bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cross-talk between 4-1BB and TLR1–TLR2 Signaling in CD8+ T Cells Regulates TLR2′s Costimulatory Effects
Authors: Joseph Ann Mary , Srivastava Ratika , Zabaleta Jovanny , Davila Eduardo 
Published: June 2016

AbstractThe activation of TLR-MyD88 (Toll-like receptor-myeloid differentiation factor 88) signaling within T cells functions as a potent costimulatory signal that boosts antitumor and antiviral responses. However, the molecular mechanisms underlying the costimulatory processes are poorly understood. We compared microarray gene analysis data between TLR1–TLR2-stimulated and unstimulated T-cell receptor transgenic “pmel” and MyD88−/− pmel CD8+ T cells and identified changes in the expression of several TNF family members. In particular, TLR stimulation increased 4-1BB levels in pmel but not in MyD88−/−pmel T cells. A link between 4-1BB and TLR1–TLR2 signaling in CD8+ T cells was highlighted by the suboptimal responses of 4-1BB−/− T cells to TLR1–TLR2 agonist, but their normal response to CD28 or OX40 costimulation. Blocking 4-1BB signaling with antibodies also hindered the costimulatory effects of the TLR1–TLR2 agonist. The elevated levels of 4-1BB transcripts in TLR1–TLR2-stimulated cells were not due to increased mRNA stability nor increased histone activation, but instead were associated with increased binding of p65 and c-Jun to two distinct 4-1BB promoter sites. Combining TLR1–TLR2 ligand with an agonistic antibody to 4-1BB enhanced the antitumor activity in mice with established melanoma tumors. These studies reveal that the costimulatory effects of TLR1–TLR2 signaling in CD8+ T cells are in part mediated by 4-1BB and are important for mounting an effective antitumor immune response. Cancer Immunol Res; 4(8); 708–16. ©2016 AACR.
Combining Diuretic Response and Hemoconcentration to Predict Rehospitalization After Admission for Acute Heart Failure
Authors: ter Maaten Jozine M. , Valente Mattia A.E. , Damman Kevin , Cleland John G. , Givertz Michael M. , Metra Marco , O’Connor Christopher M. , Teerlink John R. , Ponikowski Piotr , Bloomfield Daniel M. , Cotter Gadi , Davison Beth , Subacius Haris , van Veldhuisen Dirk J. , van der Meer Peter , Hillege Hans L. , Gheorghiade Mihai , Voors Adriaan A. 
Published: June 2016

Background—
Both diuretic response and hemoconcentration are indicators of decongestion and have individually been found to predict rehospitalization after admission for acute heart failure (HF). This study examines the value of combining diuretic response and hemoconcentration to better predict patients at low risk for rehospitalization after admission for acute HF.

Methods and Results—

Diuretic response (defined as weight change per 40 mg of furosemide on day 4 after admission) and hemoconcentration (change in hemoglobin at discharge or day 7) were tested both individually and combined to predict the risk of HF and cardiovascular rehospitalization 60 days after hospitalization for acute HF. Analyses were performed in 1180 patients enrolled in the Placebo-Controlled Randomized Study of the Selective Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized With Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function (PROTECT) trial and validated in 1776 patients enrolled in the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) trial. Poor diuretic response was associated with low systolic blood pressure, high blood urea nitrogen, and history of coronary revascularization in both data sets (all
P
<0.05). Hemoconcentration was mainly associated with better renal function (
P
<0.05). Patients who displayed both favorable diuretic response and hemoconcentration had a markedly lower risk of rehospitalization for HF in PROTECT (multivariable HR, 0.41; 95% CI, 0.24 to 0.70;
P
<0.001) compared with all other patients. This finding was confirmed in EVEREST (multivariable HR, 0.52; 95% CI, 0.33 to 0.82;
P
=0.004) for patients with favorable diuretic response and hemoconcentration compared with all other patients.

Conclusions—
Combining 2 indicators of decongestion, hemoconcentration and diuretic response improves risk prediction for early rehospitalization after an admission for acute HF and may provide clinicians with an easily accessible tool to identify low-risk patients.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifiers: NCT00354458 and NCT00071331.
Cognitive Machine-Learning Algorithm for Cardiac Imaging
Authors: Sengupta Partho P. , Huang Yen-Min , Bansal Manish , Ashrafi Ali , Fisher Matt , Shameer Khader , Gall Walt , Dudley Joel T. 
Published: June 2016

Background—
Associating a patient’s profile with the memories of prototypical patients built through previous repeat clinical experience is a key process in clinical judgment. We hypothesized that a similar process using a cognitive computing tool would be well suited for learning and recalling multidimensional attributes of speckle tracking echocardiography data sets derived from patients with known constrictive pericarditis and restrictive cardiomyopathy.

Methods and Results—
Clinical and echocardiographic data of 50 patients with constrictive pericarditis and 44 with restrictive cardiomyopathy were used for developing an associative memory classifier–based machine-learning algorithm. The speckle tracking echocardiography data were normalized in reference to 47 controls with no structural heart disease, and the diagnostic area under the receiver operating characteristic curve of the associative memory classifier was evaluated for differentiating constrictive pericarditis from restrictive cardiomyopathy. Using only speckle tracking echocardiography variables, associative memory classifier achieved a diagnostic area under the curve of 89.2%, which improved to 96.2% with addition of 4 echocardiographic variables. In comparison, the area under the curve of early diastolic mitral annular velocity and left ventricular longitudinal strain were 82.1% and 63.7%, respectively. Furthermore, the associative memory classifier demonstrated greater accuracy and shorter learning curves than other machine-learning approaches, with accuracy asymptotically approaching 90% after a training fraction of 0.3 and remaining flat at higher training fractions.

Conclusions—
This study demonstrates feasibility of a cognitive machine-learning approach for learning and recalling patterns observed during echocardiographic evaluations. Incorporation of machine-learning algorithms in cardiac imaging may aid standardized assessments and support the quality of interpretations, particularly for novice readers with limited experience.
Role of Horizontal Advection of Seasonal-Mean Moisture in the Madden–Julian Oscillation: A Theoretical Model Analysis
Authors: Liu Fei , Wang Bin 
Published: June 2016

Abstract
The impact of horizontal advection of seasonal-mean moisture (SMM) on Madden–Julian oscillation (MJO) dynamics is investigated here using a theoretical model that includes moisture advection processes. The zonal advection of SMM with an eastward gradient is found to produce planetary-scale instability and promote slow eastward propagation corresponding to an intraseasonal periodicity. This is because the SMM advection by an anomalous easterly of the Kelvin waves generates a moisture source to the east of precipitation, which favors eastward propagation and unstable growth. On the other hand, the advection of SMM with a westward gradient results in a westward-propagating unstable mode. For a realistic SMM distribution, the simulated eastward propagation is enhanced over the Indo-Pacific warm pool, while the westward propagation prevails over the central-eastern Pacific. In contrast to the zonal advection of SMM, the meridional advection of SMM only affects short waves and leaves planetary waves nearly unaffected.
The effect of zonal advection of SMM suggests an important mechanism for explaining the eastward propagation and growth of the MJO over the Indo-Pacific warm pool when the SMM increases eastward. However, this mechanism alone produces unrealistic Kelvin wave–like structure and strong westward propagation in the central-eastern Pacific; both disagree with observations. These caveats, however, can be remitted if the planetary boundary layer (PBL) moisture convergence feedback is included, which couples the Kelvin wave and the Rossby wave via precipitation heating, producing a realistic horizontal structure and also substantially suppressing the unrealistically growing, westward-propagating mode in the central-eastern Pacific.
WRF Forecasts of Great Plains Nocturnal Low-Level Jet-Driven MCSs. Part I: Correlation between Low-Level Jet Forecast Accuracy and MCS Precipitation Forecast Skill
Authors: Squitieri Brian J. , Gallus William A. 
Published: June 2016

AbstractThe Great Plains low-level jet (LLJ) fosters an environment that supports nocturnal mesoscale convective systems (MCSs) across the central United States during the summer months. The current study examines if LLJ forecast accuracy correlates with MCS precipitation forecast skill in 4-km WRF runs. LLJs were classified based on their synoptic background as either strongly forced, cyclonic flow (type C) or weakly forced, anticyclonic flow inertial oscillation driven (type A). Large-scale variables associated with the LLJ were examined. For all LLJs inclusive and the subset of type C LLJs alone, the forecast accuracy of the LLJ total wind direction significantly correlated with MCS precipitation forecast skill. For type C LLJ cases, where predictive skill for MCSs was higher overall, the LLJ ageostrophic wind direction forecast accuracy significantly correlated with MCS precipitation forecast skill during the LLJ and MCS developmental stages, with potential temperature and moisture forecast accuracy correlating well with the forecast skill of mature MCSs. Statistically significant correlations were mainly absent between MCS precipitation forecast skill and LLJ forecast accuracy for type A cases. It is thus suggested that either non-LLJ factors like most unstable convective available potential energy (MUCAPE) or most unstable convective inhibition (MUCIN) fields within close proximity of MCSs, or factors on smaller scales than analyzed (such as gravity waves or bores), may have the greatest potential influence on MCS precipitation forecast skill in LLJ-induced MCS cases in an ambient weakly forced synoptic regime.
Intraoperative Frozen Section in “Suspicious for Papillary Thyroid Carcinoma” after Adoption of the Bethesda System
Authors: Abu‐Ghanem Sara , Cohen Oded , Raz Yarkoni Tom , Fliss Dan M. , Yehuda Moshe 
Published: June 2016

ObjectiveTo evaluate the accuracy and utility of intraoperative frozen section examination (iFSE) in patients with a preoperative fine‐needle aspiration (FNA) cytology of “suspicious for malignancy” (SFM)–Bethesda V, after the adoption of the Bethesda System for Reporting Thyroid Cytopathology.Study DesignCase series with chart review.SettingTertiary medical center.Subjects and MethodsAll patients with SFM–Bethesda V who underwent thyroid surgery with iFSE between 2010 and 2015 were included. In cases where the iFSE was reported to be malignant, a total thyroidectomy was performed; otherwise, thyroid lobectomy (hemithyroidectomy) was performed.ResultsThe current series included 47 patients diagnosed preoperatively with FNA cytology of SFM–Bethesda V. The malignancy rate was 74.5% (35 of 47). Twenty‐four patients with nonmalignant iFSE results underwent lobectomy during their initial surgery: 12 were subsequently found with benign final histology and did not undergo completion thyroidectomy; the other 12 patients had malignant results on final histology, but only 4 of them underwent completion thyroidectomy. iFSE resulted in a sensitivity and specificity of 65.7% and 100%, respectively, with a positive predictive value of 100% (23 of 23) and a negative predictive value of 50% (12 of 24). Accuracy of the iFSE methodology was 74.5% (35 of 47).ConclusionsWith no significant preoperative clinical or sonographic predictors for thyroid malignancy and given the high specificity of iFSE, our results support the use of iFSE for patients with preoperative FNA cytology of SFM–Bethesda V who are undergoing thyroid surgery, to determine the extent of required surgery.
A Law for the Social Sciences Regarding Us Human Beings
Authors: Cardao-Pito Tiago 
Published: June 2016

This article proposes a feasible law for the social sciences asserting that we human beings are not commodities, assets, capital or resources. Mainstream economics and Marxism describe human participation in economic and societal production through a human-commodity framework. Intangible flow theory aims to replace that framework and interrelated conjectures as human capital, human assets and human resources. This theory is not exclusively applicable to capitalist/market organization forms. It suggests that (a) commodities are physical goods, and exhibit known characteristics differentiating them from human-related flows as service or knowledge flows; (b) human work has properties that make it akin to quasi-service production; (c) humans are not commodities, capital, assets or resources; (d) machines can obtain the skills necessary to replace human work or perform novel tasks when previously intangible dimensions are turned tangible (tangibilization); and (e) cash-flows generated or saved by those machines tend to flow to human beings who own or control them. According to this theory, greater attention must be paid to flows of economic material elements that display a relevant degree of empirical precision (e.g., cash and physical goods flows). JEL: A1, B1, B2, B4, B5
Does Age Influence the Risk of Incident Knee Osteoarthritis After a Traumatic Anterior Cruciate Ligament Injury?
Authors: Johnson Victoria L. , Roe Justin P. , Salmon Lucy J. , Pinczewski Leo A. , Hunter David J. 
Published: June 2016

Background: The development of radiographic knee osteoarthritis (OA) after an anterior cruciate ligament (ACL) rupture has long been studied and proven in the adolescent population. However, similar exhaustive investigations have not been conducted in mature-aged athletes or in older populations. Purpose: To identify whether an older adult population had an increased risk of incident radiographic knee OA after a traumatic knee injury compared with a young adult population. Study Design: Cohort study; Level of evidence, 3. Methods: Patients with ACL ruptures who underwent primary reconstruction were enrolled in a prospective, longitudinal single-center study over 15 years. The adult cohort was defined as participants aged ≥35 years who had a knee injury resulting in an ACL tear, the adolescent-young cohort suffered similar knee injuries and were aged ≤25 years, and a third cohort of participants aged 26 to 34 years who suffered a knee injury was included to identify the existence of any age-related dose-response relationship for the onset of radiographic knee OA. A Kaplan-Meier survival analysis was employed to determine the occurrence of incident radiographic OA across the study populations at 2, 5, 10, and 15 years after reconstruction. Significance at each time point was analyzed using chi-square tests. Results: A total of 215 patients, including 112 adolescents (mean age, 20.4 years; 50.9% female), 71 patients aged 26 to 34 years (mean age, 29.2 years; 42.3% female), and 32 adults (mean age, 40.2 years; 59.4% female), were assessed for International Knee Documentation Committee (IKDC) grading on knee radiographs. It was found that 53.0% and 77.8% of adults at a respective 10 and 15 years after reconstruction had an IKDC grade of B or greater compared with 17.7% and 61.6% of the adolescent-young cohort. Chi-square testing found that adults developed OA earlier than adolescents at 5 and 10 years after reconstruction ( P = .017 and P < .0001, respectively). However, survival analysis did not demonstrate that adults were more likely to develop radiographic knee OA at 15 years after reconstruction compared with the adolescent-young cohort ( P = .4). Conclusion: The age at which an ACL injury is sustained does not appear to influence the rate of incident radiographic knee OA, although mature-aged athletes are likely to arrive at the OA endpoint sooner.
Case Series With Histopathologic and Radiographic Analyses Following Failure of Fresh Osteochondral Allografts of the Talus
Authors: Pomajzl Ryan Joseph , Baker Erin Ann , Baker Kevin Charles , Fleischer Mackenzie Marie , Salisbury Meagan R. , Phillips Dylan M. , Fortin Paul Thomas 
Published: June 2016

Background: Fresh osteochondral allografting of the talus is one treatment option for large chondral defects. Following positive early term results, failure rates of up to 35% have been reported. A retrieval study was performed to characterize failed talar allografts. Methods: Failed fresh osteochondral allografts of the talus were retrieved on revision. Cases of deep infection were excluded. After tissue fixation, samples were decalcified, embedded, and stained with Safranin-O/Fast Green, osteocalcin, tumor necrosis factor alpha (TNF-α), CD4, CD8, and CD68. Slides were graded according to the modified Mankin scoring system or severity scale. Medical record review was performed. Results: Eight allografts (7 patients) were retrieved from patients, following an average term of implantation of 31 months (range, 12-58). There were 3 types of allografts in this series (hemidome, n=5; segmental, n=2; bipolar, n=1). Reasons for transplantation were post-traumatic arthritis or osteonecrosis; reasons for revision were graft failure/collapse, nonunion, progressive arthritis, and/or pain. Prior to revision, all grafts exhibited collapse and subchondral lucencies. At the graft host interface, Safranin-O staining demonstrated substantial loss of sulfated glycosaminoglycans, Osteocalcin immunostaning was nearly absent, CD68 (indicating osteoclast activity) was predominantly exhibited, and CD4+ helper T cells as well as CD8+ cytotoxic T cells and NK cells—cell types commonly implicated in allogeneic organ transplant rejection—were found in high concentrations. TNF-α was present throughout the graft. Conclusion: A histopathologic analysis of 8 retrieved, failed talar allografts was performed. Graft failure appeared to be primarily biologic, with an extensive loss of viable cartilaginous and osseous tissue at the graft-host interface. This study provides the first evidence of a potential CD4+ and CD8+ lymphocyte-mediated failure mechanism in fresh osteochondral allografts that were revised following collapse. Level of Evidence: Level IV, case series.
Quantifying over-estimation in early stopped clinical trials and the “freezing effect” on subsequent research
Authors: Wang Hao , Rosner Gary L , Goodman Steven N 
Published: June 2016

Background: Despite the wide use of the design with statistical stopping guidelines to stop a randomized clinical trial early for efficacy, there are unsettled debates of potential harmful consequences of such designs. These concerns include the possible over-estimation of treatment effects in early stopped trials and a newer argument of a “freezing effect” that will halt future randomized clinical trials on the same comparison since an early stopped trial represents an effective declaration that randomization to the unfavored arm is unethical. The purpose of this study is to determine the degree of bias in designs that allow for early stopping and to assess the impact on estimation if indeed future experimentation is “frozen” by an early stopped trial. Methods: We perform simulations to study the effect of early stopping. We simulate a collection of trials and contrast the treatment-effect estimates (risk differences and ratios) with the simulation truth. Simulations consider various scenarios of between-study variation, including an empirically derived distribution of effects from the clinical literature. Results: Across the trials whose true effects are sampled from a uniform distribution, estimates from trials that stop early for efficacy deviate minimally from the simulation truth (median bias of the estimate of risk difference is 0.005). Over-estimation becomes appreciable only when the true effect is close to the null value 0 (median bias of the risk difference estimate is 0.04) or when stopping happens with 40% information or less; however, stopping under these situations is rare. We also find slight reverse bias of the estimated treatment effect (median bias of the risk difference estimate is −0.002) among trials that do not cross the early stopping boundaries but continue to the final analysis. Similar results occur with relative risk estimates. In contrast, Bayesian estimation of the treatment effect shrinks the estimate from trials stopping early and pulls back under-estimation from completed trials, largely rectifying any over-estimation among trials that terminate early. Regarding the so-called freezing effect, the pooled effects from meta-analyses that include truncated randomized clinical trials show an unimportant deviation from the true value, even when no subsequent trials are conducted after a truncated randomized clinical trial. Conclusion: Group sequential designs with stopping rules seek to minimize exposure of patients to a disfavored therapy and speed dissemination of results, and such designs do not lead to materially biased estimates. The likelihood and magnitude of a “freezing effect” is minimal. Superiority demonstrated in a randomized clinical trial stopping early and designed with appropriate statistical stopping rules is likely a valid inference, even if the estimate may be slightly inflated.
Spinal neurons that contain gastrin-releasing peptide seldom express Fos or phosphorylate extracellular signal-regulated kinases in response to intradermal chloroquine
Authors: Bell Andrew M , Gutierrez-Mecinas Maria , Polgár Erika , Todd Andrew J 
Published: June 2016

Background Gastrin-releasing peptide (GRP) is thought to play a role in the itch evoked by intradermal injection of chloroquine. Although some early studies suggested that GRP was expressed in pruriceptive primary afferents, it is now thought that GRP in the spinal cord is derived mainly from a population of excitatory interneurons in lamina II, and it has been suggested that these are involved in the itch pathway. To test this hypothesis, we used the transcription factor Fos and phosphorylation of extracellular signal-regulated kinases (ERK) to look for evidence that interneurons expressing GRP were activated following intradermal injection of chloroquine into the calf, in mice that express enhanced green fluorescent protein (EGFP) in these cells. Results Injection of chloroquine resulted in numerous Fos- or phospho-ERK (pERK) positive cells in the somatotopically appropriate part of the superficial dorsal horn. The proportion of all neurons in this region that showed Fos or pERK was 18% and 21%, respectively. However, among the GRP–EGFP, only 7% were Fos-positive and 3% were pERK-positive. As such, GRP–EGFP cells were significantly less likely than other neurons to express Fos or to phosphorylate ERK. Conclusions Both expression of Fos and phosphorylation of ERK can be used to identify dorsal horn neurons activated by chloroquine injection. However, these results do not support the hypothesis that interneurons expressing GRP are critical components in the itch pathway.