Executive Summary Surgical ablation for atrial fibrillation (AF) can be performed without additional risk of operative mortality or major morbidity, and is recommended at the time of concomitant ...mitral operations to restore sinus rhythm. (Class I, Level A) Surgical ablation for AF can be performed without additional operative risk of mortality or major morbidity, and is recommended at the time of concomitant isolated aortic valve replacement, isolated coronary artery bypass graft surgery, and aortic valve replacement plus coronary artery bypass graft operations to restore sinus rhythm. (Class I, Level B nonrandomized) Surgical ablation for symptomatic AF in the absence of structural heart disease that is refractory to class I/III antiarrhythmic drugs or catheter-based therapy or both is reasonable as a primary stand-alone procedure, to restore sinus rhythm. (Class IIA, Level B randomized) Surgical ablation for symptomatic persistent or longstanding persistent AF in the absence of structural heart disease is reasonable, as a stand-alone procedure using the Cox-Maze III/IV lesion set compared with pulmonary vein isolation alone. (Class IIA, Level B nonrandomized) Surgical ablation for symptomatic AF in the setting of left atrial enlargement (≥4.5 cm) or more than moderate mitral regurgitation by pulmonary vein isolation alone is not recommended. (Class III no benefit, Level C expert opinion) It is reasonable to perform left atrial appendage excision or exclusion in conjunction with surgical ablation for AF for longitudinal thromboembolic morbidity prevention. (Class IIA, Level C limited data) At the time of concomitant cardiac operations in patients with AF, it is reasonable to surgically manage the left atrial appendage for longitudinal thromboembolic morbidity prevention. (Class IIA, Level C expert opinion) In the treatment of AF, multidisciplinary heart team assessment, treatment planning, and long-term follow-up can be useful and beneficial to optimize patient outcomes. (Class I, Level C expert opinion)
The human proteome is a major source of therapeutic targets. Recent genetic association analyses of the plasma proteome enable systematic evaluation of the causal consequences of variation in plasma ...protein levels. Here we estimated the effects of 1,002 proteins on 225 phenotypes using two-sample Mendelian randomization (MR) and colocalization. Of 413 associations supported by evidence from MR, 130 (31.5%) were not supported by results of colocalization analyses, suggesting that genetic confounding due to linkage disequilibrium is widespread in naïve phenome-wide association studies of proteins. Combining MR and colocalization evidence in cis-only analyses, we identified 111 putatively causal effects between 65 proteins and 52 disease-related phenotypes ( https://www.epigraphdb.org/pqtl/ ). Evaluation of data from historic drug development programs showed that target-indication pairs with MR and colocalization support were more likely to be approved, evidencing the value of this approach in identifying and prioritizing potential therapeutic targets.
Diet-related inflammation is associated with adiposity. Obesity and inflammation in early life may have adverse health outcomes in later life; however, the socio-ecological predictors of a ...pro-inflammatory diet in childhood and adolescence are not well understood. This rapid scoping review aims to summarise the current state of research from observational studies investigating socio-ecological predictors (childhood, parental, familial, demographic and chronobiological risk factors) and their association with diet-associated inflammation and adiposity in children and adolescents.
This scoping review will be conducted using the frameworks based on the Joanna Briggs Institute and Arksey and O'Malley and the Population, Concept and Context (PCC) mnemonic. Searches were conducted in OVID Medline, Cinahl and Embase, with adaptations as required. The piloted study selection process will utilise two reviewers for study selection, with reference lists checked for included studies. A third reviewer will moderate disagreements. Data will be extracted by one reviewer and calibrated by a second reviewer.
The results will be reported using the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) checklist and PRISMA-ScR flow diagram. The main findings will be synthesised into themes and concepts narratively. Tables and graphs will present frequencies, study details and categorical descriptions.
This scoping review will provide an overview of the research conducted to date regarding predictors of diet-related inflammation in childhood and their associations with adiposity. Better understanding of the factors associated with a more inflammatory diet in childhood may be useful for clinicians and policy makers when designing and implementing health interventions.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
4.
RB Loss Promotes Prostate Cancer Metastasis Thangavel, Chellappagounder; Boopathi, Ettickan; Liu, Yi ...
Cancer research (Chicago, Ill.),
02/2017, Letnik:
77, Številka:
4
Journal Article
Recenzirano
Odprti dostop
RB loss occurs commonly in neoplasia but its contributions to advanced cancer have not been assessed directly. Here we show that RB loss in multiple murine models of cancer produces a prometastatic ...phenotype. Gene expression analyses showed that regulation of the cell motility receptor RHAMM by the RB/E2F pathway was critical for epithelial-mesenchymal transition, motility, and invasion by cancer cells. Genetic modulation or pharmacologic inhibition of RHAMM activity was sufficient and necessary for metastatic phenotypes induced by RB loss in prostate cancer. Mechanistic studies in this setting established that RHAMM stabilized F-actin polymerization by controlling ROCK signaling. Collectively, our findings show how RB loss drives metastatic capacity and highlight RHAMM as a candidate therapeutic target for treating advanced prostate cancer.
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In this study, two types of single polymer films have been inserted in a composite laminate to examine their toughening effects on mechanical properties. The first is a thermoplastic polyurethane ...(PU) film, and the second is an adhesive epoxy film featuring a polyester net. The laminates were manufactured either using a co-curing (CC) process or a secondary bonding (SB) process used for the epoxy film. Mode I and mode II interlaminar fracture toughness were measured for laminates manufactured by both processes and compared with the corresponding reference laminate toughness. A significant increase in both mode I and mode II toughness resulted when introducing a single PU film, approximately 290% and 50%, respectively. Similarly, the epoxy film improved the interlaminar fracture properties; the CC process produced an increase of 175% for mode II toughness, while the SB adhesive film showed an increase of 75% for mode II toughness.
Background Recent policy clarifications by the Centers for Medicare & Medicaid Services have changed access to outpatient dialysis care at end-stage renal disease (ESRD) facilities for individuals ...with acute kidney injury in the United States. Tools to predict “ESRD” and “acute” status in terms of kidney function recovery among patients who previously initiated dialysis therapy in the hospital could help inform patient management decisions. Study Design Historical cohort study. Setting & Participants Incident hemodialysis patients in the Mayo Clinic Health System who initiated in-hospital renal replacement therapy (RRT) and continued outpatient dialysis following hospital dismissal (2006 through 2009). Predictor Baseline estimated glomerular filtration rate (eGFR), acute tubular necrosis from sepsis or surgery, heart failure, intensive care unit, and dialysis access. Outcomes Kidney function recovery defined as sufficient kidney function for outpatient hemodialysis therapy discontinuation. Results Cohort consisted of 281 patients with a mean age of 64 years, 63% men, 45% with heart failure, and baseline eGFR ≥ 30 mL/min/1.73 m2 in 46%. During a median of 8 months, 52 (19%) recovered, most (94%) within 6 months. Higher baseline eGFR (HR per 10–mL/min/1.73 m2 increase eGFR, 1.27; 95% CI, 1.16-1.39; P < 0.001), acute tubular necrosis from sepsis or surgery (HR, 3.34; 95% CI, 1.83-6.24; P < 0.001), and heart failure (HR, 0.40; 95% CI, 0.19-0.78, P = 0.007) were independent predictors of recovery within 6 months, whereas first RRT in the intensive care unit and catheter dialysis access were not. There was a positive interaction between absence of heart failure and eGFR ≥ 30 mL/min/1.73 m2 for predicting kidney function recovery ( P < 0.001). Limitations Sample size. Conclusions Kidney function recovery in the outpatient hemodialysis unit following in-hospital RRT initiation is not rare. As expected, higher baseline eGFR is an important determinant of recovery. However, patients with heart failure are less likely to recover even with a higher baseline eGFR. Consideration of these factors at hospital discharge informs decisions on ESRD status designation and long-term hemodialysis care.
Solution processed polymer/fullerene blend films are receiving extensive attention as the photoactive layer of organic solar cells. In this paper we report a range of photophysical, electrochemical, ...physicochemical and structural data which provide evidence that formation of a relatively pure, molecularly ordered phase of the fullerene component, phenyl-C61-butyric acid methyl ester (PCBM), may be the key factor driving the spatial separation of photogenerated electrons and holes in many of these devices. PCBM crystallisation is shown to result in an increase in its electron affinity, providing an energetic driving force for spatial separation of electrons and holes. Based upon our observations, we propose a functional model applicable to many organic bulk heterojunction devices based upon charge generation in a finely intermixed polymer/fullerene phase followed by spatial separation of electrons and holes at the interface of this mixed phase with crystalline PCBM domains. This model has significant implications for the design of alternative acceptor materials to PCBM for organic solar cells.
Introduction: Callous-unemotional (CU) traits in the presence of conduct problems are associated with increased risk of severe antisocial behavior. Developmentally sensitive methods of assessing CU ...traits have recently been generated, but their construct validity in relation to neurocognitive underpinnings of CU has not been demonstrated. The current study sought to investigate whether the fear-specific emotion recognition deficits associated with CU traits in older individuals are developmentally expressed in young children as low concern for others and punishment insensitivity. Method: A subsample of 337 preschoolers (mean age 4.8 years, SD = 0.8) who completed neurocognitive tasks was taken from a larger project of preschool psychopathology. Children completed an emotional recognition task in which they were asked to identify the emotional face from the neutral faces in an array. CU traits were assessed using the Low Concern (LC) and Punishment Insensitivity (PI) subscales of the Multidimensional Assessment Profile of Disruptive Behavior (MAP-DB), which were specifically designed to differentiate the normative misbehavior of early childhood from atypical patterns. Results: High LC, but not PI, scores were associated with a fear-specific deficit in emotion recognition. Girls were more accurate than boys in identifying emotional expressions but no significant interaction between LC or PI and sex was observed. Conclusions: Fear recognition deficits associated with CU traits in older individuals were observed in preschoolers with developmentally defined patterns of low concern for others. Confirming that the link between CU-related impairments in empathy and distinct neurocognitive deficits is present in very young children suggests that developmentally specified measurement can detect the substrates of these severe behavioral patterns beginning much earlier than prior work. Exploring the development of CU traits and disruptive behavior disorders at very early ages may provide insights critical to early intervention and prevention of severe antisocial behavior.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
An investigation into the inspection capabilities of in-field advanced ultrasound detection for use on ultra-thick (20 to 100 mm) glass fibre-reinforced polyester composites is presented. Plates were ...manufactured using custom moulding techniques, such that delamination flaws were created at calibrated depths. The full matrix capture technique with an on-board total focussing method was used to detect flaws scanned by a 0.5 MHz linear array probe. Flaw through-thickness dimensions were altered to assess the threshold for crack face separation at which delaminations could be identified. Furthermore, part thickness and in-plane flaw dimensions were varied to identify the inspection capability limitations of advanced ultrasonics for thick composites. The results presented in this study demonstrate an inverse relationship between the ability to find delaminations and plate thicknesses, with inspections successful at depths up to 74 mm. When the delamination thickness exhibited surface-to-surface contact, the inspection capability was reduced to 35 mm. There was an exponential decay relationship between the accuracy of the flaw depth measurement and plate thickness, likely due to the necessity of low probe frequencies. The effective inspection depth was determined to be in the range of 1 to 20 times the wavelength. It is speculated that the accuracy of measurements could be improved using probes with novel coupling solutions, and detectors with optimised signal processing/filtration algorithms.
BackgroundWe conducted the first trial of neoadjuvant PD-1 blockade in resectable non-small cell lung cancer (NSCLC), finding nivolumab monotherapy to be safe and feasible with an encouraging rate of ...pathologic response. Building on these results, and promising data for nivolumab plus ipilimumab (anti-CTLA-4) in advanced NSCLC, we expanded our study to include an arm investigating neoadjuvant nivolumab plus ipilimumab.MethodsPatients with resectable stage IB (≥4 cm)–IIIA (American Joint Committee on Cancer Tumor Node Metastases seventh edition), histologically confirmed, treatment-naïve NSCLC received nivolumab 3 mg/kg intravenously plus ipilimumab 1 mg/kg intravenously 6 weeks prior to planned resection. Nivolumab 3 mg/kg was given again approximately 4 and 2 weeks preoperatively. Primary endpoints were safety and feasibility with a planned enrollment of 15 patients. Pathologic response was a key secondary endpoint.ResultsWhile the treatment regimen was feasible per protocol, due to toxicity, the study arm was terminated early by investigator consensus after 9 of 15 patients were enrolled. All patients received every scheduled dose of therapy and were fit for planned surgery; however, 6 of 9 (67%) experienced treatment-related adverse events (TRAEs) and 3 (33%) experienced grade ≥3 TRAEs. Three of 9 patients (33%) had biopsy-confirmed tumor progression precluding definitive surgery. Of the 6 patients who underwent resection, 3 are alive and disease-free, 2 experienced recurrence and are actively receiving systemic treatment, and one died postoperatively due to acute respiratory distress syndrome. Two patients who underwent resection had tumor pathologic complete responses (pCRs) and continue to remain disease-free over 24 months since surgery. Pathologic response correlated with pre-treatment tumor PD-L1 expression, but not tumor mutation burden. Tumor KRAS/STK11 co-mutations were identified in 5 of 9 patients (59%), of whom two with disease progression precluding surgery had tumor KRAS/STK11/KEAP1 co-mutations.ConclusionsThough treatment was feasible, due to toxicity the study arm was terminated early by investigator consensus. In light of this, and while the long-term disease-free status of patients who achieved pCR is encouraging, further investigation of neoadjuvant nivolumab plus ipilimumab in patients with resectable NSCLC requires the identification of predictive biomarkers that enrich for response.
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