Summary
Circulating microRNAs (miRNA) have been intensely investigated as biomarkers in disease and therapy. Several studies have identified miR‐122 as an important regulator of HCV replication. The ...effect of new therapies that directly target the HCV replication life cycle on circulating microRNA levels has not been elucidated. We performed expression profiling of circulating miRNA in serum in subjects treated with HCV direct‐acting antiviral agents (DAAs). Serum miRNA levels were evaluated from two studies in HCV GT1‐infected treatment‐naïve subjects and prior nonresponders to pegylated interferon (pegIFN) and ribavirin (RBV) who received paritaprevir/ritonavir + dasabuvir + RBV for 12 weeks, and in treatment‐naïve genotype (GT)1‐3‐infected subjects who received paritaprevir/ritonavir + ombitasvir ± RBV for 12 weeks. Over 100 different miRNA species were detected in serum. Of these, levels of miR‐122 showed the most consistent change in response to treatment across all HCV genotypes. In all subjects, miR‐122 showed an average four‐fold reduction between baseline and week 2, and remained below baseline through post‐treatment week 12 in subjects who achieved sustained virological response. In contrast, in subjects who did not achieve SVR, miR‐122 levels began to return to baseline levels after the second week of treatment. The change in miR‐122 levels was similar across genotypes, and was comparable with or without RBV. This is the first report comparing expression levels of circulating miRNA in HCV GT1‐3 subjects treated with IFN‐free combinations of DAAs. The results suggest that serum levels of miR‐122 are reduced following treatment in subjects who achieve SVR, and correlate with HCV RNA levels across genotypes.
Summary
High rates of sustained virologic response at post‐treatment week 12 (SVR12) were achieved in six phase 3 trials of ombitasvir (OBV, an NS5A inhibitor), paritaprevir (an NS3/4A protease ...inhibitor) co‐dosed with ritonavir (PTV/r) + dasabuvir (DSV, an NS5B RNA polymerase inhibitor) (ie, 3D regimen) with or without ribavirin (RBV) in adults with chronic genotype (GT) 1 hepatitis C virus (HCV) infection. We assessed whether time to first HCV RNA value below the lower limit of quantification in patients with and without cirrhosis was associated with achievement of SVR12. Data were analysed from GT1‐infected patients enrolled in six phase 3 studies of 3D ± RBV. Patients who experienced non‐virologic failure were excluded from analysis. HCV RNA was determined using the Roche COBAS TaqMan RT‐PCR assay (lower limit of quantification, LLOQ =25 IU/mL). SVR12 was analysed by week of first HCV RNA suppression, defined as HCV RNA <LLOQ. The analysis included a total of 2027 patients. Cumulative proportions of subjects with initial HCV RNA suppression <LLOQ at weeks 1, 2, 4 and 6 were 31%, 81%, 99% and 100%, respectively. SVR12 was achieved by 98%, 97%, 98% and 92% of patients with initial suppression at Weeks 1, 2, 4 and 6, respectively (P=.42, trend test). Across six phase 3 trials of 3D ± RBV, most patients achieved viral suppression by week 2. Time to viral suppression was not associated with subsequent achievement of SVR12, suggesting that on‐treatment virologic monitoring may not be necessary with this regimen.
Genetic variants of inosine triphosphatase (ITPA) that confer reduced ITPase activity are associated with protection against ribavirin(RBV)-induced hemolytic anemia in peginterferon(IFN)/RBV-based ...treatment of hepatitis C virus (HCV). Patients with reduced ITPase activity showed improved treatment efficacy when treated with IFN/RBV. In addition, a genetic polymorphism near the IL28B gene is associated with an improved response to IFN/RBV treatment. RBV has been an important component of IFN-containing regimens, and is currently recommended in combination with several IFN-free regimens for treatment of harder to cure HCV infections.
To evaluate whether genetic variations that reduce ITPase activity impact RBV-induced anemia in IFN-free/RBV regimens.
In this study, genetic analyses were conducted in the PEARL-IV trial to investigate the effect of activity-reducing ITPA variants as well as IL28B polymorphism on anemia, platelet (PLT) counts, and virologic response in HCV genotype1a-infected patients treated with the direct-acting antiviral (DAA) regimen of ombitasvir/paritaprevir/ritonavir and dasabuvir±RBV.
Reduction in ITPase activity and homozygosity for the IL28Brs12979860 CC genotype protected against RBV-induced anemia. In patients receiving RBV, reduced ITPase activity was associated with reduced plasma RBV concentration and higher PLT counts. ITPase activity had no impact on response to DAA treatment, viral kinetics, or baseline IP-10 levels.
Our study demonstrates that genetics of ITPA and IL28B may help identify patients protected from RBV-induced anemia when treated with IFN-free regimens. Our work demonstrates for the first time that IL28B genetics may also have an impact on RBV-induced anemia. This may be of particular significance in patients with difficult-to-cure HCV infections, such as patients with decompensated cirrhosis where RBV-containing regimens likely will continue to be recommended.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Summary
High rates of sustained virologic response at post‐treatment week 12 (
SVR
12) were achieved in six phase 3 trials of ombitasvir (
OBV
, an
NS
5A inhibitor), paritaprevir (an
NS
3/4A protease ...inhibitor) co‐dosed with ritonavir (
PTV
/r) + dasabuvir (
DSV
, an
NS
5B
RNA
polymerase inhibitor) (ie, 3D regimen) with or without ribavirin (
RBV
) in adults with chronic genotype (
GT
) 1 hepatitis C virus (
HCV
) infection. We assessed whether time to first
HCV RNA
value below the lower limit of quantification in patients with and without cirrhosis was associated with achievement of
SVR
12. Data were analysed from
GT
1‐infected patients enrolled in six phase 3 studies of 3D ±
RBV
. Patients who experienced non‐virologic failure were excluded from analysis.
HCV RNA
was determined using the Roche
COBAS
TaqMan
RT
‐
PCR
assay (lower limit of quantification,
LLOQ
=25
IU
/
mL
).
SVR
12 was analysed by week of first
HCV RNA
suppression, defined as
HCV RNA
<
LLOQ
. The analysis included a total of 2027 patients. Cumulative proportions of subjects with initial
HCV RNA
suppression <
LLOQ
at weeks 1, 2, 4 and 6 were 31%, 81%, 99% and 100%, respectively.
SVR
12 was achieved by 98%, 97%, 98% and 92% of patients with initial suppression at Weeks 1, 2, 4 and 6, respectively (
P
=.42, trend test). Across six phase 3 trials of 3D ±
RBV
, most patients achieved viral suppression by week 2. Time to viral suppression was not associated with subsequent achievement of
SVR
12, suggesting that on‐treatment virologic monitoring may not be necessary with this regimen.
The Thermodynamics of Advanced Fuels – International Database (TAF-ID) was developed using the Calphad method to provide a computational tool to perform thermodynamic calculations on nuclear fuel ...materials under normal and off-normal conditions. Different kinds of fuels are considered: oxide, metallic, carbide and nitride fuels. Many fission products are introduced as well as structural materials (e.g., zirconium, steel, concrete, SiC) and absorbers (e.g., B4C), in order to investigate the thermochemistry of irradiated fuels and to predict their chemical interaction with the surrounding materials. The approach to develop the database and the models implemented in the database are described. Examples of models for key chemical systems are presented. Finally, a few examples of application calculations on severe accidents with UO2 fuels, irradiated fuel chemistry of MOX and metallic fuels and metallic fuel/cladding interaction show how this tool can be used. To validate the database, the calculations are compared to the available experimental data. A good agreement is obtained which gives confidence in the maturity degree and quality of the TAF-ID database. The working version is only accessible to the participants of the TAF-ID project (Canada, France, Japan, the Netherlands, Republic of Korea, United Kingdom, USA). A public version is accessible by all the NEA countries. The current version contains models on the Am–Fe, Am–Np, Am-O-Pu, Am–U, Am–Zr, C–O–U-Pu, Cr–U, Np–U, Np–Zr, O–U–Zr, Re–U, Ru–U, Si–U, Ti–U, U-Pu-Zr, U–W systems. It is progressively extended with our published assessments. Information on how to join the project is available on the website: https://www.oecd-nea.org/science/taf-id/.
•The TAF-ID international thermodynamic database is a computational tool for nuclear fuel applications.•Key systems for nuclear fuels are modelled using the Calphad method.•Fission product chemistry of irradiated fuels is predicted.•Chemical interaction with structural materials can be predicted under normal and severe accident conditions.•Coupling with kinetics, phase-field, Fuel Performance Code is being performed.
Background
Sparse data are available on the relationship between prenatal exposures and asthma during later childhood. In a longitudinal study of adolescents and their mothers, we examined the ...association of (i) maternal prepregnancy body mass index (BMI) and (ii) gestational weight gain (GWG), with incidence of allergic and nonallergic asthma in offspring.
Methods
Analyses were conducted using data from 12 963 children aged 9–14 years at enrolment in the Growing Up Today Study, and their mothers, who are participants in the Nurses’ Health Study II. Physician‐diagnosed asthma and allergies were assessed by questionnaires sent regularly to participants and their mothers. Logistic regression was used to evaluate associations of maternal BMI and GWG with offspring asthma, overall and by subtype.
Results
Physician‐diagnosed asthma during childhood or adolescence was reported by 2694 children (21%). Maternal prepregnancy overweight (OR: 1.19, 95% CI: 1.03–1.38) and obesity (1.34, 1.08–1.68) were associated with offspring asthma. In asthma subtype analyses, the association was seen only for asthma onset before age 12 years. Moreover, the association of maternal obesity with nonallergic asthma was observed in boys (2.39, 1.40–4.09) and not in girls (0.96, 0.50–1.85; Pinteraction = 0.03); the opposite pattern was suggested for allergic asthma. With regard to GWG, an association was suggested between gains of <15 lb and higher risk of offspring asthma (1.28, 0.98–1.66), without clear allergy‐ or sex‐related patterns.
Conclusion
The relation of several prenatal factors to risk of childhood asthma supports the early origins hypothesis for asthma. The observed allergy‐ and sex‐specific patterns suggest multiple etiologic pathways.
Previous microbiome and metabolome analyses exploring non-communicable diseases have paid scant attention to major confounders of study outcomes, such as common, pre-morbid and co-morbid conditions, ...or polypharmacy. Here, in the context of ischemic heart disease (IHD), we used a study design that recapitulates disease initiation, escalation and response to treatment over time, mirroring a longitudinal study that would otherwise be difficult to perform given the protracted nature of IHD pathogenesis. We recruited 1,241 middle-aged Europeans, including healthy individuals, individuals with dysmetabolic morbidities (obesity and type 2 diabetes) but lacking overt IHD diagnosis and individuals with IHD at three distinct clinical stages-acute coronary syndrome, chronic IHD and IHD with heart failure-and characterized their phenome, gut metagenome and serum and urine metabolome. We found that about 75% of microbiome and metabolome features that distinguish individuals with IHD from healthy individuals after adjustment for effects of medication and lifestyle are present in individuals exhibiting dysmetabolism, suggesting that major alterations of the gut microbiome and metabolome might begin long before clinical onset of IHD. We further categorized microbiome and metabolome signatures related to prodromal dysmetabolism, specific to IHD in general or to each of its three subtypes or related to escalation or de-escalation of IHD. Discriminant analysis based on specific IHD microbiome and metabolome features could better differentiate individuals with IHD from healthy individuals or metabolically matched individuals as compared to the conventional risk markers, pointing to a pathophysiological relevance of these features.
Abstract Bone defects, such as compressive fractures in the vertebral bodies, are frequently treated with acrylic bone cements (e.g., PMMA). Although these biomaterials have sufficient mechanical ...properties for fixing the fracture, they are non-degradable and do not remodel or integrate with host tissue. In an alternative approach, biodegradable polyurethane (PUR) networks have been synthesized that are designed to integrate with host tissue and degrade to non-cytotoxic decomposition products. PUR networks have been prepared by two-component reactive liquid molding of low-viscosity quasi-prepolymers derived from lysine polyisocyanates and poly(ε-caprolactone- co - dl -lactide- co -glycolide) triols. The composition, thermal transitions, and mechanical properties of the biomaterials were measured. The values of Young's modulus ranged from 1.20–1.43 GPa, and the compressive yield strength varied from 82 to 111 MPa, which is comparable to the strength of PMMA bone cements. In vitro , the materials underwent controlled biodegradation to non-cytotoxic decomposition products, and supported the attachment and proliferation of MC3T3 cells. When cultured in osteogenic medium on the PUR networks, MC3T3 cells deposited mineralized extracellular matrix, as evidenced by von Kossa staining and tetracycline labeling. Considering the favorable mechanical and biological properties, as well as the low-viscosity of the reactive intermediates used to prepare the PUR networks, these biomaterials are potentially useful as injectable, biodegradable bone cements for fracture healing.
EBV viremia and post-transplantation lymphoproliferative disorders (PTLDs) have been associated with high mortality rates after allogeneic hematopoietic SCT (allo-HSCT). Few retrospective studies, ...without EBV load monitoring postulated that umbilical cord blood transplantation (UCBT) might be associated with high incidence of EBV events. We retrospectively studied 175 UCBT recipients for whom RQ-PCR was used to monitor EBV blood load at least once a week during the first 3 months after UCBT. Median age was 23 years, 74% had leukemia. Conditioning was myeloablative in 54% and reduced intensity conditioning (RIC) was used in 46%. A total of 24 patients presented an EBV reactivation. For 15 patients, the reactivation occurred during the first 100 days (cumulative incidence: 8%) and included 4 EBV-PTLD. Rituximab as preemptive treatment was used in 12 of these 15 patients. In univariate analysis, the increased risk of early EBV reactivation was associated with RIC in combination with antithymocyte globulin (P=0.03) and previous history of auto-HSCT (P=0.01). Multivariate analysis did not find any independent risk factor. EBV reactivation as time-dependent covariate was not statistically associated with survival. Therefore, EBV events were not major complications after UCBT when EBV load is weekly monitored and preemptive treatment started.
PDF
