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Clinical and Genetic Markers of Vascular Toxicity in Glioblastoma Patients: Insights From Nrg Oncology Rtog-0825
No full textBackground: Glioblastoma (GBM) is an aggressive form of brain cancer in which treatment is associated with toxicities that can result in therapy discontinuation or death. This analysis investigated clinical and genetic markers of vascular toxicities in GBM patients during active treatment.
Methods: In total, 591 non-Hispanic White GBM patients with clinical data were included in the analysis from NRG RTOG-0825. Genome-wide association studies (GWAS) were performed from genotyped blood samples (N = 367) by occurrence of thrombosis or hypertension (grade ≥ 2). A clinical prediction model was produced for each vascular toxicity. Significant GWAS variants were then added to the clinical model as a single nucleotide polymorphism (SNP)-dose-effect variable to produce the final genetic models.
Results: Thrombosis and hypertension were experienced by 62 (11%) and 59 (10%) patients, respectively. Patients who experienced hypertension displayed improved survival over those without hypertension (median overall survival: 25.72 vs. 15.47 months, p = 0.002). The genetic model of thrombosis included corticosteroid use (odds ratio [OR]: 7.13, p = 0.02), absolute neutrophil count (OR: 1.008, p = 0.19), body surface area (OR: 18.87, p = 0.0008), and SNP-dose effect (3 variants; OR: 3.79, p \u3c 0.0001). The genetic model of hypertension included bevacizumab use (OR: 0.97, p = 0.95) and the SNP-dose effect (6 variants; OR: 4.44, p \u3c 0.0001).
Conclusions: In this study, germline variants were superior in predicting hypertension than clinical variables alone. Additionally, corticosteroid use was a considerable risk factor for thrombosis. Future investigations should confirm the hazard of corticosteroid use on thrombosis and the impact of bevacizumab in other malignancies after accounting for the genetic risk of hypertension
Incidence of and Risk Factors for Hospital-Acquired Bleeding in People With Cancer: A Systematic Review
No full textBackground: Hospital-acquired (HA) bleeding (bleeding occurring during hospitalization) in cancer patients is poorly characterized, potentially increasing morbidity and mortality due to under- or overprescription of low-dose anticoagulation for venous thromboembolism prevention.
Objectives: To perform a systematic review and meta-analysis (as appropriate) to identify the incidence of and risk factors for HA bleeding in people with cancer.
Methods: A systematic English-language search was conducted using Ovid MEDLINE, Ovid EMBASE, Google Scholar, and Cochrane Library. Keywords and controlled vocabulary related to bleeding risk in hospitalized cancer patients were iteratively refined. Studies assessing HA bleeding as a primary or coprimary endpoint were included, excluding those focused solely on bleeding associated with venous thromboembolism prophylaxis or full-dose anticoagulation. Results were reviewed independently by 3 team members.
Results: Six studies met the inclusion criteria. Three studies were conference abstracts, and 3 were peer-reviewed articles. The incidence of HA major bleeding ranged from 1% in all cancer patients admitted to the general medical floor to 14% in hematologic malignancy patients in the intensive care unit.
Conclusion: Limited data suggest unique cancer- and patient-related characteristics are associated with risk of HA bleeding. The paucity of objective data on the incidence of and risk factors for HA bleeding in people with cancer underscores the need for further research to define the epidemiology of, improve risk stratification for, and assess clinical outcomes for HA bleeding in people with cancer
Role of Systemic Therapy in Localized Renal Cell Carcinoma: Where Do We Stand and Where Are We Heading?
No full textThe effectiveness of immunotherapy and targeted therapy has been well established in metastatic renal cell cancer (mRCC). These therapies demonstrated higher overall response rates and led to prolonged survival. In contrast, in localized RCC, conventional treatment is either partial or complete nephrectomy. While surgery is a curative option in early stages, high recurrence rates remain a concern, with survival rates ranging from 53% to 85%, depending on the initial stage at the time of diagnosis. Given favorable outcomes with systemic therapies in the metastatic setting, there has also been an increased interest in utilizing these therapies for the localized stage with the rationale to eradicate the micro-metastatic clone, thereby reducing the recurrence rates. Despite these encouraging developments, challenges regarding the optimal timing, duration, and combination of systemic therapies are still under investigation. Adding to that, balancing the benefits of systemic therapies with potential toxicities is also crucial, especially in patients who might otherwise benefit from surgery alone. This review describes the current landscape, ongoing clinical trials, and future directions of systemic therapy in the management of localized RCC
Baseline Predictors for 28-Day COVID-19 Severity and Mortality Among Hospitalized Patients: Results From the IMPACC Study
No full textIntroduction: The coronavirus disease 2019 (COVID-19) pandemic threatened public health and placed a significant burden on medical resources. The Immunophenotyping Assessment in a COVID-19 Cohort (IMPACC) study collected clinical, demographic, blood cytometry, serum receptor-binding domain (RBD) antibody titers, metabolomics, targeted proteomics, nasal metagenomics, Olink, nasal viral load, autoantibody, SARS-CoV-2 antibody titers, and nasal and peripheral blood mononuclear cell (PBMC) transcriptomics data from patients hospitalized with COVID-19. The aim of this study is to select baseline biomarkers and build predictive models for 28-day in-hospital COVID-19 severity and mortality with most predictive variables while prioritizing routinely collected variables.
Methods: We analyzed 1102 hospitalized COVID-19 participants. We used the lasso and forward selection to select top predictors for severity and mortality, and built predictive models based on balanced training data. We then validated the models on testing data.
Results: Severity was best predicted by the baseline SpO2/FiO2 ratio obtained from COVID-19 patients (test AUC: 0.874). Adding patient age, BMI, FGF23, IL-6, and LTA to the disease severity prediction model improves the test AUC by an additional 3%. The clinical mortality prediction model using SpO2/FiO2 ratio, age, and BMI resulted in a test AUC of 0.83. Adding laboratory results such as TNFRSF11B and plasma ribitol count increased the prediction model by 3.5%. The severity and mortality prediction models developed outperform the Sequential Organ Failure Assessment (SOFA) score among inpatients and perform similarly to the SOFA score among ICU patients.
Conclusion: This study identifies clinical data and laboratory biomarkers of COVID-19 severity and mortality using machine learning models. The study identifies SpO2/FiO2 ratio to be the most important predictor for both severity and mortality. Several biomarkers were identified to modestly improve the predictions. The results also provide a baseline of SARS-CoV-2 infection during the early stages of the coronavirus emergence and can serve as a baseline for future studies that inform how the genetic evolution of the coronavirus affects the host response to new variants
Lung NR3C1+ and CXCR6high T Cells Distinguish Immunopathogenesis of Human Emphysema
No full textThere is a significant knowledge gap in how T cells promote emphysema in smokers with chronic obstructive pulmonary disease (COPD). Single-cell RNA sequencing (scRNA seq) analysis of human samples and relevant clinical data can provide new mechanistic insights into disease pathogenesis. We generated a human lung scRNA seq dataset with extensive disease characteristic annotation and analyzed a second independent scRNA seq dataset to examine the pathophysiological role of T cells in emphysema. Comparisons of pulmonary immune landscapes in emphysematous (E)-COPD, non-emphysematous (NE)-COPD, and control showed positive enrichment of T cells in E-COPD. Pathway analyses identified upregulated inflammatory states in CD4 T cells as a distinguishing feature of E-COPD. Compared to controls, glucocorticoid receptor NR3C1 CD4 T cells were enriched in NE-COPD but were reduced in E-COPD. Interactions between macrophages and NR3C1+ CD4 T cell subsets via CXCL signaling were strongly predicted in E-COPD but were absent in NE-COPD and control. The relative abundance of CD4 CXCR6high effector memory T cells positively correlated with preserved lung function in E-COPD but not in NE-COPD. These findings suggest that NR3C1+ and CXCR6high effector memory subsets of CD4 T cells distinguish the immune-pathophysiological features of emphysema in human lungs. Targeting relevant T cell subsets in emphysema might provide new therapeutic opportunities
Impact of a Cerebrospinal Fluid Diagnostic Stewardship Intervention on Quantity of Tests, Length of Stay, Antibiotic Prescriptions, and Cost
No full textRedundant and low-value cerebrospinal fluid analysis for suspected meningitis can increase costs and antimicrobial use. Our diagnostic stewardship intervention limited available infectious disease cerebrospinal fluid assays to seven common tests, including a multiplex polymerase chain reaction panel. There was no significant difference in the cost of testing or clinical outcomes
BE FASTER Community of Practice to Increase Rapid Initiation of Antiretroviral Therapy in Houston, Texas: A Pre-Post Intervention Study
No full textBackground: Rapid initiation of antiretroviral therapy (Rapid ART) is a key strategy of the Ending the HIV Epidemic (EHE) initiative. The Baylor College of Medicine Extension for Community Healthcare Outcomes (ECHO) Facilitating Antiretroviral Start Earlier (BE FASTER) program was developed to address this call-to-action. The program uses the ProjectECHO tele-mentoring model as an implementation tool in Harris County, a priority EHE jurisdiction. The authors present results on the acceptability and feasibility of the BE FASTER program.
Methods: Multidisciplinary health professionals from 5 Ryan White Part A funded agencies formed the community of practice. The BE FASTER program included 9 monthly virtual sessions, consisting of a brief didactic presentation and case-based discussions focused on Rapid ART implementation. Surveys to measure cross-agency collaboration, sense of professional support, organization efficacy, and self-knowledge and skills were administered at baseline and 9 months. Data were collected on the number of clients initiated on Rapid ART through EHE funding over the course of BE FASTER.
Results: Overall, 64 unique participants attended the 9 ECHO sessions, with an average attendance of 26 participants. Self-knowledge and skills significantly increased at 9 months (3.63 vs 3.96, P \u3c .01). Satisfaction scores were high; 80% of participants were mostly or completely satisfied with the program, and 97% of participants would probably or definitely recommend the program. The number of clients started on Rapid ART through EHE funding since BE FASTER started has increased each year of the program.
Conclusions: The BE FASTER community of practice is an acceptable and feasible intervention to bring organizations together to develop, disseminate, and adopt vital initiatives for Rapid ART
Self-Powered Rapid Antigen-Specific T-cell Response Assay for Mycobacterium tuberculosis Infections
No full textInterferon-gamma release assays (IGRAs) that evaluate an individual’s T-cell activation response to Mycobacterium tuberculosis (M.tb)-specific peptides serve an important role in diagnosing tuberculosis (TB). However, there are substantial challenges to the use of IGRAs in resource-limited settings. Further, IGRA diagnostic performance can also be compromised in anergic individuals. Here we describe a microfluidic chip-based antigen-specific T-cell response assay (ASTRA) that automates the detection of M.tb-specific T-cell activation responses to facilitate screening for latent M.tb infection and TB. We observe that ASTRA demonstrates high specificity for M.tb infection in independent patient cohorts. Compared with IGRA, ASTRA shows greater diagnostic sensitivity in individuals with HIV-1 co-infections (93.8% versus 67%), comparable diagnostic sensitivity in HIV-negative individuals (92.8%) and faster detection (4 h versus 24–48 h). We also find that a self-powered ASTRA chip that analysed microsample (~25 μl) whole-blood samples produced comparable results. ASTRA holds the potential to facilitate efforts to control the global TB epidemic and serve as a versatile platform for analysing T-cell responses across various infectious diseases and immunotherapeutic interventions
A Fascination with Gastrointestinal Viruses
No full textMy arrival into this world came quickly, according to my mother, and it feels like my life has mirrored that rapid beginning. I have enjoyed a rich, varied, and stimulating life and career that have gone through several phases. I credit genetics, my family, technological advances, and many environmental factors for shaping my career. Being a virologist allowed me to be curious and creative and to make several unexpected discoveries. This has been a fun and rewarding journey, but it wasn\u27t always easy. I am not accustomed to talking about myself, but I am happy to share some scientific achievements and professional challenges with the hope that they illustrate the joy of research and the need for resilience and persistence to assure progress and acceptance of unexpected results