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AimsGiant cell arteritis (GCA) is a systemic vasculitis affecting medium and large arteries in patients aged over 50 years. Involvement of temporal arteries (TA) can lead to complications such as blindness and stroke. While the diagnostic gold standard is temporal artery biopsy (TAB), comorbidities and age‐related changes can make interpretation of such specimens difficult. This study aims to establish a baseline of TA changes in subjects without GCA to facilitate the interpretation of TAB.Methods and resultsBilateral TA specimens were collected from 100 consecutive eligible postmortem examinations. Subjects were divided into four age groups and specimens semiquantitatively evaluated for eccentric intimal fibroplasia, disruption and calcification of the internal elastic lamina (IEL), medial attenuation and degree of lymphocytic inflammation of the peri‐adventitia, adventitia, media and intima. The individual scores of intimal fibroplasia, IEL disruption and medial attenuation were added to yield a ‘combined score (CS)’. Seventy‐eight 78 decedents were included in the final analysis following exclusion of 22 individuals for either lack of clinical information or inability to collect TA tissue. A total of 128 temporal artery specimens (50 bilateral from individual decedents, 28 unilateral) were available for examination. Intimal proliferation, IEL loss, IEL calcification and CS increased with age in a statistically significant fashion. Comparison of the oldest age group with the others showed statistically significant differences, although this was not uniformly preserved in comparison between the three youngest groups.ConclusionSenescent arterial changes and healed GCA exhibit histological similarity and such changes increase proportionally with age. The CS demonstrates significant association with age overall and represents a potential avenue for development to ‘normalise’ TA biopsies from older individuals.

Background: The existence and contribution of microglia with senescent-like alterations in the pathogenesis of age-related neurodegenerative diseases like Alzheimer’s disease (AD) have been suggested in recent years. However, the identification of this distinct microglial population in vivo has proven challenging, largely due to overlaps in the inflammatory phenotype of activated and senescent microglia. Furthermore, attempts at recapitulating senescence in microglia in vitro are limited. Objective: To identify and characterize senescent microglia that occur in vivo in an animal model of neurodegeneration driven by pathologic tau. Methods: We analyzed the RNA expression patterns of individual microglia from normal mice and the pathogenic tau P301 S PS19 mouse model. We have previously demonstrated that p16-expressing senescent microglia occur in these mice when neurodegeneration has occurred. Results: Here we identify a subset of disease-associated microglia with senescent features, notably characterized by the expression of Ccl4 . This signature overlaps with established markers of senescence from other cell types. Conclusion: Our characterization of senescent microglia can be used to better understand the role of senescent microglia in various age-related contexts, including whether clearance of senescent microglia represents a viable therapeutic option.

AbstractBackgroundCOVID‐19 convalescent plasma (CCP) is an important therapeutic option for outpatients at high risk of hospitalization from SARS‐CoV‐2 infection. We assessed the safety of outpatient CCP transfusions administered during clinical trials.Study Design and MethodsWe analyzed data pertaining to transfusion‐related reactions from two randomized controlled trials in the U.S. that evaluated the efficacy of CCP versus control plasma in various ambulatory settings. Multivariable logistic regression was used to assess whether CCP was associated with transfusion reactions, after adjusting for potential confounders.ResultsThe combined study reported 79/1351 (5.9%) adverse events during the transfusion visit, with the majority 62/1351 (4.6%) characterized by mild, allergic‐type findings of urticaria, and/or pruritus consistent with minor allergic transfusion reactions; the other reported events were attributed to the patients' underlying disease, COVID‐19, or vasovagal in nature. We found no difference in the likelihood of allergic transfusion reactions between those receiving CCP versus control plasma (adjusted odds ratio [AOR], 0.75; 95% CI, 0.43–1.31). Risk of urticaria and/or pruritus increased with a pre‐existing diagnosis of asthma (AOR, 2.33; 95% CI, 1.16–4.67). We did not observe any CCP‐attributed antibody disease enhancement in participants with COVID‐19 or increased risk of infection. There were no life‐threatening severe transfusion reactions and no patients required hospitalization related to transfusion‐associated complications.DiscussionOutpatient plasma administration was safely performed for nearly 1400 participants. CCP is a safe therapeutic option for outpatients at risk of hospitalization from COVID‐19.

PURPOSE A multi-cancer detection test using a targeted methylation assay and machine learning classifiers was validated and optimized for screening in prospective, case-controlled Circulating Cell-free Genome Atlas (ClinicalTrials.gov identifier: NCT02889978 ) substudy 3. Here, we report test performance in a subgroup of participants with symptoms suspicious for cancer to assess the test's ability to potentially facilitate efficient diagnostic evaluation in symptomatic individuals. METHODS We evaluated test performance (sensitivity, specificity, and accuracy of cancer signal origin [CSO] prediction accuracy) in participants with clinically presenting cancers (CPCs) and noncancer with underlying medical conditions and among two subgroups (65 years and older and GI cancers). Overall survival (OS) of participants who had a cancer signal detected/not detected was compared with SEER-based expected survival. RESULTS A total of 2,036 cancer and 1,472 noncancer participants were included. Specificity was high in all noncancer participants (99.5% [95% CI, 98.4 to 99.8]). In participants with CPCs, the overall sensitivity was 64.3% (95% CI, 62.2 to 66.4) and the overall accuracy of CSO prediction in true positives was 90.3%. For GI cancers, the overall sensitivity was 84.1% (95% CI, 80.6 to 87.1). In participants 65 years and older, test performance was similar to that of all participants. Individuals with cancers not detected had a significantly better OS than that expected from SEER ( P < .01). CONCLUSION This test detected a cancer signal with high specificity and CSO prediction accuracy and moderate sensitivity in symptomatic individuals, with especially high performance in participants with GI cancers. The survival analysis implied that the cancers not detected were less clinically aggressive than cancers detected by the test, providing prognostic insights to physicians. This multi-cancer detection test could facilitate efficient workup and stratify cancer risk in symptomatic individuals.

Objective: To describe outcomes after elective and non-elective fenestrated-branched endovascular aortic repair (FB-EVAR) for thoracoabdominal aortic aneurysms (TAAAs). Background: FB-EVAR has been increasingly utilized to treat TAAAs; however, outcomes after non-elective versus elective repair are not well described. Methods: Clinical data of consecutive patients undergoing FB-EVAR for TAAAs at 24 centers (2006–2021) were reviewed. Endpoints including early mortality and major adverse events (MAEs), all-cause mortality, and aortic-related mortality (ARM), were analyzed and compared in patients who had non-elective versus elective repair. Results: A total of 2603 patients (69% males; mean age 72±10 year old) underwent FB-EVAR for TAAAs. Elective repair was performed in 2187 patients (84%) and non-elective repair in 416 patients [16%; 268 (64%) symptomatic, 148 (36%) ruptured]. Non-elective FB-EVAR was associated with higher early mortality (17% vs 5%, P<0.001) and rates of MAEs (34% vs 20%, P<0.001). Median follow-up was 15 months (interquartile range, 7–37 months). Survival and cumulative incidence of ARM at 3 years were both lower for non-elective versus elective patients (50±4% vs 70±1% and 21±3% vs 7±1%, P<0.001). On multivariable analysis, non-elective repair was associated with increased risk of all-cause mortality (hazard ratio, 1.92; 95% CI] 1.50–2.44; P<0.001) and ARM (hazard ratio, 2.43; 95% CI, 1.63–3.62; P<0.001). Conclusions: Non-elective FB-EVAR of symptomatic or ruptured TAAAs is feasible, but carries higher incidence of early MAEs and increased all-cause mortality and ARM than elective repair. Long-term follow-up is warranted to justify the treatment.

Background: Complete brachial plexus injuries are devastating injuries. A viable C5 spinal nerve can offer additional sources of axons and alter surgical treatment. We aimed to determine factors that portend C5 nerve root avulsion. Methods: A retrospective study of 200 consecutive patients with complete brachial plexus injuries at two international centers (Mayo Clinic in the United States and Chang Gung Memorial Hospital in Taiwan) was performed. Demographic information, concomitant injuries, mechanism, and details of the injury were determined, and kinetic energy (KE) and Injury Severity Score were calculated. C5 nerve root was evaluated by preoperative imaging, intraoperative exploration, and/or intraoperative neuromonitoring. A spinal nerve was considered viable if it was grafted during surgery. Results: Complete five-nerve root avulsions of the brachial plexus were present in 62% of US and 43% of Taiwanese patients, which was significantly different. Increasing age, the time from injury to surgery, weight, body mass index of patient, motor vehicle accident, KE, Injury Severity Score, and presence of vascular injury significantly increased the risk of C5 avulsion. Motorcycle (≤150cc) or bicycle accident decreased the risk of avulsion. Significant differences were found between demographic variables between the two institutions: age of injury, body mass index, time to surgery, vehicle type, speed of injury, KE, Injury Severity Score, and presence of vascular injury. Conclusions: The rate of complete avulsion injury was high in both centers. Although there are a number of demographic differences between the United States and Taiwan, overall the KE of the accident increased the risk of C5 avulsion.

Abstract Funding Acknowledgements Type of funding sources: None. Background Severe aortic-stenosis (AS) is the guideline-based indication for aortic-valve-replacement (AVR) performance, which has markedly increased with transcatheter approaches, suggesting possible increasing AS incidence. However, reported secular trends of AS incidence remain contradictory, uncertain and lacking quantitative Doppler-Echocardiographic ascertainment. Thus, population-based trends in presentation, treatment and outcome are unknown. Methods All adults residents our County (MN,USA) diagnosed with incident (first-diagnosis) severe AS based on quantitative Doppler-Echocardiography (aortic-valve-area≤1cm2, aortic-valve-area-index≤0.6cm2/m2, mean-gradient≥40mmHg, peak-velocity≥4m/s, Doppler-velocity-index≤0.25) between 1997–2016, were accounted for and trends for incidence, presentation, treatment and outcome analysed. Results Incident severe-AS was diagnosed in 1069 community-residents over 20-years. Incidence-rate was 52.5[49.4–55.8] per 100.000 patient/year, slightly higher in male vs. female and was almost unchanged after age and sex adjustment for the US population 53.8[50.6–57.0] per-100000 residents/year. Over 20-years severe AS-incidence remained stable (p = 0.20) but absolute-burden of incident-cases markedly increased (p = 0.0004) due to population growth. Incidence-trend differed by sex, stable in men (incidence-rate-ratio 0.99, p = 0.72) but declining in women: (incidence-rate-ratio 0.93, p = 0.024). AS clinical-presentation, age, symptoms, comorbidity, ventricular size/function, valve-area-index, low-flow or low-ejection-fraction AS, remained stable. Over the study 20 years, AVR performance grew (1997–2001 to 2012–2016, at 3-month:14% to 21%, p = 0.02; at 1-year 19% to 33%,p&lt;0.0001), and was more prompt (from 1.3[0.11–3.3]years in 1997–2001 to 0.48[0.15–2.11]years in 2013–2016, p = 0.001) but severe AS undertreatment remained prominent (&gt;40%). Early-AVR (within 3-months) was associated with survival benefit (adjusted-hazard-ratio 0.55[0.42–0.71], p&lt;0.0001) stable throughout the 20-years. Despite these improvements, overall mortality, 8.3% within 3-months, 17.8% within 1-year, 36% within 3-years, was swift, considerable and unabated (all p≥0.44) throughout the 20-year study. Conclusion Over 20 years, the population incidence of severe-AS remained stable with increased absolute case-burden purely related to population growth. Despite stable severe-AS presentation, AVR performance grew notably, but while declining, undertreatment remained substantial and disease-lethality did not decline. These findings have important population-health management implications.

AbstractBackgroundPartners of persons with mild cognitive impairment (pwMCI) show increased rates of depression and other mental health problems compared to the general population. While dyadic behavioral interventions such as cognitive rehabilitation have shown beneficial effects in reducing caregiver burden, research to date lacks consistent outcome measures and rarely focuses on distressed partners. Therefore, this study explored the longitudinal effect of the Healthy Action to Benefit Independence & Thinking® (HABIT) program on partners with relatively low initial adjustment level. We hypothesized that the HABIT program would improve partner adjustment in those who were distressed.MethodData from 322 pwMCI and partners were utilized from the HABIT IRB research registry. Among them, 240 completed HABIT while 82 served as an untreated control group. Consistent with our previous exploratory factor analysis, a composite partner adjustment score was calculated using the Center for Epidemiologic Studies Depression scale (CES‐D), the REACH Anxiety Inventory Form, and the Quality of Life scale for adults with Alzheimer’s Disease (QOL‐AD). We included partners with an adjustment score below the median of each group to focus on partners with low levels of baseline adjustment. Latent growth curve models were conducted at baseline, 3‐month, 6‐month, and 1‐year follow‐ups to investigate the trajectories of partner adjustment level.ResultIn the low adjustment subsample, no between group difference was found at baseline. An overall improvement in partner adjustment scores was observed only in the treatment group (b = 5.00, p<.001). The slope of change was larger (b = 3.75, p = .016) in the treatment group, indicating a faster improvement in adjustment level in HABIT partners with marginally lower baseline and higher follow‐up scores. This difference in the improvement rates was most evident at the 3‐month follow‐up (t(1, 94) = ‐2.63, p = .010) and gradually reduced in subsequent visits.ConclusionIn partners of those with MCI who have low levels of emotional adjustment, behavioral interventions like HABIT can be beneficial in accelerating improvement in their overall adjustment level and facilitate adaptation to their loved ones’ MCI symptoms compared to untreated controls. Techniques taught in dyadic interventions may serve as protective factors for mental health problems in primary caregivers of pwMCI.

Senescence induced by various stresses reprograms cancer cells to acquire senescence-associated (SA) cell growth (SACG), which allows them to escape senescence-induced cell cycle arrest with enhanced growth potential. ERK5 is a dual kinase-transcription factor, containing an N-terminal kinase domain and transactivation domains in the C-terminal half. Recent data have raised questions regarding the functional role of ERK5 kinase inhibitors in cancer and inflammatory diseases. We aimed to investigate how ERK5 reprograms myeloid cells (MC) to the SA secretory phenotype (SASP) and SACG, consequently leading to atherosclerosis (AthS). AthS was inhibited in ERK5 S496A knock-in (KI) mice. Single-cell analysis of p53 and Ki67 with imaging mass cytometry revealed three groups of MCs with different p53 and Ki67 expression patterns in the plaque. One group showed that p53 and Ki67 were co-expressed lineally, suggesting that this group of cells escaped from the growth-suppression effects of p53, which is also known as a senescence marker. The % of ERK5 S496A KI cells in this group was significantly lower than in wild-type (WT). Also, we found an increase of SA β-gal (SAβ-gal) + Ki67 + and 53BP1 + Ki67 + cells in bone narrow-derived macrophage (BMDMs) isolated from hypercholesterolemia (H-chol) WT mice, suggesting H-chol-induced MC SACG. MC SACG were significantly inhibited in ERK5 S496A KI mice, supporting the role of ERK5 S496 phosphorylation on SACG. RNA sequencing analysis identified the ERK5 S496 phosphorylation-dependent AHR induction by H-chol, and AHR depletion significantly inhibited SACG. We also discovered a critical effect of ERK5 S496 phosphorylation on SUMOylation at a novel site of NRF2 (i.e., K518), which inhibited NRF2 transcriptional activity without affecting ERK5 kinase activity and antagonized oxidized LDL (oxLDL)-induced SASP. Specific ERK5 kinase inhibitors (AX15836 and XMD8-92) inhibited oxLDL-induced ERK5 S496 phosphorylation, suggesting that ERK5 S496 phosphorylation was involved at least in part of the effects of these inhibitors. We have discovered a novel mechanism in which ERK5 S496 phosphorylation directly inhibits NRF2 activity by upregulating NRF2 K518 SUMOylation and AHR induction, subsequently inducing SACG and AthS.

9037 Background: The clinical outcomes for patients with NSCLC remain suboptimal despite recent advancements in anti-PD-1/PD-L1 immunotherapies. Thus, identification of rational combinations of novel immune checkpoint (IC) strategies is imperative. This study aimed to comprehensively characterize the expression of IC targets to inform drug development and design effective combinatorial strategies, to advance the search for optimized therapies for NSCLC. Methods: We analyzed the differential gene expression of IC targets in 537 primary lung adenocarcinoma (LUAD) samples and 59 normal lung tissue samples pre-immunotherapy receipt using RNA-sequencing data from The Cancer Genome Atlas. Gene expression of IC-targets including PDCD1 (PD-1), CD274 (PD-L1), CTLA4, TIGIT, LAG3, HAVCR2 (TIM-3), VSIR (VISTA), ICOS, CD276 (B7-H3), BTLA, IDO1, KLRD1 (CD94/NKG2A), NT5E (CD73), TNFRSF4 (OX-40), TNFRSF18 (GITR), and TNFRSF9 (4-1BB) were obtained. Differential gene expression was determined intra-tumorally by comparison of transcripts per million and inter-tumorally using the DESeq2 algorithm. Log2 fold change >0.5 and false discovery rate adjusted P<0.05 were used as criteria for significant differential expression. Hierarchical clustering was used to identify subsets of tumors with similar profiles of IC-targetable gene expression. Results: Tumors showed significantly increased expression of TNFRSF18 (GITR), NT5E (CD73), TNFRSF9 (4-1BB), LAG3, TIGIT, CTLA4, PD-1, BTLA, B7-H3, and OX-40 (Table 1). On the other hand, tumors exhibited significant downregulation of CD274 (PD-L1), HAVCR2 (TIM-3), ICOS, KLRD1 (CD94/NKG2A), and VSIR (VISTA). Hierarchical clustering revealed recurrent patterns of IC gene overexpression which were characterized by: 1) IDO1-hi, 2) CD276-mid + TNFRSF18-mid, 3) VSIR-hi, 4) CD276-hi, 5) NT5E-hi, and 6) CD276-mid + NT5E-mid. Interestingly, patterns of IC gene expression distinguish tumors from controls. Of note, high VSIR expression was specific to normal tissue rather than tumors. Conclusions: Our study identified many IC targetable genes that were significantly overexpressed in tumors. However, subsets of tumors showed distinct and segregable combinations of overexpressed IC genes. These results suggest heterogeneous mechanisms of immune evasion in NSCLC, which may explain suboptimal outcomes with anti-PD-1/PD-L1 based strategies in this patient population. Our findings emphasize the importance of biomarker-guided approaches for the optimal selection of ICs and the development of rational combinatorial immunotherapies in NSCLC.