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Background Documentation of patterns and long-term trends in mortality in young people, which reflect huge changes in demographic and social determinants of adolescent health, enables identification of global investment priorities for this age group. We aimed to analyse data on the number of deaths, years of life lost, and mortality rates by sex and age group in people aged 10–24 years in 204 countries and territories from 1950 to 2019 by use of estimates from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019. Methods We report trends in estimated total numbers of deaths and mortality rate per 100 000 population in young people aged 10–24 years by age group (10–14 years, 15–19 years, and 20–24 years) and sex in 204 countries and territories between 1950 and 2019 for all causes, and between 1980 and 2019 by cause of death. We analyse variation in outcomes by region, age group, and sex, and compare annual rate of change in mortality in young people aged 10–24 years with that in children aged 0–9 years from 1990 to 2019. We then analyse the association between mortality in people aged 10–24 years and socioeconomic development using the GBD Socio-demographic Index (SDI), a composite measure based on average national educational attainment in people older than 15 years, total fertility rate in people younger than 25 years, and income per capita. We assess the association between SDI and all-cause mortality in 2019, and analyse the ratio of observed to expected mortality by SDI using the most recent available data release (2017). Findings In 2019 there were 1·49 million deaths (95% uncertainty interval 1·39–1·59) worldwide in people aged 10–24 years, of which 61% occurred in males. 32·7% of all adolescent deaths were due to transport injuries, unintentional injuries, or interpersonal violence and conflict; 32·1% were due to communicable, nutritional, or maternal causes; 27·0% were due to non-communicable diseases; and 8·2% were due to self-harm. Since 1950, deaths in this age group decreased by 30·0% in females and 15·3% in males, and sex-based differences in mortality rate have widened in most regions of the world. Geographical variation has also increased, particularly in people aged 10–14 years. Since 1980, communicable and maternal causes of death have decreased sharply as a proportion of total deaths in most GBD super-regions, but remain some of the most common causes in sub-Saharan Africa and south Asia, where more than half of all adolescent deaths occur. Annual percentage decrease in all-cause mortality rate since 1990 in adolescents aged 15–19 years was 1·3% in males and 1·6% in females, almost half that of males aged 1–4 years (2·4%), and around a third less than in females aged 1–4 years (2·5%). The proportion of global deaths in people aged 0–24 years that occurred in people aged 10–24 years more than doubled between 1950 and 2019, from 9·5% to 21·6%. Interpretation Variation in adolescent mortality between countries and by sex is widening, driven by poor progress in reducing deaths in males and older adolescents. Improving global adolescent mortality will require action to address the specific vulnerabilities of this age group, which are being overlooked. Furthermore, indirect effects of the COVID-19 pandemic are likely to jeopardise efforts to improve health outcomes including mortality in young people aged 10–24 years. There is an urgent need to respond to the changing global burden of adolescent mortality, address inequities where they occur, and improve the availability and quality of primary mortality data in this age group. Funding Bill & Melinda Gates Foundation.

Low-density lipoprotein cholesterol (LDL-C) is typically estimated from total cholesterol, high-density lipoprotein cholesterol, and triglycerides. The Friedewald, Martin-Hopkins, and National Institutes of Health equations are widely used but may estimate LDL-C inaccurately in certain patient populations, such as those with HIV. We sought to investigate the utility of machine learning for LDL-C estimation in a large cohort of women with and without HIV.We identified 7397 direct LDL-C measurements (5219 from HIV-infected individuals, 2127 from uninfected controls, and 51 from seroconvertors) from 2414 participants (age 39.4 ± 9.3 years) in the Women's Interagency HIV Study and estimated LDL-C using the Friedewald, Martin-Hopkins, and National Institutes of Health equations. We also optimized 5 machine learning methods [linear regression, random forest, gradient boosting, support vector machine (SVM), and neural network] using 80% of the data (training set). We compared the performance of each method using root mean square error, mean absolute error, and coefficient of determination (R2) in the holdout (20%) set.SVM outperformed all 3 existing equations and other machine learning methods, achieving the lowest root mean square error and mean absolute error, and the highest R2 (11.79 and 7.98 mg/dL, 0.87, respectively, compared with those obtained using the Friedewald equation: 12.45 and 9.14 mg/dL, 0.87). SVM performance remained superior in subgroups with and without HIV, with nonfasting measurements, in LDL70 mg/dL and triglycerides400 mg/dL.In this proof-of-concept study, SVM is a robust method that predicts directly measured LDL-C more accurately than clinically used methods in women with and without HIV. Further studies should explore the utility in broader populations.

The periodontium is an integrated, functional unit of multiple tissues surrounding and supporting the tooth, including but not limited to cementum (CM), periodontal ligament (PDL) and alveolar bone (AB). Periodontal tissues can be destructed by chronic periodontal disease, which can lead to tooth loss. In support of the treatment for periodontally diseased tooth, various biomaterials have been applied starting as a contact inhibition membrane in the guided tissue regeneration (GTR) that is the current gold standard in dental clinic. Recently, various biomaterials have been prepared in a form of tissue engineering scaffold to facilitate the regeneration of damaged periodontal tissues. From a physical substrate to support healing of a single type of periodontal tissue to multi-phase/bioactive scaffold system to guide an integrated regeneration of periodontium, technologies for scaffold fabrication have emerged in last years. This review covers the recent advancements in development of scaffolds designed for periodontal tissue regeneration and their efficacy tested in vitro and in vivo. Pros and Cons of different biomaterials and design parameters implemented for periodontal tissue regeneration are also discussed, including future perspectives., Graphical abstract Image 1, Highlights • Periodontal diseases are a major cause of tooth loss and the current treatment suffers from limitations. • Biomaterial scaffold-guided regeneration of periodontal tissues have recently emerged. • This review addresses the recent advance in bioactive scaffold for integrated regeneration of multiple periodontal tissues. • The outstanding limitations and future perspectives are also discussed.

Natural or synthetic materials designed to adhere to biological components, bioadhesives, have received significant attention in clinics and surgeries. As a result, there are several commercially available, FDA-approved bioadhesives used for skin wound closure, hemostasis, and sealing tissue gaps or cracks in soft tissues. Recently, the application of bioadhesives has been expanded to various areas including musculoskeletal tissue engineering and regenerative medicine. The instant establishment of a strong adhesion force on tissue surfaces has shown potential to augment repair of connective tissues. Bioadhesives have also been applied to secure tissue grafts to host bodies and to fill or seal gaps in musculoskeletal tissues caused by injuries or degenerative diseases. In addition, the injectability equipped with the instant adhesion formation may provide the great potential of bioadhesives as vehicles for localized delivery of cells, growth factors, and small molecules to facilitate tissue healing and regeneration. This review covers recent research progress in bioadhesives as focused on their applications in musculoskeletal tissue repair and regeneration. We also discuss the advantages and outstanding challenges of bioadhesives, as well as the future perspective toward regeneration of connective tissues with high mechanical demand.

Background: Despite advances in therapy of Hodgkin's lymphoma (HL), a proportion of patients will not respond or relapse. The authors had previously identified CD25, IL-2Rα, as a target for systemic radioimmunotherapy of HL since most normal cells do not express CD25, but it is expressed by a minority of Hodgkin/Reed-Sternberg (HRS) cells and most Tregs rosetting around HRS cells. Study Design and Treatment: This was a single institution, nonrandomized, open-label phase I/II trial of radiolabeled (90)Y-daclizumab, an anti-CD25 monoclonal antibody, BEAM (carmustine, etoposide, cytarabine, and melphalan) conditioning treatment followed by autologous hematopoietic stem cell transplant (ASCT). Four patients with refractory and relapsed HL were treated in this trial with 3 patients receiving a single dose of 564.6–574.6 MBq (90)Y-daclizumab and the fourth patient receiving two doses of 580.9–566.1 MBq (90)Y-daclizumab followed by high-dose chemotherapy and ASCT. Results: All 4 evaluable patients treated with (90)Y-daclizumab obtained complete responses (CRs) that are ongoing 4.5–7 years following their stem cell transplant. The spectrum and severity of adverse events were mild and more importantly none of the patients, including several with multiple therapies before this treatment, developed the myelodysplastic syndrome. Discussion: Targeting by daclizumab was not directed primarily at tumor cells, but rather the nonmalignant CD25-expressing T cells adjacent to the HRS cells and (90)Y-daclizumab provided strong enough β emissions to kill CD25-negative tumor cells at a distance by a crossfire effect. Furthermore, the strong β irradiation killed normal cells in the tumor microenvironment. Conclusions: (90)Y-daclizumab (anti-CD25), high-dose BEAM chemotherapy and ASCT was well tolerated and yielded sustained complete remissions in all 4 patients with recurrent HL patients who completed their treatment. Significance: Despite advances, a proportion of patients with HL will not have a CR to their initial treatment, and some with CRs will relapse. They demonstrated that the addition of (90)Y-daclizumab into the preconditioning regimen for refractory and relapsed HL patients with high-dose BEAM chemotherapy and ASCT provided sustained CRs in the 4 patients studied. Two of these patients were highly refractory to multiple prior treatments with bulky disease at entry into this study, including 1 patient who never entered a remission and had failed 6 different therapeutic regimens. Despite the small number of patients treated in this study, the sustained clinical benefit in these patients indicates a highly effective treatment. The daclizumab was directed primarily not at HRS cells themselves but toward nonmalignant T cells rosetting around malignant cells. (90)Y provided strong β emissions that killed antigen nonexpressing tumor cells at a distance by a crossfire effect. Furthermore, the strong β radiation killed normal cells in the tumor microenvironment that nurtured the malignant cells in the lymphomatous mass. The present study supports expanded analysis of (90)Y-daclizumab as part of the regimen of ASCT in patients with refractory and relapsed HL.

Glucagon-like peptide 1 receptor agonists (GLP1Ra) are commonly used in type 2 diabetes mellitus (T2DM). However, differential risk of various cancers among GLP1Ra recipients is unknown. We inquired an aggregated electronic health record database, Explorys, and compared the adjusted odds ratio (aOR) of cancers between GLP1Ra and metformin users. Findings were validated in the FDA Adverse Event Reporting System (FDA FAERS). From 1/2005 to 6/2019, we identified 619 340 and 64 230 patients in the metformin and GLP1Ra group, respectively. Within 5 years of starting antidiabetic medications, GLP1Ra was associated with significantly lower incident risk of prostate (aOR 0.81, p = .03), lung (aOR 0.81, p = .05), and colon cancer (aOR 0.85, p = .03), while the risk of thyroid cancer was significantly higher (aOR 1.65, p p = .08), lung (aOR 0.52, p p = .31), and higher risk of thyroid cancer (aOR 4.33, p GLP1Ra is associated with lower risks of prostate, lung, and colon cancer, but higher risk of thyroid cancer.

BackgroundThe value of the electrocardiogram (ECG) for predicting long-term cardiovascular outcomes is not well defined. Machine learning methods are well suited for analysis of highly correlated data such as that from the ECG.MethodsUsing demographic, clinical, and 12-lead ECG data from the Third National Health and Nutrition Examination Survey (NHANES III), machine learning models were trained to predict 10-year cardiovascular mortality in ambulatory U.S. adults. Predictive performance of each model was assessed using area under receiver operating characteristic curve (AUROC), area under precision-recall curve (AUPRC), sensitivity, and specificity. These were compared to the 2013 American College of Cardiology/American Heart Association Pooled Cohort Equations (PCE).Results7,067 study participants (mean age: 59.2 ± 13.4 years, female: 52.5%, white: 73.9%, black: 23.3%) were included. At 10 years of follow up, 338 (4.8%) had died from cardiac causes. Compared to the PCE (AUROC: 0.668, AUPRC: 0.125, sensitivity: 0.492, specificity: 0.859), machine learning models only required demographic and ECG data to achieve comparable performance: logistic regression (AUROC: 0.754, AUPRC: 0.141, sensitivity: 0.747, specificity: 0.759), neural network (AUROC: 0.764, AUPRC: 0.149, sensitivity: 0.722, specificity: 0.787), and ensemble model (AUROC: 0.695, AUPRC: 0.166, sensitivity: 0.468, specificity: 0.912). Additional clinical data did not improve the predictive performance of machine learning models. In variable importance analysis, important ECG features clustered in inferior and lateral leads.ConclusionsMachine learning can be applied to demographic and ECG data to predict 10-year cardiovascular mortality in ambulatory adults, with potentially important implications for primary prevention.

Background: Pediatric intraspinal space-occupying lesions are relatively uncommon. However, these lesions can result in neurological disabilities due to misdiagnosis and delayed treatment. The main goal of the present study is to evaluate the clinical and radiological features and treatment options of pediatric intraspinal space-occupying lesions in order to improve the clinical recognition and management. Methods: Clinical data of 27 children with intraspinal space-occupying lesions who underwent surgery treatment in a tertiary-care hospital between 2010 and 2018 were retrospectively reviewed and analyzed. Results: Of these 27 patients, 14 (51.85%) were girls and 13 (48.15%) were boys. The most common age group affected was 10~14 years (62.96%, 9 girls and 8 boys in this age group). The mean age was 10.11 years old. Pain and weakness were the most common clinical symptoms. Preoperative magnetic resonance imaging (MRI) identified intramedullary (10 cases, 37.04%), intradural extramedullary (10 cases, 37.04%) and extradural (7 cases, 25.92%) lesions, respectively. The majority of the lesions were intraspinal tumors (23 cases, 85.19%). The histological diagnosis of tumors included embryonic residual tumors (6 cases, 22.22%), ependymoma (5 cases, 18.52%), primitive neuroectodermal tumors (PNET) (3 cases, 11.11%), schwannomas (2 cases, 7.4%), ganglioneuroma (1 case, 3.7%), Ewing’s sarc (1 case, 3.7%), B-cell non Hodgkin lymphoma (1 case, 3.7%), Hodgkin lymphoma (1 case, 3.7%), chondrosarcoma (1 case, 3.7%), ganglioglioma (1 case, 3.7%), and glioma (1 case, 3.7%). Conclusions: The incidence of pediatric intraspinal space-occupying lesions is low, and the clinical manifestation is lack of specificity. The prognosis for children with malignant tumors is poor and surgical resection is still the primary treatment option.

In this paper the results of particular studies of multiple Bragg reflection (MBR) effects accompanying a strong Si(111) reflection in the cylindrically bent perfect crystal at the neutron wavelength of 0.162 nm are presented. Contrary to a common view that MBR effects could be considered negligible or represent maximally a few percent of an effect related to a single allowed reflection, it is shown that in the case of a homogeneously deformed perfect single crystal (in this case cylindrically bent Si crystal) and particular diffraction geometry they can be even several times higher.

Background: Scarce information exists on the relationship between lumbar lordosis (LL) and health-related quality of life (HRQOL) after lumbar surgery. The aim of this study was to derive a predictive equation for lordosis using pelvic incidence and to establish a simple lumbar lordosis prediction method to improve the quality of life after surgery.Methods: A number of 146 patients with lumbar surgery were included in the study. Spinopelvic parameters and Oswestry Disability Index (ODI) were measured at the final follow-up. At the 75th percentile cut-off value, patients with ODI were assigned to a good HRQOL group. Stepwise multiple regression analysis was used to analyze the correlation between parameters and ODI, and simple linear regression analysis was conducted to deduce the predictive equation for the recovery of reasonable LL by posterior lumbar interbody fusion (PLIF).Results: In the good HRQOL group, we included 108 patients with an ODI score less than 29 (75% cut-off value) at the last follow-up. All patients had had completed their posterior lumbar interbody fusion (L4-S1) by the same experienced surgeon. Multiple regression analysis revealed that LL (P < 0.001) was significantly associated with ODI as radiological parameters. The close relationship between PI and LL is highly evident from the value of the regression coefficient (r = 0.765, P < 0.001). Based on the correlation established between the above parameters, the following prediction equation for PI and LL was derived: LL = 0.59 × PI + 12 (r = 0.765, P < 0.001). Conclusions: This simple calculation method can provide a more effective and simple prediction of lumbar lordosis in the Chinese population. This approach can be used as a decision-making tool for restoring LL in lumbar correction surgery and plays an important role in improving the quality of life of patients after lumbar surgery.

Background: Low-density lipoprotein cholesterol (LDL-C) is commonly estimated from total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG) using predefined equations which assume fixed or varying relationships between these parameters and may under- or overestimate LDL-C. Machine learning (ML) algorithms allow prediction of complex non-linear relationships. We, therefore, sought to investigate the utility of ML to predict LDL-C in comparison with two widely-used methods (Friedewald and Hopkins). Methods: We identified 7397 direct LDL-C (4716 HIV, 2060 uninfected controls) measurements in the Women's Interagency HIV Study (WIHS), a prospective study of women with and without HIV undergoing serial assessments. We trained and optimized 5 ML methods (linear regression, random forest, gradient boosting machine, support vector machine, and neural networks) to predict LDL-C using TC, HDL-C, and TG in 80% of the measurements and tested model performance in a holdout test set (20% of the measurements). Results: Overall, the support vector machine model had the best performance characteristics, outperforming Friedewald’s and Hopkins methods with higher R 2 , lower root mean square error and lower mean absolute error. The support vector machine model performance remained superior in participant subgroups with and without HIV and those with non-fasting measurements. Model performance parameters for the test dataset are shown in the Figure. Conclusions: A support vector machine learning model predicts directly measured LDL-C more accurately than Friedewald and Hopkins methods, especially in non-fasting patients with HIV. Further studies are needed to provide external validation.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease where substantial heterogeneity in clinical presentation urgently requires a better stratification of patients for the development of drug trials and clinical care. In this study we explored stratification through a crowdsourcing approach, the DREAM Prize4Life ALS Stratification Challenge. Using data from >10,000 patients from ALS clinical trials and 1479 patients from community-based patient registers, more than 30 teams developed new approaches for machine learning and clustering, outperforming the best current predictions of disease outcome. We propose a new method to integrate and analyze patient clusters across methods, showing a clear pattern of consistent and clinically relevant sub-groups of patients that also enabled the reliable classification of new patients. Our analyses reveal novel insights in ALS and describe for the first time the potential of a crowdsourcing to uncover hidden patient sub-populations, and to accelerate disease understanding and therapeutic development. ispartof: SCIENTIFIC REPORTS vol:9 issue:1 ispartof: location:England status: published

Background Low-density lipoprotein cholesterol (LDL-C) is estimated from total cholesterol, high-density lipoprotein cholesterol and triglycerides using predefined equations which assume fixed or varying relationships between these parameters and may underestimate or overestimate LDL-C. Data on the performance of these equations in persons with HIV are limited. We sought to investigate the utility of the 3 most widely used methods (Friedewald, Hopkins, and the recently proposed NIH equation) to predict LDL-C in persons with HIV. Methods We identified 7397 direct LDL-C (5219 HIV, 2127 uninfected controls, 51 seroconvertors) measurements in the Women's Interagency HIV Study, and used the 3 equations (Friedewald, Hopkins, and NIH) to calculate LDL-C. We compared the performance of the 3 equations using root mean square error and coefficient of determination (R2). Results Overall, the Friedewald equation had the best performance characteristics, outperforming Hopkins and NIH methods with lower root mean square error and higher R2 at lower triglyceride levels. However, this association did not hold true at higher triglyceride levels (quartiles 3 and 4), whereas the Hopkins equation had better performance characteristics in quartile 3, none of the 3 equations were optimal in quartile 4. After adjusting for fasting status and triglycerides levels, HIV+ had larger mean difference compared with directly measured LDL using all 3 methods. Conclusions All 3 methods have lower accuracy in HIV+ vs HIV- women, even after adjusting for triglyceride levels and fasting status. Further research should focus on identifying methods to estimate LDL-C in HIV.

In March 2020, the New York City metropolitan area became the epicenter of the United States' SARS-CoV-2 pandemic and the surge of new cases threatened to overwhelm the area's hospital systems. This article describes how an anesthesiology department at a large urban academic hospital rapidly adapted and deployed to meet the threat head-on. Topics included are preparatory efforts, development of a team-based staffing model, and a new strategy for resource management. While still maintaining a fully functioning operating theater, discrete teams were deployed to both COVID-19 and non-COVID-19 intensive care units, rapid response/airway management team, the difficult airway response team, and labor and delivery. Additional topics include the creation of a temporary 'pop-up' anesthesiology-run COVID-19 intensive care unit utilizing anesthesia machines for monitoring and ventilatory support as well as the development of a simulation and innovation team that was instrumental in the rapid prototyping of a controlled split-ventilation system and conversion of readily available BIPAP units into emergency ventilators. As the course of the disease is uncertain, the goal of this article is to assist others in preparation for what may come next with COVID-19 as well as potential future pandemics.

Objective To describe the temporal association and identify risk factors between cancer diagnosis and various types of arterial thromboembolism (ATE). Patients and Methods We inquired an aggregated electronic health record database (Explorys, IBM Corp., Armonk, New York) and identified patients with cancer from January 1999 to October 2019, with various types of ATE, including myocardial infarction, acute ischemic stroke, acute limb ischemia, acute mesenteric ischemia, acute renal infarction, and retinal artery occlusion. We investigated the temporal relationship between cancer diagnosis and ATE events by examining the incidence ratio (IR) of ATE before and after diagnosis of cancer. Results We identified 305,384 patients with cancer and ATE. The 30-day interval IR of total ATE was elevated shortly before and after cancer diagnosis, which was consistent among different ATE and cancer types. The incidence was highest within a 330-day window (90 days before and 240 days after cancer diagnosis), and IR peaked at 13.9 (95% confidence interval [CI], 13.6 to 14.2) in the first 30 days following diagnosis of cancer. Compared with patients with cancer who never developed ATE, patients with ATE had more cardiovascular risk factors at baseline. Patients with brain cancer, lung cancer, colorectal cancer, and pancreatic cancer had the highest risk of developing ATE, whereas ATE type was anatomically associated with cancer type. Conclusion In this observational study of an aggregated US patient population, those with newly diagnosed cancer had increased risk of ATE events. This risk was most elevated in a 330-day window around cancer diagnosis and was consistent across different types of ATE and cancer.

Purpose/Aim: Knee meniscus is a wedge-shaped fibrocartilaginous tissue, playing important roles in maintaining joint stability and function. Injuries to the meniscus, particularly with the avascular inner third zone, hardly heal and frequently progress into structural breakdown, followed by the initiation of osteoarthritis. As the importance of meniscus in joint function and diseases is being recognized, the field of meniscus research is growing. Not only development, biology, and metabolism but also injury, repair, and healing of meniscus are being actively investigated. As meniscus functions as an integrated unit of a knee joint, in vivo models with various species have been the predominant method for studying meniscus pathophysiology and for testing healing/regeneration strategies. However, in vivo models for meniscus studies suffer from low reproducibility and high cost. To complement the limitations of in vivo animal models, several types of meniscus explants have been applied as highly controlled, standardized in vitro models to investigate meniscus metabolism, pathophysiology, and repair or regeneration process. This review summarizes and compares the existing meniscus explant models. We also discuss the advantages and disadvantages of each explant model.Conclusion: Despite few outstanding challenges, meniscus explant models have potential to serve as an effective tool for investigations of meniscus metabolism, injury, repair and healing.

Simple Summary Thyroid cancer is one of the most common cancers worldwide, and its incidence has increased over the last few decades. It is difficult to diagnose different types of thyroid cancer. Tumor tissues from papillary thyroid cancer patient showed higher expression of mature NAG-1, whereas adjacent normal tissues showed higher expression of pro-NAG-1. Several anti-cancer compounds increased pro-NAG-1 expression in thyroid cancer cell line. Quercetin (3,3’,4’,5,7-pentahydroxyflavone) is a flavonoid that is a major component of various plants, including raspberries, grapes, and onions. Quercetin induced apoptosis by inducing only pro-NAG-1 expression, but not mature NAG-1, mediated by the transcription factor C/EBP. This study indicates that pro-NAG-1 could be used as a useful biomarker for thyroid cancer and also provides a potential therapeutic target for the treatment of thyroid cancer with quercetin. Abstract Although the treatment of thyroid cancer has improved, unnecessary surgeries are performed due to a lack of specific diagnostic and prognostic markers. Therefore, the identification of novel biomarkers should be considered in the diagnosis and treatment of thyroid cancer. In this study, antibody arrays were performed using tumor and adjacent normal tissues of patients with papillary thyroid cancer, and several potential biomarkers were identified. Among the candidate proteins chosen based on the antibody array data, mature NAG-1 exhibited increased expression in tumor tissues compared to adjacent normal tissues. In contrast, pro-NAG-1 expression increased in normal tissues, as assessed by western blot analysis. Furthermore, pro-NAG-1 expression was increased when the thyroid cancer cells were treated with phytochemicals and nonsteroidal anti-inflammatory drugs in a dose-dependent manner. In particular, quercetin highly induced the expression of pro-NAG-1 but not that of mature NAG-1, with enhanced anticancer activity, including apoptosis induction and cell cycle arrest. Examination of the NAG-1 promoter activity showed that p53, C/EBPα, or C/EBPδ played a role in quercetin-induced NAG-1 expression. Overall, our study indicated that NAG-1 may serve as a novel biomarker for thyroid cancer prognosis and may be used as a therapeutic target for thyroid cancers.

// Ido D. Weiss 1 , Lyn M. Huff 2 , Moses O. Evbuomwan 3 , Xin Xu 1 , Hong Duc Dang 1 , Daniel S. Velez 1 , Satya P. Singh 1 , Hongwei H. Zhang 1 , Paul J. Gardina 4 , Jae-Ho Lee 5 , Liza Lindenberg 6 , Timothy G. Myers 4 , Chang H. Paik 5 , David S. Schrump 7 , Stefania Pittaluga 3 , Peter L. Choyke 6 , Tito Fojo 2 and Joshua M. Farber 1 1 Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA 2 Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA 3 Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA 4 Genomic Technologies Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA 5 Radiopharmaceutical Laboratory, Nuclear Medicine Division, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD, USA 6 Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA 7 Thoracic Epigenetics Section, Thoracic and GI Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA Correspondence to: Joshua M. Farber, email: // Keywords : CXCR4, cancer, PET, plerixafor, adrenal Received : December 21, 2016 Accepted : June 16, 2017 Published : August 04, 2017 Abstract Expression of the chemokine receptor CXCR4 by many cancers correlates with aggressive clinical behavior. As part of the initial studies in a project whose goal was to quantify CXCR4 expression on cancers non-invasively, we examined CXCR4 expression in cancer samples by immunohistochemistry using a validated anti-CXCR4 antibody. Among solid tumors, we found expression of CXCR4 on significant percentages of major types of kidney, lung, and pancreatic adenocarcinomas, and, notably, on metastases of clear cell renal cell carcinoma and squamous cell carcinoma of the lung. We found particularly high expression of CXCR4 on adrenocortical cancer (ACC) metastases. Microarrays of ACC metastases revealed correlations between expression of CXCR4 and other chemokine system genes, particularly CXCR7/ACKR3 , which encodes an atypical chemokine receptor that shares a ligand, CXCL12, with CXCR4. A first-in-human study using 64 Cu-plerixafor for PET in an ACC patient prior to resection of metastases showed heterogeneity among metastatic nodules and good correlations among PET SUVs, CXCR4 staining, and CXCR4 mRNA. Additionally, we were able to show that CXCR4 expression correlated with the rates of growth of the pulmonary lesions in this patient. Further studies are needed to understand better the role of CXCR4 in ACC and whether targeting it may be beneficial. In this regard, non-invasive methods for assessing CXCR4 expression, such as PET using 64 Cu-plerixafor, should be important investigative tools.

3D printing is an emerging tool to fabricate scaffolds for tissue engineering and regenerative medicine, benefited by customized design, tunable internal microstructure and a wide range of applicable materials. As a recent technical advancement, 3D-printed scaffolds have been incorporated with a controlled delivery of growth factors and/or other bioactive cues to facilitate tissue regeneration, in addition to providing a temporal structural substrate for cell and tissue ingrowth. This review covers a number of the existing approaches to incorporate a controlled delivery system in 3D-printed scaffolds from hydrogel adsorption and surface coating to chemical integration and embedding microspheres. In addition, we discuss the advantages and disadvantages of each delivery method integrated in 3D-printed scaffolds, outstanding challenges and future directions.

Haptic systems render virtual reality by providing kinesthetic, tactile senses to an operator through a haptic device. Previous researchers analyzed haptic systems’ stability and performance issues. On haptic frameworks, a virtual coupling network that provides compliance between the haptic device and the virtual proxy for passivity distorts realistic interaction with virtual environment. That is, the operator will experience resistance even when the environment simulates free-motion. This paper suggests a virtual coupling triggering algorithm for improving free-motion performance of a haptic interface. A 1DOF exoskeleton for a knee joint is designed, and admittance control is used instead of compensating device dynamics to enable wide implementation of the haptic interface, up to a heavy and bulky haptic device. The algorithm utilizes surface EMG (sEMG) signal, which is easily collected from operators. Proper virtual coupling is designed according to previously derived guidelines for unconditional stability criteria. A method for pattern recognition of sEMG signal and a triggering algorithm corresponding to the recognized patterns are explained. The suggested algorithm successfully reduces peak of interaction force between the device and the operator by about half when the haptic interface simulates free-motion. Corresponding simulations and experiments are presented.

We have previously reported on the anti-inflammatory effects of a water-soluble chitosan derivative, zwitterionic chitosan (ZWC). In the present study, we hypothesized that orally-administered ZWC would provide local anti-inflammatory effects in the intestinal lumen. ZWC indeed showed anti-inflammatory effects in various in-vitro models including peritoneal macrophages, engineered THP1 monocytes, and Caco-2 cells. In Caco-2 cells, ZWC applied before the lipopolysaccharide (LPS) challenge was more effective than when it was applied after it in preventing LPS-induced cell damage. When administered to mice via drinking water as a prophylactic measure, ZWC protected the animals from 2,4,6-trinitrobenzene sulphonic acid (TNBS)-induced colitis, helping them to recover the body weight, restore the gross and histological appearance of the colon, and generate FoxP3+ T cells. In contrast, orally-administered ZWC did not protect the animals from LPS-induced systemic inflammation. These results indicate that orally-administered ZWC reaches the colon with minimal absorption through the upper gastrointestinal tract and provides a local anti-inflammatory effect.

The aim of this study was to evaluate the effect of gemigliptin vs sitagliptin or glimepiride as initial combination therapy with metformin on glycaemic variability and to assess the correlation between glycaemic variability reduction and the dipeptidyl peptidase-4 (DPP-4) inhibition in patients with type 2 diabetes. This multicentre, randomized, active-controlled, open-label exploratory study included 69 patients with HbA1c > 7.5%. Subjects were randomized to receive gemigliptin 50 mg (n = 24), sitagliptin 100 mg (n = 23) or glimepiride 2 mg (n = 22) for 12 weeks. After 12 weeks, the change in mean amplitude of glycaemic excursion (MAGE) compared with baseline was significantly lower in the DPP-4 inhibitor groups compared with that in patients who received glimepiride. Furthermore, the standard deviation (SD) of glucose was significantly lower in patients who received gemigliptin than that in patients who received sitagliptin or glimepiride. The DPP-4 inhibition was significantly correlated with changes in MAGE and SD of glucose. In conclusion, gemigliptin and sitagliptin were more effective than glimepiride in reducing glycaemic variability as initial combination therapy with metformin in patients with type 2 diabetes, and the DPP-4 inhibition was associated with a reduction in glycaemic variability.

Background: Stroke is a morbid and potentially mortal complication among patients hospitalized with acute medical illness. The potential of extended-duration thromboprophylaxis with the factor Xa inhibitor betrixaban to reduce the risk of stroke compared with standard-dose enoxaparin in this population was assessed in this retrospective APEX trial substudy (Acute Medically Ill Venous Thromboembolism Prevention With Extended Duration Betrixaban). Methods: Hospitalized acutely medically ill subjects (n=7513) were randomized in a double-dummy double-blind fashion to either extended-duration oral betrixaban (80 mg once daily for 35–42 days) or standard-dose subcutaneous enoxaparin (40 mg once daily for 10±4 days) for venous thromboprophylaxis. Stroke events were adjudicated by an independent, blinded event adjudication committee. Results: The mean age of study participants was 76 years; 45% were male; 13% had had a stroke; and 45% had congestive heart failure. There were fewer all-cause strokes (0.54% versus 0.97%; relative risk [RR]=0.56; 95% confidence interval, 0.32–0.96; P =0.032; adjusted RR=0.43%; number needed to treat=233) and ischemic strokes (0.48% versus 0.91%; RR=0.53; 95% confidence interval, 0.30–0.94; P =0.026; adjusted RR=0.43%; number needed to treat=233) among patients treated with betrixaban versus enoxaparin through 77 days of follow-up. Among high-risk subjects, those with congestive heart failure or ischemic stroke as their index event, betrixaban reduced the risk of all-cause stroke (0.72% versus 1.48%; RR=0.49; 95% confidence interval, 0.26–0.90; P =0.019; adjusted RR=0.76%; number needed to treat=132) and ischemic stroke (0.63% versus 1.38%; RR=0.45; 95% confidence interval, 0.24–0.87; P =0.014; adjusted RR=0.75%; number needed to treat=134) compared with enoxaparin. Conclusions: Among hospitalized medically ill patients, extended-duration betrixaban significantly reduced all-cause stroke and ischemic stroke through 77 days of follow-up Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01583218.

Background:Artificial meniscal scaffolds are being developed to prevent development of osteoarthritis after meniscectomy. Previously, it was reported that 3-dimensional (3D) anatomic scaffolds loaded with connective tissue growth factor (CTGF) and transforming growth factor β3 (TGF-β3) achieved meniscal regeneration in an ovine model. This was a relatively short-term study (3 months postoperative), and outcome analyses did not include magnetic resonance imaging (MRI).Purpose:To evaluate long-term outcome of meniscal replacement with growth factor–laden poly-ε-caprolactone (PCL) scaffolds.Study Design:Controlled laboratory study.Methods:Anatomically shaped ovine meniscal scaffolds were fabricated from PCL with a 3D printer based on MRI data. Skeletally mature sheep (N = 34) were randomly allocated to 3 groups: scaffold without growth factor (0-µg group), scaffold with CTGF microspheres (µS) (5 µg) + TGF-β3 µS (5 µg) (5-µg group), and scaffold with CTGF µS (10 µg) + TGF-β3 µS (10 µg) (10-µg group). Unilateral medial meniscal replacement was performed. Animals were euthanized at 6 or 12 months. Regenerated meniscus, articular cartilage status, and synovial reaction were evaluated quantitatively with gross inspection, histology, and MRI. Kruskal-Wallis and Dunn tests were used to compare the 3 groups.Results:Remnants of the PCL scaffold were evident in the 6-month specimens and were decreased but still present at 12 months in most animals. There were no significant differences among groups in gross inspection, histology, or MRI for either meniscal regeneration or articular cartilage protection. All experimental groups exhibited articular cartilage degeneration as compared with control (nonoperated). In terms of synovitis, there were no clear differences among groups, suggesting that growth factors did not increase inflammation and fibrosis. MRI revealed that meniscal extrusion was observed in most animals (82.7%).Conclusion:Previously, the combination of CTGF and TGF-β3 was shown to stimulate mesenchymal stem cells into a fibrochondrocyte lineage. CTGF and TGF-β3 did not aggravate synovitis, suggesting no adverse response to the combination of 3D-printed PCL scaffold combined with CTGF and TGF-β3. Further work will be required to improve scaffold fixation to avoid meniscal extrusion.Clinical Relevance:A significant advantage of this technique is the ability to print custom-fit scaffolds from MRI-generated templates. In addition, average-size menisci could be printed and available for off-the-shelf applications. Based on the 1-year duration of the study, the approach appears to be promising for meniscal regeneration in humans.

Background: A botulinum toxin (BTX) injection can be a simple and safe alternative to calf reduction surgery or liposuction without interrupting daily life. However, its optimum dosage and clinical response are not yet well known. Objectives: This study aimed to evaluate the effect of BTX on calf muscles on the basis of PrabotulinumtoxinA (PBoNT) injection dosage using diverse proportional injection techniques. Methods: A total of 40 patients with bilateral gastrocnemius muscle hypertrophy were enrolled in this study. All volunteers were randomly categorized into four groups and then administered different amounts of BTX (160U or 200U) on the medial and lateral aspects of their calves. Results: All subjects showed clinical improvement with a reduction in the gastrocnemius muscle size after BTX injection. However, our results showed that the decrease in leg circumference was not dose dependent. No side effects of the injections, such as weakness of the legs, deformity, or abnormal sensation, were observed. There were also no cases of swelling, edema, hematoma, or infection. Conclusion: The results of this study suggest that BTX at both dosages can be safely and effectively applied for calf muscle contouring without gait disturbance during walking or running.

The International Space Station (ISS) crew health and safety depend on ventilation system performance. The ISS ventilation system comprises of numerous air supply diffusers. For each ISS module design of the ventilation system and, in particular, supply diffuser distribution and configuration, is based on the assumption that the cabin aisle way is clear of any objects. However, on-orbit operations could lead to short- or long-term blockage of the area near the air supply diffuser due to some items or stowed bags necessary for the station operation. Partial blockage of the diffuser could disrupt the free jet airflow or change its intended direction. The current contribution is devoted to examination of the ISS research module – the U.S. Laboratory – ventilation system performance in case of partial inlet diffuser blockage with objects, such as Cargo Transfer Bag. The goal of the study is to assess the localized effects when the blockage occurs in the module interior for a possible stagnant zones formation. The paper presents detailed analysis of the diffuser blockage effects on airflow characteristics in various zones in the ISS habitat.

Meniscus tears in the avascular region rarely functionally heal due to poor intrinsic healing capacity, frequently resulting in tear propagation, followed by meniscus deterioration. Recently, we have reported that time-controlled application of connective tissue growth factor (CTGF) and transforming tissue growth factor β3 (TGFβ3) significantly improved healing of avascular meniscus tears by inducing recruitment and step-wise fibrocartilaginous differentiation of mesenchymal stem/progenitor cells (MSCs). In this study, we investigated effects of the dose of CTGF and the release rate of TGFβ3 on avascular meniscus healing in our existing explant model. Our hypothesis was that dose and release rate of CTGF and TGFβ3 are contributing factors for functional outcome in avascular meniscus healing by stem cell recruitment. Low (100 ng/ml) and high (1,000 ng/ml) doses of CTGF as well as fast (0.46 ± 0.2 ng/day) and slow (0.29 ± 0.1 ng/day) release rates of TGFβ3 were applied to our established meniscus explant model for meniscus tears in the inner-third avascular region. The release rate of TGFβ3 was controlled by varying compositions of poly(lactic-co-glycolic acids) (PLGA) microspheres. The meniscus explants were then cultured for 8 weeks on top of mesenchymal stem/progenitor cells (MSCs). Among the tested combinations, we found that a high CTGF dose and slow TGFβ3 release are most effective for integrated healing of avascular meniscus, demonstrating improvements in alignment of collagen fibers, fibrocartilaginous matrix elaboration and mechanical properties. This study may represent an important step toward the development of a regenerative therapy to improve healing of avascular meniscus tears by stem cell recruitment. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:1555-1562, 2019.

Oral cancer is one of the most common malignancies worldwide, with a two- or three-fold prevalence among men than among women. Except for lifestyle-related risk factors including smoking, drinking, and betel chewing, family history is a major determinant of risk in the absence of exposure to carcinogens. Genes predicting the susceptibility to oral cancer are associated with cell proliferation, cell invasion, angiogenesis, and DNA repair. Few studies have investigated sex-dependent X-linked gene expression in oral cancer. Hence, this study aimed to analyze salivary X-linked lncRNA-XIST, XIST anti-transcript TSIX, and X-linked tumor suppressor gene LDOC1 expression levels, their role in oral squamous cell carcinoma (OSCC) and correlations among clinicopathological data. Expression levels of these three genes were analyzed via quantitative polymerase chain reaction (qPCR) in the saliva of 59 OSCC patients and 43 healthy controls. Correlations among gene expression levels and clinicopathological characteristics were analyzed. Women lacking salivary XIST were 26-fold more susceptible (P < 0.0001) to OSCC than healthy women. TSIX and LDOC1 expression levels were positively correlated in all subjects, except for men with OSCC. LDOC1 was significantly downregulated in men with OSCC (P = 0.016) and significantly correlated with well-differentiated tumors (P = 0.001).

The Korean writing system, Hangul, is an alphabetic syllabary which permits a unique opportunity to investigate how both the syllabic and letter similarity structure of the Korean mental lexicon influences lexical processing. We capitalized on the availability of lexical decision behavioral data for thousands of Korean words, and the tools of network science to quantify the similarity structure of Korean words, to investigate the relative and interacting influences of syllable and letter similarity effects on Korean word recognition. Syllable and letter similarity measures were computed at both local and global levels of the lexicon, by considering the immediate neighbors of the target word (i.e., local) and the centrality of the target word with respect to the entire lexicon (i.e., global). Regression analyses showed that both local and global syllable and letter similarity influenced lexical decision performance, revealing a complex pattern of similarity effects where greater local similarity inhibited word recognition, and greater global distinctiveness facilitated word recognition. Furthermore, there were significant interaction effects between syllable and letter levels, suggesting that both syllabic and letter information are processed in an interactive fashion by Korean readers. Our findings demonstrate the importance of adopting computational methods that go beyond standard neighborhood measures and that can quantify the similarity relationships between words at multiple levels.

Although case series suggest a higher burden of cardiovascular risk factors in patients with systemic lupus erythematosus (SLE) compared with the general population, the association between SLE and heart failure (HF) remains undefined. We sought to investigate the incidence and risk of HF in patients with SLE.In April 2016, we performed a retrospective cohort analysis using the Explorys platform, which provides aggregated electronic medical record data from 26 major integrated healthcare systems across the USA from 1999 to present. Demographic and regression analyses were performed to assess the impact of SLE on HF incidence.Among 45 284 540 individuals in the database, we identified 95 400 (0.21%) with SLE and 98 900 (0.22%) with a new diagnosis of HF between May 2015 and April 2016. HF incidence was markedly higher in the SLE group compared with controls (0.97% vs 0.22%, relative risk (RR): 4.6 (95% CI 4.3 to 4.9)), as were other cardiovascular risk factors. In regression analysis, SLE was an independent predictor of HF (adjusted OR: 3.17 (2.63 to 3.83), p0.0001). RR of HF was highest in young males with SLE (65.2 (35.3 to 120.5) for age 20-24), with an overall trend of increasing absolute risk but decreasing RR with advancing age in both sexes. Renal involvement in SLE correlated with earlier and higher incidence of HF.The findings of this study suggest that patients with SLE have significantly higher risk of developing HF and a worse cardiovascular risk profile compared with the general population. These results need to be confirmed by prospective studies.

An air-ingress accident is considered to be one of the design basis accidents of a very high-temperature gas-cooled reactor (VHTR). The air-ingress accident is initiated, in its worst-case scenario, by a complete break of the hot duct in what is referred to as a double-ended guillotine break. This leads to an initial loss of the primary helium coolant via depressurization. Following the depressurization process, the air–helium mixture in the reactor cavity could enter the reactor core via the hot duct and hot exit plenum. In the event that air ingresses into the reactor vessel, the high-temperature graphite structures in the reactor core and hot plenum will chemically react with the air, which could lead to damage of in-core graphite structures and fuel, release of carbon monoxide and carbon dioxide, core heat up, failure of the structural integrity of the system, and eventually the release of radionuclides to the environment. Studies in the available literature focus on the phenomena of the air ingress accident that occur after the termination of the depressurization, such as density-driven stratified flow, molecular diffusion, and natural circulation. However, a recent study shows that flow reversal could occur due to Taylor wave expansion near the end of the depressurization, which could affect subsequent stages of the air ingress accident scenario. Therefore, to properly understand and evaluate the depressurization effects, numerical simulations are performed for the double-ended guillotine break of the Gas Turbine-Modular Helium Reactor (GT-MHR) cross vessel with a computational fluid dynamics (CFD) tool, ANSYS FLUENT. A benchmark and error quantification study of the depressurization shows that the ANSYS FLUENT model can predict the depressurization problem with relatively low uncertainty. In addition, the computational results show that the depressurization of a double-ended guillotine break behaves as an isentropic process. The observed flow oscillations near the end of the depressurization promote mixing of helium gas and air near the break. The results of the CFD analyses also show that the density-driven stratified flow, which is postulated to be the next stage of the air-ingress accident scenario, is strongly dependent on the density difference between the air–helium mixture in the containment and the helium in the reactor vessel. Therefore, the flow oscillations near the end of the depressurization stage may have a minor, yet notable, effect to slow down the air ingress due to density-driven stratified flow by decreasing the bulk density of the gas mixture in the containment through the addition of helium and increasing the bulk density in the reactor vessel through the addition of air.

Bronchopulmonary dysplasia (BPD) is an important complication of mechanical ventilation in preterm infants, and no definite therapy can eliminate this complication. Pulmonary inflammation plays a crucial role in its pathogenesis, and glucocorticoid is one potential therapy to prevent BPD.To compare the effect of intratracheal administration of surfactant/budesonide with that of surfactant alone on the incidence of death or BPD.A clinical trial was conducted in three tertiary neonatal centers in the United States and Taiwan, in which 265 very-low-birth-weight infants with severe respiratory distress syndrome who required mechanical ventilation and inspired oxygen (fraction of inspired oxygen, ≥50%) within 4 hours of birth were randomly assigned to one of two groups (131 intervention and 134 control). The intervention infants received surfactant (100 mg/kg) and budesonide (0.25 mg/kg), and the control infants received surfactant only (100 mg/kg), until each infant required inspired O2 at less than 30% or was extubated.The intervention group had a significantly lower incidence of BPD or death (55 of 131 [42.0%] vs. 89 of 134 [66%]; risk ratio, 0.58; 95% confidence interval, 0.44-0.77; P 0.001; number needed to treat, 4.1; 95% confidence interval, 2.8-7.8). The intervention group required significantly fewer doses of surfactant than did the control group. The intervention group had significantly lower interleukin levels (IL-1, IL-6, IL-8) in tracheal aspirates at 12 hours and lower IL-8 at 3-5 and 7-8 days.In very-low-birth-weight infants with severe respiratory distress syndrome, intratracheal administration of surfactant/budesonide compared with surfactant alone significantly decreased the incidence of BPD or death without immediate adverse effect. Clinical trial registered with www.clinicaltrials.gov (NCT-00883532).

Over the past decades, survival of patients with Hodgkin lymphoma (HL) has increased but remains curtailed by cardiovascular mortality (CVM). HL survivors at greatest risk for cardiovascular death have not been clearly identified. We sought to report trends of CVM identify HL survivors at highest risk.The Surveillance, Epidemiology, and End Results (SEER) database was queried for all adult patients diagnosed with HL (age 20-49 years) between 1990 and 2011. The trend of CVM and disparities are presented.Of 19,781 HL patients, 53% were male and 83% were white; patients had a mean age of 33 ± 8.3 years at diagnosis. Eighteen percent had stage I disease, 45% stage II, 18% stage III, and 15% stage IV. The risk for CVM was higher in blacks (adjusted hazard ratio [HR], 1.97; P = .002), men (adjusted HR, 2.2; P .001), and patients with older age at diagnosis (adjusted HR, 1.073 per year; P .001). CVM has decreased, with 5-year cumulative incidence decreasing from 1.17% in 1990 to 0.18% in 2006, averaging 7% per year (adjusted HR, 0.927; P .001). This trend was seen only in patients with early disease (P .001) but not with advanced disease (P = NS). CVM as a proportion of all-cause mortality increases sharply at 50 years of age, constituting more than 30% of all causes of death.Despite an overall decrease in CVM in HL survivors over the last decades, older patients, black patients, and men, especially those who have advanced-stage disease at diagnosis, are at the highest risk of cardiovascular death. Cardiovascular screening and risk modification should be intensified in HL patients with these characteristics.

*Corresponding author: Guilherme H. Oliveira, MD, FACC Associate Professor of Medicine Chief, Heart Failure Section Director, Onco-Cardiology Program Seidman Cancer Center Director, Advanced Heart Failure and Transplantation Center Harrington Heart and Vascular Institute Case Western Reserve University School of Medicine University Hospitals Case Medical Center 11100 Euclid Ave. Cleveland OH 44106, USA E-mail: guilherme.oliveira@uhhospitals.org

While various electrocardiogram (ECG) characteristics have been associated with increased cardiovascular mortality (CVM), utility of aggregated, machine-derived ECG measurements for prediction of CVM remains unknown. Using data from 8,432 participants in the third National Health and Nutrition

Objective The study objective was to determine whether targeted therapy to optimize cerebral oxygenation is associated with improved neurocognitive and perioperative outcomes. Methods In a prospective trial, intraoperative cerebral oximetry monitoring using bilateral forehead probes was performed in cardiac surgical patients who were randomly assigned to an intervention group in which episodes of cerebral oxygen desaturation ( 60 consecutive seconds at either probe) triggered an intervention protocol or a control group in which the cerebral oximetry data were hidden from the clinical team, and no intervention protocol was applied. Cognitive testing was performed preoperatively and at postoperative months 3 and 6; domains studied were response speed, processing speed, attention, and memory. Perioperative outcomes studied were death, hospital length of stay, intensive care unit length of stay, postoperative day of extubation, time on mechanical ventilation, intensive care unit delirium, Sequential Organ Failure Assessment on intensive care unit admission, and intensive care unit blood transfusion. Results Group mean memory change scores were significantly better in the intervention group at 6 months (0.60 [standard error, 0.30] vs −0.17 [standard error, 0.33], adjusted P = .008). However, presence, duration, and severity of cerebral desaturation were not associated with cognitive change scores. Perioperative outcomes did not differ between the intervention and control groups. Conclusions Targeted therapy to optimize cerebral oxygenation was associated with better memory outcome in a group of cardiac surgical patients. Some aspects of the protocol other than desaturation duration and severity contributed to the observed neuroprotective effect.

Neuronal cell death in the central nervous system has always been a challenging process to decipher. In physiological condition, neuronal cell death is restricted in the adult brain even as people ages. However, in pathological conditions of various neurodegenerative diseases, the cell death and shrinkage of a specific brain region represent a fundamental pathological feature across different neurodegenerative diseases. In this review, we will briefly go through the general pathways of cell death and describe the evidence of the cell deaths in the context of common neurodegenerative diseases individually, discussing our current understandings of cell death in connecting with the renowned pathogenic proteins, including tau, amyloid-beta, alpha-synuclein, huntingtin, and TDP-43.

Lung cancer is the leading cause of cancer-associated death worldwide. Early metastasis and the recurrence remain major challenges for lung cancer treatment in clinic. Targeting the cancer stemness could be a potential strategy to restrain tumor progression. In the current study, we found that in lung adenocarcinoma (LAC), BMI1 and MCL1 play crucial roles in invasion, chemo-resistance, and tumor initiation. JNK signaling is a link between oncogenic pathway or environment stress to cancer stemness. The activation of JNK, either by EGFR or chemotherapy agent, stabilized BMI1 and MCL1 proteins through suppressing the expression of E3-ubiquitin ligase HUWE1. In lung cancer patient samples, high level of BMI1 is correlated with poor survival, and the expression of BMI1 is positively correlated with MCL1. A novel small-molecule BI-44 was synthesized, which effectively suppressed BMI1/MCL1 expression and inhibited tumor formation and progression in preclinical models. Targeting BMI1/MCL1 provides the basis for a new therapeutic approach in the treatment of LAC.

Meniscus injuries are extremely common with approximately one million patients undergoing surgical treatment annually in the U.S. alone. Upon injury, the outer zone of the meniscus can be repaired and expected to functionally heal but tears in the inner avascular region are unlikely to heal. To date, no regenerative therapy has been proven successful for consistently promoting healing in inner-zone meniscus tears. Here, we show that controlled applications of connective tissue growth factor (CTGF) and transforming growth factor beta 3 (TGFβ3) can induce seamless healing of avascular meniscus tears by inducing recruitment and step-wise differentiation of synovial mesenchymal stem/progenitor cells (syMSCs). A short-term release of CTGF, a selected chemotactic and profibrogenic cue, successfully recruited syMSCs into the incision site and formed an integrated fibrous matrix. Sustain-released TGFβ3 then led to a remodeling of the intermediate fibrous matrix into fibrocartilaginous matrix, fully integrating incised meniscal tissues with improved functional properties. Our data may represent a novel clinically relevant strategy to improve healing of avascular meniscus tears by recruiting endogenous stem/progenitor cells.

BACKGROUND: Empagliflozin slowed the progression of CKD in patients with type 2 diabetes and cardiovascular disease in the EMPA-REG OUTCOME Trial. In a prespecified statistical approach, we assessed treatment differences in kidney function by analyzing slopes of eGFR changes.METHODS: Participants (n=7020) were randomized (1:1:1) to empagliflozin 10 mg/d, empagliflozin 25 mg/d, or placebo added to standard of care. We calculated eGFR slopes using random-intercept/random-coefficient models for prespecified study periods: treatment initiation (baseline to week 4), chronic maintenance treatment (week 4 to last value on treatment), and post-treatment (last value on treatment to follow-up).RESULTS: Compared with placebo, empagliflozin was associated with uniform shifts in individual eGFR slopes across all periods. On treatment initiation, adjusted mean slope (eGFR change per week, ml/min per 1.73 m2) decreased with empagliflozin (-0.77; 95% confidence interval, -0.83 to -0.71; placebo: 0.01; 95% confidence interval, -0.08 to 0.10; PCONCLUSIONS: The hemodynamic effects of empagliflozin, associated with reduction in intraglomerular pressure, may contribute to long-term preservation of kidney function.

Molecular oxygen (O2) is of paramount importance in biomedical science; thus monitoring O2 has been a research focus for decades, and various methods to measure and image oxygen have been reported. In this chapter, we introduce O2 monitoring and imaging through photoacoustic (PA) spectroscopy. Because PA imaging is directly correlated with optical absorption, it has been first utilized for direct measurements of oxy- and deoxy- hemoglobin and/or other oxygen carrying proteins for indirect O2 monitoring. More recently, tissue O2 monitoring by PA was introduced, by the PALT (PA lifetime) method, using the same mechanism as conventional phosphorescence quenching based oxygen sensing. The theoretical backgrounds as well as some recent examples of PA oxygen monitoring are introduced.

Despite significant advances in the treatment of Hodgkin's lymphoma (HL), a significant proportion of patients will not respond or will subsequently relapse. We identified CD25, the IL-2 receptor alpha subunit, as a favorable target for systemic radioimmunotherapy of HL. The scientific basis for the clinical trial was that, although most normal cells with exception of Treg cells do not express CD25, it is expressed by a minority of Reed-Sternberg cells and by most polyclonal T cells rosetting around Reed-Sternberg cells. Forty-six patients with refractory and relapsed HL were evaluated with up to seven i.v. infusions of the radiolabeled anti-CD25 antibody (90)Y-daclizumab. (90)Y provides strong β emissions that kill tumor cells at a distance by a crossfire effect. In 46 evaluable HL patients treated with (90)Y-daclizumab there were 14 complete responses and nine partial responses; 14 patients had stable disease, and nine progressed. Responses were observed both in patients whose Reed-Sternberg cells expressed CD25 and in those whose neoplastic cells were CD25(-) provided that associated rosetting T cells expressed CD25. As assessed using phosphorylated H2AX (γ-H2AX) as a bioindicator of the effects of radiation exposure, predominantly nonmalignant cells in the tumor microenvironment manifested DNA damage, as reflected by increased expression of γ-H2AX. Toxicities were transient bone-marrow suppression and myelodysplastic syndrome in six patients who had not been evaluated with bone-marrow karyotype analyses before therapy. In conclusion, repeated (90)Y-daclizumab infusions directed predominantly toward nonmalignant T cells rosetting around Reed-Sternberg cells provided meaningful therapy for select HL patients.

A critical event in the safety analysis of the very high-temperature gas-cooled reactor (VHTR) is an air-ingress accident. This accident is initiated, in its worst case scenario, by a double-ended guillotine break of the coaxial cross vessel, which leads to a rapid reactor vessel depressurization. In a VHTR, the reactor vessel is located within a reactor cavity that is filled with air during normal operating conditions. Following the vessel depressurization, the dominant mode of ingress of an air–helium mixture into the reactor vessel will either be molecular diffusion or density-driven stratified flow. The mode of ingress is hypothesized to depend largely on the break conditions of the cross vessel. Since the time scales of these two ingress phenomena differ by orders of magnitude, it is imperative to understand under which conditions each of these mechanisms will dominate in the air ingress process. Computer models have been developed to analyze this type of accident scenario. There are, however, limited experimental data available to understand the phenomenology of the air-ingress accident and to validate these models. Therefore, there is a need to design and construct a scaled-down experimental test facility to simulate the air-ingress accident scenarios and to collect experimental data. The current paper focuses on the analyses performed for the design and operation of a 1/8th geometric scale (by height and diameter), high-temperature test facility. A geometric scaling analysis for the VHTR, a time scale analysis of the air-ingress phenomenon, a transient depressurization analysis of the reactor vessel, a hydraulic similarity analysis of the test facility, a heat transfer characterization of the hot plenum, a power scaling analysis for the reactor system, and a design analysis of the containment vessel are discussed.

Background Extended‐duration betrixaban showed a significant reduction in venous thromboembolism in the APEX trial (Acute Medically Ill VTE Prevention With Extended Duration Betrixaban Study). Given the variable clinical impact of different efficacy and safety events, one approach to assess net clinical outcomes is to include only those events that are either fatal or cause irreversible harm. Methods and Results This was a post hoc analysis of the APEX trial—a multicenter, double‐blind, randomized controlled trial comparing extended‐duration betrixaban versus standard‐of‐care enoxaparin. A composite of all fatal or irreversible safety (fatal bleeding or intracranial hemorrhage) and efficacy events (cardiopulmonary death, myocardial infarction, pulmonary embolism, and ischemic stroke) was evaluated in a time‐to‐first event analysis. In patients with positive D‐dimer results, betrixaban reduced fatal or irreversible events at 35 to 42 days (4.80% versus 3.54%; hazard ratio, 0.73; absolute risk reduction, 1.26%; number needed to treat, 79 [ P =0.033]) and at study end at 77 days (6.27% versus 4.36%; hazard ratio, 0.70; absolute risk reduction, 1.91%; number needed to treat, 52 [ P =0.005]) versus enoxaparin. In all patients, betrixaban reduced fatal or irreversible events at 35 to 42 days (4.08% versus 2.90%; hazard ratio, 0.71; absolute risk reduction, 1.18%; number needed to treat, 86 [ P =0.006]) and 77 days (5.17% versus 3.64%; hazard ratio, 0.70; absolute risk reduction, 1.53%; number needed to treat, 65 [ P =0.002]). Conclusions Among hospitalized medically ill patients, extended‐duration betrixaban demonstrated an ≈30% reduction in fatal or irreversible ischemic or bleeding events compared with standard‐duration enoxaparin. A total of 65 patients would require treatment with betrixaban to prevent 1 fatal or irreversible event versus enoxaparin. Clinical Trial Registration URL : http://www.ClinicalTrials.gov . Unique identifier: NCT 01583218.

Background Venetoclax (ABT-199), a first-in-class orally bioavailable BCL-2-selective inhibitor, was recently approved by the FDA for use in patients with 17p-deleted chronic lymphocytic leukemia who have received prior therapy. It is also being evaluated in numerous clinical trials for treating patients with various hematologic malignancies. As with any targeted cancer therapy, it is critically important to identify potential mechanisms of resistance, both for patient stratification and developing strategies to overcome resistance, either before it develops or as it emerges. Methods In order to gain a more comprehensive insight into the nature of venetoclax resistance mechanisms, we evaluated the changes in the BCL-2 family members at the genetic and expression levels in seven different venetoclax-resistant derived leukemia and lymphoma cell lines. Results Gene and protein expression analyses identified a number of different alterations in the expression of pro- and anti-apoptotic BCL-2 family members. In the resistant derived cells, an increase in either or both the anti-apoptotic proteins BCL-XL or MCL-1, which are not targeted by venetoclax was observed, and either concomitant or exclusive with a decrease in one or more pro-apoptotic proteins. In addition, mutational analysis also revealed a mutation in the BH3 binding groove (F104L) that could potentially interfere with venetoclax-binding. Not all changes may be causally related to venetoclax resistance and may only be an epiphenomenon. For resistant cell lines showing elevations in BCL-XL or MCL-1, strong synergistic cell killing was observed when venetoclax was combined with either BCL-XL- or MCL-1-selective inhibitors, respectively. This highlights the importance of BCL-XL- and MCL-1 as causally contributing to venetoclax resistance. Conclusions Overall our study identified numerous changes in multiple resistant lines; the changes were neither mutually exclusive nor universal across the cell lines tested, thus exemplifying the complexity and heterogeneity of potential resistance mechanisms. Identifying and evaluating their contribution has important implications for both patient selection and the rational development of strategies to overcome resistance. Electronic supplementary material The online version of this article (doi:10.1186/s12885-017-3383-5) contains supplementary material, which is available to authorized users.

Supplemental Digital Content is available in the text., Background and Purpose— In the EMPA-REG OUTCOME trial (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients), empagliflozin added to standard of care in patients with type 2 diabetes mellitus and high cardiovascular risk reduced the risk of 3-point major adverse cardiovascular events, driven by a reduction in cardiovascular mortality, with no significant difference between empagliflozin and placebo in risk of myocardial infarction or stroke. In a modified intent-to-treat analysis, the hazard ratio for stroke was 1.18 (95% confidence interval, 0.89–1.56; P=0.26). We further investigated cerebrovascular events. Methods— Patients were randomized to empagliflozin 10 mg, empagliflozin 25 mg, or placebo; 7020 patients were treated. Median observation time was 3.1 years. Results— The numeric difference in stroke between empagliflozin and placebo in the modified intent-to-treat analysis was primarily because of 18 patients in the empagliflozin group with a first event >90 days after last intake of study drug (versus 3 on placebo). In a sensitivity analysis based on events during treatment or ≤90 days after last dose of drug, the hazard ratio for stroke with empagliflozin versus placebo was 1.08 (95% confidence interval, 0.81–1.45; P=0.60). There were no differences in risk of recurrent, fatal, or disabling strokes, or transient ischemic attack, with empagliflozin versus placebo. Patients with the largest increases in hematocrit or largest decreases in systolic blood pressure did not have an increased risk of stroke. Conclusions— In patients with type 2 diabetes mellitus and high cardiovascular risk, there was no significant difference in the risk of cerebrovascular events with empagliflozin versus placebo. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01131676.