Baseline Stroke Risk and Efficacy of Dual-Antiplatelet Therapy: A Post Hoc Analysis of the POINT Trial.

BACKGROUND: High-risk transient ischemic attacks and minor ischemic strokes are followed by a variable risk of ischemic stroke. We aimed to determine how baseline stroke risk modified the efficacy of clopidogrel-aspirin (referred to here as dual-antiplatelet therapy [DAPT]) for transient ischemic attack and minor ischemic stroke. METHODS: We performed an unplanned secondary analysis of the POINT trial (Platelet-Oriented Inhibition in New Transient Ischemic Attack and Minor Ischemic Stroke). We first evaluated the associations of the CHA2DS2-VASc and stroke prognosis instrument II (SPI-II) scores with the risk of incident ischemic stroke and major hemorrhage (intracranial hemorrhage or major systemic hemorrhage). We then tested for heterogeneity of the relative and absolute treatment effect of DAPT relative to aspirin across low- and high-risk patient subgroups. RESULTS: A total of 4841 trial participants were included in this analysis, with 2400 participants assigned to treatment with short-term DAPT and 2430 participants to treatment with aspirin and placebo. The dichotomized SPI-II score, but not the CHA2DS2-VASc score (P=0.18), was associated with the risk of incident ischemic stroke. A high-risk SPI-II score (>3) was associated with greater risk of incident ischemic stroke (hazard ratio of incident ischemic stroke relative to low-risk SPI-II score of 1.84 [95% CI, 1.44-2.35]; P<0.001) and numerically greater risk of major hemorrhage though not meeting statistical significance (hazard ratio, 1.80 [95% CI, 0.90-3.57]; P=0.10). The relative risk reduction with DAPT was similar across SPI-II strata (Pinteraction=0.31). The absolute risk reduction for ischemic stroke with DAPT compared with aspirin was nearly 4-fold higher (2.80% versus 0.76%; number needed to treat, 31 versus 131) in the high-risk SPI-II stratum relative to the low-risk stratum. The absolute risk increase for major hemorrhage with DAPT compared with aspirin was 3-fold higher (0.84% versus 0.30%; number needed to harm, 119 versus 331) in the high-risk SPI-II stratum relative to the low-risk stratum. CONCLUSIONS: Stratification by baseline stroke risk identifies a patient subgroup that derives greater absolute benefit from treatment with DAPT. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00991029.

Heterogeneity of State Stroke Center Certification and Designation Processes.

BACKGROUND: Stroke centers are critical for the timely diagnosis and treatment of acute stroke and have been associated with improved treatment and outcomes; however, variability exists in the definitions and processes used to certify and designate these centers. Our study categorizes state stroke center certification and designation processes and provides examples of state processes across the United States, specifically in states with independent designation processes that do not rely on national certification. METHODS: In this cross-sectional study from September 2022 to April 2023, we used peer-reviewed literature, primary source documents from states, and communication with state officials in all 50 states to capture each state's process for stroke center certification and designation. We categorized this information and outlined examples of processes in each category. RESULTS: Our cross-sectional study of state-level stroke center certification and designation processes across states reveals significant heterogeneity in the terminology used to describe state processes and the processes themselves. We identify 3 main categories of state processes: No State Certification or Designation Process (category A; n=12), State Designation Reliant on National Certification Only (category B; n=24), and State Has Option for Self-Certification or Independent Designation (category C; n=14). Furthermore, we describe 3 subcategories of self-certification or independent state designation processes: State Relies on Self-Certification or Independent Designation for Acute Stroke Ready Hospital or Equivalent (category C1; n=3), State Has Hybrid Model for Acute Stroke Ready Hospital or Equivalent (category C2; n=5), and State Has Hybrid Model for Primary Stroke Center and Above (category C3; n=6). CONCLUSIONS: Our study found significant heterogeneity in state-level processes. A better understanding of how these differences may impact the rigor of each process and clinical performance of stroke centers is worthy of further investigation.

Sudden Cardiac Death and Myocardial Fibrosis, Determined by Autopsy, in Persons with HIV.

BACKGROUND: The incidence of sudden cardiac death and sudden death caused by arrhythmia, as determined by autopsy, in persons with human immunodeficiency virus (HIV) infection has not been clearly established. METHODS: Between February 1, 2011, and September 16, 2016, we prospectively identified all new deaths due to out-of-hospital cardiac arrest among persons 18 to 90 years of age, with or without known HIV infection, for comprehensive autopsy and toxicologic and histologic testing. We compared the rates of sudden cardiac death and sudden death caused by arrhythmia between groups. RESULTS: Of 109 deaths from out-of-hospital cardiac arrest among 610 unexpected deaths in HIV-positive persons, 48 met World Health Organization criteria for presumed sudden cardiac death; of those, fewer than half (22) had an arrhythmic cause. A total of 505 presumed sudden cardiac deaths occurred between February 1, 2011, and March 1, 2014, in persons without known HIV infection. Observed incidence rates of presumed sudden cardiac death were 53.3 deaths per 100,000 person-years among persons with known HIV infection and 23.7 deaths per 100,000 person-years among persons without known HIV infection (incidence rate ratio, 2.25; 95% confidence interval [CI], 1.37 to 3.70). Observed incidence rates of sudden death caused by arrhythmia were 25.0 and 13.3 deaths per 100,000 person-years, respectively (incidence rate ratio, 1.87; 95% CI, 0.93 to 3.78). Among all presumed sudden cardiac deaths, death due to occult drug overdose was more common in persons with known HIV infection than in persons without known HIV infection (34% vs. 13%). Persons who were HIV-positive had higher histologic levels of interstitial myocardial fibrosis than persons without known HIV infection. CONCLUSIONS: In this postmortem study, the rates of presumed sudden cardiac death and myocardial fibrosis were higher among HIV-positive persons than among those without known HIV infection. One third of apparent sudden cardiac deaths in HIV-positive persons were due to occult drug overdose. (Supported by the National Heart, Lung, and Blood Institute.).

Multi-bounce self-mixing in terahertz metasurface external-cavity lasers.

The effects of optical feedback on a terahertz (THz) quantum-cascade metasurface vertical-external-cavity surface-emitting laser (QC-VECSEL) are investigated via self-mixing. A single-mode 2.80 THz QC-VECSEL operating in continuous-wave is subjected to various optical feedback conditions (i.e., feedback strength, round-trip time, and angular misalignment) while variations in its terminal voltage associated with self-mixing are monitored. Due to its large radiating aperture and near-Gaussian beam shape, we find that the QC-VECSEL is strongly susceptible to optical feedback, which is robust against misalignment of external optics. This, in addition to the use of a high-reflectance flat output coupler, results in high feedback levels associated with multiple round-trips within the external cavity-a phenomenon not typically observed for ridge-waveguide QC-lasers. Thus, a new theoretical model is established to describe self-mixing in the QC-VECSEL. The stability of the device under variable optical feedback conditions is also studied. Any mechanical instabilities of the external cavity (such as vibrations of the output coupler), are enhanced due to feedback and result in low-frequency oscillations of the terminal voltage. The work reveals how the self-mixing response differs for the QC-VECSEL architecture, informs other systems in which optical feedback is unavoidable, and paves the way for QC-VECSEL self-mixing applications.

Delayed esophagectomy for adenocarcinoma is associated with a negative impact on long-term survival and an increased risk of perioperative morbidity.

OBJECTIVE: Delayed esophagectomy (DE) following chemoradiation therapy (CXRT) for esophageal carcinoma is undertaken in selected patients. This study aimed to assess both short-term outcomes and long-term survival for patients with adenocarcinoma undergoing DE. METHODS: The National Cancer Database was queried for patients with American Joint Committee on Cancer clinical stage II-III esophageal adenocarcinoma undergoing esophagectomy after CXRT. Patients were categorized as (1) DE, ≥90 days between completion of CXRT and surgery or (2) nondelayed esophagectomy (NDE), <90 days. Cox regression was performed to identify factors associated with mortality. RESULTS: A total of 8157 patients met criteria. Age >69, nonwhite race, Medicare/Medicaid insured patients preferentially underwent DE. Five-year overall survival (OS) favored NDE (36% vs. 31%, p = 0.008). Cox regression identified DE, clinical stage >T2, or >N0 as factors associated with mortality. Within the DE group, OS favored early cT-status. DE fared worse than NDE in 30- and 90-day mortality (4.5%/11.1% vs. 2.9%/6.5%, p < 0.01/p < 0.001) and margin positive resection (7.1% vs. 4.2%, p < 0.001). CONCLUSIONS: For esophageal adenocarcinoma, DE is associated with decreased OS compared to NDE. For DE, cT-status is prognostic for OS, while cN-status was not. Increased 30-/90-day mortality and margin positive resection rates for DE question whether patients with locally advanced (cT3/T4) primary esophageal adenocarcinoma should undergo intentional DE.

What's new in thoracic oncology.

Many changes have occurred in the field of thoracic surgery over the last several years. In this review, we will discuss new diagnostic techniques for lung cancer, innovations in surgery, and major updates on latest treatment options including immunotherapy. All these have significantly started to change our approach toward the management of lung cancer and have great potential to improve the lives of our patients afflicted with this disease.

Abnormal TP53 Predicts Risk of Progression in Patients With Barrett's Esophagus Regardless of a Diagnosis of Dysplasia.

BACKGROUND AND AIMS: Barrett's esophagus (BE) is the precursor to esophageal adenocarcinoma. A major challenge is identifying the small group with BE who will progress to advanced disease from the many who will not. Assessment of p53 status has promise as a predictive biomarker, but analytic limitations and lack of validation have precluded its use. The aim of this study was to develop a robust criteria for grading abnormal immunohistochemical (IHC) expression of p53 and to test its utility as a biomarker for progression in BE. METHODS: Criteria for abnormal IHC of p53 were developed in BE biopsies and validated with sequencing to assess TP53 mutations. The utility of p53 IHC as a biomarker for progression of BE was tested retrospectively in 561 patients with BE with or without known progression. The findings were prospectively validated in a clinical practice setting in 1487 patients with BE. RESULTS: Abnormal p53 IHC highly correlated with TP53 mutation status (90.6% agreement) and was strongly associated with neoplastic progression in the retrospective cohorts, regardless of histologic diagnosis (P < .001). In the retrospective cohort, abnormal p53 was associated with a hazard ratio of 5.03 (95% confidence interval, 3.88-6.5) and a hazard ratio of 5.27 (95% confidence interval, 3.93-7.07) for patients with exclusively nondysplastic disease before progression. In the prospective validation cohort, p53 IHC predicted progression among nondysplastic BE, indefinite for dysplasia, and low-grade dysplasia (P < .001). CONCLUSIONS: p53 IHC identifies patients with BE at higher risk of progression, including in patients without evidence of dysplasia. p53 IHC is inexpensive, easily integrated into routine practice, and should be considered in biopsies from all BE patients without high-grade dysplasia or cancer.

Optical injection locking of a THz quantum-cascade VECSEL with an electronic source.

Optical injection locking of a metasurface quantum-cascade (QC) vertical-external-cavity surface-emitting laser (VECSEL) is demonstrated at 2.5 THz using a Schottky diode frequency multiplier chain as the injection source. The spectral properties of the source are transferred to the laser output with a locked linewidth of ∼1 Hz, as measured by a separate subharmonic diode mixer, and a locking bandwidth of ∼300 MHz is achieved. The large locking range is enabled by the microwatt power levels available from modern diode multipliers. The interplay between the injected signal and feedback from external reflections is studied and demonstrated to increase or decrease the locking bandwidth relative to the classic locking range depending on the phase of the feedback.

Fn14-Directed DART Nanoparticles Selectively Target Neoplastic Cells in Preclinical Models of Triple-Negative Breast Cancer Brain Metastasis.

Triple-negative breast cancer (TNBC) patients with brain metastasis (BM) face dismal prognosis due to the limited therapeutic efficacy of the currently available treatment options. We previously demonstrated that paclitaxel-loaded PLGA-PEG nanoparticles (NPs) directed to the Fn14 receptor, termed "DARTs", are more efficacious than Abraxane─an FDA-approved paclitaxel nanoformulation─following intravenous delivery in a mouse model of TNBC BM. However, the precise basis for this difference was not investigated. Here, we further examine the utility of the DART drug delivery platform in complementary xenograft and syngeneic TNBC BM models. First, we demonstrated that, in comparison to nontargeted NPs, DART NPs exhibit preferential association with Fn14-positive human and murine TNBC cell lines cultured in vitro. We next identified tumor cells as the predominant source of Fn14 expression in the TNBC BM-immune microenvironment with minimal expression by microglia, infiltrating macrophages, monocytes, or lymphocytes. We then show that despite similar accumulation in brains harboring TNBC tumors, Fn14-targeted DARTs exhibit significant and specific association with Fn14-positive TNBC cells compared to nontargeted NPs or Abraxane. Together, these results indicate that Fn14 expression primarily by tumor cells in TNBC BMs enables selective DART NP delivery to these cells, likely driving the significantly improved therapeutic efficacy observed in our prior work.

Heart transplantation for pediatric foreign nationals in the United States.

BACKGROUND: This study aimed to clarify survival outcomes, waitlist mortality, and waitlist days of heart transplantation of pediatric foreign nationals compared to pediatric United States (US) citizens. METHODS: We retrieved data from March 2012 to June 2021 in the United Network Organ Sharing (UNOS) registry. RESULTS: Of 5857 pediatric patients newly waitlisted, 133 (2.27%) patients were non-US citizen/non-US residents (non-citizen non-resident [NCNR]). Patients with congenital heart disease were higher in the US citizen group than in the NCNR group (51.9% vs. 22.6%, p < .001); 76.7% of patients in the NCNR group (102/133) had cardiomyopathy. Of the 133 NCNRs, 111 patients (83.5%) underwent heart transplantation, which was significantly higher than that in the US citizen group (68.6%, p < .001). The median waitlist time was 71 days (IQR, 22-172 days) in the NCNR group and 74 days (29-184 days) in the US citizen group (p = .48). Survival after heart transplant was significantly better in the NCNR group than in the US citizen group (n = 3982; logrank test p = .015). CONCLUSIONS: Heart transplantation for pediatric foreign nationals was mostly indicated for cardiomyopathy, and their transplant rate was significantly higher than that in the US citizen group, with better survival outcomes. The better survival outcomes in the NCNR group compared to the US citizen group can likely be attributed to the differing diagnoses for which transplantation was performed.

The evolving landscape of thoracic surgical oncology.

The history of Thoracic Surgical Oncology warrants attribution to the strong foundational contributions of the past. Current surgical approaches and techniques along with newer systemic therapies are the product of iterative modifications to prior successes. Progress also fosters traditional thinking to be challenged and other classic topics to be revisited with a contemporary perspective. Cumulatively, past and present clinical and scientific efforts point toward a promising future in the evolving landscape of Thoracic Surgical Oncology.

Body Schema as Assessed by Upper Limb Left/Right Judgment Tasks Is Altered in Stroke: Implications for Motor Imagery Training.

BACKGROUND AND PURPOSE: Individuals with stroke often experience significant impairment of the upper limb. Rehabilitation interventions targeting the upper limb are typically associated with only small to moderate gains. The knowledge that body schema can be altered in other upper limb conditions has contributed to the development of tailored rehabilitation approaches. This study investigated whether individuals with stroke experienced alterations in body schema of the upper limb. If so, this knowledge may have implications for rehabilitation approaches such as motor imagery. METHODS: An observational study performed online consisting of left/right judgment tasks assessed by response time and accuracy of: (i) left/right direction recognition; (ii) left/right shoulder laterality recognition; (iii) left/right hand laterality recognition; (iv) mental rotation of nonembodied objects. Comparisons were made between individuals with and without stroke. Secondary comparisons were made in the stroke population according to side of stroke and side of pain if experienced. RESULTS: A total of 895 individuals (445 with stroke) participated. Individuals with stroke took longer for all tasks compared to those without stroke, and were less accurate in correctly identifying the laterality of shoulder (P < 0.001) and hand (P < 0.001) images, and the orientation of nonembodied objects (P < 0.001). Moreover, the differences observed in the hand and shoulder tasks were greater than what was observed for the control tasks of directional recognition and nonembodied mental rotation. No significant differences were found between left/right judgments of individuals with stroke according to stroke-affected side or side of pain. DISCUSSION AND CONCLUSIONS: Left/right judgments of upper limb are frequently impaired after stroke, providing evidence of alterations in body schema. The knowledge that body schemas are altered in individuals with longstanding stroke may assist in the development of optimal, well-accepted motor imagery programs for the upper limb.Video Abstract available for more insights from the authors (see the Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A394).

Centers for Disease Control (CDC) Wound Classification is Prognostic of 30-Day Readmission Following Surgery.

BACKGROUND: The goal of this study was to investigate factors associated with 30-day readmission in a multivariate model, including the CDC wound classes "clean," "clean/contaminated," "contaminated," and "dirty/infected." METHODS: The 2017-2020 American College of Surgeons-National Surgical Quality Improvement Program (ACS-NSQIP) database was queried for all patients undergoing total hip replacement, coronary artery bypass grafting, Ivor Lewis esophagectomy, pancreaticoduodenectomy, distal pancreatectomy, pneumonectomy, and colectomies. ACS-defined wound classes were concordant with CDC definitions. Multivariate linear mixed regression was used to determine risk factors for readmission while adjusting for type of surgery as a random intercept. RESULTS: 477,964 cases were identified, with 38,734 (8.1%) patients having experienced readmission within 30 days of surgery. There were 181,243 (37.9%) cases classified as wound class "clean", 215,729 (45.1%) cases classified as "clean/contaminated", 40,684 cases (8.5%) classified as "contaminated", and 40,308 (8.4%) cases classified as "dirty/infected". In the multivariate generalized mixed linear model adjusting for type of surgery, sex, body mass index, race, American Society of Anesthesiologists class, presence of comorbidity, length of stay, urgency of surgery, and discharge destination, "clean/contaminated" (p < .001), "contaminated" (p < .001), and "dirty/infected" (p < .001) wound classes (when compared to "clean") were significantly associated with 30-day readmission. Organ/space surgical site infection and sepsis were among the most common reasons for readmission in all wound classes. CONCLUSIONS: Wound classification was strongly prognostic for readmission in multivariable models, suggesting that it may serve as a marker of readmissions. Surgical procedures that are "non-clean" are at significantly greater risk for 30-day readmission. Readmissions may be due to infectious complications; optimizing antibiotic use or source control to prevent readmission are areas of future study.

Randomized Trial of Medical versus Surgical Treatment for Refractory Heartburn.

BACKGROUND: Heartburn that persists despite proton-pump inhibitor (PPI) treatment is a frequent clinical problem with multiple potential causes. Treatments for PPI-refractory heartburn are of unproven efficacy and focus on controlling gastroesophageal reflux with reflux-reducing medication (e.g., baclofen) or antireflux surgery or on dampening visceral hypersensitivity with neuromodulators (e.g., desipramine). METHODS: Patients who were referred to Veterans Affairs (VA) gastroenterology clinics for PPI-refractory heartburn received 20 mg of omeprazole twice daily for 2 weeks, and those with persistent heartburn underwent endoscopy, esophageal biopsy, esophageal manometry, and multichannel intraluminal impedance-pH monitoring. If patients were found to have reflux-related heartburn, we randomly assigned them to receive surgical treatment (laparoscopic Nissen fundoplication), active medical treatment (omeprazole plus baclofen, with desipramine added depending on symptoms), or control medical treatment (omeprazole plus placebo). The primary outcome was treatment success, defined as a decrease of 50% or more in the Gastroesophageal Reflux Disease (GERD)-Health Related Quality of Life score (range, 0 to 50, with higher scores indicating worse symptoms) at 1 year. RESULTS: A total of 366 patients (mean age, 48.5 years; 280 men) were enrolled. Prerandomization procedures excluded 288 patients: 42 had relief of their heartburn during the 2-week omeprazole trial, 70 did not complete trial procedures, 54 were excluded for other reasons, 23 had non-GERD esophageal disorders, and 99 had functional heartburn (not due to GERD or other histopathologic, motility, or structural abnormality). The remaining 78 patients underwent randomization. The incidence of treatment success with surgery (18 of 27 patients, 67%) was significantly superior to that with active medical treatment (7 of 25 patients, 28%; P = 0.007) or control medical treatment (3 of 26 patients, 12%; P<0.001). The difference in the incidence of treatment success between the active medical group and the control medical group was 16 percentage points (95% confidence interval, -5 to 38; P = 0.17). CONCLUSIONS: Among patients referred to VA gastroenterology clinics for PPI-refractory heartburn, systematic workup revealed truly PPI-refractory and reflux-related heartburn in a minority of patients. For that highly selected subgroup, surgery was superior to medical treatment. (Funded by the Department of Veterans Affairs Cooperative Studies Program; ClinicalTrials.gov number, NCT01265550.).

Inhaled gene therapy of preclinical muco-obstructive lung diseases by nanoparticles capable of breaching the airway mucus barrier.

INTRODUCTION: Inhaled gene therapy of muco-obstructive lung diseases requires a strategy to achieve therapeutically relevant gene transfer to airway epithelium covered by particularly dehydrated and condensed mucus gel layer. Here, we introduce a synthetic DNA-loaded mucus-penetrating particle (DNA-MPP) capable of providing safe, widespread and robust transgene expression in in vivo and in vitro models of muco-obstructive lung diseases. METHODS: We investigated the ability of DNA-MPP to mediate reporter and/or therapeutic transgene expression in lung airways of a transgenic mouse model of muco-obstructive lung diseases (ie, Scnn1b-Tg) and in air-liquid interface cultures of primary human bronchial epithelial cells harvested from an individual with cystic fibrosis. A plasmid designed to silence epithelial sodium channel (ENaC) hyperactivity, which causes airway surface dehydration and mucus stasis, was intratracheally administered via DNA-MPP to evaluate therapeutic effects in vivo with or without pretreatment with hypertonic saline, a clinically used mucus-rehydrating agent. RESULTS: DNA-MPP exhibited marked greater reporter transgene expression compared with a mucus-impermeable formulation in in vivo and in vitro models of muco-obstructive lung diseases. DNA-MPP carrying ENaC-silencing plasmids provided efficient downregulation of ENaC and reduction of mucus burden in the lungs of Scnn1b-Tg mice, and synergistic impacts on both gene transfer efficacy and therapeutic effects were achieved when DNA-MPP was adjuvanted with hypertonic saline. DISCUSSION: DNA-MPP constitutes one of the rare gene delivery systems providing therapeutically meaningful gene transfer efficacy in highly relevant in vivo and in vitro models of muco-obstructive lung diseases due to its unique ability to efficiently penetrate airway mucus.

Leveraging the replication-competent avian-like sarcoma virus/tumor virus receptor-A system for modeling human gliomas.

Gliomas are the most common primary intrinsic brain tumors occurring in adults. Of all malignant gliomas, glioblastoma (GBM) is considered the deadliest tumor type due to diffuse brain invasion, immune evasion, cellular, and molecular heterogeneity, and resistance to treatments resulting in high rates of recurrence. An extensive understanding of the genomic and microenvironmental landscape of gliomas gathered over the past decade has renewed interest in pursuing novel therapeutics, including immune checkpoint inhibitors, glioma-associated macrophage/microglia (GAMs) modulators, and others. In light of this, predictive animal models that closely recreate the conditions and findings found in human gliomas will serve an increasingly important role in identifying new, effective therapeutic strategies. Although numerous syngeneic, xenograft, and transgenic rodent models have been developed, few include the full complement of pathobiological features found in human tumors, and therefore few accurately predict bench-to-bedside success. This review provides an update on how genetically engineered rodent models based on the replication-competent avian-like sarcoma (RCAS) virus/tumor virus receptor-A (tv-a) system have been used to recapitulate key elements of human gliomas in an immunologically intact host microenvironment and highlights new approaches using this model system as a predictive tool for advancing translational glioma research.

Elevated fibroblast growth factor-inducible 14 expression transforms proneural-like gliomas into more aggressive and lethal brain cancer.

High-grade gliomas (HGGs) are aggressive, treatment-resistant, and often fatal human brain cancers. The TNF-like weak inducer of apoptosis (TWEAK)/fibroblast growth factor-inducible 14 (Fn14) signaling axis is involved in tissue repair after injury and constitutive signaling has been implicated in the pathogenesis of numerous solid cancers. The Fn14 gene is expressed at low levels in the normal, uninjured brain but is highly expressed in primary isocitrate dehydrogenase wild-type and recurrent HGGs. Fn14 signaling is implicated in numerous aspects of glioma biology including brain invasion and chemotherapy resistance, but whether Fn14 overexpression can directly promote tumor malignancy has not been reported. Here, we used the replication-competent avian sarcoma-leukosis virus/tumor virus A system to examine the impact of Fn14 expression on glioma development and pathobiology. We found that the sole addition of Fn14 to an established oncogenic cocktail previously shown to generate proneural-like gliomas led to the development of highly invasive and lethal brain cancer with striking biological features including extensive pseudopalisading necrosis, constitutive canonical and noncanonical NF-κB pathway signaling, and high plasminogen activator inhibitor-1 (PAI-1) expression. Analyses of HGG patient datasets revealed that high human PAI-1 gene (SERPINE1) expression correlates with shorter patient survival, and that the SERPINE1 and Fn14 (TNFRSF12A) genes are frequently co-expressed in bulk tumor tissues, in tumor subregions, and in malignant cells residing in the tumor microenvironment. These findings provide new insights into the potential importance of Fn14 in human HGG pathobiology and designate both the NF-κB signaling node and PAI-1 as potential targets for therapeutic intervention. MAIN POINTS: This work demonstrates that elevated levels of the TWEAK receptor Fn14 in tumor-initiating, neural progenitor cells leads to the transformation of proneural-like gliomas into more aggressive and lethal tumors that exhibit constitutive NF-κB pathway activation and plasminogen activator inhibitor-1 overexpression.

Temporal Trends in Stroke-Related Memory Change: Results From a US National Cohort 1998-2016.

BACKGROUND AND PURPOSE: Findings from the Framingham Heart Study suggest that declines in dementia incidence rates over recent decades are partially due to decreases in stroke incidence and mortality; however, whether trends of declining dementia rates extend to survivors of incident stroke remains unclear. We investigated evidence for temporal trends in memory change related to incident stroke in a nationally representative cohort. METHODS: Adults age 50+ in the HRS (Health and Retirement Study) were followed across three successive 6-year epochs (epoch 1: 1998-2004, n=16 781; epoch 2: 2004-2010, n=15 345; and epoch 3: 2010-2016; n=15 949). Participants were included in an epoch if they were stroke-free at the start of that epoch. Annual rates of change in a composite z-standardized memory score were compared using demographic-adjusted linear regression models for stroke-free participants, those who survived after stroke, and those who died after stroke, considering memory change before stroke, at the time of stroke, and for years following stroke. RESULTS: Crude stroke incidence rates decreased from 8.5 per 1000 person-years in epoch 1 to 6.8 per 1000 person-years in epoch 3. Rates of memory change before and following stroke onset were similar across epochs. Memory decrement immediately after stroke onset attenuated from -0.37 points (95% CI, -0.44 to -0.29) in epoch 1 to -0.26 (95% CI, -0.33 to -0.18) points in epoch 2 and -0.25 (95% CI, -0.33 to -0.17) points in epoch 3 (P value for linear trend=0.02). CONCLUSIONS: Decreases in stroke-related dementia in recent years may be partially attributable to smaller memory decrements immediately after stroke onset. Findings suggest reductions in stroke incidence and improvements in stroke care may also reduce population burden of dementia. Further investigations into whether temporal trends are attributable to improvements in stroke care are needed.

Antiplatelet Use and Ischemic Stroke Risk in Minor Stroke or Transient Ischemic Attack: A Post Hoc Analysis of the POINT Trial.

BACKGROUND AND PURPOSE: Dual antiplatelet therapy has been shown to reduce the risk of recurrent stroke in patients with minor stroke or transient ischemic attack. However, whether the effect of dual antiplatelet therapy is modified by pretreatment antiplatelet status is unclear. METHODS: This is a post hoc analysis of the POINT trial (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke). Patients were divided into 2 groups based on pretreatment antiplatelet use. The primary outcome was ischemic stroke within 90 days of randomization. RESULTS: We included 4881 patients of whom 41% belonged to the no pretreatment antiplatelet. Ischemic stroke occurred in 6% and 5% in the antiplatelet pretreatment and no antiplatelet pretreatment, respectively. Antiplatelet pretreatment was not associated with the risk of ischemic stroke (adjusted hazard ratio, 1.05 [95% CI, 0.81-137]) or risk of major hemorrhage (hazard ratio, 1.10 [95% CI, 0.55-2.21]; P=0.794). The effect of dual antiplatelet therapy on recurrent ischemic stroke risk was not different in patients who were on antiplatelet before randomization (adjusted hazard ratio, 0.69 [95% CI, 0.50-0.94]) as opposed to those who were not (adjusted hazard ratio, 0.75 [95% CI, 0.50-1.12]), P for interaction = 0.685. CONCLUSIONS: In patients with minor stroke and high-risk transient ischemic attack, dual antiplatelet therapy reduces the risk of ischemic stroke regardless of premorbid antiplatelet use.

Carotid Stenosis and Recurrent Ischemic Stroke: A Post-Hoc Analysis of the POINT Trial.

BACKGROUND AND PURPOSE: Randomized trials demonstrated the benefit of dual antiplatelet therapy in patients with minor ischemic stroke or high-risk transient ischemic attack. We sought to determine whether the presence of carotid stenosis was associated with increased risk of ischemic stroke and whether the addition of clopidogrel to aspirin was associated with more benefit in patients with versus without carotid stenosis. METHODS: This is a post-hoc analysis of the POINT trial (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke) that randomized patients with minor ischemic stroke or high-risk transient ischemic attack within 12 hours from last known normal to receive either clopidogrel plus aspirin or aspirin alone. The primary predictor was the presence of ≥50% stenosis in either cervical internal carotid artery. The primary outcome was ischemic stroke. We built Cox regression models to determine the association between carotid stenosis and ischemic stroke and whether the effect of clopidogrel was modified by ≥50% carotid stenosis. RESULTS: Among 4881 patients enrolled POINT, 3941 patients met the inclusion criteria. In adjusted models, ≥50% carotid stenosis was associated with ischemic stroke risk (hazard ratio, 2.45 [95% CI, 1.68-3.57], P<0.001). The effect of clopidogrel (versus placebo) on ischemic stroke risk was not significantly different in patients with <50% carotid stenosis (adjusted hazard ratio, 0.68 [95% CI, 0.50-0.93], P=0.014) versus those with ≥50% carotid stenosis (adjusted hazard ratio, 0.88 [95% CI, 0.45-1.72], P=0.703), P value for interaction=0.573. CONCLUSIONS: The presence of carotid stenosis was associated with increased risk of ischemic stroke during follow-up. The effect of added clopidogrel was not significantly different in patients with versus without carotid stenosis. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03354429.