In this study we examine the relationship between supply network's topology and its robustness in the presence of random failures and targeted attacks. The agent-based model developed in this paper ...uses the basic framework and parameters in the experimental game presented in Sterman 1989, Modeling managerial behavior: Misperceptions of feedback in a dynamic decision making context. Management Science, 35 (3), 321-339 for modelling adaptive managerial decision making in an inventory management context. The study extends the linear supply chain context to a complex supply network and undertakes a rigorous examination of robustness of these supply networks that are characterised by distinct network characteristics. We theorise that network characteristics such as average path length, clustering coefficient, size of the largest connected component in the network and the maximum distance between nodes in the largest connected component are related to the robustness of supply networks, and test the research hypotheses using data from several simulation runs. Simulations were carried out using 20 distinct network topologies where 10 of these topologies were generated using preferential attachment approach (based on the theory of scale-free networks) and the remaining 10 topologies were generated using random attachment approach (using random graph theory as a foundation). These 20 supply networks were subjected to random demand and their performances were evaluated by considering varying probabilities of random failures of nodes and targeted attacks on nodes. We also consider the severity of these disruptions by considering the downtime of the affected nodes. Using the data collected from a series of simulation experiments, we test the research hypotheses by means of binomial logistic regression analysis. The results point towards a significant association between network characteristics and supply network robustness assessed using multiple performance measures. We discuss the implications of the study and present directions for future research.
•UV–VIS–NIR was evaluated as a rapid method to quantify polyphenols of red wines.•For wines of Rías Baixas feasible models were obtained for all polyphenols.•For wines of Ribeira sacra models were ...obtained for quercetin, epicatechin, oenin and syringic acid.•For red wines from mencía grapes, models were obtained for catechin and oenin.•Results obtained demonstrate that UV–VIS–NIR can be used to determine polyphenols.
Spectral analysis is a quick and non-destructive method to analyse wine. In this work, trans-resveratrol, oenin, malvin, catechin, epicatechin, quercetin and syringic acid were determined in commercial red wines from DO Rías Baixas and DO Ribeira Sacra (Spain) by UV–VIS–NIR spectroscopy. Calibration models were developed using principal component regression (PCR) or partial least squares (PLS) regression. HPLC was used as reference method. The results showed that reliable PLS models were obtained to quantify all polyphenols for Rías Baixas wines. For Ribeira Sacra, feasible models were obtained to determine quercetin, epicatechin, oenin and syringic acid. PCR calibration models showed worst reliable of prediction than PLS models. For red wines from mencía grapes, feasible models were obtained for catechin and oenin, regardless the geographical origin. The results obtained demonstrate that UV–VIS–NIR spectroscopy can be used to determine individual polyphenolic compounds in red wines.
Germline mutations in DNA damage repair (DDR) genes are identified in a significant proportion of patients with metastatic prostate cancer, but the clinical implications of these genes remain ...unclear. This prospective multicenter cohort study evaluated the prevalence and effect of germline DDR (gDDR) mutations on metastatic castration-resistance prostate cancer (mCRPC) outcomes.
Unselected patients were enrolled at diagnosis of mCRPC and were screened for gDDR mutations in 107 genes. The primary aim was to assess the impact of ATM/BRCA1/BRCA2/ PALB2 germline mutations on cause-specific survival (CSS) from diagnosis of mCRPC. Secondary aims included the association of gDDR subgroups with response outcomes for mCRPC treatments. Combined progression-free survival from the first systemic therapy (PFS) until progression on the second systemic therapy (PFS2) was also explored.
We identified 68 carriers (16.2%) of 419 eligible patients, including 14 with BRCA2, eight with ATM, four with BRCA1, and none with PALB2 mutations. The study did not reach its primary end point, because the difference in CSS between ATM/BRCA1/BRCA2/PALB2 carriers and noncarriers was not statistically significant (23.3 v 33.2 months; P = .264). CSS was halved in germline BRCA2 (g BRCA2) carriers (17.4 v 33.2 months; P = .027), and g BRCA2 mutations were identified as an independent prognostic factor for CCS (hazard ratio HR, 2.11; P = .033). Significant interactions between g BRCA2 status and treatment type (androgen signaling inhibitor v taxane therapy) were observed (CSS adjusted P = .014; PFS2 adjusted P = .005). CSS (24.0 v 17.0 months) and PFS2 (18.9 v 8.6 months) were greater in g BRCA2 carriers treated in first line with abiraterone or enzalutamide compared with taxanes. Clinical outcomes did not differ by treatment type in noncarriers.
g BRCA2 mutations have a deleterious impact on mCRPC outcomes that may be affected by the first line of treatment used. Determination of g BRCA2 status may be of assistance for the selection of the initial treatment in mCRPC. Nonetheless, confirmatory studies are required before these results can support a change in clinical practice.
Polar ice core records attest to a colossal volcanic eruption that took place ca. A.D. 1257 or 1258, most probably in the tropics. Estimates based on sulfate deposition in these records suggest that ...it yielded the largest volcanic sulfur release to the stratosphere of the past 7,000 y. Tree rings, medieval chronicles, and computational models corroborate the expected worldwide atmospheric and climatic effects of this eruption. However, until now there has been no convincing candidate for the mid-13th century “mystery eruption.” Drawing upon compelling evidence from stratigraphic and geomorphic data, physical volcanology, radiocarbon dating, tephra geochemistry, and chronicles, we argue the source of this long-sought eruption is the Samalas volcano, adjacent to Mount Rinjani on Lombok Island, Indonesia. At least 40 km ³ (dense-rock equivalent) of tephra were deposited and the eruption column reached an altitude of up to 43 km. Three principal pumice fallout deposits mantle the region and thick pyroclastic flow deposits are found at the coast, 25 km from source. With an estimated magnitude of 7, this event ranks among the largest Holocene explosive eruptions. Radiocarbon dates on charcoal are consistent with a mid-13th century eruption. In addition, glass geochemistry of the associated pumice deposits matches that of shards found in both Arctic and Antarctic ice cores, providing compelling evidence to link the prominent A.D. 1258/1259 ice core sulfate spike to Samalas. We further constrain the timing of the mystery eruption based on tephra dispersal and historical records, suggesting it occurred between May and October A.D. 1257.
Introduction De nombreuses études utilisant un paradigme de double tâche (posture-cognition) ont suggéré que le contrôle postural requiert des ressources attentionnelles. Les tâches cognitives ...utilisées dans ces études allaient d’un simple comptage à rebours à des tâches plus complexes (e.g. : tâche de Stroop modifiée). Cependant, l’influence du contrôle postural sur les capacités attentionnelles n’a jamais été testée directement. L’objectif de cette étude était d’investiguer l’impact du contrôle postural sur les différentes composantes attentionnelles en utilisant une tâche attentionnelle spécifique. Matériel et méthode Nous avons utilisé l’Attention Network Test (ANT) qui évalue, à l’aide d’un paradigme unique, les 3 composantes attentionnelles : l’alerte, l’orientation et le contrôle exécutif. Quarante-deux participants ont réalisé l’ANT dans trois conditions posturales : une position très stable (sujets allongés sur le dos) ; une position intermédiaire (assis sur une chaise) et une position très instable (debout, les pieds alignés l’un derrière l’autre). Résultats Les résultats ont révélé que la modulation de la difficulté du contrôle postural a graduellement influencé l’état d’alerte des participants. Concernant les composantes attentionnelles d’orientation et de contrôle exécutif, les résultats ont montré que les performances étaient similaires lorsque les participants étaient debout ou assis alors qu’en position couchée les performances étaient spécifiquement réduites. Conclusion Le fort impact du contrôle postural sur le système d’alerte suggère que ces deux processus pourraient partager des circuits neuronaux. De plus, les résultats observés sur les composantes d’orientation et de contrôle exécutif suggèrent que la position allongée a un effet intrinsèque et spécifique sur les activités cognitives.
High inspiratory oxygen fraction ( FIO2) may improve tissue oxygenation but also impair pulmonary function. We aimed to assess whether the use of high intraoperative FIO2 increases the risk of major ...respiratory complications.
We studied patients undergoing non-cardiothoracic surgery involving mechanical ventilation in this hospital-based registry study. The cases were divided into five groups based on the median FIO2 between intubation and extubation. The primary outcome was a composite of major respiratory complications (re-intubation, respiratory failure, pulmonary oedema, and pneumonia) developed within 7 days after surgery. Secondary outcomes included 30-day mortality. Several predefined covariates were included in a multivariate logistic regression model.
The primary analysis included 73 922 cases, of whom 3035 (4.1%) developed a major respiratory complication within 7 days of surgery. For patients in the high- and low-oxygen groups, the median FIO2 was 0.79 range 0.64–1.00 and 0.31 0.16–0.34, respectively. Multivariate logistic regression analysis revealed that the median FIO2 was associated in a dose-dependent manner with increased risk of respiratory complications (adjusted odds ratio for high vs low FIO2 1.99, 95% confidence interval 1.72–2.31, P-value for trend <0.001). This finding was robust in a series of sensitivity analyses including adjustment for intraoperative oxygenation. High median FIO2 was also associated with 30-day mortality (odds ratio for high vs low FIO2 1.97, 95% confidence interval 1.30–2.99, P-value for trend <0.001).
In this analysis of administrative data on file, high intraoperative FIO2 was associated in a dose-dependent manner with major respiratory complications and with 30-day mortality. The effect remained stable in a sensitivity analysis controlled for oxygenation.
NCT02399878.
Dopamine is one of the neurotransmitters whose transmission is altered in a number of neural pathways in the brain of schizophrenic patients. Current evidence indicates that these alterations involve ...hyperactive dopaminergic transmission in mesolimbic areas, striatum, and hippocampus, whereas hypoactive dopaminergic transmission has been reported in the prefrontal cortex of schizophrenic patients. Consequently, schizophrenia is associated with several cognitive and behavioral alterations. Of note, the immune system has been found to collaborate with the central nervous system in a number of cognitive and behavioral functions, which are dysregulated in schizophrenia. Moreover, emerging evidence has associated schizophrenia and inflammation. Importantly, different lines of evidence have shown dopamine as a major regulator of inflammation. In this regard, dopamine might exert strong regulation in the activity, migration, differentiation, and proliferation of immune cells that have been shown to contribute to cognitive functions, including T-cells, microglial cells, and peripheral monocytes. Thereby, alterations in dopamine levels associated to schizophrenia might affect inflammatory response of immune cells and consequently some behavioral functions, including reference memory, learning, social behavior, and stress resilience. Altogether these findings support the involvement of an active cross-talk between the dopaminergic and immune systems in the physiopathology of schizophrenia. In this review we summarize, integrate, and discuss the current evidence indicating the involvement of an altered dopaminergic regulation of immunity in schizophrenia.
There is an urgent need to identify biomarkers to guide personalized therapy in castration-resistant prostate cancer (CRPC). We aimed to clinically qualify androgen receptor (AR) gene status ...measurement in plasma DNA using multiplex droplet digital PCR (ddPCR) in pre- and post-chemotherapy CRPC.
We optimized ddPCR assays for AR copy number and mutations and retrospectively analyzed plasma DNA from patients recruited to one of the three biomarker protocols with prospectively collected clinical data. We evaluated associations between plasma AR and overall survival (OS) and progression-free survival (PFS) in 73 chemotherapy-naïve and 98 post-docetaxel CRPC patients treated with enzalutamide or abiraterone (Primary cohort) and 94 chemotherapy-naïve patients treated with enzalutamide (Secondary cohort; PREMIERE trial).
In the primary cohort, AR gain was observed in 10 (14%) chemotherapy-naïve and 33 (34%) post-docetaxel patients and associated with worse OS hazard ratio (HR), 3.98; 95% CI 1.74–9.10; P < 0.001 and HR 3.81; 95% CI 2.28–6.37; P < 0.001, respectively, PFS (HR 2.18; 95% CI 1.08–4.39; P = 0.03, and HR 1.95; 95% CI 1.23–3.11; P = 0.01, respectively) and rate of PSA decline≥50% odds ratio (OR), 4.7; 95% CI 1.17–19.17; P = 0.035 and OR, 5.0; 95% CI 1.70–14.91; P = 0.003, respectively. AR mutations 2105T>A (p.L702H) and 2632A>G (p.T878A) were observed in eight (11%) post-docetaxel but no chemotherapy-naïve abiraterone-treated patients and were also associated with worse OS (HR 3.26; 95% CI 1.47–not reached; P = 0.004). There was no interaction between AR and docetaxel status (P = 0.83 for OS, P = 0.99 for PFS). In the PREMIERE trial, 11 patients (12%) with AR gain had worse PSA-PFS (sPFS) (HR 4.33; 95% CI 1.94–9.68; P < 0.001), radiographic-PFS (rPFS) (HR 8.06; 95% CI 3.26–19.93; P < 0.001) and OS (HR 11.08; 95% CI 2.16–56.95; P = 0.004). Plasma AR was an independent predictor of outcome on multivariable analyses in both cohorts.
Plasma AR status assessment using ddPCR identifies CRPC with worse outcome to enzalutamide or abiraterone. Prospective evaluation of treatment decisions based on plasma AR is now required.
NCT02288936 (PREMIERE trial).
The continuous interactions between host and pathogens during their coevolution have shaped both the immune system and the countermeasures used by pathogens. Natural killer (NK) cells are innate ...lymphocytes that are considered central players in the antiviral response. Not only do they express a variety of inhibitory and activating receptors to discriminate and eliminate target cells but they can also produce immunoregulatory cytokines to alert the immune system. Reciprocally, several unrelated viruses including cytomegalovirus, human immunodeficiency virus, influenza virus, and dengue virus have evolved a multitude of mechanisms to evade NK cell function, such as the targeting of pathways for NK cell receptors and their ligands, apoptosis, and cytokine-mediated signaling. The studies discussed in this article provide further insights into the antiviral function of NK cells and the pathways involved, their constituent proteins, and ways in which they could be manipulated for host benefit.
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