Comprehensive functional evaluation of head and neck squamous cell carcinoma with BH3-profiling demonstrates apoptotic competency and therapeutic efficacy of BH3-mimetics.

Evasion of apoptosis promotes tumor survival and contributes to resistance to cancer therapeutics in head and neck squamous cell carcinoma (HNSCC). Our recent work has demonstrated that HNSCC's highly express pro-survival anti-apoptotic proteins Bcl-xL and Mcl-1. Nevertheless, the mechanism of HNSCC to evade apoptosis is still not well understood. We used BH3 profiling, a functional assay which measures mitochondrial depolarization in response to the introduction of BH3 peptides, to evaluate apoptosis competency and dependency upon BCL-2 family anti-apoptotic proteins in a panel of immortalized and patient-derived HNSCC lines. We assessed response to BH3 mimetics including ABT-263 (navitoclax), an inhibitor of Bcl-2/Bcl-xL/Bcl-w, and S63845, an inhibitor of Mcl-1, both as single agents and in combination. We demonstrate that apoptosis signaling appears to be intact in the majority of HNSCC cells, and they are co-dependent upon Bcl-xL and Mcl-1 for survival. We found the combination to be highly synergistic in 2D culture and in 3D organoid models of HHNSCC. Given our findings that co-dependency on Bcl-xL and Mcl-1 is common, and co-inhibition of these molecules is synergistic for growth suppression in HNSCC cells, these results elucidate the therapeutic potential of BCL-xL and MCL-1 inhibition in HNSCC.

Assessing 129Xe multi-breath washout MRI response to elexacaftor/tezacaftor/ivacaftor intervention in pediatric CF.

BACKGROUND: Monitoring multiple-breath washout (MBW) of a xenon tracer using magnetic resonance imaging (MBW Xe-MRI) provides quantitative regional measures of gas washout (fractional ventilation, FV) and spatial ventilation heterogeneity (coefficient of variation, CoVFV) in pediatric CF lung disease, but has yet to be evaluated in an interventional setting. METHODS: 12 pediatric CF participants (median age 15.3 ± 2 years) completed MBW Xe-MRI, pulmonary function tests (PFTs) (spirometry, N2 MBW for lung clearance index (LCI)) and single-breath Xe-MRI ventilation defect percent (VDP) measurements at baseline and 1-month post-initiation of elexacaftor/tezacaftor/ivacaftor (ETI) therapy. FV maps were calculated from MBW Xe-MRI washout images, and CoVFV maps were derived from FV maps. Significant changes between visits were determined using a paired Wilcoxon signed-rank test. For correlations between absolute changes, Pearson's correlation was used. RESULTS: All measures changed significantly 1-month post-ETI therapy compared to baseline. For MRI metrics, median [IQR] VDP was significantly (P < 0.001) lower at 1 month (8.0 [3.7 12.4]) compared to baseline (17.8 [8.3 22.5]), FV was significantly (P < 0.05) higher at 1 month (0.42 [0.41 0.46]) compared to baseline (0.38 [0.33 0.44]), and CoVFV was significantly (P < 0.001) lower at 1 month (0.06 [0.05 0.07]) compared to baseline (0.09 [0.08 0.12]). Both absolute and relative differences in CoVFV and LCI were found to correlate highly (R = 0.92, P < 0.0001 and R = 0.91, P < 0.0001, respectively). CONCLUSIONS: Functional information derived from MBW Xe-MRI, particularly CoVFV, can be used to assess regional lung function in pediatric CF patients in an interventional setting and may be complementary to VDP and pulmonary function tests.

Prognostic Value of Circulating Fibrosis Biomarkers in Dilated Cardiomyopathy (DCM): Insights into Clinical Outcomes.

BACKGROUND: Dilated cardiomyopathy (DCM) involves myocardial remodeling, characterized by significant fibrosis and extracellular matrix expansion. These changes impair heart function, increasing the risk of heart failure and sudden cardiac death. This study investigates the prognostic value of circulating fibrosis biomarkers as a less invasive method in DCM patients. METHODS: Plasma samples from 185 patients with confirmed DCM were analyzed to measure 13 circulating biomarkers using Luminex bead-based multiplex assays and ELISA. The prognostic value of these biomarkers was evaluated concerning heart failure-associated events and all-cause mortality. RESULTS: Elevated MMP-2 levels (>1519.3 ng/mL) were linked to older age, higher diabetes prevalence, lower HDL, increased NT-proBNP and hs-TnT levels, and severe systolic dysfunction. High TIMP-1 levels (>124.9 ng/mL) correlated with elevated NT-proBNP, more atrial fibrillation, reduced exercise capacity, and larger right ventricles. Increased GDF-15 levels (>1213.9 ng/mL) were associated with older age, systemic inflammation, renal impairment, and poor exercise performance. Elevated OPN levels (>81.7 ng/mL) were linked to higher serum creatinine and NT-proBNP levels. Over a median follow-up of 32.4 months, higher levels of these biomarkers predicted worse outcomes, including increased risks of heart failure-related events and mortality. CONCLUSIONS: Circulating fibrosis biomarkers, particularly MMP-2, TIMP-1, GDF-15, and OPN, are valuable prognostic tools in DCM. They reflect the severity of myocardial remodeling and systemic disease burden, aiding in risk stratification and therapeutic intervention. Integrating these biomarkers into clinical practice could improve DCM management and patient prognosis.

Uncovering individualised treatment effects for educational trials.

Large-scale Randomised Controlled Trials (RCTs) are widely regarded as "the gold standard" for testing the causal effects of school-based interventions. RCTs typically present the statistical significance of the average treatment effect (ATE), which captures the effect an intervention has had on average for a given population. However, key decisions in child health and education are often about individuals who may be very different from those averages. One way to identify heterogeneous treatment effects across different individuals, not captured by the ATE, is to conduct subgroup analyses. For example, free school meal (FSM) pupils as required for projects funded by the Education Endowment Foundation (EEF) in England. These subgroup analyses, as we demonstrate in 48 EEF-funded RCTs involving over 200,000 students, are usually not standardised across studies and offer flexible degrees of freedom to researchers, potentially leading to mixed, if not misleading, results. Here, we develop and deploy an alternative to ATE and subgroup analysis, a machine-learning and regression-based framework to predict individualised treatment effects (ITEs). ITEs could show where an intervention worked, for which individuals, and to what extent. Our findings have implications for decision-makers in fields like education, healthcare, law, and clinical practices concerning children and adolescents.

Comparison of 3D UTE free-breathing lung MRI with hyperpolarized 129Xe MRI in pediatric cystic fibrosis.

PURPOSE: To compare phase-resolved functional lung (PREFUL) regional ventilation derived from a free breathing 3D UTE radial MRI acquisition to hyperpolarized 129Xe-MRI (Xe-MRI), conventional 2D multi-slice PREFUL MRI, and pulmonary function tests in pediatric cystic fibrosis (CF) lung disease. METHODS: Free-breathing 3D UTE and 2D multi-slice 1H MRI as well as Xe-MRI were acquired in 12 stable pediatric CF patients. Using PREFUL, regional ventilation (RVent) maps were calculated from the free-breathing data. Ventilation defect percentage (VDP) was determined from 3D and 2D RVent maps (2D VDPRVent and 3D VDPRVent, respectively) and Xe-MRI ventilation (VDPXe). VDP was calculated for the whole lung and for eight regions based on left/right, anterior/posterior, and superior/inferior divisions of the lung. Global and regional VDP was compared between the three methods using Bland-Altman analysis, linear mixed model-based correlation, and one-way analysis of variance and multiple comparisons tests. RESULTS: Global 3D VDPRVent, VDPXe, and 2D VDPRVent were all strongly correlated (all R2 > 0.62, p < 0.0001) and showed minimal, non-significant bias (all <2%, p > 0.05). Three dimensional and 2D VDPRVent significantly correlated to VDPXe in most of the separate lung regions (R2 = 0.18-0.74, p < 0.04), but showed lower inter-agreement. The superior/anterior lung regions showed the least agreement between all three methods (all p > 0.12). CONCLUSION: Absolute VDP assessed by 3D UTE PREFUL MRI showed good global agreement with Xe-MRI and 2D multi-slice PREFUL MRI in pediatric CF lung disease. Therefore, 3D UTE PREFUL MRI offers a sensitive and potentially more accessible alternative to Xe-MRI for regional volumetric evaluation of ventilation.

A cell and transcriptome atlas of the human arterial vasculature.

Vascular beds show different propensities for different vascular pathologies, yet mechanisms explaining these fundamental differences remain unknown. We sought to build a transcriptomic, cellular, and spatial atlas of human arterial cells across multiple different arterial segments to understand this phenomenon. We found significant cell type-specific segmental heterogeneity. Determinants of arterial identity are predominantly encoded in fibroblasts and smooth muscle cells, and their differentially expressed genes are particularly enriched for vascular disease-associated loci and genes. Adventitial fibroblast-specific heterogeneity in gene expression coincides with numerous vascular disease risk genes, suggesting a previously unrecognized role for this cell type in disease risk. Adult arterial cells from different segments cluster not by anatomical proximity but by embryonic origin, with differentially regulated genes heavily influenced by developmental master regulators. Non-coding transcriptomes across arterial cells contain extensive variation in lnc-RNAs expressed in cell type- and segment-specific patterns, rivaling heterogeneity in protein coding transcriptomes, and show enrichment for non-coding genetic signals for vascular diseases.

Smooth muscle expression of RNA editing enzyme ADAR1 controls vascular integrity and progression of atherosclerosis.

Mapping the genomic architecture of complex disease has been predicated on the understanding that genetic variants influence disease risk through modifying gene expression. However, recent discoveries have revealed that a significant burden of disease heritability in common autoinflammatory disorders and coronary artery disease is mediated through genetic variation modifying post-transcriptional modification of RNA through adenosine-to-inosine (A-to-I) RNA editing. This common RNA modification is catalyzed by ADAR enzymes, where ADAR1 edits specific immunogenic double stranded RNA (dsRNA) to prevent activation of the double strand RNA (dsRNA) sensor MDA5 ( IFIH1 ) and stimulation of an interferon stimulated gene (ISG) response. Multiple lines of human genetic data indicate impaired RNA editing and increased dsRNA sensing to be an important mechanism of coronary artery disease (CAD) risk. Here, we provide a crucial link between observations in human genetics and mechanistic cell biology leading to progression of CAD. Through analysis of human atherosclerotic plaque, we implicate the vascular smooth muscle cell (SMC) to have a unique requirement for RNA editing, and that ISG induction occurs in SMC phenotypic modulation, implicating MDA5 activation. Through culture of human coronary artery SMCs, generation of a conditional SMC specific Adar1 deletion mouse model on a pro-atherosclerosis background, and with incorporation of single cell RNA sequencing cellular profiling, we further show that Adar1 controls SMC phenotypic state, is required to maintain vascular integrity, and controls progression of atherosclerosis and vascular calcification. Through this work, we describe a fundamental mechanism of CAD, where cell type and context specific RNA editing and sensing of dsRNA mediates disease progression, bridging our understanding of human genetics and disease causality.

Generation of Hydrogen Peroxide in Cancer Cells: Advancing Therapeutic Approaches for Cancer Treatment.

Cancer cells show altered antioxidant defense systems, dysregulated redox signaling, and increased generation of reactive oxygen species (ROS). Targeting cancer cells through ROS-mediated mechanisms has emerged as a significant therapeutic strategy due to its implications in cancer progression, survival, and resistance. Extensive research has focused on selective generation of H2O2 in cancer cells for selective cancer cell killing by employing various strategies such as metal-based prodrugs, photodynamic therapy, enzyme-based systems, nano-particle mediated approaches, chemical modulators, and combination therapies. Many of these H2O2-amplifying approaches have demonstrated promising anticancer effects and selectivity in preclinical investigations. They selectively induce cytotoxicity in cancer cells while sparing normal cells, sensitize resistant cells, and modulate the tumor microenvironment. However, challenges remain in achieving selectivity, addressing tumor heterogeneity, ensuring efficient delivery, and managing safety and toxicity. To address those issues, H2O2-generating agents have been combined with other treatments leading to optimized combination therapies. This review focuses on various chemical agents/approaches that kill cancer cells via H2O2-mediated mechanisms. Different categories of compounds that selectively generate H2O2 in cancer cells are summarized, their underlying mechanisms and function are elucidated, preclinical and clinical studies as well as recent advancements are discussed, and their prospects as targeted therapeutic agents and their therapeutic utility in combination with other treatments are explored. By understanding the potential of these compounds, researchers can pave the way for the development of effective and personalized cancer treatments.

Personalizing cardiovascular risk prediction for patients with systemic lupus erythematosus.

OBJECTIVE: Cardiovascular disease (CVD) risk is increased in SLE and underestimated by general population prediction algorithms. We aimed to develop a novel SLE-specific prediction tool, SLECRISK, to provide a more accurate estimate of CVD risk in SLE. METHODS: We studied patients in the Brigham and Women's Hospital SLE cohort. We collected one-year baseline data including the presence of traditional CVD factors and SLE-related features at cohort enrollment. Ten-year follow-up for the first major adverse cardiovascular event (MACE; myocardial infarction (MI), stroke, or cardiac death) began at day +1 following the baseline period (index date). ICD-9/10 codes identified MACE were adjudicated by board-certified cardiologists. Least absolute shrinkage and selection operator regression selected SLE-related variables to add to the American College of Cardiology/American Heart Association (ACC/AHA) Pooled Cohort Risk Equations 10-year risk Cox regression model. Model fit statistics and performance (sensitivity, specificity, positive/negative predictive value, c-statistic) for predicting moderate/high 10-year risk (≥7.5 %) of MACE were assessed and compared to ACC/AHA, Framingham risk score (FRS), and modified FRS (mFRS). Optimism adjustment internal validation was performed using bootstrapping. RESULTS: We included 1,243 patients with 90 MACEs (46 MIs, 36 strokes, 19 cardiac deaths) over 8946.5 person-years of follow-up. SLE variables selected for the new prediction algorithm (SLECRISK) were SLE activity (remission/mild vs. moderate/severe), disease duration (years), creatinine (mg/dL), anti-dsDNA, anti-RNP, lupus anticoagulant, anti-Ro positivity, and low C4. The sensitivity for detecting moderate/high-risk (≥7.5 %) of MACE using SLECRISK was 0.74 (95 %CI: 0.65, 0.83), which was better than the sensitivity of the ACC/AHA model (0.38 (95 %CI: 0.28, 0.48)). It also identified 3.4-fold more moderate/high-risk patients than the ACC/AHA. Patients who were moderate/high-risk according to SLECRISK but not ACC/AHA, were more likely to be young women with severe SLE and few other traditional CVD risk factors. Model performance between SLECRISK, FRS, and mFRS were similar. CONCLUSION: The novel SLECRISK tool is more sensitive than the ACC/AHA for predicting moderate/high 10-year risk for MACE and may be particularly useful in predicting risk for young females with severe SLE. Future external validation studies utilizing cohorts with more severe SLE are needed.

Design and sample size determination for multiple-dose randomized phase II trials for dose optimization.

The U.S. Food and Drug Administration (FDA) has launched Project Optimus to shift dose selection from the maximum tolerated dose (MTD) to the dose that produces the optimal risk-benefit tradeoff. One approach highlighted in the FDA's guidance involves conducting a randomized phase II trial following the completion of a phase I trial, where multiple doses (typically including the MTD and one or two doses lower than the MTD) are compared to identify the optimal dose that maximizes the benefit-risk tradeoff. This article focuses on the design of such a multiple-dose randomized trial, specifically the determination of the sample size. We generalized the standard definitions of type I error and power to accommodate the unique characteristics of dose optimization and derived a decision rule along with an algorithm to determine the optimal sample size. The resulting design is referred to as MERIT (Multiple-dosE RandomIzed Trial design for dose optimization based on toxicity and efficacy). Simulation studies demonstrate that MERIT has desirable operating characteristics, and a sample size between 20 and 40 per dosage arm often offers reasonable power and type I errors to ensure patient safety and benefit. To facilitate the implementation of the MERIT design, we provide software, available at https://www.trialdesign.org.

Challenges and Lessons Learned in Autologous Chimeric Antigen Receptor T-Cell Therapy Development from a Statistical Perspective.

Chimeric antigen receptor (CAR) T-cell therapy is a human gene therapy product where T cells from a patient are genetically modified to enable them to recognize desired target antigen(s) more effectively. In recent years, promising antitumor activity has been seen with autologous CAR T cells. Since 2017, six CAR T-cell therapies for the treatment of hematological malignancies have been approved by the Food and Drug Administration (FDA). Despite the rapid progress of CAR T-cell therapies, considerable statistical challenges still exist for this category of products across all phases of clinical development that need to be addressed. These include (but not limited to) dose finding strategy, implementation of the estimand framework, use of real-world data in contextualizing single-arm CAR T trials, analysis of safety data and long-term follow-up studies. This paper is the first step in summarizing and addressing these statistical hurdles based on the development of the six approved CAR T-cell products.

Short-term Comparison of Survivorship and Functional Outcomes for Metaphyseal Cones with Short and Long Stems in Revision Total Knee Arthroplasty.

Printed porous titanium metaphyseal cones have become a mainstay for managing bone loss in revision total knee arthroplasty (rTKA). A short or long stem is routinely used when implanting a cone to augment fixation and offload stresses. This retrospective analysis compared the short-term survivorships and functional outcomes for use of a short or long stem with a metaphyseal cone.A total of 179 cases using metaphyseal cones and stems with median follow-up of 1.95 years (interquartile range, 1.00-2.14) were compared based on stem type. There were 55 cases with long stem(s) and 124 cases with short stem(s). Cases with both long and short stems were excluded. Demographics, Kaplan-Meier survivorships, and preoperative and 1-year postoperative patient-reported outcome measures (PROMs; 2011 Knee Society Score [KSS] objective knee score, function, and satisfaction scores; EuroQol five-dimension scale; and Short Form Survey Physical Component Summary and Mental Component Summary scores) were compared using t-tests with a significance level of α = 0.05. There were no significant differences in body mass index (mean ± standard deviation) or sex (men [%]) between the short and long stem cohorts (32.3 ± 5.3, 36.3% and 31.5 ± 5.5, 38.2%, respectively; p > 0.05). Patients who had short stems were younger (65.9 ± 8.8 vs. 69.0 ± 9.4, p = 0.0323).Revision-free survivorship for the femoral or tibial component was 100% for long stems and 98.2% for short stems at 1 and 2 years, respectively (log-rank p = 0.6330). The two revisions in the short group were for infection, thus the survivorship for aseptic loosening was 100% at 2 years for both cohorts. There were no significant differences in preoperative or postoperative PROMs.This study demonstrated that highly porous printed metaphyseal cones provided rTKA with excellent early survivorship and similar PROMs whether a short or long stem was used. Additional studies will be needed to discern longer term differences.

A patient-specific circle of Willis blood flow model in predicting outcomes of balloon test occlusion.

BACKGROUND AND PURPOSE: Balloon test occlusion (BTO) evaluates cerebral ischemic tolerance before internal carotid artery (ICA) sacrifice but carries risks like dissection and thrombosis. This study introduces a new approach using a patient-specific circle of Willis (COW) blood flow model, based on non-invasive quantitative MR angiography (qMRA) measurements, to predict the outcomes of BTO. METHODS: We developed individualized COW blood flow models for 43 patients undergoing BTO. These models simulated blood flow and pressure under normal conditions and with the ICA occlusion. We then compared the model's predictions of blood flow changes due to the simulated ICA occlusion to actual qMRA measurements before the BTO. RESULTS: For all 31 BTO failures, the ipsilateral hemisphere showed an average flow decrease of 15 ± 10% (mean ± standard deviation), compared to 3 ± 2% in the contralateral hemisphere. In all 12 BTO passes, these figures were 6 ± 3% and 1 ± 0.8%, respectively. Notably, all BTO passes had less than a 10% reduction in the ipsilateral hemisphere. In contrast, 65% of BTO failures and 67% single-photon emission computed tomography (SPECT) failures exhibited a decrease of 10% or more in the same region. CONCLUSION: Blood flow reduction exceeding 10% in the ipsilateral hemisphere during BTO is a strong predictor of failure in both BTO and SPECT. Our patient-specific COW blood flow models, incorporating detailed flow and arterial geometry data, offered valuable insights for predicting BTO outcomes. These models are especially beneficial for situations where conducting BTO or SPECT is clinically impractical.

Accelerating drug development at Bristol Myers Squibb through innovation.

This paper focuses on the use of novel technologies and innovative trial designs to accelerate evidence generation and increase pharmaceutical Research and Development (R&D) productivity, at Bristol Myers Squibb. We summarize learnings with case examples, on how we prepared and continuously evolved to address the increasing cost, complexities, and external pressures in drug development, to bring innovative medicines to patients much faster. These learnings were based on review of internal efforts toward accelerating R&D focusing on four key areas: adopting innovative trial designs, optimizing trial designs, leveraging external control data, and implementing novel methods using artificial intelligence and machine learning.

Characterization of a Diverse Set of Conditionally Reprogrammed Head and Neck Cancer Cell Cultures.

OBJECTIVE: To establish and characterize a diverse library of head and neck squamous cell cancer (HNSCC) cultures using conditional reprogramming (CR). METHODS: Patients enrolled on an IRB-approved protocol to generate tumor cell cultures using CR methods. Tumor and blood samples were collected and clinical information was recorded. Successful CR cultures were validated against banked reference tumors with short tandem repeat genotyping. Cell morphology was archived with photodocumentation. Clinical and demographic factors were evaluated for associations with successful establishment of CR culture. Human papilloma virus (HPV) genotyping, clonogenic survival, MTT assays, spheroid growth, and whole exome sequencing were carried out in selected cultures. RESULTS: Forty four patients were enrolled, with 31 (70%) successful CR cultures, 32% derived from patients who identified as Black and 61% as Hispanic. All major head and neck disease sites were represented, including 15 (48%) oral cavity and 8 (26%) p16-positive oropharynx cancers. Hispanic ethnicity and first primary tumors (vs. second primary or recurrent tumors) were significantly associated with successful CR culture. HPV expression was conserved in CR cultures, including CR-024, which carried a novel HPV-69 serotype. CR cultures were used to test cisplatin responses using MTT assays. Previous work has also demonstrated these models can be used to assess response to radiation and can be engrafted in mouse models. Whole exome sequencing demonstrated that CR cultures preserved tumor mutation burden and driver mutations. CONCLUSION: CR culture is highly successful in propagating HNSCC cells. This study included a high proportion of patients from underrepresented minority groups. LEVEL OF EVIDENCE: Not Applicable Laryngoscope, 134:2748-2756, 2024.

Harnessing In Situ Simulation to Identify Human Errors and Latent Safety Threats in Adult Tracheostomy Care.

BACKGROUND: Tracheostomies are associated with high rates of complications and preventable harm. Safe tracheostomy management requires highly functioning teams and systems, but health care providers are poorly equipped with tracheostomy knowledge and resources. In situ simulation has been used as a quality improvement tool to audit multidisciplinary team emergency response in the actual clinical environment where care is delivered but has been underexplored for tracheostomy care. METHODS: From July 2021 to May 2022, the study team conducted in situ simulations of a tracheostomy emergency scenario at Montefiore Medical Center to identify human errors and latent safety threats (LSTs). Simulations included structured debriefs as well as audiovisual recording that allowed for blind rating of these human errors and LSTs. Provider knowledge deficits were further characterized using pre-simulation quizzes. RESULTS: Twelve human errors and 15 LSTs were identified over 20 simulations with 88 participants overall. LSTs were divided into the following categories: communication, equipment, and infection control. Only 50.0% of teams successfully replaced the tracheostomy tube within the scenario's five-minute time limit. In addition, knowledge gaps were highly prevalent, with a median pre-simulation quiz score of 46% (interquartile range 36-64) among participants. CONCLUSION: An in situ simulation-based quality improvement approach shed light on human errors and LSTs associated with tracheostomy care across multiple settings in one health system. This method of engaging frontline health care provider key stakeholders will inform the development, adaptation, and implementation of interventions.

Genome-Wide Genetic Associations Prioritize Evaluation of Causal Mechanisms of Atherosclerotic Disease Risk.

OBJECTIVE: The goal of this review is to discuss the implementation of genome-wide association studies to identify causal mechanisms of vascular disease risk. APPROACH AND RESULTS: The history of genome-wide association studies is described, the use of imputation and the creation of consortia to conduct meta-analyses with sufficient power to arrive at consistent associated loci for vascular disease. Genomic methods are described that allow the identification of causal variants and causal genes and how they impact the disease process. The power of single-cell analyses to promote genome-wide association studies of causal gene function is described. CONCLUSIONS: Genome-wide association studies represent a paradigm shift in the study of cardiovascular disease, providing identification of genes, cellular phenotypes, and disease pathways that empower the future of targeted drug development.

Factors associated with eosinophilic esophagitis in an urban, tertiary care pediatric aerodigestive population undergoing triple endoscopy.

BACKGROUND: Children with aerodigestive dysfunction often undergo triple endoscopy (flexible bronchoscopy, rigid direct laryngoscopy and bronchoscopy, and esophagogastroduodenoscopy) for diagnostic evaluation as well as screening prior to airway reconstruction. Prevalence and risk factors for eosinophilic esophagitis (EoE) in this population are poorly understood. METHODS: A retrospective chart review was performed for pediatric patients, aged 0-21 years, who received a triple endoscopy with biopsy from January 1, 2015, to December 31, 2019, at the Children's Hospital at Montefiore (CHAM). Bivariate and multivariable analyses were used to compare the baseline characteristics between patients with and without EoE to assess for potential predictors of EoE. RESULTS: Of the 119 cases included in the analysis, 16.0 % (19) received a histopathologic diagnosis of EoE following triple endoscopy. Patients with EoE were more likely to have a family history of eczema (p = 0.02) and a dairy-free diet (p = 0.02). Age, sex, history of environmental allergies, and recency of initiating oral diet were not significantly associated with increased odds of an EoE diagnosis. CONCLUSIONS: A family history of eczema and a diet lacking allergenic foods, such as milk, may be associated with an increased risk of a future diagnosis of EoE in patients with aerodigestive dysfunction. Larger, multi-institutional studies are needed to identify early predictors of EoE.

Repetitive Transcranial Magnetic Stimulation With and Without Text4Support for the Treatment of Resistant Depression: Protocol for a Patient-Centered Multicenter Randomized Controlled Pilot Trial.

BACKGROUND: Treatment-resistant depression (TRD) is the inability of a patient with major depressive disorder (MDD) to accomplish or achieve remission after an adequate trial of antidepressant treatments. Several combinations and augmentation treatment strategies for TRD exist, including the use of repetitive transcranial magnetic stimulation (rTMS), and new therapeutic options are being introduced. Text4Support, a text message-based form of cognitive behavioral therapy that allows patients with MDD to receive daily supportive text messages for correcting or altering negative thought patterns through positive reinforcement, may be a useful augmentation treatment strategy for patients with TRD. It is however currently unknown if adding the Text4Support intervention will enhance the response of patients with TRD to rTMS treatment. OBJECTIVE: This study aims to assess the initial comparative clinical effectiveness of rTMS with and without the Text4Support program as an innovative patient-centered intervention for the management of patients diagnosed with TRD. METHODS: This study is a multicenter, prospective, parallel-design, 2-arm, rater-blinded randomized controlled pilot trial. The recruitment process is scheduled to last 12 months. It will involve active treatment for 6 weeks, observation, and a follow-up period of 6 months for participants in the study arms. In total, 200 participants diagnosed with TRD at rTMS care clinics in Edmonton, Alberta, and rTMS clinics in Halifax, Nova Scotia will be randomized to 1 of 2 treatment arms (rTMS sessions alone or rTMS sessions plus Text4Support intervention). Participants in each group will be made to complete evaluation measures at baseline, and 1, 3, and 6 months. The primary outcome measure will be the mean change in the scores of the Patient Health Questionnaire-9 (PHQ-9). The secondary outcome measures will involve the scores of the 7-item Generalized Anxiety Disorders Scale (GAD-7), Columbia-Suicide Severity Rating Scale (CSSRS), and World Health Organization-Five Well-Being Index (WHO-5). Patient data will be analyzed with descriptive statistics, repeated measures, and correlational analyses. Qualitative data will be analyzed using the thematic analysis framework. RESULTS: The results of the study are expected to be available 18 months from the start of recruitment. We hypothesize that participants enrolled in the rTMS plus Text4Support intervention treatment arm of the study will achieve superior outcomes compared with the outcomes of participants enrolled in the rTMS alone arm. CONCLUSIONS: The application of the combination of rTMS and Text4Support has not been investigated previously. Therefore, we hope that this study will provide a concrete base of data to evaluate the practical application and efficacy of using the novel combination of these 2 treatment modalities. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/46830.

H2 O2 -Inducible DNA Cross-linking Agents Capable of Releasing Multiple DNA Alkylators as Anticancer Prodrugs.

Three compounds with arylboronate esters conjugated with two equivalent nitrogen mustards [bis(2-chloroethyl)methylamine, HN2] have been synthesized and characterized. These inactive small molecules selectively react with H2 O2 to produce multiple DNA cross-linkers, such as two HN2 molecules alongside a bisquinone methide (bisQM), leading to efficient DNA ICL formation. In comparison to other amine functional groups, using HN2 as a leaving group greatly improves the DNA cross-linking efficiency of these arylboronate esters as well as cellular activity. The introduction of HN2 in these arylboronate ester analogues favored the generation of bisQM that can directly cross-link DNA. Two equivalents of HN2 are also generated from these compounds upon treatment with H2 O2 , which directly produces DNA ICL products. The cumulative effects of HN2 and bisQM on DNA cross-linking makes these molecules highly effective H2 O2 -inducible DNA ICL agents. The three compounds with HN2 as a leaving group showed greatly enhanced cytotoxicity towards cancer cells in comparison to those containing trimethyl amine as a leaving group. This provides an effective strategy for further design of novel potential ROS-activated anticancer prodrugs.