Direct‐acting antivirals for HCV treatment in older patients: A systematic review and meta‐analysis

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Bubbles and outflows: the novel JWST/NIRSpec view of the z=1.59 obscured quasar XID2028

Quasar feedback in the form of powerful outflows is invoked as a key mechanism to quench star formation in galaxies, although direct observational evidence is still scarce and debated. Here we present Early Release Science JWST NIRSpec IFU observations of the z=1.59 prototypical obscured quasar XID2028: this target represents a unique test case to study QSO feedback at the peak epoch of AGN-galaxy co-evolution thanks to its existing extensive multi-wavelength coverage and massive and extended outflow detected both in the ionised and molecular components. With the unprecedented sensitivity and spatial resolution of JWST, the NIRSpec dataset reveals a wealth of structures in the ionised gas kinematics and morphology previously hidden in the seeing-limited ground-based data. In particular, we find evidence of interaction between the interstellar medium of the galaxy and the QSO-driven outflow and radio jet, which is producing an expanding bubble from which the fast and extended wind detected in previous observations is emerging. The new observations confirm the complex interplay between the AGN jet/wind and the ISM of the host galaxy, highlighting the role of low luminosity radio jets in AGN feedback, and showcase the new window opened by NIRSpec on the detailed study of feedback at high redshift.Comment: 12 pages, 11 figures, submitted to A&A. Comments welcom

GaAs epilayers grown on patterned (001) silicon substrates via suspended Ge layers

We demonstrate the growth of low density anti-phase boundaries, crack-free GaAs epilayers, by Molecular Beam Epitaxy on silicon (001) substrates. The method relies on the deposition of thick GaAs on a suspended Ge buffer realized on top of deeply patterned Si substrates by means of a three-temperature procedure for the growth. This approach allows to suppress, at the same time, both threading dislocations and thermal strain in the epilayer and to remove anti-phase boundaries even in absence of substrate tilt. Photoluminescence measurements show the good uniformity and the high optical quality of AlGaAs/GaAs quantum well structures realized on top of such GaAs layer

Bleeding symptoms in patients diagnosed as type 3 von Willebrand disease : Results from 3WINTERS-IPS, an international and collaborative cross-sectional study

Background Type 3 von Willebrand's disease (VWD) patients present markedly reduced levels of von Willebrand factor and factor VIII. Because of its rarity, the bleeding phenotype of type 3 VWD is poorly described, as compared to type 1 VWD. Aims To evaluate the frequency and the severity of bleeding symptoms across age and sex groups in type 3 patients and to compare these with those observed in type 1 VWD patients to investigate any possible clustering of bleeding symptoms within type 3 patients. Methods We compared the bleeding phenotype and computed the bleeding score (BS) using the MCMDM-1VWD bleeding questionnaire in patients enrolled in the 3WINTERS-IPS and MCMDM-1VWD studies. Results In 223 unrelated type 3 VWD patients, both the BS and the number of clinically relevant bleeding symptoms were increased in type 3 as compared to type 1 VWD patients (15 versus 6 and 5 versus 3). Intracranial bleeding, oral cavity, hemarthroses, and deep hematomas were at least five-fold over-represented in type 3 VWD. A more severe bleeding phenotype was evident in patients having von Willebrand factor antigen levels <20 IU/dL at diagnosis in the two merged cohorts. In type 3 patients, there was an apparent clustering of hemarthrosis with gastrointestinal bleeding and epistaxis, whereas bleeding after surgery or tooth extraction clusters with oral bleeding and menorrhagia. Conclusions In the largest cohort of type 3 VWD patients, we were able to describe a distinct clinical phenotype that is associated with the presence of a more severe hemostatic defect.Peer reviewe

Assessment of the olfactory function in Italian patients with type 3 von Willebrand disease caused by a homozygous 253 Kb deletion involving VWF and TMEM16B/ANO2.

Type 3 Von Willebrand disease is an autosomal recessive disease caused by the virtual absence of the von Willebrand factor (VWF). A rare 253 kb gene deletion on chromosome 12, identified only in Italian and German families, involves both the VWF gene and the N-terminus of the neighbouring TMEM16B/ANO2 gene, a member of the family named transmembrane 16 (TMEM16) or anoctamin (ANO). TMEM16B is a calcium-activated chloride channel expressed in the olfactory epithelium. As a patient homozygous for the 253 kb deletion has been reported to have an olfactory impairment possibly related to the partial deletion of TMEM16B, we assessed the olfactory function in other patients using the University of Pennsylvania Smell Identification Test (UPSIT). The average UPSIT score of 4 homozygous patients was significantly lower than that of 5 healthy subjects with similar sex, age and education. However, 4 other members of the same family, 3 heterozygous for the deletion and 1 wild type, had a slightly reduced olfactory function indicating that socio-cultural or other factors were likely to be responsible for the observed difference. These results show that the ability to identify odorants of the homozygous patients for the deletion was not significantly different from that of the other members of the family, showing that the 253 kb deletion does not affect the olfactory performance. As other genes may compensate for the lack of TMEM16B, we identified some predicted functional partners from in silico studies of the protein-protein network of TMEM16B. Calculation of diversity for the corresponding genes for individuals of the 1000 Genomes Project showed that TMEM16B has the highest level of diversity among all genes of the network, indicating that TMEM16B may not be under purifying selection and suggesting that other genes in the network could compensate for its function for olfactory ability

Direct‐acting antivirals for HCV treatment in older patients: A systematic review and meta‐analysis

The advent of highly effective and well-tolerated direct antiviral antivirals (DAAs) has dramatically changed the landscape of chronic hepatitis C. The effect of DAAs in older adults is difficult to determine since patients aged &gt;= 65 years were too few in most clinical trials and data mainly come from observational studies. We performed a systematic review and meta-analysis to evaluate the efficacy and safety of DAAs in patients aged 65 and older. PubMed, Scopus, Web of Science, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, HCV-Trials.com databases were searched for literature published until 1 December 2017. English language articles reporting results of phase 2 or 3 randomized controlled trials (RCTs), single-arm clinical trials (SATs) and observational studies were included in the final analysis. All studies included subgroups of older patients and compared their outcomes with younger individuals. By using a random-effects or fixed-effects model, odds ratio (OR) was calculated for the efficacy and safety. Heterogeneity was tested using I-2 statistics. Thirty-seven studies reported data on the DAA efficacy. The OR was 1.66 (95%CI: 1.00-2.75; P = 0.06) in meta-analysis of RCTs, and similar results were found in SATs and observational studies. HCV genotype, stage of fibrosis or HIV co-infection did not affect the rate of SVR in older persons. Prevalence of anaemia (OR 0.26 95%CI: 0.09-0.69; P = 0.007) (OR 0.25 95%CI: 0.09-0.69; P = 0.007) and skin complaints (OR 0.61 95%CI: 0.45-0.83; P = 0.001) was higher in older adults. Finally, geriatric patients affected by chronic HCV infection can be safely treated with DAAs with the same efficacy reported in younger adults

A natural prothrombin mutant reveals an unexpected influence of the A-chain&apos;s structure on the activity of human &#945;-thrombin

We have recently identified in two unrelated patients with bleeding tendency a homozygous mutation causing a deletion of one of the two contiguous Lys(9)/Lys(10) residues in the A-chain of alpha-thrombin (DeltaK9). We used in vitro expression analysis to clarify the role of the deletion of Lys(9) or Lys(10) in the thrombin function. The k(cat)/K(m) value of the hydrolysis by DeltaK9 of the synthetic substrate Phe-Pip-Arg-p-nitroanilide (where Pip represents l-pipecolyl) and fibrinopeptide A was 18- and 60-fold lower, respectively, compared with wild type (WT). Interaction with antithrombin was also reduced in the mutant, the association rate being about 20-fold lower than in the WT thrombin. The sensitivity to sodium ion of DeltaK9 was found significantly attenuated compared with the WT form. DeltaK9 has a very weak platelet-activating capacity, attributed to a severely defective PAR1 interaction, whereas the binding to the platelet glycoprotein Ibalpha was unaffected. Likewise, the interaction with protein C was severely impaired, whereas interaction with thrombomodulin had a normal K(d) value. At variance with these findings, both low affinity (basic pancreatic trypsin inhibitor) and high affinity (N-alpha-[2-naphthylsulfonyl-glycyl]-4-amidinophenylalanine-piperidide) thrombin inhibitors displayed a better binding to DeltaK9 than to the WT form, indicating a better accommodation of these inhibitors into the catalytic pocket of DeltaK9. A molecular dynamics simulation of the DeltaK9 thrombin in full explicit water solvent provided support to the role of the A-chain in affecting conformation and catalytic properties of the B-chain, especially in some insertion loops of the enzyme, such as the 60-loop, as well as in the geometry of the catalytic triad residues