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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Hikikomori: A Society-Bound Syndrome of Severe Social Withdrawal.

Background: Hikikomori, a severe and often prolonged social withdrawal observed primarily in young people, was first described in Japan, but cases have now been reported in many other countries. Methods: A review paper on hikikomori has been prepared following the literature searches in 3 databases. Search terms related to hikikomori included epidemiology, globalization, diagnosis, treatment, comorbidity, and COVID-19. Conclusions: Hikikomori was first reported in Japan and has been described in detail by researchers there, but there are now reports in many countries of hikikomori-like cases. It occurs primarily in young people, often men in their late teens and early twenties who isolate themselves, sometimes confining themselves to their homes for months or even years. It has been proposed that hikikomori has increased in recent years in part because of advances in information technology that result in decreased socialization. Hikikomori was originally considered a non-psychotic phenomenon, but comorbidity with psychiatric disorders is often present and should be considered during diagnosis. Considerable efforts have been made in recent years to establish reliable, widely applicable guidelines for the diagnosis and treatment of hikikomori. There is very little information with regard to neurobiology, although involvement of the immune system, oxidative stress, and the social brain network has been proposed. It is widely agreed that hikikomori must be treated in a multi-dimensional fashion, with family support very important. Lessons learned from these treatment approaches are relevant to the potential increased risk of social withdrawal arising from COVID-19 pandemic lockdowns.