A relative entropy rate method for path space sensitivity analysis of stationary complex stochastic dynamics

We propose a new sensitivity analysis methodology for complex stochastic dynamics based on the Relative Entropy Rate. The method becomes computationally feasible at the stationary regime of the process and involves the calculation of suitable observables in path space for the Relative Entropy Rate and the corresponding Fisher Information Matrix. The stationary regime is crucial for stochastic dynamics and here allows us to address the sensitivity analysis of complex systems, including examples of processes with complex landscapes that exhibit metastability, non-reversible systems from a statistical mechanics perspective, and high-dimensional, spatially distributed models. All these systems exhibit, typically non-gaussian stationary probability distributions, while in the case of high-dimensionality, histograms are impossible to construct directly. Our proposed methods bypass these challenges relying on the direct Monte Carlo simulation of rigorously derived observables for the Relative Entropy Rate and Fisher Information in path space rather than on the stationary probability distribution itself. We demonstrate the capabilities of the proposed methodology by focusing here on two classes of problems: (a) Langevin particle systems with either reversible (gradient) or non-reversible (non-gradient) forcing, highlighting the ability of the method to carry out sensitivity analysis in non-equilibrium systems; and, (b) spatially extended Kinetic Monte Carlo models, showing that the method can handle high-dimensional problems

Lake surface temperature [in “State of the Climate in 2017”]

Observed lake surface water temperature anomalies in 2017 are placed in the context of the recent warming observed in global surface air temperature by collating long-term in situ lake surface temperature observations from some of the world’s best-studied lakes and a satellite-derived global lake surface water temperature dataset. The period 1996–2015, 20 years for which satellite-derived lake temperatures are available, is used as the base period for all lake temperature anomaly calculations

ASSOCIAZIONE TRA SCORE GENETICO GRS E RISCHIO DI EPATOCARCINOMA IN PAZIENTI CON CIRROSI HCV TRATTATI CON FARMACI ANTIVIRALI DIRETTI

Background and aim: Several single nucleotide polymorphisms (SNPs) have been associated with hepatocellular carcinoma (HCC) in hepatitis C virus (HCV) cirrhotics, however their role in patients cured by direct-acting antivirals (DAA) is still undefined. We assessed the association between a genetic risk score (GRS) based on the combination of 4 SNPs (PNPLA3 rs738409, MBOAT7 rs641738, TM6SF2 rs5842926 and GCKR rs1260326) and HCC in a cohort of DAA-treated patients. Methods: Consecutive HCV cirrhotics receiving DAA between December 2014-2016 in a single Center were genotyped for the 4 SNPs. Cirrhosis was defined histologically or non-invasively (Liver stiffness measurement [LSM] 6512 kPa). HCC was diagnosed and staged according to international recommendations. Results: 509 patients were analyzed: median age 64 (28-87) years, 58% males, LSM 19.4 (12.0-75.0) kPa, 87% Child-Pugh score A (CPT) A, 11% with previous HCC history. Genotypes distribution was as follows: PNPLA3 CC (46%), CG (41%) GG (13%); MBOAT7 CC (29%), CT (49%), TT (22%); TM6SF2 CC (91%), CT (8%), TT (1%); GCKR CC (26%), CT (48%), TT (26%). Median GRS score in the overall population was 0.3 (0-1.1). Patients\u2019 demography and clinical features were similar across SNPs genotypes. Following antiviral treatment, 491 (96%) patients achieved viral eradication. During a median follow-up of 43 (3-57) months from DAA start, HCC developed in 36/452 (8%) patients without a history of HCC (de novo HCC), 4-year estimated cumulative probability of HCC being 9% (95% CI 7-12%). Male sex (Hazard Ratio [HR] 2.54; 95% CI 1.15-5.63; p=0.02), diabetes (HR 2.39; 95% CI 1.20-4.74; p=0.01), albumin (HR 0.35; 95% CI 0.19-0.64; p=0.001) and GRS score >0.6 (HR 2.30; 95% CI 1.03-5.11; p=0.04) were independently associated with de novo HCC. Indeed, 4-year cumulative rates of de novo HCC resulted 6% (95% CI 1-10%) vs. 12% (95% CI 8-16%) in males vs. females (p=0.01); 17% (95% CI 9-24%) vs. 7% (95% CI 5-10%) in diabetic vs. non-diabetic (p=0.001); 21% (95% 10-34%) vs. 7% (95% CI 4-11%) in patients with albumin 64 or >3.5 g/dl (p<0.001) and 16% (95% CI 8-28%) vs. 7% (95% CI 5-11%) in patients with a GRS score > or 640.6 (p=0.01), respectively. Main tumor features did not significantly differ according to the 4 SNPs genotypes. By combining independent risk factors for HCC, 4-year cumulative incidence resulted 20% (95% CI 12-28%) vs. 5% (95% CI 3-7%) in patients with or without two different risk factors, respectively (p<0.0001). HCC developed in 28/57 (49%) patients with a previous HCC history, corresponding to a 4-year cumulative HCC recurrence of 49% (95% CI 27-63%). At multivariate analysis, only diabetes (HR 2.77, 95% CI 1.15-6.67; p=0.02) was independently associated with recurrent HCC, while GRS score was not significant. Indeed, 4-year cumulative incidence of HCC resulted 88% (95% CI 64-100%) vs. 40% (95% CI 25-55%) in diabetic vs. non-diabetic patients, respectively (p=0.002). Conclusions: In a large, single-center cohort of consecutive HCV patients with cirrhosis who received DAA treatment, a genetic risk score was independently associated with de novo HCC, together with clinical predictors (male sex, diabetes, albumin values). Combination of clinical and genetic predictors could allow a better HCC risk stratification in HCV cirrhotic patients after viral cure, in order to develop personalized HCC surveillance programs

High Susceptibility Of Activated Lymphocytes To Oxidative Stress-induced Cell Death.

The present study provides evidence that activated spleen lymphocytes from Walker 256 tumor bearing rats are more susceptible than controls to tert-butyl hydroperoxide (t-BOOH)-induced necrotic cell death in vitro. The iron chelator and antioxidant deferoxamine, the intracellular Ca2+ chelator BAPTA, the L-type Ca2+ channel antagonist nifedipine or the mitochondrial permeability transition inhibitor cyclosporin A, but not the calcineurin inhibitor FK-506, render control and activated lymphocytes equally resistant to the toxic effects of t-BOOH. Incubation of activated lymphocytes in the presence of t-BOOH resulted in a cyclosporin A-sensitive decrease in mitochondrial membrane potential. These results indicate that the higher cytosolic Ca2+ level in activated lymphocytes increases their susceptibility to oxidative stress-induced cell death in a mechanism involving the participation of mitochondrial permeability transition.80137-4

Ester content of blueberry fruit can be ruled by tailored controlled atmosphere storage management

This study examines the effects of controlled atmosphere (CA) storage with high CO2 concentration (16 KPa) on the volatile organic compound (VOC) profile of blueberries (Vaccinium spp.), considering their genetic variability. The research focuses on the denovo production of esters and their association with fermentation related VOCs, employing complementary analytical techniques for comprehensive VOC profiling: direct injection mass spectrometry using Proton Transfer Reaction - Time of Flight - Mass Spectrometry (PTR-ToF-MS) and gas chromatography utilizing Solid-phase microextraction coupled to gas chromatography-mass spectrometry (SPME/GC-MS). In the first experiment, PTR-ToF-MS and SPME/GC-MS were applied to analyze the volatilome of seven blueberry cultivars under regular (RA) and controlled (CA) atmosphere storage conditions for 42 days. In the second experiment, 39 cultivars were tested to evaluate genetic variability in response to CA storage using PTR-ToF-MS. The third experiment focused on the effect of different oxygen concentrations during storage (1, 7, and 12 kPa O2), studying four cultivars using PTR-ToF-MS. Results of the three experiments revealed high variability among Vaccinium genotypes for all quality traits, which was amplified during storage, particularly under modified atmosphere conditions. CA storage generally enhanced the positive effects of cold storage by reducing texture decay and water loss and improving VOC profiles. Several ester compounds were synthesized de novo under low oxygen conditions, possibly as a response to hypoxic stress. The study concludes that CA storage offers potential to enhance postharvest fruit quality beyond shelf-life extension. The increase in fruity ester compounds during storage may improve blueberries' organoleptic properties. However, the variability in responses among cultivars needs tailored storage protocols. This research provides valuable insights for market segmentation and breeding programs aimed at enhancing blueberry quality and storability, while also validating PTR-ToF-MS as a rapid phenotyping tool for blueberry assessmen

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes

Diel surface temperature range scales with lake size

Ecological and biogeochemical processes in lakes are strongly dependent upon water temperature. Long-term surface warming of many lakes is unequivocal, but little is known about the comparative magnitude of temperature variation at diel timescales, due to a lack of appropriately resolved data. Here we quantify the pattern and magnitude of diel temperature variability of surface waters using high-frequency data from 100 lakes. We show that the near-surface diel temperature range can be substantial in summer relative to long-term change and, for lakes smaller than 3 km2, increases sharply and predictably with decreasing lake area. Most small lakes included in this study experience average summer diel ranges in their near-surface temperatures of between 4 and 7°C. Large diel temperature fluctuations in the majority of lakes undoubtedly influence their structure, function and role in biogeochemical cycles, but the full implications remain largely unexplored

The relationship between liver histology and thyroid function tests in patients with nonalcoholic fatty liver disease (NAFLD)

Background Data on the role of hypothyroidism in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) and liver fibrosis are conflicting, although selective Thyroid Hormone Receptor (THR)-β agonists have been identified as potential therapy in patients with non-alcoholic steatohepatitis (NASH). Therefore, we investigated the association between hypothyroidism and NAFLD histological features potentially associated with progressive liver disease. Methods Between 2014 and 2016, consecutive patients with histologically proven NAFLD and frozen serum available for thyroid function tests assessment were included. NAFLD was staged according to the NAFLD Activity Score (NAS), and fibrosis according to Kleiner. NASH was defined as NAS 4, significant fibrosis as F2-F4 and significant steatosis as S2-S3. Thyroid function tests (TFT; TSH, FT3, FT4, rT3), TPO-Ab and Tg-Ab were also assessed. Results Fifty-two patients were analyzed: Median age 54 years, 58% females, LSM 7.8 kPa, 27% diabetics, 14% hypothyroid. At histology, NASH was present in 21 (40%), F2-F4 in 28 (54%) and S2-S3 in 30 (58%) patients. Rates of hypothyroidism were similar independently of the presence of NASH (p = 0.11), significant fibrosis (p = 0.21) or steatosis (p = 0.75). However, hypothyroid patients displayed a higher NAS (p = 0.02) and NASH (p = 0.06) prevalence. At multivariate analysis, TFT were not independently associated with histology. Conclusion Hypothyroidism was highly prevalent in NAFLD patients, and was associated with increased NAFLD activity, but not with fibrosis and steatosis severity. Thus, thyroid dysfunction might play a direct and/or indirect in the pathogenesis of NAFLD and NASH

Challenges in treating patients with inflammatory bowel disease and concurrent viral hepatitis infection

Introduction: Inflammatory bowel diseases (IBD) require long-term administration of immunomodulatory treatments to maintain disease remission. Due to the high worldwide prevalence of hepatitis B (HBV) or C (HCV) virus infections, presence of concurrent hepatitis can be a relevant clinical issue to manage when treating IBD. Areas covered: The paper summarizes epidemiological data about IBD and HBV/HCV infection and reviews current knowledge about the natural history of HBV and HCV in the IBD setting, concentrating on risk of hepatitis reactivation during immunosuppressive treatment. Most updated recommendations for management of HBV and HCV infections in IBD patients are discussed. Expert commentary: The development of new drugs for IBD with different molecular targets and the availability of potent and efficacious antiviral drugs for HBV and HCV will simplify management of hepatitis infection in IBD patients in the near future

Limited utility of ITPA deficiency to predict early anemia in HCV patients with advanced fibrosis receiving telaprevir

Background: Severe anemia is a common side effect of Pegylated Interferon + Ribavirin (PR) and Telaprevir (TVR) in hepatitis C virus (HCV) genotype 1 patients with advanced fibrosis or cirrhosis (F3-F4). Inosine triphosphatase (ITPA) genetic variants are associated with RBV- induced anemia and dose reduction. Aim: To test the association of ITPA polymorphisms rs1127354 and rs7270101 with hemoglobin (Hb) decline, need for RBV dose reduction (RBV DR), erythropoietin (EPO) support and blood transfusions during the first 12 weeks of TVR triple therapy. Materials and Methods: 69 consecutive HCV-1 patients (mean age 57 years) with F3-F4 who received PR and TVR were genotyped for ITPA polymorphisms rs1127354 and rs7270101. Estimated ITPA deficiency was graded on severity (0-3, no deficiency/mild/moderate/severe). Results: ITPA deficiency was absent in 48 patients (70%), mild in 12 (17%) and moderate in 9 patients (13%). Mean week 4 Hb decline was higher in non ITPA deficient patients (3,85 g/dL) than in mildly or moderately ITPA deficient patients (3,07 g/dL and 1,67 g/dL, p<0.0001). Grade 3-4 anemia developed in 81% non ITPA deficient patients versus 67% mild deficient and 55% moderate deficient patients (p = ns). Grade of ITPA deficiency was not associated with RbvDR (no deficiency: 60%, mild: 58%, moderate: 67%; p = ns), EPO use (no deficiency: 65%, mild: 58%, moderate:56%; p = ns) or need for blood transfusion (no deficiency: 27%, mild: 17%, moderate: 33%; p = ns). Conclusions: In patients with F3-F4 chronic hepatitis C receiving TVR based therapy, ITPA genotype does not impact on the management of early anemia. \ua9 2014 Aghemo et al