cost, and duration. A too optimistic use of the data, however, may result in bias under prior-data conflict. Motivated by well-publicized two-arm comparative trials in stroke, we propose a Bayesian design that both adaptively incorporates historical control data and selectively adapt the treatment allocation ratios within an ongoing trial responsively to the relative treatment effects.

Evolution of Pediatric Inflammatory Bowel Disease Unclassified (IBD-U): Incorporated With Serological and Gene Expression Profiles.

Background: Inflammatory bowel disease (IBD) mainly consists of Crohn's disease (CD) and ulcerative colitis (UC). About 10%-15% of patients with IBD cannot be firmly diagnosed with CD or UC; hence, they are initially diagnosed as inflammatory bowel disease unclassified (IBD-U). Having a firm diagnosis is clearly preferred to guide treatment choices, and better understanding of the nature of IBD-U is required.

Reduction of incorrect record accessing and charting patient electronic medical records in the perioperative environment.

Opening and charting in the incorrect patient electronic record presents a patient safety issue. The authors investigated the prevalence of reported errors and whether efforts utilizing the anesthesia time-out and barcoding have decreased the incidence of errors in opening and charting in the patient electronic medical record in the perioperative environment. The authors queried the database for all surgeries and procedures requiring anesthesia from January 2009 to September 2012.

Using computed tomography scans and patient demographic data to estimate thoracic epidural space depth.

Background and Objectives. Previous studies have used varying methods to estimate the depth of the epidural space prior to placement of an epidural catheter. We aim to use computed tomography scans, patient demographics, and vertebral level to estimate the depth of the loss of resistance for placement of thoracic epidural catheters.

A phase I/II study combining erlotinib and dasatinib for non-small cell lung cancer.

Background: EGFR and Src are frequently activated in non-small cell lung cancer (NSCLC). In preclinical models, combining EGFR and Src inhibition has additive synergistic effects. We conducted a phase I/II trial of the combination of Src inhibitor dasatinib with EGFR inhibitor erlotinib to determine the maximum tolerated dose (MTD), pharmacokinetic drug interactions, biomarkers, and efficacy in NSCLC.