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BACKGROUND Mesothelin is a cell surface glycoprotein overexpressed in 28%-58% of colorectal cancer (CRC). We hypothesized that CRC mesothelin expression contributes to peritoneal spread and that it is selectively overexpressed in those with peritoneal metastasis versus distant metastasis. METHODS This case-controlled study involved mesothelin immunohistochemistry staining of tumor specimens from patients with metastatic CRC/appendiceal cancers between 2017 and 2019. Staining reactivity was graded from trace to 4+ (low ≤1+; high >1+). Staining patterns were characterized on global (focal/patchy/diffuse) and cellular (apical/cytoplasmic) levels. Immunostaining of normal mesothelial cells served as internal control. RESULTS Thirty-one patients were identified: 11 peritoneal (study) and 20 distant metastasis (control). The control group did not include appendiceal cancers. The study group had greater proportion of high staining reactivity (55% vs. 5%; odds ratio [OR] = 20.4, 95% confidence interval [CI] 1.96-211.8). The study group had more diffuse (36% vs. 0%; OR = 22.2, 95% CI 1.1-465.3) and cytoplasmic staining patterns (73% vs. 28%; OR = 6.9, 95% CI 1.3-37.2). CONCLUSION Mesothelin expression is higher in CRC/appendiceal cancers with peritoneal metastasis than those with distant metastasis. Immunohistochemistry staining patterns suggestive of propensity towards peritoneal metastasis include diffuse and cytoplasmic staining. Mesothelin may be a potential target for novel treatments of CRC/appendiceal carcinoma with peritoneal involvement.

We improved the quality and reduced the time to produce machine learned models for use in small molecule antiviral design. Our globally asynchronous multi-level parallel training approach strong scales to all of Sierra with up to 97.7% efficiency. We trained a novel, character-based Wasserstein autoencoder that produces a higher quality model trained on 1.613 billion compounds in 23 minutes while the previous state of the art takes a day on 1 million compounds. Reducing training time from a day to minutes shifts the model creation bottleneck from computer job turnaround time to human innovation time. Our implementation achieves 318 PFLOPs for 17.1% of half-precision peak. We will incorporate this model into our molecular design loop enabling the generation of more diverse compounds; searching for novel, candidate antiviral drugs improves and reduces the time to synthesize compounds to be tested in the lab.

Objective A high rate of cerebral aneurysm recurrence following endovascular coiling has prompted the use of digital subtraction angiography (DSA) for interval follow-up. However, the utility of skull x-rays as an alternative screening method for aneurysm recurrence is unproperly characterized. Methods Retrospective review of a prospective registry of ruptured and unruptured cerebral aneurysms. Anteroposterior and lateral skull x-rays were obtained immediately at the end of the procedure and at 6-month follow-up. Aneurysm recurrence was defined by comparing post-procedure and 6-month DSA imaging. A true positive was defined as a change in coil mass morphology on at least one projection with aneurysm recurrence on DSA, and a true negative defined as a stable coil mass on both projections and no recurrence on DSA. Receiver operating characteristic area under the curve (AUC) statistics was used to assess the performance of skull x-rays in identifying aneurysm recurrence. Results A total of 118 cerebral aneurysms were evaluated with DSA imaging and skull x-rays. A change in coil mass morphology on one projection of skull x-rays correctly detected all true recurrences with a sensitivity of 100% (95% confidence interval [CI], 91-100%). Skull x-rays failed to identify a stable aneurysm coil mass in 15 cases, with a specificity of 79% (68-88%). Skull x-rays performed with AUC 0.8958 (95% CI, 0.8490-0.9431) in identifying aneurysm recurrence. Conclusions The findings of our study suggest that skull x-rays may represent a low-cost, non-invasive screening tool to rule out aneurysm recurrence, which can potentially aid in decreasing the utilization of DSA in the follow-up of patients with coiled cerebral aneurysms.

Background and Purpose: The optimal endovascular stroke therapy (EVT) care delivery structure is unknown. Here, we present our experience in creating an integrated stroke system (ISS) to expand EVT availability throughout our region while maintaining hospital and physician quality standards. Methods: We identified all consecutive patients with large vessel occlusion acute ischemic stroke treated with EVT from January 2014 to February 2019 in our health care system. In October 2017, we implemented the ISS, in which 3 additional hospitals (4 total) became EVT-performing hospitals (EPHs) and physicians were rotated between all centers. The cohort was divided by time into pre-ISS and post-ISS, and the primary outcome was time from stroke onset to EPH arrival. Secondary outcomes included hospital and procedural quality metrics. We performed an external validation using data from the Southeast Texas Regional Advisory Council. Results: Among 513 patients with large vessel occlusion acute ischemic stroke treated with EVT, 58% were treated pre-ISS and 43% post-ISS. Over the study period, EVT procedural volume increased overall but remained relatively low at the 3 new EPHs (P P P Conclusions: In our system, increasing EVT availability decreased time from stroke onset to EPH arrival. The ISS provides a framework to maintain quality in lower volume hospitals.

INTRODUCTION: Despite aggressive treatment, glioblastoma invariably recurs. The optimal treatment for recurrent glioblastoma (rGBM) is not well defined. Stereotactic radiosurgery (SRS) for rGBM has demonstrated favorable outcomes for selected patients; however, its efficacy in molecular GBM subtypes is unknown. We sought to identify genetic alterations that predict response/outcomes from SRS in rGBM-IDH-wild-type (IDH-WT). METHODS: rGBM-IDH-WT patients undergoing SRS at first recurrence and tested by next-generation sequencing (NGS) were reviewed (2009–2018). Demographic, clinical, and molecular characteristics were evaluated. NGS interrogating 205-genes was performed. Primary outcome was survival from GK-SRS assessed by Kaplan-Meier method and multivariable Cox proportional-hazards. RESULTS: Sixty-three lesions (43-patients) were treated at 1st recurrence. Median age was 61-years. All patients were treated with resection and chemoradiotherapy. Median time from diagnosis to 1st recurrence was 8.7-months. Median cumulative volume was 2.895 cm(3) and SRS median marginal dose was 18 Gy (median isodose-54%). Bevacizumab was administered in 81.4% patients. PFS from SRS was 12.9-months. Survival from SRS was 18.2-months. PTEN-mutant patients had a longer PFS (p = 0.049) and survival from SRS (p = 0.013) in multivariable analysis. Although no statistically significant PTEN-mutants patients had higher frequency of radiation necrosis (21.4% vs. 3.4%) and lower in-field recurrence (28.6% vs. 37.9%) compared to PTEN-WT patients. CONCLUSIONS: SRS is a safe and effective treatment option for selected rGBM-IDH-WT patients following first recurrence. rGBM-IDH-WT harboring PTEN-mutation have improved survival with salvage SRS compared to PTEN-WT patients. PTEN may be used as a molecular biomarker to identify a subset of rGBM patients who may benefit the most from SRS.

An approach to reproducibility problems related to porting software across machines and compilers.

BACKGROUND Trimethylamine-N-oxide (TMAO) is a compound that is present in seafood and produced through human gut microbial metabolism of its precursors. Previous studies have suggested that elevated TMAO concentrations are associated with an increased risk of cardiovascular events. However, the association between diet and TMAO concentrations in free-living adult populations has not been adequately described. OBJECTIVES The objective of this study was to identify dietary predictors of plasma TMAO concentrations. METHODS TMAO concentrations were assessed in 2 fasting plasma samples collected 6 mo apart among 620 healthy men. Short-term and long-term dietary intakes were assessed during the same time-frame of blood collections via repeated 7-d dietary records (7DDRs) and a semiquantitative food-frequency questionnaire (SFFQ), respectively. We grouped individual food items into 21 groups and regressed against averaged TMAO concentrations. We also assessed the association between dietary scores and TMAO concentrations. RESULTS In models adjusted for demographic characteristics and mutually adjusted for food groups, SFFQ-assessments of fish and egg intakes were significantly associated with increased TMAO concentration (β = 0.082; 95% CI: 0.021, 0.14; P = 0.009 for fish; β = 0.065; 95% CI: 0.004, 0.13; P = 0.039 for egg). The positive association between fish consumption and TMAO concentration was replicated in the 7DDR-assessments (β = 0.12; 95% CI: 0.060, 0.18; P

Different than covalently bonded magnetic multilayer systems, high-quality interfaces without dangling bonds in van der Waals (vdW) junctions of two-dimensional (2D) layered magnetic materials offer opportunities to realize novel functionalities. Here, we report the fabrication of multi-state vertical spin valves without spacer layers by using vdW homo-junctions in which exfoliated Fe3GeTe2 nanoflakes act as ferromagnetic electrodes and/or interlayers. We demonstrate the typical behavior of two-state and three-state magnetoresistance for devices with two and three Fe3GeTe2 nanoflakes, respectively. Distinct from traditional spin valves with sandwich structures, our novel homo-junction-based spin-valve structure allows the straightforward realization of multi-state magnetic devices. Our work demonstrates the possibility of extend multi-state, non-volatile spin information to 2D magnetic homo-junctions, and it emphasizes the utility of vdW interface as a fundamental building block for spintronic devices.

Patients with cerebral vasospasm caused by aneurysmal subarachnoid hemorrhage (aSAH) are often treated with intra-arterial (IA) vasodilator infusion. However, the optimal drug regimen is yet to be elucidated. A retrospective review of patients with aSAH and cerebral vasospasm treated with IA vasodilator infusion was performed. Patients in group 1 (2008–2011) were treated with a single agent, either nicardipine or verapamil, and patients in group 2 (2010–2016) were treated with a regimen of nitroglycerin, verapamil, and nicardipine. The post-infusion improvement ratio (PIIR) was compared between groups. Adjusted multivariate logistic regression models were utilized to determine whether patients treated with multiple vasodilators had an improved functional outcome, defined by the modified Rankin Scale, at discharge and 90-day follow-up. Among 116 patients from group 1 (N = 47) and group 2 (N = 69), the median age was 54.5 years [IQR, 46–53 years] and 78% were female. Use of multiple-agent therapy resulted in a 24.36% improvement in vessel diameter over single-agent therapy (median PIIR: group 1, 10.5% [IQR, 5.3–21.1%] vs group 2, 34.9% [IQR, 21.4–66.0%]; p < 0.0001). In the adjusted multivariate logistic regression, the use of multiple-agent therapy was associated with a better functional outcome at discharge (OR 0.15, 95% CI [0.04–0.55]; p < 0.01) and at 90-day follow-up (OR 0.20, 95% CI [0.05–0.77]; p < 0.05) when compared to single-agent therapy. In this study, we found that patients treated for cerebral vasospasm with IA infusion of multiple vasodilators had an increased vessel response and better functional outcomes compared to those treated with a single agent.

Background: Cancer-associated adipocytes (CAAs) have been suggested to promote tumor progression. Yet, the role of CAAs in triple-negative breast cancer (TNBC) is poorly investigated. Methods: We compared the expression of secretory protein-encoding genes in CAAs and control adipocytes. The effect of key secretory protein(s) on TNBC cell behaviors was explored. Results: CAAs expressed and secreted FUCA2 at greater levels than control adipocytes. When FUCA2 activity was blocked with a neutralizing antibody, TNBC cell proliferation and migration induced by CAA conditioned medium was impaired. In contrast, supplement of exogenous FUCA2 protein reinforced the proliferation, colony formation, and migration of TNBC cells. In vivo studies confirmed that FUCA2 exposure enhanced tumorigenesis and metastasis of TNBC cells. Mechanistic investigation revealed that FUCA2 induced TNBC aggressiveness through TM9SF3-dependent signaling. Depletion of TM9SF3 blocked CAA- and FUCA2-induced TNBC cell proliferation and migration. Compared to adjacent breast tissues, TNBC tissues had increased expression of TM9SF3. Moreover, high TM9SF3 expression was associated with advanced TNM stage, lymph node metastasis, and shorter overall survival of TNBC patients. Conclusions: Altogether, CAAs secrete FUCA2 to promote TNBC growth and metastasis through interaction with TM9SF3. Inhibition of TM9SF3 may represent a potential therapeutic strategy in the treatment of TNBC.

Objective: Current guidelines recommend active surveillance with serial magnetic resonance angiography (MRA) for management of small, asymptomatic unruptured anterior circulation aneurysms (UIAs). We sought to determine the cost-effectiveness of active surveillance compared to immediate surgery. Methods: We developed a Markov cost-effectiveness model simulating patients with small (Results: Immediate surgical treatment was the most cost-effective management strategy for small UIAs with ICER of USD 45,772 relative to active surveillance. Sensitivity analysis demonstrated immediate surgery was the preferred strategy, if rupture rate was >0.1%/year and if the diagnosis age was 11%. Probabilistic sensitivity analysis demonstrated that at a willingness-to-pay of USD 100,000/QALY, immediate surgical treatment was the most cost-effective strategy in 64% of iterations. Conclusion: Immediate surgical treatment is a cost-effective strategy for initial management of small UIAs in patients

BACKGROUND: Early diagnosis of Alzheimer’s disease (AD) remains challenging. It is speculated that structural atrophy in white matter tracts commences prior to the onset of AD symptoms. OBJECTIVE: We hypothesize that disruptions in white matter tract connectivity precedes the onset of AD symptoms and these disruptions could be leveraged for early prediction of AD. METHODS: Diffusion tensor images (DTI) from 52 subjects with mild cognitive impairment (MCI) were selected. Subjects were dichotomized into two age and gender matched groups; the MCI-AD group (22 subjects who progressed to develop AD) and the MCI-control group (who did not develop AD). DTI images were anatomically parcellated into 90 distinct regions ROIs followed by tractography methods to obtain different biophysical networks. Features extracted from these networks were used to train predictive algorithms with the objective of discriminating the MCI-AD and MCI-control groups. Model performance and best features are reported. RESULTS: Up to 80% prediction accuracy was achieved using a combination of features from the ‘right anterior cingulum’ and ‘right frontal superior medial’. Additionally, local network features were more useful than global in improving the model’s performance. CONCLUSION: Connectivity-based characterization of white matter tracts offers potential for early detection of MCI-AD and in the discovery of novel imaging biomarkers.

Background：There is an increasing attention on miRNAs because of their functional effect on polarization of CD4+ T cells. This study explores the mechanism of miR-493-5p regulating Th9 cell differentiation in allergic asthma. Methods: The allergic airway inflammation is induced by Ovalbumin(OVA)in mice. CD4+ T cells from normal mice are cultured under Th9 cell conditions. IL-9 levels in mice and CD4+T cells are analyzed by RT-qPCR, ELISA, flow cytometry and western blot. The miR-493-5p levels in mice and cells are detected by RT-qPCR. The interaction between FOXO1 and miR-493-5p is predicted by TargetScan and confirmed by dual luciferase assay. The pathological state is evaluated by H&E staining and Lung resistance is measured in the allergic mice treated with miR-493-5p agomiR before stimulation. Results: The miR-493-5p expression in OVA-induced mice decreases significantly, accompanied by a significant upregulation in IL-9, IRF4 and FOXO1 expression and proportion of CD4+Th9 cells. MiR-493-5p mimic inhibits the expression of IL-9, IRF4 and FOXO1 and Th9 cell differentiation, while the inhibitor promotes these effects. MiR-493-5p mimic represses FOXO1 expression through interacting with 3’UTR of FOXO1 mRNA. The rescue experiment proves that miR-493-5p regulates the differentiation of Th9 cell and the expression of IL-9 by targeting FOXO1. In addition, we find that miR-493-5p agomiR treatment inhibits the FOXO1, IL-9 and IRF4 expression, decreases the proportion of CD4+ Th9 cells, alleviates the pathological state of lung tissue and airway hyperreactivity in OVA-induced asthma mice. Conclusions: Our study confirmed that miR-493-5p inhibited Th9 cell differentiation in allergic asthma by targeting FOXO1.

Background Prior retrospective and prospective studies suggest improved survival with the use of stereotactic radiosurgery (SRS) and bevacizumab in the treatment of limited-volume glioblastoma (GBM) recurrences. Methods We retrospectively reviewed our experience with gamma knife SRS in combination with bevacizumab for the treatment of focal GBM recurrence during 2009–2015. Outcomes include overall survival, progression free survival (PFS), and radiation-related adverse events. Kaplan–Meier methods and multivariable Cox proportional hazards models were performed for survival analysis. Results Within a median of 13.7 months after diagnosis, a total of 45 patients with GBM underwent gamma knife SRS and bevacizumab treatment. Median age was 57 years (range: 20–78 years) and 63.3% were women. The median Karnofsky Performance Score (KPS) at recurrence was 80 (range: 40–100). Sixty-four percent of patients had single radiosurgery target (range: 1–4) and median target volume and margin dose were 2.2 cm3 (range: 0.1–25.2 cm3) and 17.0 gray (Gy) (range: 13–24 Gy), respectively. Median PFS and overall survival were 9.3, 31.0 months following diagnosis, and 5.2, 13.3 months after SRS, respectively. Factors associated with poor outcomes were KPS ≤70, SRS dose Conclusions SRS in combination with bevacizumab can be safely used to treat focal GBM recurrence. KPS, radiation dose, and multi-agent chemotherapy usage prior to SRS demonstrated significant impact on PFS. Bevacizumab may provide clinically relevant radioprotection.

Objective Variance between providers in neurosurgery can lead to inefficiencies and poor patient outcomes. Evidence-based guidelines (EBGs) have been developed; however, they have not been well implemented into the clinician workflow. Therefore, clinicians have been left to make decisions with incomplete information. Equally underused are the electronic health records (EHRs), which house enormous amounts of health data, but the power of that “big data” has failed to be capitalized on. Methods Early attempts at EBGs were rigid and nonadaptive; however, with the current advances in data informatics and machine learning algorithms, it is now possible to integrate “big data” and rapid data processing into clinical decision support tools. We have presented an overview of the background of EHRs and EBGs in neurosurgery and explored the possibility of integrating them to reduce unwanted variance. Results As we strive toward variance reduction in healthcare, the integration of “big data” and EBGs for decision-making will be key. We have proposed that EHRs are an ideal platform for integrating EBGs into the clinician workflow and have presented as an example of a successful early generation model, Neurocore. With this approach, it will be possible to build EBGs into the EHR software, to continuously update and optimize EBGs according to the flow of patient data into the EHR, and to present data-driven clinical decision support at the point of care. Conclusions Variance reduction in neurosurgery through the integration of evidence-based decision support in EHRs will lead to improved patient safety, a reduction in medical errors, maximization of the use of the available data, and enhanced decision-making power for clinicians.

Aims The relationship between high-density lipoprotein cholesterol and the severity of coronary artery disease beyond low-density lipoprotein cholesterol, the primary target of cholesterol-lowering therapy, remains uncertain. We evaluated the association between high-density lipoprotein cholesterol and obstructive coronary artery disease using parameters of any obstructive plaque, obstructive plaque in the left main coronary artery or proximal left anterior descending artery, and obstructive plaque in multi-vessels, according to low-density lipoprotein cholesterol levels. Methods and results We analyzed 5130 asymptomatic non-diabetics who underwent coronary computed tomography angiography for general health examination. Obstructive plaque was defined as a plaque with ≥50% luminal diameter stenosis. The participants were divided into three groups based on low-density lipoprotein cholesterol levels of ≤129, 130–159, and ≥160 mg/dl. The prevalence of any obstructive plaque (5.9% vs 6.4% vs 10.6%) and obstructive plaque in the left main coronary artery or proximal left anterior descending artery (2.1% vs 2.1% vs 4.3%) significantly increased with low-density lipoprotein cholesterol category (all p Conclusion Increased high-density lipoprotein cholesterol levels were independently associated with a lower risk of obstructive coronary artery disease in asymptomatic non-diabetics with low low-density lipoprotein cholesterol levels.

Background Unregulated inflammatory and thrombotic responses have been proposed to be important causes of early brain injury and worse clinical outcomes after subarachnoid hemorrhage (SAH). Objective We hypothesize that SAH is characterized by an increased inflammatory and thrombotic state and disruption of associations between these states. Methods This is a retrospective cohort study of 60 patients with SAH. 23 patients with unruptured aneurysms (UA) and 77 patients with traumatic brain injury (TBI) were chosen as controls. Plasma cytokine levels were measured using a 41-plex human immunoassay kit, and cytokine patterns associated with SAH, UA and TBI were identified using statistical and informatics methods. Results SAH was characterized by an increase in several cytokines and chemokines, platelet-derived factors, and growth factors. Cluster analysis identified several cytokine clusters common in SAH, UA and TBI groups – generally grouped as platelet-derived, vascular and pro-inflammatory clusters. In the UA group, the platelet-derived cluster had an inverse relationship with the inflammatory cluster which was absent in SAH. Additionally, a cluster comprising of growth and colony stimulating factors was unique to SAH. Conclusions A cluster of cytokines involved in growth and colony stimulation was unique to SAH. Negative associations between the thrombotic and inflammatory molecules were observed in UA but not in SAH. Further studies to examine the pathophysiology behind the cluster unique to SAH and the associations between the thrombotic and inflammatory cytokines are required.

Background: This study aimed to investigate the morphological features and 2D/3D coverage parameters of the true acetabulum of Crowe type IV hips and to identify the optimal component center of standard-sized cup implantation.Methods: A total of 42 Crowe IV hips in 37 patients and 36 normal hips were included in the present study. Based on 3D reconstruction, anatomy and volume of the true acetabulum were measured quantitatively. Through simulated implantation, the feasibility of standard-sized cup implantation was evaluated by cup-based morphological assessments and coverage parameters. Eventually, bony landmarks for optimal component center location were determined. Mean follow-up was 4.7 years (1.2 to 6.3 years).Results: All the dysplastic hips were placed with standard-size acetabular implant (44.67mm, 44 to 48mm) successfully, with no acetabular implant loosening during the follow-up period. Compared with control group, the dysplastic acetabulum was more anteverted and abductive, with a thicker medial wall. According to the true acetabulum, bone stock is relatively sufficient in the posterior direction and prominently deficient in the anterosuperior and superior direction. Average 3D component coverage can reach 79.89% by standard-sized cup implantation at the true acetabulum. Regarding the component opening plane, the optimal component center located at the midpoint between the superolateral and posteroinferior point of the true acetabulum. Conclusion: Standard cup implantation is feasible and available in Crowe IV hip at the true acetabulum. The optimal component center was determined to be relatively constant based on the useful bony landmarks.Level of evidence: Therapeutic Level 3b.

Background Hypothermia is neuroprotective in some ischemia–reperfusion injuries. Ischemia–reperfusion injury may occur with traumatic subdural hematoma (SDH). This study aimed to determine whether early induction and maintenance of hypothermia in patients with acute SDH would lead to decreased ischemia–reperfusion injury and improve global neurologic outcome. Methods This international, multicenter randomized controlled trial enrolled adult patients with SDH requiring evacuation of hematoma within 6 h of injury. The intervention was controlled temperature management of hypothermia to 35 °C prior to dura opening followed by 33 °C for 48 h compared with normothermia (37 °C). Investigators randomly assigned patients at a 1:1 ratio between hypothermia and normothermia. Blinded evaluators assessed outcome using a 6-month Glasgow Outcome Scale Extended score. Investigators measured circulating glial fibrillary acidic protein and ubiquitin C-terminal hydrolase L1 levels. Results Independent statisticians performed an interim analysis of 31 patients to assess the predictive probability of success and the Data and Safety Monitoring Board recommended the early termination of the study because of futility. Thirty-two patients, 16 per arm, were analyzed. Favorable 6-month Glasgow Outcome Scale Extended outcomes were not statistically significantly different between hypothermia vs. normothermia groups (6 of 16, 38% vs. 4 of 16, 25%; odds ratio 1.8 [95% confidence interval 0.39 to ∞], p = .35). Plasma levels of glial fibrillary acidic protein (p = .036), but not ubiquitin C-terminal hydrolase L1 (p = .26), were lower in the patients with favorable outcome compared with those with unfavorable outcome, but differences were not identified by temperature group. Adverse events were similar between groups. Conclusions This trial of hypothermia after acute SDH evacuation was terminated because of a low predictive probability of meeting the study objectives. There was no statistically significant difference in functional outcome identified between temperature groups.

Background: COVID-19 nucleic acid swab tests have a high false positive rate; therefore, diagnosing COVID-19 pneumonia and predicting prognosis by CT scan are very important. Methods: In this retrospective single-centre study, we included consecutive suspected critical COVID-19 pneumonia cases in the intensive care unit of Wuhan Third Hospital from January 31, 2020, to March 16, 2020. 204 cases were confirmed by real-time RT-PCR, and all patients were evaluated with CT, cut-off values were obtained according to the Youden index and were divided into a high CT score group and a low CT score group. Epidemiological, demographic, clinical, and laboratory data were collected. Finally, Through multi-factor logistic regression model, a prediction model based on multiple prediction indicators was formed, and new joint predictive factors were calculated. The prediction model of mortality in COVID-19 pneumonia based on CT score and lymphocyte count was constructed through data processing analysis. Results: The major imaging feature of COVID-19 pneumonia is Ground Glass Opacities (GGOs). Multivariate regression analysis found that the CT score and absolute lymphocyte count were independent risk factors for death and that the CT score predicted mortality (AUC-ROC =0.7, cut-off=1.45). When the absolute lymphocyte count was lower, the patient’s CT score was also lower. Based on this, a prediction model was established. The prediction model was: In [P/(1-P)]=0.667*gender+0.057*age-0.086CT score-0.831 lymphocyte count-3.91, the goodness of fit test of the model was P=0.041, and the area under the curve of the ROC curve of the model was 0.779. Conclusion: CT score and absolute lymphocyte count are independent risk factors for mortality, and patients with a high CT score may have a worse prognosis. A lower absolute lymphocyte count may indicate that the patient’s CT score is also reduced. The model established by combining CT scores and lymphocyte count showed a good degree of calibration and differentiation.

Cancer and organ injury-such as that occurring in the perioperative period, including acute lung injury, myocardial infarction, and acute gut injury-are among the leading causes of death in the United States and impose a significant impact on quality of life. MicroRNAs (miRNAs) have been studied extensively during the last two decades for their role as regulators of gene expression, their translational application as diagnostic markers, and their potential as therapeutic targets for disease treatment. Despite promising preclinical outcomes implicating miRNA targets in disease treatment, only a few miRNAs have reached clinical trials. This likely relates to difficulties in the delivery of miRNA drugs to their targets to achieve efficient inhibition or overexpression. Therefore, understanding how to efficiently deliver miRNAs into diseased tissues and specific cell types in patients is critical. This review summarizes current knowledge on various approaches to deliver therapeutic miRNAs or miRNA inhibitors and highlights current progress in miRNA-based disease therapy that has reached clinical trials. Based on ongoing advances in miRNA delivery, we believe that additional therapeutic approaches to modulate miRNA function will soon enter routine medical treatment of human disease, particularly for cancer or perioperative organ injury. SIGNIFICANCE STATEMENT: MicroRNAs have been studied extensively during the last two decades in cancer and organ injury, including acute lung injury, myocardial infarction, and acute gut injury, for their regulation of gene expression, application as diagnostic markers, and therapeutic potentials. In this review, we specifically emphasize the pros and cons of different delivery approaches to modulate microRNAs, as well as the most recent exciting progress in the field of therapeutic targeting of microRNAs for disease treatment in patients.

Symmetry adaptation is crucial in representing a permutationally invariant potential energy surface (PES). Due to the rapid increase in computational time with respect to the molecular size, as well as the reliance on the algebra software, the previous neural network (NN) fitting with inputs of fundamental invariants (FIs) has practical limits. Here, we report an improved and efficient generation scheme of FIs based on the computational invariant theory and parallel program, which can be readily used as the input vector of NNs in fitting high-dimensional PESs with permutation symmetry. The newly developed method significantly reduces the evaluation time of FIs, thereby extending the FI-NN method for constructing highly accurate PESs to larger systems beyond five atoms. Because of the minimum size of invariants used in the inputs of the NN, the NN structure can be very flexible for FI-NN, which leads to small fitting errors. The resulting FI-NN PES is much faster on evaluating than the corresponding permutationally invariant polynomial-NN PES.

Background: It has been shown that certain severe and refractory asthma cases are due to neutrophil and not eosinophil infiltration. ICOSL (Inducible costimulatory molecular ligand) expression is closely associated with tumor and autoimmune diseases, while a limited amount of data has been published regarding the significance of ICOSL in children with neutrophilic asthma. The present study aimed to explore the abnormal expression of ICOSL in peripheral blood and bronchoalveolar lavage fluid (BALF) samples of children with neutrophilic asthma and their clinical significance. Methods: The present clinical study selected children who met the diagnostic criteria of asthma from the children's Hospital of Suchow University and excluded the patients with positive etiology. The children who were admitted to the hospital for foreign body inhalation in the same period were collected as the control group. The children with more than 50% (the percentage of neutrophils in BALF was 95% of the percentile in the control group) of neutrophils in BALF samples were assigned to the neutrophilic asthma group (NA group), whereas the remaining subjects comprised the asthma group (A group). The expression levels of ICOSL, IL-4, IL-17, IFN-, neutrophil elastase (NE) and matrix metalloproteinase (MMP)-9 were detected in plasma and BALF samples by enzyme-linked immunosorbent assays in order to analyze the differences in the levels of cytokines and clinical characteristics between children with neutrophilic asthma and non-neutrophilic asthma. Moreover, the potential mechanism of ICOSL in neutrophilic asthma was explored. Results: In strict accordance with the diagnostic criteria of asthma and following exclusion of pathogenic positive children, 32 children were finally enrolled, including 12 children in the NA group and 20 children in the A group. The mean hospitalization time of the NA group was longer than that of the A group (P

Introduction: Prior studies suggest that patients with large vessel occlusion (LVO) who undergo endovascular stroke therapy (EST) after inter-hospital transfer (IHT) have worse outcomes than those who present directly to EST centers. However, these studies were largely derived from clinical trials or registries and may not be representative of real-world clinical practice. Methods: We performed a multicenter, observational cohort study on acute ischemic stroke (AIS) patients with LVO that presented to EST-capable centers directly (LVO-D) or after IHT (LVO-T) between 1/1/2018 to 2/1/2019. The study included 11 hospitals in the Houston area, of which 4 are EST-capable. Clinical data were collected using our cerebrovascular data registry. All transfers were from non-EST capable hospitals to EST-capable hospitals. Logistic regression adjusted for age, NIHSS, occlusion location and direct vs transfer arrival was used to assess the likelihood of good outcome, defined as discharge to home or rehabilitation. Results are given as median [IQR] and OR [95% CI]. Results: Among 4,313 patients with AIS, 772 (18%) patients had LVO. Among LVO patients, median age was 68 [59-79], 47% were female, 51% were white, 378 (49%) were LVO-D and 394 (51%) were LVO-T. Median IHT time was 152 min [114-198]. LVO-D patients arrived at EST-treating hospitals with superior ASPECTS compared to LVO-T (9 [7-10] vs 7 [6-9], p Conclusion: In this real-world cohort of a multi-center stroke network, IHT was not associated with worse outcomes for patients with LVO, for both patients who did receive EST and those that did not.

Background This study sought to evaluate the effect of tumor-infiltrating lymphocyte (TIL) density and programmed death ligand 1 (PD-L1) expression on the prognosis of esophageal cancer. Methods Banked tissue specimens from 53 patients who underwent esophagectomies for malignancy at a single institution over a 6-year period were stained for cluster of differentiation 3 (CD3), CD8, and PD-L1. Tumors were characterized as staining high or low density for CD3 and CD8, as well as positive or negative for PD-L1. TIL density and PD-L1 expression were analyzed in the context of survival, recurrence, and perioperative characteristics. Results Median follow-up was 823 days, with 92.5% survival and 26.8% recurrence rates. All tumors were adenocarcinomas. Neoadjuvant chemotherapy was given in 56.6% of cases, and neoadjuvant radiotherapy was given in 37.7%. High CD3 density was found in 83%, whereas high CD8 density was found in 56.6%. A total of 18.9% of the tumors stained positive for PD-L1. Survival was significantly shorter in Kaplan-Meier analysis for patients with primary tumors staining positive for PD-L1 (log rank: p = 0.05). Multivariable analysis controlling for neoadjuvant therapy, TIL markers, PD-L1, age, and sex found no significant difference in recurrence or survival. Conclusions Positive staining for PD-L1 may be a prognostic marker for decreased survival in esophageal adenocarcinoma. Additional TIL cell types should be investigated for creation of an esophageal cancer Immunoscore. PD-L1 has potential as a therapeutic target.

Background Inflammatory mechanism has been implicated in delayed cerebral ischemia (DCI) and poor functional outcomes after subarachnoid hemorrhage (SAH). Identification of cytokine patterns associated with inflammation in acute SAH will provide insights into underlying biological processes of DCI and poor outcomes that may be amenable to interventions. Methods Serum samples were collected from a prospective cohort of 60 patients with acute non-traumatic SAH at four time periods ( Results Of the 60 patients enrolled in the study, 14 (23.3%) developed DCI and 16 (26.7%) had poor functional outcomes at 3 months. DCI was associated with increased levels of PDGF-ABBB and CCL5 and decreased levels of IP-10 and MIP-1α. Poor functional outcome was associated with increased levels of IL-6 and MCP-1α. Network analysis identified distinct cytokine clusters associated with DCI and functional outcomes. Conclusions Serum cytokine patterns in early SAH are associated with poor functional outcomes and DCI. The significant cytokines primarily modulate the inflammatory response. This supports earlier SAH studies linking inflammation and poor outcomes. In particular, this study identifies novel cytokine patterns over time that may indicate impending DCI.

Due to the complex process of copper flotation and the frequently diversified conditions of ore sources, it is difficult to identify rougher flotation conditions and maintain the stability of production process. By deeply analyzing the characteristics of the copper flotation process, the recognition system for working conditions in copper rougher is established and the cascaded recognition method is presented. At the first stage, the recognition model is built to identify feeding ore types based on fusion information of froth image local colour features and process parameters. At the second stage, the asymmetry binary tree SVM multi-class classification method with working condition priority rating (WCP-BTSVM) is used to recognize copper rougher flotation conditions. As demonstrated in the industrial experiment, the proposed method can relatively accurate identify the working conditions in copper rougher and thus can provide a solid foundation for decision-making in follow-up process control.

The red imported fire ant, Solenopsis invicta Buren, is a serious invasive pest of quarantine significance. Potential establishment of this ant is of great concern in S. invicta free countries such as South Korea, where there have been multiple recent interceptions. The majority of those detections have been concentrated around main port areas of imported common trade containers, suggesting that disinfestation of the containers, in addition to inspection and disinfestation of containers with agricultural commodities, is necessary for the prevention of S. invicta introduction. So far, however, no regulations and protocols are in place for inspection, detection, and disinfestation of S. invicta in such containers. As a first step toward supporting such regulation, we investigated whether S. invicta could be effectively controlled using ethyl formate, a methyl bromide alternative. Ethyl formate fumigation treatment was effective in controlling 99.9% of S. invicta workers and female alates at 46.1 and 37.7 g h m −3 at 13 °C and 23 °C respectively. Our results provide evidence to support its use to disinfest S. invicta in containers. We discuss additional factors that need to be considered to develop disinfestation protocols for S. invicta in commerce shipping containers.

This article considers nine different predictive techniques, including state-of-the-art machine learning methods for forecasting corporate bond yield spreads with other input variables. We examine each method’s out-of-sample forecasting performance using two different forecast horizons: (1) the in-sample dataset over 2003–2007 is used for one-year-ahead and two-year-ahead forecasts of non-callable corporate bond yield spreads; and (2) the in-sample dataset over 2003–2008 is considered to forecast the yield spreads in 2009. Evaluations of forecasting accuracy have shown that neural network forecasts are superior to the other methods considered here in both the short and longer horizon. Furthermore, we visualize the determinants of yield spreads and find that a firm’s equity volatility is a critical factor in yield spreads.

Oral squamous cell carcinoma (SCC) pain is more prevalent and severe than pain generated by any other form of cancer. We previously showed that protease-activated receptor-2 (PAR2) contributes to oral SCC pain. Cathepsin S is a lysosomal cysteine protease released during injury and disease that can activate PAR2. We report here a role for cathepsin S in PAR2-dependent cancer pain. We report that cathepsin S was more active in human oral SCC than matched normal tissue, and in an orthotopic xenograft tongue cancer model than normal tongue. The multiplex immunolocalization of cathepsin S in human oral cancers suggests that carcinoma and macrophages generate cathepsin S in the oral cancer microenvironment. After cheek or paw injection, cathepsin S evoked nociception in wild-type mice but not in mice lacking PAR2 in Nav1.8-positive neurons (Par2Nav1.8), nor in mice treated with LY3000328 or an endogenous cathepsin S inhibitor (cystatin C). The human oral SCC cell line (HSC-3) with homozygous deletion of the gene for cathepsin S (CTSS) with CRISPR/Cas9 provoked significantly less mechanical allodynia and thermal hyperalgesia, as did those treated with LY3000328, compared to the control cancer mice. Our results indicate that cathepsin S is activated in oral SCC, and that cathepsin S contributes to cancer pain through PAR2 on neurons.

Background Early brain injury (EBI) after subarachnoid hemorrhage (SAH) is an important determinant of clinical outcomes. However, a major hindrance to studies of EBI is the lack of radiographic surrogate marker. Objective To propose a scoring system based on early changes in clinically obtained computed tomography (CT), called the Subarachnoid hemorrhage Early Brain Edema Score (SEBES). Methods Patients with spontaneous aneurysmal SAH and a CT within 24 h of ictus were included. We defined SEBES as a scale of 0 to 4 points according to the (1) absence of visible sulci caused by effacement of sulci or (2) absence of visible sulci with disruption of the gray-white matter junction at 2 predetermined levels in each hemisphere. Prognostic value of the SEBES grade for the prediction of delayed cerebral ischemia (DCI) and unfavorable outcomes was assessed. A separate cohort of patients was used as a validation cohort. Results Of the 164 subjects in our study, high-grade SEBES (3 or 4 points) was identified in 48 patients (29.3%). CT interobserver reliability of SEBES grades was high with a Kappa value of 0.89. After adjusting for covariables, SEBES was identified as an independent predictor of DCI (OR = 2.24, 95% CI: 1.58-3.17) and unfavorable outcome (OR = 3.45, 95% CI: 1.95-6.07). In our validation cohort, 84 subjects showed similar predictive power of SEBES for a prediction of DCI and unfavorable long-term outcome. Conclusion SEBES may be a surrogate marker of EBI and predicts DCI and clinical outcomes after SAH.

Propofol is an intravenous anesthetic that has been widely used in clinics. Besides its anesthetic effects, propofol has also been reported to influence the regulation of the autonomic system. Controversies exist with regard to whether propofol exposure is safe for pregnant women and young children. In this work, human-induced pluripotent stem cell- (hiPSC-) derived neural progenitor cells (NPCs) were treated with propofol at 20, 50, 100, or 300 μM for 6 h or 24 h, and acute and subacute cell injury, cell proliferation, and apoptosis were evaluated. Comparison of genome-wide gene expression profiles was performed for treated and control iPSC-NPCs. Propofol treatment for 6 h at the clinically relevant concentration (20 or 50 μM) did not affect cell viability, apoptosis, or proliferation, while propofol at higher concentration (100 or 300 μM) decreased NPC viability and induced apoptosis. In addition, 20 μM propofol treatment for 6 h did not alter global gene expression. In summary, propofol treatment at commonly practiced clinical doses for 6 h did not have adverse effects on hiPSC-derived NPCs. In contrast, longer exposure and/or higher concentration could decrease NPC viability and induce apoptosis.

Background and Purpose— A ruptured intracranial aneurysm (IA) is the leading cause of a subarachnoid hemorrhage. This study seeks to define a specific gene whose mutation leads to disease. Methods— More than 500 IA probands and 100 affected families were enrolled and clinically characterized. Whole exome sequencing was performed on a large family, revealing a segregating THSD1 (thrombospondin type 1 domain containing protein 1) mutation. THSD1 was sequenced in other probands and controls. Thsd1 loss-of-function studies in zebrafish and mice were used for in vivo analyses and functional studies performed using an in vitro endothelial cell model. Results— A nonsense mutation in THSD1 was identified that segregated with the 9 affected (3 suffered subarachnoid hemorrhage and 6 had unruptured IA) and was absent in 13 unaffected family members (LOD score 4.69). Targeted THSD1 sequencing identified mutations in 8 of 507 unrelated IA probands, including 3 who had suffered subarachnoid hemorrhage (1.6% [95% confidence interval, 0.8%–3.1%]). These THSD1 mutations/rare variants were highly enriched in our IA patient cohort relative to 89 040 chromosomes in Exome Aggregation Consortium (ExAC) database ( P THSD1 loss impaired endothelial cell focal adhesion to the basement membrane. These adhesion defects could be rescued by expression of wild-type THSD1 but not THSD1 mutants identified in IA patients. Conclusions— This report identifies THSD1 mutations in familial and sporadic IA patients and shows that THSD1 loss results in cerebral bleeding in 2 animal models. This finding provides new insight into IA and subarachnoid hemorrhage pathogenesis and provides new understanding of THSD1 function, which includes endothelial cell to extracellular matrix adhesion.

Objective: The safety and effect of intra-arterial (IA) tirofiban, a glycoprotein IIb/IIIa inhibitor, during the stent retriever mechanical thrombectomy (MT) was investigated. Methods: From January 2015 to May 2019, a total of 327 patients underwent mechanical thrombectomy of large artery occlusions (LAO). Patients were classified into two groups: MT with IA tirofiban (MTT) group and MT only (MTO, without IA tirofiban) group. Clinical outcomes, radiological results, and various complications, such as post thrombectomy hemorrhage, symptomatic hemorrhage, other systemic bleeding, and hemorrhagic transformation of infarct were evaluated by comparing the MTT group and MTO group. In addition, subgroup analysis was performed for patients who underwent MT with prior intravenous (IV) tissue plasminogen activator (t-PA). Results: The MTT group needed a lower mean number of stent passes and showed a re-occlusion rate as compared with the MTO group (P=0.038 and 0.022, respectively). Between the two groups, there were no statistically significant differences in post thrombectomy hemorrhage, symptomatic hemorrhage, other systemic bleeding complications, or hemorrhagic transformation of infarct (P = 0.511, 0.397, 0.429, and 0.355, respectively). In the subgroup analysis, similar findings were observed. Conclusion: The use of IA tirofiban during MT seems to be safe and potentially more effective than only MT without IA tirofiban, even in patients who used IV t-PA before MT.

Successful HPC software applications are long-lived. When ported across machines and their compilers, these applications often produce different numerical results, many of which are unacceptable. Such variability is also a concern while optimizing the code more aggressively to gain performance. Efficient tools that help locate the program units (files and functions) within which most of the variability occurs are badly needed, both to plan for code ports and to root-cause errors due to variability when they happen in the field. In this work, we offer an enhanced version of the open-source testing framework FLiT to serve these roles. Key new features of FLiT include a suite of bisection algorithms that help locate the root causes of variability. Another added feature allows an analysis of the tradeoffs between performance and the degree of variability. Our new contributions also include a collection of case studies. Results on the MFEM finite-element library include variability/performance tradeoffs, and the identification of a (hitherto unknown) abnormal level of result-variability even under mild compiler optimizations. Results from studying the Laghos proxy application include identifying a significantly divergent floating-point result-variability and successful root-causing down to the problematic function over as little as 14 program executions. Finally, in an evaluation of 4,376 controlled injections of floating-point perturbations on the LULESH proxy application, we showed that the FLiT framework has 100 precision and recall in discovering the file and function locations of the injections all within an average of only 15 program executions., 12 pages, 11 figures, accepted in HPDC 2019

Intracranial aneurysms (IA) are local dilatations in cerebral arteries that predominantly affect the circle of Willis. Occurring in approximately 2–5% of adults, these weakened areas are susceptible to rupture, leading to subarachnoid hemorrhage (SAH), a type of hemorrhagic stroke. Due to its early age of onset and poor prognosis, SAH accounts for > 25% of years lost for all stroke victims under the age of 65. In this review, we describe the cerebrovascular pathology associated with intracranial aneurysms. To understand IA genetics, we summarize syndromes with elevated incidence, genome-wide association studies (GWAS), whole exome studies on IA-affected families, and recent research that established definitive roles for Thsd1 (Thrombospondin Type 1 Domain Containing Protein 1) and Sox17 (SRY-box 17) in IA using genetically engineered mouse models. Lastly, we discuss the underlying molecular mechanisms of IA, including defects in vascular endothelial and smooth muscle cells caused by dysfunction in mechanotransduction, Thsd1/FAK (Focal Adhesion Kinase) signaling, and the Transforming Growth Factor β (TGF-β) pathway. As illustrated by THSD1 research, cell adhesion may play a significant role in IA.

Introduction: Memorial Hermann (MH) Healthcare System in Houston historically did not have a coordinated approach to triage of incoming neuroscience transfers. From July 2015 to June 2016, there were a total of 867 cancellations/denials for neurology or neurosurgery transfers that could not be accommodated through the existing acceptance process where the majority were sent to the MH-Texas Medical Center (TMC). Hypothesis: We hypothesized that creation of a streamlined approach to triaging transfer requests would allow for the following outcomes: Reduction in time of initial transfer request to acceptance Elimination of denials/cancellations due to capacity Leveraging of integrated physician network across TMC, Southwest, and Memorial City campuses Methods: In collaboration with the MH System Transfer Center, we created a model where one physician or “quarterback” is able to triage system transfers and accept on behalf of the admitting/specialist physicians at a MH receiving facility. We met with all stakeholders to understand individual campus challenges related to universal acceptance process, established a script/resource tool, and built up tertiary capabilities (comprehensive stroke) in the community so we could ensure a high-quality alternative to our TMC quaternary hospital. Results: Both stroke and neurosurgery populations are managed through the Rapid Transfer Program as of January 2017. Since the start of this program, there has been an approximate 18% increase in neuroscience transfers in the system and a drastic reduction of denials dues to capacity. Time of initial transfer request to time of acceptance decreased from almost 60 min to an average of 20 minutes. In June 2018, we had zero denials for neuroscience and 297 patients accepted by MH. Conclusion: The creation of an integrated and efficient model improved the customer experience for our referring partners. We met all goals and increased overall neuroscience transfer volume to our system.

BACKGROUND: Perioperative corticosteroid use may reduce acute kidney injury. We sought to test whether methylprednisolone reduces the risk of acute kidney injury after cardiac surgery. METHODS: We conducted a prespecified substudy of a randomized controlled trial involving patients undergoing cardiac surgery with cardiopulmonary bypass (2007-2014); patients were recruited from 79 centres in 18 countries. Eligibility criteria included a moderate-to-high risk of perioperative death based on a preoperative score of 6 or greater on the European System for Cardiac Operative Risk Evaluation I. Patients (n = 7286) were randomly assigned (1:1) to receive intravenous methylprednisolone (250 mg at anesthetic induction and 250 mg at initiation of cardiopulmonary bypass) or placebo. Patients, caregivers, data collectors and outcome adjudicators were unaware of the assigned intervention. The primary outcome was postoperative acute kidney injury, defined as an increase in the serum creatinine concentration (from the preoperative value) of 0.3 mg/dL or greater (≥ 26.5 μmol/L) or 50% or greater in the 14-day period after surgery, or use of dialysis within 30 days after surgery. RESULTS: Acute kidney injury occurred in 1479/3647 patients (40.6%) in the methylprednisolone group and in 1426/3639 patients (39.2%) in the placebo group (adjusted relative risk 1.04, 95% confidence interval 0.96 to 1.11). Results were consistent across several definitions of acute kidney injury and in patients with preoperative chronic kidney disease. INTERPRETATION: Intraoperative corticosteroid use did not reduce the risk of acute kidney injury in patients with a moderate-to-high risk of perioperative death who had cardiac surgery with cardiopulmonary bypass. Our results do not support the prophylactic use of steroids during cardiopulmonary bypass surgery. Trial registration: ClinicalTrials.gov, no. NCT00427388. ispartof: CANADIAN MEDICAL ASSOCIATION JOURNAL vol:191 issue:9 pages:E247-E256 ispartof: location:Canada status: published

The objective of this study is to investigate whether central sensitization (CS) was associated with patient dissatisfaction after revision total knee arthroplasty (TKA).Between 2012 and 2016, 68 cases (68 patients) of revision TKA performed by a single surgeon were included in this study with a minimum follow-up of 2 years. Patients were categorized into 2 groups by 40-point preoperative Central Sensitization Inventory (CSI) scores. The control group consisted of 48 patients (48 knees) with CSI scores of less than 40 points, while the CS group consisted of 20 patients (20 knees) with CSI scores of 40 points or more. Clinical outcomes were evaluated using an 11-point visual analog scale (VAS) and Western Ontario and McMaster Universities Osteoarthritis Index scores. Patient satisfaction was evaluated using the satisfaction items of the new Knee Society Scores, where scores ≥20 indicated satisfaction.Higher preoperative pain VAS scores in the CS group were maintained 3, 6, 12, and 24 months postoperatively (all P.05). The CS group showed significantly worse pain, function subscores, and total scores of the Western Ontario and McMaster Universities Osteoarthritis Index preoperatively and at 2 years postoperatively. Forty-four (91.7%) patients in the control group and 3 (15.0%) patients in the CS group were satisfied with their revision TKAs (P.001). Multivariate logistic regression analysis demonstrated that the odds of dissatisfaction after revision TKAs were increased 39.081 times (95% confidence interval 6.926-220.504, P.001) in patients with CSI scores ≥40. Higher VAS intensity 2 years postoperatively also predicted dissatisfaction following revision TKA (odds ratio 1.864, 95% confidence interval 1.086-3.199, P = .024).CS is a risk factor for persistent postoperative pain and dissatisfaction in patients undergoing revision TKAs.III.

Background The pathophysiology of osteoarthritis (OA) involves wear and tear, and a state of low-grade inflammation. Tissue repair responses include transforming growth factor beta (TGFβ)-induced myofibroblast production of extracellular matrix. Fibronectins are an essential part of the extracellular matrix, and injection of fibronectin fragments into rabbit joints is a previously established animal model of OA. Fibronectin containing the ED-A domain is currently being used as drug delivery target in the development of anti-inflammatory drugs (e.g. Dekavil). Methods In this study, samples of synovial membrane were obtained from patients with knee OA undergoing joint replacement surgery. Immunostaining for ED-A fibronectin and the myofibroblast marker alpha smooth muscle actin (αSMA) was performed on fibroblast-like synovial cells (FLS) and synovial membranes. RAW 264.7 macrophages were incubated with recombinant ED-A fibronectin. Results The staining of ED-A fibronectin in OA FLS was increased by TGFβ but not by TNFα, lipopolysaccharide, or IL-6 (n = 3). ED-A fibronectin co-stained with the myofibroblast marker αSMA in both the OA FLS (n = 3) and in the OA synovial membranes (n = 8). ED-A fibronectin staining was associated with both number of lining layer cells (rho = 0.85 and p = 0.011) and sublining cells (rho = 0.88 and p = 0.007) in the OA synovium (n = 8), and co-distributed with TNFα (n = 5). Recombinant ED-A fibronectin increased the production of TNFα by RAW 264.7 macrophages (n = 3). Conclusions The disease process in OA shares features with the chronic wound healing response. Our findings support utilizing ED-A fibronectin for drug delivery or therapeutic targeting to reduce pro-inflammatory responses in OA.

Despite the development of sensors and LED lighting technologies, smart lighting technology is a still challenging topic. No smart lighting system with built-in RADAR and camera has yet been reported that is both energy-saving and efficient for searching for missing persons. Herein we design a smart lighting system based on RADAR and a camera sensor. The RADAR detects moving obstacles including pedestrians and the camera records by means of RADAR motion detection in event mode. Selected images corresponding to persons of interest are very useful for quick searching for missing persons.

Many emerging scientific workflows that target high-end HPC systems require complex interplay with the resource and job management software~(RJMS). However, portable, efficient and easy-to-use scheduling and execution of these workflows is still an unsolved problem. We present Flux, a novel, hierarchical RJMS infrastructure that addresses the key scheduling challenges of modern workflows in a scalable, easy-to-use, and portable manner. At the heart of Flux lies its ability to be nested seamlessly within batch allocations created by other schedulers as well as itself. Once a hierarchy of Flux instance is created within each allocation, its consistent and rich set of well-defined APIs portably and efficiently support those workflows that can often feature non-traditional execution patterns such as requirements for complex co-scheduling, massive ensembles of small jobs and coordination among jobs in an ensemble.

// Seung Ho Yang 1, 2, 3, * , Shenglan Li 1, 3, * , Guangrong Lu 1 , Haipeng Xue 1, 3 , Dong H. Kim 1, 3 , Jay-Jiguang Zhu 1, ** , Ying Liu 1, 3, ** 1 Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA 2 Department of Neurosurgery, St. Vincent’s Hospital, College of Medicine, The Catholic University of Korea, Suwon, South Korea 3 Center for Stem Cell and Regenerative Medicine, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas, USA * These authors contributed equally to this work ** These authors contributed equally to this work Correspondence to: Jay-Jiguang Zhu, email: jay.jiguang.zhu@uth.tmc.edu Ying Liu, email: ying.liu@uth.tmc.edu Keywords: glioblastoma, metformin, temozolomide resistance, SOX2, global gene expression Received: September 07, 2016 Accepted: October 14, 2016 Published: October 24, 2016 ABSTRACT It has been reported that metformin acts synergistically with temozolomide (TMZ) to inhibit proliferation of glioma cells including glioblastoma multiforme (GBM). However, the molecular mechanism underlying how metformin exerts its anti-cancer effects remains elusive. We used a combined experimental and bioinformatics approach to identify genes and complex regulatory/signal transduction networks that are involved in restoring TMZ sensitivity of GBM cells after metformin treatment. First, we established TMZ resistant GBM cell lines and found that the resistant cells regained TMZ sensitivity after metformin treatment. We further identified that metformin down-regulates SOX2 expression in TMZ-resistant glioma cells, reduces neurosphere formation capacity of glioblastoma cells, and inhibits GBM xenograft growth in vivo . Finally, the global gene expression profiling data reveals that multiple pathways are involved in metformin treatment related gene expression changes, including fatty acid metabolism and RNA binding and splicing pathways. Our work provided insight of the mechanisms on potential synergistic effects of TMZ and metformin in the treatment of glioblastoma, which will in turn yield potentially translational value for clinical applications.

For job allocation decision, current batch schedulers have access to and use only information on the number of nodes and runtime because it is readily available at submission time from user job scripts. User-provided runtimes are typically inaccurate because users overestimate or lack understanding of job resource requirements. Beyond the number of nodes and runtime, other system resources, including IO and network, are not available but play a key role in system performance. There is the need for automatic, general, and scalable tools that provide accurate resource usage information to schedulers so that, by becoming resource-aware, they can better manage system resources. We tackle this need by presenting a tool for Predicting Runtime and IO using Neural Networks (PRIONN). PRIONN automates prediction of per-job runtime and IO resource usage, enabling IO-aware scheduling on HPC systems. The novelty of our tool is the input of whole job scripts into deep learning models that allows complete automation of runtime and IO resource predictions. We demonstrate the power of PRIONN with runtime and IO resource predictions applied to IO-aware scheduling for real HPC data. Specifically, we achieve over 75% mean and 98% median accuracy for runtime and IO predictions across 300,000 jobs from a real HPC machine. We combine our per-job runtime and IO predictions with queue and system simulations to predict future system IO usage accurately. We predict over 50% of IO bursts in advance on a real HPC system.

Background Cost-effectiveness analyses for the treatment of aneurysmal subarachnoid hemorrhage are necessary to determine health policy, treatment guidelines, and screening protocols for cerebral aneurysms. To perform these modeling studies, detailed cost data are necessary and are currently lacking. Objective The goal of this study was to determine detailed inpatient cost of aneurysmal subarachnoid hemorrhage. Methods A retrospective review of our ruptured subarachnoid hemorrhage database was performed to identify consecutive patients between January 2013 and December 2015. Patients were searched by International Classification of Disease 9 diagnosis and procedure codes. Patient demographics and clinical characteristics were acquired. The cost breakdown was compiled into a comprehensive itemized list encompassing all aspects of hospitalization. A mean cost based on resource used per patient was obtained. Results There were 269 patients treated, 209 were coiled and 60 were clipped. Mean age in the clipping group was 49 years and 55 years in the coil group (P = 0.006). Other patient demographics and clinical characteristics were found to be statistically similar for both groups. Total cost per patient for treatment and hospital stay was $74,192 for clipping and $85,553 for coiling (P = 0.06). Cost amplified with increasing Hunt and Hess grade in both clipping and coiling groups. Conclusions The detailed cost information reported in this article can be used to help establish appropriate, standardized costs nationally by improving transparency. It can also help provide critical information necessary to develop cost-effective treatment algorithms and screening protocols.

This paper reports design optimization of vibration based energy harvest device fabricated by simple printing and laminating process using polymeric piezoelectric material (VDF/TrFE). Modified trapezoidal design increased the output voltage and energy dramatically by adhesion strength as well as improvement of internal stress distribution of the device. The process guaranteed simple (fast and low cost) fabrication of energy harvest device and the new design achieved 277 V and 1014 nJ outputs which is about 3 times higher than that of our previous device. Furthermore, by stacking the devices and connecting them in parallel, we increased the output energy into about $\mathbf{2.58}\ \mu \mathbf{J}$.

Aim To analyze the metabolic parameters and adipose tissue inflammation via NLRP3 inflammasome following chronic treatment of mouse models of obesity with AJ5018 as the peripherally restricted cannabinoid 1 receptor (CB1R) antagonist. Materials and methods The selectivity for CB1R over CB2R, brain/plasma concentration ratio, and centrally mediated neurobehavioural effects of AJ5018, were assessed. The long-term effects of AJ5018 and rimonabant on the metabolic parameters and adipose tissue inflammation were analyzed in diet-induced obese (DIO) mice and diabetic db/db mice. Results AJ5018 had a higher degree of selectivity for CB1R over CB2R and markedly reduced brain penetrance, as reflected by the lower brain/plasma concentration ratio and the attenuated centrally mediated neurobehavioural effects, compared with its brain-penetrant parent compound rimonabant. In DIO and db/db mice, AJ5018 exhibited comparable effects to rimonabant in improving metabolic abnormalities and suppressing macrophage infiltration into white adipose tissue, activation of the NLRP3 inflammasome, and production of proinflammatory cytokines. Conclusions These results suggest that peripheral CB1R blockade improves obesity-induced insulin resistance by suppressing adipose tissue inflammation via the NLRP3 inflammasome.

Currently, there is an incomplete understanding of the molecular pathogenesis of meningiomas, the most common primary brain tumor. Several familial syndromes are characterized by increased meningioma risk, and the genetics of these syndromes provides mechanistic insight into sporadic disease. The best defined of these syndromes is neurofibromatosis type 2, which is caused by a mutation in the NF2 gene and has a meningioma incidence of approximately 50%. This finding led to the subsequent discovery that NF2 loss-of-function occurs in up to 60% of sporadic tumors. Other important familial diseases with increased meningioma risk include nevoid basal cell carcinoma syndrome, multiple endocrine neoplasia 1 (MEN1), Cowden syndrome, Werner syndrome, BAP1 tumor predisposition syndrome, Rubinstein-Taybi syndrome, and familial meningiomatosis caused by germline mutations in the SMARCB1 and SMARCE1 genes. For each of these syndromes, the diagnostic criteria, incidence in the population, and frequency of meningioma are presented to review the relevant clinical information for these conditions. The genetic mutations, molecular pathway derangements, and relationship to sporadic disease for each syndrome are described in detail to identify targets for further investigation. Familial syndromes characterized by meningiomas often affect genes and pathways that are also implicated in a subset of sporadic cases, suggesting key molecular targets for therapeutic intervention. Further studies are needed to resolve the functional relevance of specific genes whose significance in sporadic disease remains to be elucidated.