A Phase 1/2 Study to Evaluate the Safety and Activity of Nivolumab in Combination With Vorolanib, a Vascular Endothelial Growth Factor Tyrosine Kinase Inhibitor, in Patients With Refractory Thoracic Tumors.

Introduction: Targeting the tumor microenvironment may enhance response to immunotherapy (immune checkpoint inhibitors) and improve outcomes for patients. This study tested the safety and efficacy of vorolanib, a novel tyrosine kinase inhibitor of vascular endothelial growth factor, platelet-derived growth factor, and c-KIT, in combination with programmed cell death protein 1 blockade using nivolumab for refractory thoracic malignancies.

Methods: This single-arm multicenter study enrolled patients with extensive-stage SCLC, thymic carcinoma, and NSCLC, either naive or had progressed on previous chemotherapy or immune checkpoint inhibitors (either primary or acquired resistance).

A four-component reaction to access 3,3-disubstituted indolines the palladium-norbornene-catalyzed amination/ conjunctive coupling.

As an important class of multicomponent reactions, the palladium/norbornene (Pd/NBE) cooperative catalysis has been mainly restricted to the coupling of an aryl halide, an electrophile and a nucleophile. Here, we report the development of a Pd/NBE-catalyzed four-component reaction, which involves C-H amination/ conjunctive coupling using an alkene and an external nucleophile. The use of alkene-tethered nitrogen electrophiles provides a rapid and modular synthesis of 3,3-disubstituted indolines from readily available aryl iodides.

Effectiveness of road safety interventions: An evidence and gap map.

Background: Road Traffic injuries (RTI) are among the top ten leading causes of death in the world resulting in 1.35 million deaths every year, about 93% of which occur in low- and middle-income countries (LMICs). Despite several global resolutions to reduce traffic injuries, they have continued to grow in many countries.

Modified oncoplastic lift, lymphatic excision, and reconstruction: Introduction of a novel technique in oncoplastic breast surgery with simple surgical principles.

Introduction: Oncoplastic surgery is an important component of the management of breast cancer. As prognosis has improved, the need for proficient techniques to achieve disease eradication while maintaining cosmesis for naturally appearing breasts has gained importance. This study describes an easy-to-learn modified oncoplastic technique for patients undergoing breast-conserving treatment.

Hospital-Level Variability in Reporting of Ischemic Stroke Subtypes and Supporting Diagnostic Evaluation in GWTG-Stroke Registry.

Background: Secondary prevention of ischemic stroke (IS) requires adequate diagnostic evaluation to identify the likely etiologic subtype. We describe hospital-level variability in diagnostic testing and IS subtyping in a large nationwide registry.

Methods And Results: We used the GWTG-Stroke (Get With The Guidelines-Stroke) registry to identify patients hospitalized with a diagnosis of acute IS at 1906 hospitals between January 1, 2016, and September 30, 2017.

Newly synthesized 6-substituted piperazine/phenyl-9-cyclopentyl containing purine nucleobase analogs act as potent anticancer agents and induce apoptosis inhibiting Src in hepatocellular carcinoma cells.

Newly synthesized 6-substituted piperazine/phenyl-9-cyclopentyl-containing purine nucleobase analogs were tested for their anticancer activity against human cancer cells. Compounds 15, 17-24, 49, and 56 with IC values less than 10 μM were selected for further examination on an enlarged panel of liver cancer cell lines. Experiments revealed that compound 19 utilizes its high cytotoxic potential (IC < 5 μM) to induce apoptosis .

Framework for Classifying Explainable Artificial Intelligence (XAI) Algorithms in Clinical Medicine.

Artificial intelligence (AI) applied to medicine offers immense promise, in addition to safety and regulatory concerns. Traditional AI produces a core algorithm result, typically without a measure of statistical confidence or an explanation of its biological-theoretical basis. Efforts are underway to develop explainable AI (XAI) algorithms that not only produce a result but also an explanation to support that result.

Disparities in care and outcomes for adolescent and young adult lymphoma patients.

Though survival outcomes among adolescents and young adults (AYAs) with lymphoma have improved over the last three decades, socially vulnerable populations including non-White, low-income, and publicly insured groups continue to trail behind on survival curves. These disparities, while likely the result of both biological and non-biological factors, can be largely attributed to inequities in care over the full cancer continuum. Nationally representative studies have demonstrated that from diagnosis through therapy and into long-term survivorship, socially vulnerable AYAs with lymphoma face barriers to care that impact their short and long-term survival.

Data-driven discovery of innate immunomodulators machine learning-guided high throughput screening.

The innate immune response is vital for the success of prophylactic vaccines and immunotherapies. Control of signaling in innate immune pathways can improve prophylactic vaccines by inhibiting unfavorable systemic inflammation and immunotherapies by enhancing immune stimulation. In this work, we developed a machine learning-enabled active learning pipeline to guide experimental screening and discovery of small molecule immunomodulators that improve immune responses by altering the signaling activity of innate immune responses stimulated by traditional pattern recognition receptor agonists.

HIF-stabilizing biomaterials: from hypoxia-mimicking to hypoxia-inducing.

Recent advances in our understanding of hypoxia and hypoxia-mediated mechanisms shed light on the critical implications of the hypoxic stress on cellular behavior. However, tools emulating hypoxic conditions (, low oxygen tensions) for research are limited and often suffer from major shortcomings, such as lack of reliability and off-target effects, and they usually fail to recapitulate the complexity of the tissue microenvironment. Fortunately, the field of biomaterials is constantly evolving and has a central role to play in the development of new technologies for conducting hypoxia-related research in several aspects of biomedical research, including tissue engineering, cancer modeling, and modern drug screening.

Normal Values of Echocardiographic Right Ventricular Size and Systolic Function Measurements in a Healthy Japanese Population - Subanalysis of the WASE Study.

Although accurate assessment of right ventricular (RV) morphology and function is clinically important, data regarding reference values for echocardiographic measurements of the right ventricle in the Japanese population are limited. The World Alliance Society of Echocardiography (WASE) Normal Values Study was conducted to examine normal echocardiographic values in 15 countries. Using the WASE study database, we analyzed 2-dimensional echocardiographic parameters of RV size and systolic function in 192 healthy Japanese individuals and compared them with those obtained from 153 healthy American individuals.

Association Between Urinary Biomarkers and CKD in Extremely Low Gestational Age Neonates.

Rationale & Objective: Children born before 28 weeks' gestation are at increased risk of chronic kidney disease (CKD). Urine biomarkers may shed light on mechanistic pathways and improve the ability to forecast CKD. We evaluated whether urinary biomarkers in neonates of low gestational age (GA) are associated with a reduced estimated glomerular filtration rate (eGFR) over time.

Rapid prediction of full spin systems using uncertainty-aware machine learning.

Accurate simulation of solution NMR spectra requires knowledge of all chemical shift and scalar coupling parameters, traditionally accomplished by heuristic-based techniques or computational chemistry methods. Here we present a novel machine learning technique which combines uncertainty-aware deep learning with rapid estimates of conformational geometries to generate Full Spin System Predictions with UnCertainty (FullSSPrUCe). We improve on previous state of the art in accuracy on chemical shift values, predicting protons to within 0.

Delayed Diagnosis in Cerebral Venous Thrombosis: Associated Factors and Clinical Outcomes.

Background Identifying factors associated with delayed diagnosis of cerebral venous thrombosis (CVT) can inform future strategies for early detection. Methods and Results We conducted a retrospective cohort study including all participants from ACTION-CVT (Anticoagulation in the Treatment of Cerebral Venous Thrombosis) study who had dates of neurologic symptom onset and CVT diagnosis available. Delayed diagnosis was defined as CVT diagnosis occurring in the fourth (final) quartile of days from symptom onset.

Regional distribution in female representation in US otolaryngology faculty.

Objectives: To quantify the current proportion of women in otolaryngology at different levels of professorship and determine whether these proportions differ by US region.

Methods: Academic rank and gender at all ACGME-accredited otolaryngology programs in the United States were determined from departmental websites, Doximity, and LinkedIn from November 2021 to March 2022. Individuals were then further organized using US Census Bureau-designated regions.

Presence but not number of secondary type mutations influences outcome in de novo AML without MDS-associated or recurring cytogenetic abnormalities.

A group of gene mutations has been identified to be strongly associated with secondary acute myeloid leukemias (AML) arising from prior myeloid neoplasms. The International Consensus Classification (ICC) and proposed 5th edition of the World Health Organization (WHO) classification differ by inclusion of . A recent study suggested that having two or more secondary mutations is associated with a particularly poor prognosis.

Narrative medicine workshops for emergency medicine residents: Effects on empathy and burnout.

Background: Emergency medicine (EM) residents face unique affective challenges and barriers to interpersonal connection in their clinical environment which may contribute to decreased empathy and increased burnout. Narrative medicine (NM) might address these barriers and has had beneficial impacts in various populations but has never been studied in EM residents. In this study, we sought to evaluate the effect of NM workshops on burnout and empathy and to assess resident perceptions of the workshops.

A focus on 1-azahomocubane: the new kid on the block.

Strained hydrocarbons have recently regained interest as potential drug candidates. However, the study of their heteroatom analogs has remained limited, despite differing by only a single atom. The first synthesis of 1-azahomocubane by Williams, Eaton and co-workers (T.

Seven reasons why binary diagnostic categories should be replaced with empirically sounder and less stigmatizing dimensions.

Background: An ongoing positive revolution advocates a new approach to the individual differences in human emotions, cognitions, and behavior that cause distress and impair functioning. This revolution endorses the long-proposed, but still unrealized rejection of the medical model, which attributes psychological problems to a sick brain or mind. In addition, it advocates replacing the binary diagnoses used in ICD and DSM, which assume a clear discontinuity between "normal" and "abnormal" functioning, with continuous dimensions of psychological problems.

Electron Leak From the Mitochondrial Electron Transport Chain Complex I at Site I Is Crucial for Oxygen Sensing in Rabbit and Human Ductus Arteriosus.

Background As partial pressure of oxygen (pO) rises with the first breath, the ductus arteriosus (DA) constricts, diverting blood flow to the pulmonary circulation. The DA's O sensor resides within smooth muscle cells. The DA smooth muscle cells' mitochondrial electron transport chain (ETC) produces reactive oxygen species (ROS) in proportion to oxygen tension, causing vasoconstriction by regulating redox-sensitive ion channels and enzymes.

Management of Patients With Patent Foramen Ovale and Stroke: A National Survey of Interventional Cardiologists and Vascular Neurologists.

Background Results from multiple clinical trials support patent foramen ovale closure after cryptogenic stroke in select patients, but it remains unclear how new data and updated professional society guidelines have impacted clinical practice. Here, we aimed to compare how stroke neurologists and interventional cardiologists approach patients with cryptogenic stroke with patent foramen ovale and how critical anatomic and clinical factors influence decision making. Methods and Results An electronic survey was administered to 1556 vascular neurologists and 1057 interventional cardiologists throughout the United States.