Citations

Objective Preeclampsia (PE) is a hypertensive pregnancy disorder that represents a sex‐specific risk factor for future cardiovascular disease in affected women. This study evaluated the associations of a history of PE, conventional cardiovascular risk factors and vascular activation (defined by activation of blood elements and blood‐borne microvesicles (MV)) with carotid intima‐media thickness (CIMT) in menopausal women. Methods Caucasian women residents of Olmsted County, MN who delivered between 1976 and 1982 were identified from review of their medical records and matched for parity and age at index birth: 40 with a history of preeclampsia (PE) and 40 with a history of normotensive pregnancy (NP). Blood clinical chemistries and 38 measures of intravascular activation including differential cell counts, platelet aggregation and secretion, cell‐cell interactions, and blood‐borne MV were measured in venous blood. CIMT was measured by B‐mode ultrasound. The study was approved by the IRB at Mayo Clinic and all women gave written informed consent. Results Women averaged 60 years of age at the time of testing. CIMT was greater in the PE [0.80 mm (0.75, 0.85); median (25th, 75th percentile)] compared to the NP [0.73 mm (0.70, 0.78)] group (P=0.004). Body mass index, waist circumference, fasting insulin, high‐sensitive C‐reactive protein and present day hypertension were greater in the PE group. After adjusting for potential confounding factors, the odds of having a higher CIMT value was more than 3‐fold higher for women with a history of PE [OR 3.46 (1.38, 8.68); P=0.008]. Principal components (PC) analysis identified 7 components that accounted for 63% of the variability in measures of intravascular activation. The global test for association of intravascular activation with CIMT (P=0.009) was only significant among women with a history of NP. PC#4, which conveyed measures of whole blood platelet aggregation and platelet interactions with granulocytes and monocytes, positively associated with CIMT in the overall group after adjustment for PE status (partial ρ=0.290; P=0.009). PC#6, consisting of measures of platelet activation with platelet count and interactions between monocytes and the vascular endothelium, also showed a significant interaction with pregnancy history (P=0.014). Conclusion A history of preeclampsia accompanied by metabolic and pro‐coagulant/‐inflammatory intravascular cellular activation contributes to progression of CIMT in menopausal women. Support or Funding Information This work was funded by grants from the NIH AG44170, AG034676, UL1 TR000135 and the Mayo Foundation.

Introduction Asthma is acutely aggravated and chronically worsened by cigarette smoke (CS), as well as secondhand smoke exposure. In this regard, studies show significant differences between women vs. men in their response to the detrimental effects of CS, suggesting that female sex steroids (particularly estrogen) may be involved. Airway smooth muscle (ASM) cell proliferation and airway remodeling is a key feature of asthma and COPD. Surprisingly, there is little information regarding sex steroid effects on cigarette smoke‐induced changes of airway structure and function. In the current study, we hypothesize that estrogen interferes with CSE exposure‐induced proliferation, thereby contributing to airway smooth muscle remodeling. Methods and Results Human ASM tissues (epithelium‐denuded) and isolated ASM cells were from lung samples of patients with known smoking histories undergoing thoracic surgery for non‐infectious, focal pathology. Exposure of human ASM to cigarette smoke extract (CSE, Kentucky research cigarette 1RF4) 1%CSE or 2%CSE for 24h significantly increased ASM proliferation (proliferation assay: Cell Titer Aueous One, and Cyquant). Exposure of physiological concentrations of 17‐β‐estradiol (E 2, 1nM) did not alter ASM proliferation at baseline. Interestingly, E 2 pre‐treatment (1 h prior to CSE exposure) significantly reduced CSE‐induced human ASM proliferation. This was further confirmed by Western blot analysis for proliferative markers PCNA and Cyclin E. In addition, to explore the mechanistic bases of differential effects of E 2 on ASM proliferation under basal and CSE‐exposed conditions, the estrogen receptor profile in ASM tissue was screened in parallel for patients with and without smoking histories. Human ASM tissue from smokers samples showed substantial increased ERα and β expression compared to non‐smokers. Inhibition of ERα and β prevented the effects of estrogen on CSE‐induced increases in proliferation. Conclusions Collectively, estrogen exposure decreased human ASM proliferation induced by CSE. ER expression and signaling is enhanced in CSE induced inflamed ASM, with a potential beneficial role in reducing remodeling with CS exposure. These results will lay the foundation for examining the role of estrogen signaling in pathogenesis of cigarette smoke‐induced airway remodeling and possible sex based therapeutic targets in smoking‐related diseases. Support or Funding Information Supported by Flight Attendants Medical Research Institute (VS) and NIH R01 grant HL123494 (VS)

Background Differences in quality of life (QoL) after coronary artery bypass grafting (CABG) compared with percutaneous coronary intervention (PCI) are not well characterized. We aimed to compare the short‐ and long‐term effects of CABG versus PCI on QoL. Methods and Results We performed a systematic review and meta‐analysis of randomized controlled trials comparing CABG versus PCI using the Seattle Angina Questionnaire (SAQ)‐Angina Frequency, SAQ‐QoL, SAQ‐Physical Limitations, EuroQoL‐5D, and Short‐Form Questionnaire. We calculated mean changes within each group from baseline to 1, 6, 12, and 36 to 60 months (latest follow‐up) and the weighted mean differences between groups using inverse‐variance methods. A total of 10 760 patients were enrolled in 5 trials. From baseline to 12 months and 36 to 60 months, the mean change in SAQ‐Angina Frequency was >22 points (95% CI, 21.0–25.6) after both PCI and CABG. The mean difference in SAQ‐Angina Frequency was similar between procedures at 1 month and at 36 to 60 months but favored CABG at 12 months (1.97 [95% CI, 0.68–3.26]). SAQ‐QoL favored PCI at 1 month (−2.92 [95% CI, −4.66 to −1.18]) and CABG at 6 (2.50 [95% CI, 1.02–3.97]), 12 (3.30 [95% CI, 1.78–4.82]), and 36 to 60 months (3.17 [95% CI, 0.54 5.80). SAQ‐Physical Limitations (−12.61 [95% CI, −16.16 to −9.06]) and EuroQoL‐5D (−0.07 [95% CI, −0.08 to −0.07) favored PCI at 1 month. Short‐Form Questionnaire‐Physical Component favored CABG at 12 months (1.18 [95% CI, 0.46–1.90]). Conclusions Both PCI and CABG improved long‐term disease‐specific and generic QoL.

Background: Severe adolescent idiopathic scoliosis (AIS) can be treated with instrumented fusion, but the number of anchors needed for optimal correction is controversial. Methods: We conducted a multicenter, randomized study that included patients undergoing spinal fusion for single thoracic curves between 45° and 65°, the most common form of operatively treated AIS. Of the 211 patients randomized, 108 were assigned to a high-density screw pattern and 103, to a low-density screw pattern. Surgeons were instructed to use ≥1.8 implants per spinal level fused for patients in the high-implant-density group or ≤1.4 implants per spinal level fused for patients in the low-implant-density group. The primary outcome measure was the percent correction of the coronal curve at the 2-year follow-up. The power analysis for this trial required 174 patients to show equivalence, defined as a 95% confidence interval (CI) within a ±10% correction margin with a probability of 90%. Results: In the intention-to-treat analysis, the mean percent correction of the coronal curve was equivalent between the high-density and low-density groups at the 2-year follow-up (67.6% versus 65.7%; difference, −1.9% [95% CI: −6.1%, 2.2%]). In the per-protocol cohorts, the mean percent correction of the coronal curve was also equivalent between the 2 groups at the 2-year follow-up (65.0% versus 66.1%; difference, 1.1% [95% CI: −3.0%, 5.2%]). A total of 6 patients in the low-density group and 5 patients in the high-density group required reoperation (p = 1.0). Conclusions: In the setting of spinal fusion for primary thoracic AIS curves between 45° and 65°, the percent coronal curve correction obtained with use of a low-implant-density construct and that obtained with use of a high-implant-density construct were equivalent. Level of Evidence: Therapeutic Level I . See Instructions for Authors for a complete description of levels of evidence.

Patients with advanced cancers who either do not experience initial response to or progress while on immune checkpoint inhibitors (ICIs) receive salvage radiotherapy to reduce tumor burden and tumor-related symptoms. Occasionally, some patients experience substantial global tumor regression with a rebound of cytotoxic CD8 + T cells. We have termed the rebound of cytotoxic CD8 + T cells in response to salvage therapy as T cell resilience and examined the underlying mechanisms of resilience. Resilient T cells are enriched for CX3CR1 + CD8 + T cells with low mitochondrial membrane potential, accumulate less reactive oxygen species (ROS), and express more malic enzyme 1 (ME1). ME1 overexpression enhanced the cytotoxicity and expansion of effector CD8 + T cells partially via the type I interferon pathway. ME1 also increased mitochondrial respiration while maintaining the redox state balance. ME1 increased the cytotoxicity of peripheral lymphocytes from patients with advanced cancers. Thus, preserved resilient T cells in patients rebound after salvage therapy and ME1 enhances their resiliency.

Objective: Parents frequently purchase and inquire about smartwatch devices to monitor child behaviors and functioning. This pilot study examined the feasibility and accuracy of using smartwatch monitoring for the prediction of disruptive behaviors. Methods: The study enrolled children ( N = 10) aged 7–10 years hospitalized for the treatment of disruptive behaviors. The study team completed continuous behavioral phenotyping during study participation. The machine learning protocol examined severe behavioral outbursts (operationalized as episodes that preceded physical restraint) for preparing the training data. Supervised machine learning methods were trained with cross-validation to predict three behavior states—calm, playful, and disruptive. Results: The participants had a 90% adherence rate for per protocol smartwatch use. Decision trees derived conditional dependencies of heart rate, sleep, and motor activity to predict behavior. A cross-validation demonstrated 80.89% accuracy of predicting the child's behavior state using these conditional dependencies. Conclusion: This study demonstrated the feasibility of 7-day continuous smartwatch monitoring for children with severe disruptive behaviors. A machine learning approach characterized predictive biomarkers of impending disruptive behaviors. Future validation studies will examine smartwatch physiological biomarkers to enhance behavioral interventions, increase parental engagement in treatment, and demonstrate target engagement in clinical trials of pharmacological agents for young children.

Abstract INTRODUCTION The timing of plasma biomarker changes is not well understood. The goal of this study was to evaluate the temporal co‐evolution of plasma and positron emission tomography (PET) Alzheimer's disease (AD) biomarkers. METHODS We included 1408 Mayo Clinic Study of Aging and Alzheimer's Disease Research Center participants. An accelerated failure time (AFT) model was fit with amyloid beta (Aβ) PET, tau PET, plasma p‐tau217, p‐tau181, and glial fibrillary acidic protein (GFAP) as endpoints. RESULTS Individual timing of plasma p‐tau progression was strongly associated with Aβ PET and GFAP progression. In the population, GFAP became abnormal first, then Aβ PET, plasma p‐tau, and tau PET temporal meta‐regions of interest when applying cut points based on young, cognitively unimpaired participants. DISCUSSION Plasma p‐tau is a stronger indicator of a temporally linked response to elevated brain Aβ than of tau pathology. While Aβ deposition and a rise in GFAP are upstream events associated with tau phosphorylation, the temporal link between p‐tau and Aβ PET was the strongest. Highlights Plasma p‐tau progression was more strongly associated with Aβ than tau PET. Progression on plasma p‐tau was associated with Aβ PET and GFAP progression. P‐tau181 and p‐tau217 become abnormal after Aβ PET and before tau PET. GFAP became abnormal first, before plasma p‐tau and Aβ PET.

Abstract BACKGROUND Selinexor (SEL) is a first-in-class XPO1 inhibitor with potent antitumor activity via tumor suppressor protein nuclear localization and reactivation, oncoprotein translation suppression, and DNA repair inhibition. As a single agent, SEL has demonstrated adequate brain penetration and clinically relevant responses in glioblastoma. We seek to enhance the effect and benefit of SEL by priming with temozolomide (TMZ). METHODS We developed in vitro and in vivo studies to rationally design a phase I/II trial to evaluate the safety and efficacy of the sequential combination of SEL+TMZ. Sequential treatment of U87 cells and intracranial mouse xenografts demonstrated superior DNA damage (ɣH2A.X, cleaved PARP) and overall survival compared to combination or single-agent therapy (HR 0.25 [95% CI, 0.07-0.84]; p = 0.01, log-rank). We used the top-scoring pair method to identify a 6 gene-pair RNAseq signature associated with response to SEL. RESULTS Based on preclinical findings, we developed and opened a multi-institutional phase I/II clinical trial in October 2022. Eligibility includes histologically confirmed 1st recurrent MGMT promoter methylated glioblastoma. Primary objectives are safety and preliminary efficacy. Secondary objectives are overall response rate, efficacy, and prospective validation of a molecular signature of response. Phase I dose finding by IQ 3 + 3 (n = 12) involves TMZ 150mg/m2 on days 1-5 of a 28-day cycle plus SEL on days 8 and 15. Phase II will involve randomization (n = 72) to the RP2D of SEL+TMZ versus monotherapy TMZ. Using proportional hazards regression, RHR 0.5 with p < 0.1 will demonstrate sufficient efficacy. We have enrolled 3 participants in dose level 1 (SEL 60mg) with no dose-limiting toxicities (DLTs) observed. Additional preliminary results will be presented. CONCLUSION Preliminary results suggest that a sequential dosing regimen of SEL+TMZ is feasible and initial dose is well-tolerated and may minimize the cumulative toxicity of SEL. The trial is currently enrolling nationwide (NCI #10505, NCT05432804).

Background: Vertebral body tethering and other non-fusion techniques for the treatment of pediatric idiopathic scoliosis are increasing in popularity. There is limited physician consensus on this topic as the result of a paucity of published data regarding which patients most benefit from non-fusion strategies. Thus, much of the decision-making is left to patients and parents, who must select a treatment based on their goals and values and the information available from health-care providers, the internet, and social media. We sought to understand patient and family preferences regarding the attributes of fusion versus non-fusion surgery that drive these choices. Methods: Patients and families were recruited from 7 pediatric spine centers and were asked to complete a survey-based choice experiment that had been jointly developed with the U.S. Food and Drug Administration (FDA) to evaluate patient preferences. Choices between experimentally designed alternatives were analyzed to estimate the relative importance of outcomes and requirements associated with the choice options (attributes). The attributes included appearance, confidence in the planned correction, spinal motion, device failure, reoperation, and recovery period. The inclusion criteria were (1) an age of 10 to 21 years and (2) a diagnosis of adolescent idiopathic scoliosis in patients who were considering, or who had already undergone, treatment with fusion or non-fusion surgery. Preference weights were estimated from the expected changes in choice given changes in the attributes. Results: A total of 344 respondents (124 patients, 92 parents, and 128 parent/patient dyads) completed the survey. One hundred and seventy-three patients were enrolled prior to surgery, and 171 were enrolled after surgery. Appearance and motion were found to be the most important drivers of choice. For the entire cohort, fusion was preferred over non-fusion. For patients who were considering surgery, the most important attributes were preservation of spinal motion and appearance. Conclusions: Patients and families seeking treatment for idiopathic scoliosis value appearance and preservation of spinal motion and, to a lesser extent, reoperation rates when considering fusion versus non-fusion surgery.

Background: Immune checkpoint inhibitors (ICIs) are a first-line and perioperative treatment for lung cancer. Pneumonitis is a potentially life-threatening complication of ICI treatment in 2% to 5% of patients; however, risk factors for developing ICI pneumonitis (ICI-p) remain undefined. Methods: We conducted a retrospective cohort study of consecutive patients with lung cancer who received at least one dose of ICI from 2015 through 2020 at The Ohio State University. Pneumonitis cases were documented by the treating oncologist and retrospectively evaluated for agreement between an oncologist and a pulmonologist. Patient demographic and clinical characteristics were recorded and summarized between those with and without pneumonitis for the overall cohort. Univariate and multivariable survival analyses using the Fine-Gray competing risk model were used to examine the associations. Results: A total of 471 patients with lung cancer were included, of which 402 had non–small cell lung cancer and 69 had small cell lung cancer; 39 (8%) patients in the overall cohort developed ICI-p. Preexisting interstitial abnormalities and prior chest radiation were both significantly associated with ICI-p on univariate analysis (hazard ratio [HR], 8.91; 95% CI, 4.69–16.92; P<.001; and HR, 2.81; 95% CI, 1.50–5.28; P=.001). On multivariable analyses, interstitial abnormalities remained a strong independent risk factor for ICI-p when controlling for chest radiation and type of immunotherapy (HR, 9.77; 95% CI, 5.17–18.46; P<.001). Among patients with ICI-p (n=39), those with severe (grade 3–5) pneumonitis had worse overall survival compared with those with mild (grade 1 or 2) pneumonitis (P=.001). Abnormal pulmonary function test results at both 12 and 18 months prior to ICI initiation were not significantly associated with ICI-p. Conclusions: Preexisting interstitial abnormalities on chest CT and prior chest radiation are independent risk factors that are strongly associated with ICI-p in patients with lung cancer. These findings highlight a potential need for closer observation for ICI-p among patients with these risk factors.