Faculty Bibliography

SARS-CoV-2 infection is associated with platelet hyperreactivity and increased rates of arterial and venous thrombosis. SARS-CoV-2 mutations have resulted in several variants with differences in transmissibility, infectivity, and patient outcomes. This study investigates the effects of the ancestral strain of SARS-CoV-2 (WA1) and two variants of concern, Delta and Omicron, on the human megakaryocyte (MK) phenotype and transcriptome. Human CD34⁺-derived MKs were incubated with WA1, Delta or Omicron SARS-CoV-2 variants for 24 hours. MK activation markers were measured under resting and thrombin-stimulated conditions. RNA-seq and cytokine release in response to the viruses were assessed. Plasma cytokines were measured in hospitalized COVID-19 patients. Treatment of MKs with WA1, Delta or Omicron variants of SARS-CoV-2 resulted in similar increases in classical activation markers. However, SARS-CoV-2 variants mediated distinct transcriptomic changes. Across variants, 60 genes overlapped, including CXCL8. Consistent with transcriptomic changes, SARS-CoV-2-incubated MKs secreted significantly elevated levels of IL-8. Among hospitalized COVID-19 patients, plasma IL-8 levels were highest in COVID-19 patients who subsequently experienced thrombotic events or died. In conclusion, WA1, Delta, and Omicron similarly induce classical MK activation responses while mediating distinct transcriptomic changes. Increased IL-8 levels may serve as a biomarker to inform platelet hyperreactivity and thrombotic events associated with COVID-19.

People with HIV are at increased risk of cardiovascular events; thus, care delivery strategies that increase access to comprehensive cardiovascular disease (CVD) risk management are a priority. We report the results of a multi-component telemedicine-based strategy to improve blood pressure control among people with HIV-Assess and Adapt to the Impact of COVID-19 on CVD Self-Management and Prevention Care in Adults Living with HIV (AAIM-High). The AAIM High strategy is a virtual adaptation of our previously published EXTRA-CVD strategy and consisted of hypertension education and six components: nurse-led care coordination (delivered by teleconference or telephone), home systolic blood pressure (SBP) monitoring, evidence-based treatment algorithms, electronic health records tools, technology coach, and communication preferences assessment. People with HIV (n = 74) with comorbid hypertension at three academic medical centers were enrolled in a single arm implementation study from January 2021 to December 2022. Over 12 months, the average patient-performed home SBP decreased by 7.7 mmHg (95% CI -11.5, -3.9). The percentage of patients at treatment goal, defined as average SBP <130 mmHg, increased from 46.0% to 72.5% at 12 months. By adapting to the growing use of telemedicine in healthcare delivery, our study effectively improved hypertension control in people with HIV through a virtual, nurse-led intervention.

Clinical practice guidelines for nonsmall cell lung cancer (NSCLC) and small cell lung cancer include recommendations based on high-level clinical trial evidence, but complex clinical questions are frequently seen in real-world practice that are not clearly answered by prospective trial data. To address these questions, the Bridging the Gaps Lung Cancer Consensus Conference 2024 (BtG LCCC 2024) convened to develop US-focused expert guidance for clinical situations in which level 1 evidence is lacking. At BtG LCCC 2024, a multidisciplinary expert panel discussed ongoing clinical issues in small cell lung cancer management, targeted therapy in EGFR-mutated NSCLC, management of early stage NSCLC, identification and management of non-EGFR oncogene-driven NSCLC, and use of immunotherapy in advanced/metastatic NSCLC. By using a modified Delphi process, 12 consensus recommendations were developed with the goal of providing guidance on the use of novel diagnostic methods and treatments for clinicians who manage lung cancer. This report reviews these areas of consensus and discusses ongoing questions about ways to apply current clinical evidence.

Wildfires continue to increase in size, intensity, and duration. There is growing evidence that wildfire smoke adversely impacts clinical outcomes; however, few studies have assessed the impact of wildfires on household air quality and subclinical cardiovascular health indicators. We measured continuous indoor and outdoor fine particulate matter (PM_2.5) concentrations from July-October 2022 at 20 residences in the rural, mountainous state of Montana in the United States. We used a combination of satellite-derived smoke plume data from the National Oceanic and Atmospheric Administration's Hazard Mapping System and household-level daily mean PM_2.5 concentrations to classify wildfire-impacted days. One participant from each household self-reported in-home blood pressure (BP) on weekly electronic surveys. We used linear mixed-effects regression models to assess associations between air pollution exposures (PM_2.5 concentrations; number of wildfire-impacted days) and systolic BP (SBP) and diastolic BP (DBP). Models were adjusted for potential time-variant confounders including temperature, humidity, and self-reported exercise. Compared to survey periods with 0 wildfire days, SBP was 3.83 mmHg higher (95% Confidence Interval [95% CI]: 0.22, 7.44) and DBP was 2.36 mmHg higher (95% CI: -0.06, 4.78) during periods with 4+ wildfire days. Across the entire study period, a 10 µg m^-3 increase in indoor PM_2.5 was associated with 1.34 mmHg higher SBP (95%CI: 0.39, 2.29) and 0.71 mmHg higher DBP (95% CI: 0.07, 1.35). We observed that wildfire-impacted days and increasing household-level PM_2.5 concentrations are associated with higher in-home BP. Our results support growing literature which indicates that wildfires adversely impact subclinical cardiovascular health. Clinical and public health messaging should emphasize the cardiovascular health impacts of wildfire smoke and educate on exposure-reduction strategies such as indoor air filtration.

The bone marrow (BM) is altered in obesity to promote myeloid cell generation, but the mechanisms driving these changes remain unclear. Here, we show that obesogenic stimuli promote adipose tissue macrophages to recruit neutrophils from the BM in mice. Recruitment of BM neutrophils activates hematopoietic stem cells, which produce myeloid cells that accumulate in the circulation and drive inflammation. This recruitment is not resolved by weight loss, leading to sustained myelopoiesis in previously obese mice. Inhibiting neutrophil recruitment out of the BM in obese mice or during weight loss reduces BM myelopoiesis and adipose tissue inflammation, and improves glucose tolerance. In humans with obesity, plasma neutrophil chemokines are increased, correlate with increased insulin resistance, but do not decrease with weight loss. Our results demonstrate that neutrophil recruitment is a key mediator of myelopoiesis during obesity, and targeting this pathway is a potential strategy to improve inflammation during obesity and weight loss.

Pancreatic adenocarcinoma remains a leading cause of cancer-related mortality worldwide. Although surgery can be curable for a subset of patients, the five-year overall survival remains less than 15%. Despite extensive molecular characterization of pancreatic cancer, cytotoxic chemotherapy has served as the major component in therapeutic management. A major driver of pancreatic adenocarcinoma is mutations in KRAS, present in over 90% of cases. However, attempts to inhibit KRAS through upstream and downstream targets through the mitogen-activated protein kinase pathway have not been successful in the past. Despite this, multiple KRAS inhibitors have recently entered clinical trials and have shown promising results. These inhibitors have the potential to dramatically alter the landscape of treatment. In parallel, immunological approaches utilizing vaccines and bispecific antibodies are also in clinical development. Given these rapid new developments, the future of pancreatic cancer treatment will likely be determined by discovering the appropriate combinations of targeted and immune-based treatments.

BACKGROUND AND AIMS/OBJECTIVE:The TRISCEND II trial demonstrated superior clinical benefits for patients with ≥severe tricuspid regurgitation (TR) treated with the EVOQUE transcatheter tricuspid valve replacement (TTVR) system plus medical therapy versus medical therapy alone. This work reports 1-year and 18-month outcomes in patients stratified by baseline TR severity. METHODS:The multicentre, prospective TRISCEND II trial enrolled 400 patients with symptomatic, ≥severe TR and randomised 2:1 to TTVR (n=267) or control (n=133). In a post-hoc analysis, patients were stratified into severe TR (n=172) and massive/torrential TR (n=220) cohorts. Clinical and quality-of-life outcomes were reported at 1 year, with Kaplan-Meier estimates for all-cause mortality and heart failure (HF) hospitalisation assessed at 18 months. Study oversight included an independent echocardiographic core laboratory, clinical events committee, and data safety monitoring board. RESULTS:One year after TTVR, TR was ≤mild in 95.2% of severe TR and 95.3% of massive/torrential TR patients. The primary safety and effectiveness endpoint (win ratio) favoured TTVR over control regardless of baseline TR severity: severe (1.64 [95% CI: 1.11, 2.43]) and massive/torrential (2.20 [1.55, 3.14]). At 18 months, TTVR patients had similar mortality to controls (rate difference: severe 0.2% [-11.6, 11.9], massive/torrential -5.8% [-17.6, 6.0], whereas HF hospitalisation rates favoured TTVR in the massive/torrential cohort (vs. control, severe 9.8% [-3.0, 22.7], massive/torrential -15.2% [-28.9, -1.5]). CONCLUSIONS:Patients with ≥severe TR benefit from TTVR, experiencing improvements in TR severity, functional capacity, and quality of life regardless of baseline TR severity, with a signal for greater benefit in patients with more advanced disease.

Non-small cell lung cancer (NSCLC) patients with loss of the tumor suppressor gene STK11 are resistant to immune checkpoint therapies like anti-PD-1. Here, we conducted an in vivo CRISPR screen that identified HDAC1 as a target to reverse anti-PD-1 resistance driven by loss of STK11 and developed TNG260, a potent small-molecule inhibitor of the CoREST complex with selectivity exceeding previously generated inhibitors in this class in preclinical studies. Treatment with TNG260 led to increased expression of immunomodulatory genes in STK11-deficient cancer cells. When combined with anti-PD-1, TNG260 induced immune-mediated stasis and/or regression in STK11-deficient syngeneic tumor models and autochthonous NSCLC models. In the tumors of patients with STK11-deficient cancers on a clinical trial (NCT05887492), treatment with a combination of TNG260 and pembrolizumab increased intratumoral histone acetylation, PD-L1 tumor proportion scores, and T cell infiltration into the tumor microenvironment. This study illustrates a promising treatment strategy for addressing immune evasion in STK11-mutant NSCLC patients.

BACKGROUND:Epilepsy self-management (ESM) by people living with epilepsy (PWE) can reduce seizure frequency and increase quality of life (QOL). ESM among Hispanic PWE is under-investigated and lacks adequate sampling and ESM assessment. The purpose of this study was to assess ESM and associated variables among Hispanic PWE using aggregate data from the Managing Epilepsy Well Network Integrated Database. METHODS:The sample comprised Hispanic PWE (n = 211) from nine ESM intervention studies that used common measures for socio-demographics, health status, prior 30- day seizures, depression (PHQ-9, NDDI-E), QOL (QOLIE-10), and ESM. RESULTS:The sample was 39.3 (±12.8) years, mostly female (56.1 %), preferring Spanish language (59 %), U.S. born (62.2 %), high school or college educated (35.7 %), single/partnered (43.9 %/41.0 %), employed/unemployed (33.0 %/32.1 %), with income <$25,000 (59.0 %), with depressive symptoms (35.1 %), and a seizure in the past month (52.5 %). Total ESM item mean scores were positively skewed (3.6 ± 0.4 on a 5-point scale). Medication, seizure, and safety management exceeded that for information and lifestyle management. In adjusted multivariable models, medication management was associated with age and employment (homemaker) and inversely associated with marital status (never married) and depression. Lifestyle management was associated with employment (unable to work) and inversely associated with sex (female), depression, and QOL. CONCLUSION/CONCLUSIONS:Hispanic PWE were more competent in managing the medical aspects of their condition than lifestyle and informational issues. This study is significant because it leverages the analytic power of a large aggregate Hispanic PWE sample to describe ESM and can inform future study design, data collection, and tailoring of ESM interventions.