T-cell immunity and hepatitis C virus reinfection after cure of chronic hepatitis C with an interferon-free antiviral regimen in a chimpanzee.

UNLABELLED: Memory CD8+ T cells generated by spontaneous resolution of hepatitis C virus (HCV) infection rapidly control secondary infections and reduce the risk of virus persistence. Here, CD8+ T-cell immunity and response to reinfection were assessed in a chimpanzee cured of an earlier chronic infection with an interferon (IFN)-free antiviral regimen. CD8+ T cells expanded from liver immediately before and 2 years after cure of chronic infection with two direct-acting antivirals (DAAs) targeted epitopes in the E2, nonstructural (NS)5a, and NS5b proteins. A second infection to assess CD8+ T-cell responsiveness resulted in rapid suppression of HCV replication by week 2, but viremia rebounded 3 weeks later and the infection persisted. The E2, NS5a, and NS5b proteins remained dominant CD8+ T-cell targets after reinfection. Resurgent HCV replication was temporally associated with mutational escape of NS5a and NS5b class I epitopes that had also mutated during the first chronic infection. Two epitopes in E2 remained intact throughout both persistent infections. Intrahepatic CD8+ T cells targeting intact and escape-prone epitopes differed in expression of phenotypic markers of functional exhaustion 2 years after successful DAA therapy and in the capacity to expand in liver upon reinfection. CONCLUSIONS: The intrahepatic HCV-specific CD8+ T-cell repertoire established during chronic infection was narrowly focused, but very stable, after cure with DAA. Existing intrahepatic CD8+ T cells targeting dominant epitopes of the challenge virus failed to prevent persistence. Vaccination after DAA cure may be necessary to broaden T-cell responses and reduce the risk of a second persistent infection.

Targeting vascular senescence in cardiovascular disease with aging.

Aging is a major risk factor for atherosclerosis and cardiovascular disease (CVD). Two major age-associated arterial phenotypes, endothelial dysfunction and large elastic arterial stiffness, are autonomous predictors of future CVD diagnosis and contribute to the progression of CVD in older adults. Senescent cells lose the capacity to proliferate but remain metabolically active and secrete inflammatory factors termed senescence-associated secretory phenotype (SASP), leading to an increase in inflammation and oxidative stress. Accumulation of senescent cells is linked with the progression of age-related diseases and has been known to play a role in cardiovascular disease. In this brief review, we describe the characteristics and mechanisms of senescent cell accumulation and how senescent cells promote endothelial dysfunction and arterial stiffness. We focus on a range of novel therapeutic strategies aimed at reducing the burden of endothelial dysfunction leading to atherosclerosis through targeting senescent cells. Studies have begun to investigate a specific class of drugs that are able to selectively eliminate senescent cells, termed senolytics, which have shown great promise in reversing the aging phenotype and ameliorating pathologies in age-related disorders, creating a new opportunity for aging research. Generating therapies targeting the elimination of senescent cells would improve health span and increase longevity, making senolytics a promising therapy for cardiovascular diseases.

Upcycling plastic waste into fully recyclable composites through cold sintering.

Plastics have substantial societal benefits, but their widespread use has led to a critical waste management challenge. While mechanical recycling dominates the reuse of post-consumer plastics, it is limited in efficacy, especially for composites. To address this, we propose a direct reprocessing approach that enables the creation of hybrid, long-lasting, and durable composites from difficult-to-recycle plastics. This approach utilizes cold sintering, a process that consolidates inorganic powders through fractional dissolution and precipitation at temperatures far below conventional sintering; these temperatures are compatible with plastic processing. We show that this process can create inorganic-matrix composites with significant enhancements in tensile strength and toughness over pure gypsum, which is commonly found in construction waste. These composites can be recycled multiple times through direct reprocessing with the addition of only water as a processing promoter. This approach to recycling leads to composites with orders of magnitude lower energy demand, global warming potential, and water demand, when compared against common construction products. Altogether, we demonstrate the potential for cold sintering to integrate waste into high-performance recyclable composites.

Cold Sintering Enables the Reprocessing of LLZO-Based Composites.

All-solid-state batteries have the potential for enhanced safety and capacity over conventional lithium ion batteries, and are anticipated to dominate the energy storage industry. As such, strategies to enable recycling of the individual components are crucial to minimize waste and prevent health and environmental harm. Here, we use cold sintering to reprocess solid-state composite electrolytes, specifically Mg and Sr doped Li7La3Zr2O12 with polypropylene carbonate (PPC) and lithium perchlorate (LLZO-PPC-LiClO4). The low sintering temperature allows co-sintering of ceramics, polymers and lithium salts, leading to re-densification of the composite structures with reprocessing. Reprocessed LLZO-PPC-LiClO4 exhibits densified microstructures with ionic conductivities exceeding 10-4 S/cm at room temperature after 5 recycling cycles. All-solid-state lithium batteries fabricated with reprocessed electrolytes exhibit a high discharge capacity of 168 mA h g-1 at 0.1 C, and retention of performance at 0.2 C for over 100 cycles. Life cycle assessment (LCA) suggests that recycled electrolytes outperforms the pristine electrolyte process in all environmental impact categories, highlighting cold sintering as a promising technology for recycling electrolytes.

Endothelial cell-specific reduction in mTOR ameliorates age-related arterial and metabolic dysfunction.

Systemic inhibition of the mammalian target of rapamycin (mTOR) delays aging and many age-related conditions including arterial and metabolic dysfunction. However, the mechanisms and tissues involved in these beneficial effects remain largely unknown. Here, we demonstrate that activation of S6K, a downstream target of mTOR, is increased in arteries with advancing age, and that this occurs preferentially in the endothelium compared with the vascular smooth muscle. Induced endothelial cell-specific deletion of mTOR reduced protein expression by 60-70%. Although this did not significantly alter arterial and metabolic function in young mice, endothelial mTOR reduction reversed arterial stiffening and improved endothelium-dependent dilation (EDD) in old mice, indicating an improvement in age-related arterial dysfunction. Improvement in arterial function in old mice was concomitant with reductions in arterial cellular senescence, inflammation, and oxidative stress. The reduction in endothelial mTOR also improved glucose tolerance in old mice, and this was associated with attenuated hepatic gluconeogenesis and improved lipid tolerance, but was independent of alterations in peripheral insulin sensitivity, pancreatic beta cell function, or fasted plasma lipids in old mice. Lastly, we found that endothelial mTOR reduction suppressed gene expression of senescence and inflammatory markers in endothelial-rich (i.e., lung) and metabolically active organs (i.e., liver and adipose tissue), which may have contributed to the improvement in metabolic function in old mice. This is the first evidence demonstrating that reducing endothelial mTOR in old age improves arterial and metabolic function. These findings have implications for future drug development.

Accuracy of American College of Surgeons National Surgical Quality Improvement Program Universal Surgical Risk Calculator in Predicting Complications Following Robot-Assisted Radical Cystectomy at a National Comprehensive Cancer Center.

Introduction: There is paucity of literature about the validation of the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP®) surgical risk calculator for prediction of outcomes after robot-assisted radical cystectomy (RARC). We sought to evaluate the accuracy of the ACS NSQIP surgical risk calculator in the patients who underwent RARC at our institute. Methods: We retrospectively reviewed our prospectively maintained database for patients who underwent RARC between 2005 and 2017. Accuracy of the ACS NSQIP surgical risk calculator was assessed, by comparing the rate of actual complication events after surgery with the receiver operating characteristics curve analysis by calculating the fractional area under the curve (AUC) and the Brier score (BS). We utilized the code number 51595 and 51596 in the ACS NSQIP calculator for the patients undergoing radical cystectomy and reconstructed with the ileal conduit and neobladder, respectively. Results: A total of 462 patients were included in this study: 99 (22%) had diabetes, 302 (66%) had hypertension requiring medication, and 241 (52%) were classified as high American Society of Anesthesiologists (≥3) class. The actual observed rates of any complication and serious complications were 48% and 11%, vs 29% and 25% predicted by the ACS NSQIP, respectively. The actual mean length of hospital stay (10.6 ± 7.8 days) was longer compared with the predicted length (8.5 ± 1.6 days). AUC values were low and the BSs were high for any complication (AUC: 0.50 and BS: 0.29), serious complication (AUC: 0.53 and BS: 0.12), urinary tract infection (AUC: 0.61 and BS: 0.14), renal insufficiency (AUC: 0.64 and BS: 0.08), return to operation room (AUC: 0.58 and BS: 0.07), and early readmission (AUC: 0.55 and BS: 0.11, respectively). Conclusions: The ACS NSQIP calculator demonstrated low accuracy in predicting postoperative outcomes after RARC. These findings highlight the need for development of procedure- and technique-specific RARC calculators.

To Treat or Not to Treat M2 Occlusions? The Question (and Answer) From a Single Institution.

BACKGROUND: Occlusions of the M2 segment of the middle cerebral artery may cause significant clinical effects, especially when occurring in the dominant cerebral hemisphere, yet endovascular treatment of these lesions remains controversial. OBJECTIVE: To examine the safety and efficacy of endovascular treatment of M2 occlusions at our institution. METHODS: We retrospectively examined radiographic and clinical data of 53 patients presenting with M2 occlusions to our institution. RESULTS: Successful recanalization (Thrombolysis in Cerebral Infarction grade 2b or 3) was achieved in 40 patients (76.9%). No symptomatic intracranial hemorrhage occurred. The mean National Institutes of Health Stroke Scale score at discharge was 6.4 (median, 5.5). In the 38 patients who had follow-up after discharge, the mean follow-up duration was 11.1 months (range, 0.5-36.5 months) and mean National Institutes of Health Stroke Scale score was 3.5 (median, 1). CONCLUSION: The results of our single-institution experience suggest that endovascular therapy for M2 occlusions is safe and effective. Additional evaluation with randomized, controlled studies is warranted. ABBREVIATIONS: ADAPT, direct aspiration first-pass techniqueECASS, European-Australasian Cooperative Acute Stroke StudyICH, intracranial hemorrhageIMS, Interventional Management of StrokeMERCI, Mechanical Embolus Removal in Cerebral IschemiamRS, modified Rankin ScaleNIHSS, National Institutes of Health Stroke ScalePROACT, Prolyse in Acute Cerebral ThromboembolismTICI, Thrombolysis in Cerebral Infarctiont-PA, tissue-type plasminogen activator.

Risk of acute kidney injury associated with neuroimaging obtained during triage and treatment of patients with acute ischemic stroke symptoms.

BACKGROUND: Combining non-contrast CT (NCCT), CT angiography (CTA), and CT perfusion (CTP) imaging (referred to as a CT stroke study, CTSS) provides a rapid evaluation of the cerebrovascular axis during acute ischemic stroke. Iodinated contrast-enhanced CT imaging is not without risk, which includes renal injury. If a patient's CTSS identifies vascular pathology, digital subtraction angiography (DSA) is often performed within 24-48 h. Such patients may receive multiple administrations of iodinated contrast material over a short time period. OBJECTIVE: We aimed to evaluate the incidence of acute kidney injury (AKI) in patients who underwent a CTSS and DSA for evaluation of acute ischemic symptoms or for stroke intervention within a 48 h period between August 2012 and December 2014. METHODS: We identified 84 patients for inclusion in the analysis. Patients fell into one of two cohorts: AKI, defined as a rise in the serum creatinine level of ≥0.5 mg/dL from baseline, or non-AKI. Clinical parameters included pre- and post-imaging serum creatinine level, time between CTSS and DSA, and type of angiographic procedure (diagnostic vs intervention) performed. RESULTS: Four patients (4.7%) experienced AKI, one of whom had baseline renal dysfunction (defined as baseline serum creatinine level ≥1.5 mg/dL). The mean difference between baseline and peak creatinine values was found to be significantly greater in patients with AKI than in non-AKI patients (1.65 vs -0.09, respectively; p=0.0008). CONCLUSIONS: This study provides preliminary evidence of the safety and feasibility of obtaining CTSS with additional DSA imaging, whether for diagnosis or intervention, to identify possible acute ischemic stroke.

Health Behavior Theory in Popular Calorie Counting Apps: A Content Analysis.

BACKGROUND: Although the Health & Fitness category of the Apple App Store features hundreds of calorie counting apps, the extent to which popular calorie counting apps include health behavior theory is unknown. OBJECTIVE: This study evaluates the presence of health behavior theory in calorie counting apps. METHODS: Data for this study came from an extensive content analysis of the 10 most popular calorie counting apps in the Health & Fitness category of the Apple App Store. RESULTS: Each app was given a theory score to reflect the extent to which health behavior theory was integrated into the app. The highest possible score was 60. Out of the 10 apps evaluated, My Diet Coach obtained the highest theory score of 15. MapMyFitness and Yumget received the lowest scores of 0. The average theory score among the apps was 5.6. CONCLUSIONS: Most of the calorie counting apps in the sample contained minimal health behavior theory.