In a 13-week, randomized trial involving persons 6 to 79 years of age with type 1 diabetes, use of a bionic pancreas was associated with a greater reduction in the glycated hemoglobin level than ...standard care.
In this study we examined ecosystem respiration (RECO) data from 104 sites belonging to FLUXNET, the global network of eddy covariance flux measurements. The goal was to identify the main factors ...involved in the variability of RECO: temporally and between sites as affected by climate, vegetation structure and plant functional type (PFT) (evergreen needleleaf, grasslands, etc.). We demonstrated that a model using only climate drivers as predictors of RECO failed to describe part of the temporal variability in the data and that the dependency on gross primary production (GPP) needed to be included as an additional driver of RECO. The maximum seasonal leaf area index (LAIMAX) had an additional effect that explained the spatial variability of reference respiration (the respiration at reference temperature Tref=15 °C, without stimulation introduced by photosynthetic activity and without water limitations), with a statistically significant linear relationship (r²=0.52, P<0.001, n=104) even within each PFT. Besides LAIMAX, we found that reference respiration may be explained partially by total soil carbon content (SoilC). For undisturbed temperate and boreal forests a negative control of total nitrogen deposition (Ndepo) on reference respiration was also identified. We developed a new semiempirical model incorporating abiotic factors (climate), recent productivity (daily GPP), general site productivity and canopy structure (LAIMAX) which performed well in predicting the spatio-temporal variability of RECO, explaining >70% of the variance for most vegetation types. Exceptions include tropical and Mediterranean broadleaf forests and deciduous broadleaf forests. Part of the variability in respiration that could not be described by our model may be attributed to a series of factors, including phenology in deciduous broadleaf forests and management practices in grasslands and croplands.
The complexity of the mechanical behavior of filled elastomers can be partly attributed to the fact that the duration of an applied strain plays a crucial role. In order to bring new insights into ...this still incompletely solved problem, we look for relationships between the macroscopic mechanical relaxation and the relaxation of the filler particles at the nano- to mesoscale. To this end, X-ray photon correlation spectroscopy (XPCS) in homodyne and heterodyne configurations combined with tensile stress relaxation is employed. The paper is devoted to the study of the role of the filler–filler and the filler–matrix interactions in a cross-linked elastomer on the aging mechanisms under strain. The fillers investigated are carbon black, as an example of strong filler–matrix interactions, and hydroxylated silica for which the filler–filler interaction is strong (H-bonds). Homodyne XPCS correlation reveals features of jammed systems (compressed exponential and ballistic motion) for both systems. The exponents characterizing the aging of the homodyne relaxation times are not the same in the carbon black and in the silica filled samples. For both systems, the decrease of the particle velocity determined by heterodyne detection with aging time follows a power law. The silica sample is characterized by a slow decrease of the velocity during aging. For the carbon black sample, the velocity remains small and decreases faster than for the silica sample. The reverse is observed for the behavior of the tensile force.
We use X-ray photon correlation spectroscopy (XPCS) to investigate the dynamics of a stretched elastomer by means of probe particles. The particles dispersed in the elastomer were carbon black or ...silica aggregates classically used for elastomer reinforcement but their volume fraction is very low (
< 10
−2
). We show that their dynamics is slower in the direction of the tensile strain than in the perpendicular one. For hydroxylated silica which is poorly wetted by the elastomer, there is no anisotropy. Two-time correlation functions confirm anisotropic dynamics and suggest dynamical heterogeneity already expected from the
q
−1
behavior of the relaxation times. The height
χ
* of the peak of the dynamical susceptibility, determined by the normalized variance of the instantaneous correlation function, is larger in the direction parallel to the strain than in the perpendicular one. It also appears that its
q
dependence changes with the morphology of the probe particle. Therefore, the heterogeneous dynamic probed by the particles is not related only to that of the strained elastomer matrix. In fact, it results from modification of the dynamics of the polymer chains near the surface of the particles and within the aggregate porosity (bound polymer). It is concluded that XPCS is a powerful method for investigating the dynamics, at a given strain, of the bound polymer-particle units which are responsible, at large volume fractions, for the reinforcement.
Two-time correlations determined by XPCS display anisotropic and heterogeneous dynamics in a stretched silanized silica-elastomer nanocomposite (time scale 70 minutes).
Background & Aims We performed a prospective study to investigate the effects of a sustained viral response (SVR) on outcomes of patients with hepatitis C virus (HCV) infection and compensated ...cirrhosis. Methods We collected data from 1323 patients included in the prospective Agence Nationale pour la Recherche sur le SIDA et les hépatites virales (ANRS) viral cirrhosis (CirVir) cohort, recruited from 35 clinical centers in France from 2006 through 2012. All patients had HCV infection and biopsy-proven cirrhosis, were Child–Pugh class A, and had no prior liver complications. All patients received anti-HCV treatment before or after inclusion (with interferon then with direct antiviral agents) and underwent an ultrasound examination every 6 months, as well as endoscopic evaluations. SVR was considered as a time-dependent covariate; its effect on outcome was assessed by the Cox proportional hazard regression method. We used a propensity score to minimize confounding by indication of treatment and capacity to achieve SVR. Results After a median follow-up period of 58.2 months, 668 patients (50.5%) achieved SVR. SVR was associated with a decreased incidence of hepatocellular carcinoma (hazard ratio HR compared with patients without an SVR, 0.29; 95% confidence interval CI, 0.19–0.43; P < .001) and hepatic decompensation (HR, 0.26; 95% CI, 0.17–0.39; P < .001). Patients with SVRs also had a lower risk of cardiovascular events (HR, 0.42; 95% CI, 0.25–0.69; P = .001) and bacterial infections (HR, 0.44; 95% CI, 0.29–0.68; P < .001). Metabolic features were associated with a higher risk of hepatocellular carcinoma in patients with SVRs, but not in patients with viremia. SVR affected overall mortality (HR, 0.27 compared with patients without SVR; 95% CI, 0.18–0.42; P < .001) and death from liver-related and non–liver-related causes. Similar results were obtained in a propensity score-matched population. Conclusions We confirmed a reduction in critical events, liver-related or not, in a prospective study of patients with HCV infection and compensated cirrhosis included in the CirVir cohort who achieved an SVR. We found an SVR to reduce overall mortality and risk of death from liver-related and non–liver-related causes. A longer follow-up evaluation is required to accurately describe and assess specific risk factors for complications in this population.
Retrospective studies have found an unexpectedly high incidence of hepatocellular carcinoma (HCC) among patients with hepatitis C virus (HCV)-associated cirrhosis who received direct-acting antiviral ...(DAA) agents. We analyzed data from the ANRS CO12 CirVir cohort to compare the incidence of HCC in patients with cirrhosis who received DAA therapy vs patients treated with interferon (IFN).
Data were collected from 1270 patients with compensated biopsy-proven HCV-associated cirrhosis recruited from 2006 through 2012 at 35 centers in France. For descriptive purpose, patients were classified as follows: patients who received DAA treatment (DAA group, n = 336), patients who achieved a sustained virologic response (SVR) following an IFN-based regimen (SVR-IFN group, n = 495), or patients who never received DAA treatment and never had an SVR following IFN therapy (non-SVR group, n = 439). The patients were included in HCC surveillance programs based on ultrasound examination every 6 months, and clinical and biological data were recorded. To account for confounding by indication due to differences in patient characteristics at treatment initiation, we constructed a time-dependent Cox regression model weighted by the inverse probability of treatment and censoring (IPTCW) to assess the treatment effects of DAA on time until HCC.
Compared with patients in the SVR-IFN group, patients in the DAA group were older, higher proportions had diabetes or portal hypertension, and liver function was more severely impaired. The crude 3-year cumulative incidences of HCC were 5.9% in the DAA group, 3.1% in the SVR-IFN group, and 12.7% in the non-SVR group (overall P < .001; unadjusted hazard ratio HR for HCC 2.03; 95% confidence interval CI 1.07–3.84; P = .030 for the DAA group vs the SVR-IFN group). HCC characteristics were similar among groups. Among patients with HCC, the DAA group received less-frequent HCC screening than the other 2 groups (P = .002). After Cox analyses weighted by the IPTCW, we found no statistically significant increase in risk of HCC associated with DAA use (HR 0.89; 95% CI 0.46–1.73; P = .73).
Analysis of data from the ANRS CO12 CirVir cohort reveals that the apparent increase in HCC incidence observed in patients with cirrhosis treated with DAAs compared with patients who achieved SVR following an IFN therapy can be explained by patient characteristics (age, diabetes, reduced liver function) and lower screening intensity.
Prognosis of Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL) in the elderly has improved during the imatinib era. We investigated dasatinib, another potent tyrosine kinase inhibitor, ...in combination with low-intensity chemotherapy. Patients older than age 55 years were included in the European Working Group on Adult ALL (EWALL) study number 01 for Ph+ ALL (EWALL-PH-01 international study) and were treated with dasatinib 140 mg/day (100 mg/day over 70 years) with intrathecal chemotherapy, vincristine, and dexamethasone during induction. Patients in complete remission continued consolidation with dasatinib, sequentially with cytarabine, asparaginase, and methotrexate for 6 months. Maintenance therapy was dasatinib and vincristine/dexamethasone reinductions for 18 months followed by dasatinib until relapse or death. Seventy-one patients with a median age of 69 years were enrolled; 77% had a high comorbidity score. Complete remission rate was 96% and 65% of patients achieved a 3-log reduction in BCR-ABL1 transcript levels during consolidation. Only 7 patients underwent allogeneic hematopoietic stem cell transplantation. At 5 years, overall survival was 36% and up to 45% taking into account deaths unrelated to disease or treatment as competitors. Thirty-six patients relapsed, 24 were tested for mutation by Sanger sequencing, and 75% were T315I-positive. BCR-ABL1T315I was tested by allele-specific oligonucleotide reverse transcription–quantitative polymerase chain reaction in 43 patients and detection was associated with short-term relapses. Ten patients (23%) were positive before any therapy and 8 relapsed, all with this mutation. In conclusion, dasatinib combined with low-intensity chemotherapy was well-tolerated and gave long-term survival in 36% of elderly patients with Ph+ ALL. Monitoring of BCR-ABL1T315I from diagnosis identified patients with at high risk of early relapse and may help to personalize therapy.
•Dasatinib, combined with low-intensity chemotherapy, gave 36% 5-year overall survival in Ph+ ALL patients older than age 55 years.•Prospective monitoring of mutations may be useful to personalize therapy in Ph+ ALL patients not eligible for intensive therapies.
Disruptions of the melanocortin signaling system have been linked to obesity. We investigated a possible role of the central nervous melanocortin system (CNS-Mcr) in the control of adiposity through ...effects on nutrient partitioning and cellular lipid metabolism independent of nutrient intake. We report that pharmacological inhibition of melanocortin receptors (Mcr) in rats and genetic disruption of Mc4r in mice directly and potently promoted lipid uptake, triglyceride synthesis, and fat accumulation in white adipose tissue (WAT), while increased CNS-Mcr signaling triggered lipid mobilization. These effects were independent of food intake and preceded changes in adiposity. In addition, decreased CNS-Mcr signaling promoted increased insulin sensitivity and glucose uptake in WAT while decreasing glucose utilization in muscle and brown adipose tissue. Such CNS control of peripheral nutrient partitioning depended on sympathetic nervous system function and was enhanced by synergistic effects on liver triglyceride synthesis. Our findings offer an explanation for enhanced adiposity resulting from decreased melanocortin signaling, even in the absence of hyperphagia, and are consistent with feeding-independent changes in substrate utilization as reflected by respiratory quotient, which is increased with chronic Mcr blockade in rodents and in humans with loss-of-function mutations in MC4R. We also reveal molecular underpinnings for direct control of the CNS-Mcr over lipid metabolism. These results suggest ways to design more efficient pharmacological methods for controlling adiposity.
Management of patients with cirrhosis includes endoscopic screening and surveillance to detect esophageal varices (EV) and prevent bleeding. However, the Baveno VI guidelines recommend avoiding ...endoscopies for patients with liver stiffness measurements below 20 kPa and platelet counts above 150,000 (favorable Baveno VI status) and endoscopic assessment of patients with higher levels of liver stiffness and platelet counts (unfavorable Baveno VI status). We aimed to validate the Baveno VI guidelines, evaluating outcomes of patients in the ANRS-CO12 CirVir cohort with compensated cirrhosis associated with hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, with or without a sustained response to antiviral therapy.
We performed an ancillary study using data from 891 patients in the ANRS CO12 CirVir cohort, treated at 35 centers in France, with HCV or HBV infection and biopsy-proven cirrhosis, Child-Pugh A scores, no previous complications, and no hepatocellular carcinoma who underwent an endoscopic procedure and had interpretable liver stiffness measurements and platelet counts. Progression of portal hypertension (PHT) was defined as the onset of varices needing treatment (VNT) or PHT-related bleeding. An sustained response to antiviral therapy was defined as undetectable level of HCV RNA by polymerase chain reaction assay (<50 IU/mL) 12 weeks after the end of treatment (SVR) or an undetectable level of HBV DNA. The primary aims were to validate the Baveno VI guidelines for screening and surveillance of EV in patients with compensated cirrhosis and to study the effects of an SVR on the progression of PHT.
A total of 200 patients achieved an SVR (22.4%) (94 patients with HCV infection, 98 patients with HBV infection, and 8 patients with both); 80 of these patients had favorable Baveno VI status and none had VNT. Progression of PHT was studied in 548 patients; during a follow-up period of 61.2 months (interquartile range, 39.5–80.6 months), 105 of these patients (19.1%) had progression of PHT. Lack of an SVR and grade 1 EV were independently associated with progression of PHT. At the time of PHT progression, all patients had unfavorable Baveno VI status. Achieving favorable Baveno VI status after an SVR was associated with the absence of PHT progression. Favorable Baveno VI status and SVR were independently associated with survival.
In an analysis of data from a large cohort of patients with HBV- or HCV-associated cirrhosis in France, we validated the Baveno VI guidelines on screening and surveillance of PHT, even for patients who achieved a sustained response to antiviral therapy.
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Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy, and implementation of risk-adapted therapy has been instrumental in the dramatic improvements in clinical outcomes. A key ...to risk-adapted therapies includes the identification of genomic features of individual tumors, including chromosome number (for hyper- and hypodiploidy) and gene fusions, notably ETV6-RUNX1, TCF3-PBX1, and BCR-ABL1 in B-cell ALL (B-ALL). RNA-sequencing (RNA-seq) of large ALL cohorts has expanded the number of recurrent gene fusions recognized as drivers in ALL, and identification of these new entities will contribute to refining ALL risk stratification. We used RNA-seq on 126 ALL patients from our clinical service to test the utility of including RNA-seq in standard-of-care diagnostic pipelines to detect gene rearrangements and IKZF1 deletions. RNA-seq identified 86% of rearrangements detected by standard-of-care diagnostics. KMT2A (MLL) rearrangements, although usually identified, were the most commonly missed by RNA-seq as a result of low expression. RNA-seq identified rearrangements that were not detected by standard-of-care testing in 9 patients. These were found in patients who were not classifiable using standard molecular assessment. We developed an approach to detect the most common IKZF1 deletion from RNA-seq data and validated this using an RQ-PCR assay. We applied an expression classifier to identify Philadelphia chromosome–like B-ALL patients. T-ALL proved a rich source of novel gene fusions, which have clinical implications or provide insights into disease biology. Our experience shows that RNA-seq can be implemented within an individual clinical service to enhance the current molecular diagnostic risk classification of ALL.
•RNA-seq can be implemented into a clinical service to inform risk stratification of patients with nonstandard molecular features.•RNA-seq data can be used to identify IKZF1 deletions.
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