Highly-stable, flexible delivery of microjoule-level ultrafast pulses in vacuumized anti-resonant hollow-core fibers for active synchronization

We demonstrate the stable and flexible light delivery of multi-{\mu}J, sub-200-fs pulses over a ~10-m-long vacuumized anti-resonant hollow-core fiber (AR-HCF), which was successfully used for high-performance pulse synchronization. Compared with the pulse train launched into the AR-HCF, the transmitted pulse train out of the fiber exhibits excellent stabilities in pulse power and spectrum, with pointing stability largely improved. The walk-off between the fiber-delivery and the other free-space-propagation pulse trains, in an open loop, was measured to be <6 fs root-mean-square (RMS) over 90 minutes, corresponding to a relative optical-path variation of <2x10-7. This walk-off can be further suppressed to ~2 fs RMS simply using an active control loop, highlighting the great application potentials of this AR-HCF set-up in large-scale laser and accelerator facilities

Pharmacokinetic interactions between simeprevir and ledipasvir in treatment naive hepatitis C virus genotype 1-Infected patients without cirrhosis treated with a simeprevir-sofosbuvir-ledipasvir regimen

Interactions between simeprevir (hepatitis C virus [HCV] NS3/4A protease inhibitor) and ledipasvir (HCV NS5A replication complex inhibitor) were investigated in treatment-naive HCV genotype 1-infected patients without cirrhosis, treated with simeprevir-sofosbuvir-ledipasvir in a two-panel, phase 2, open-label study. Patients had stable background treatment with sofosbuvir (400 mg once daily [QD]). In panel 1 (n = 20), the effect of ledipasvir (90 mg QD) on simeprevir (150 mg QD) was studied. Patients received simeprevir and sofosbuvir from days 1 to 14; steady-state pharmacokinetics (PK) of simeprevir was assessed (day 14). On day 15, ledipasvir was added and steady-state PK of simeprevir in the combination was evaluated (day 28). In panel 2 (n = 20), the effect of simeprevir on ledipasvir was investigated. From days 1 to 14, patients received ledipasvir and sofosbuvir and steady-state PK of ledipasvir was assessed (day 14). On day 15, simeprevir was added and a full PK profile was obtained (day 28). The least-squares mean maximum plasma concentration and area under the concentration-time curve (90% confidence interval) increased 2.3-fold (2.0- to 2.8-fold) and 3.1-fold (2.4- to 3.8-fold) for simeprevir, respectively (panel 1), and 1.6-fold (1.4- to 1.9-fold) and 1.7-fold (1.6- to 2.0-fold) for ledipasvir, respectively (panel 2), in the presence versus the absence of the other drug. All patients achieved sustained virologic responses 12 weeks after treatment end. Adverse events, mainly grade 1/2, occurred in 80% of patients; the most common was photosensitivity (45%). Due to the magnitude of interaction and the limited amount of safety data available, the use of this treatment combination is not recommended

Telaprevir twice daily is noninferior to telaprevir every 8 hours for patients with chronic hepatitis C.

Background & Aims We performed an open-label, multicenter, phase 3 study of the safety and efficacy of twice-daily telaprevir in treatment-naive patients with chronic hepatitis C virus (HCV) genotype 1 infection, including those with cirrhosis. Methods Patients were randomly assigned to groups treated with telaprevir 1125 mg twice daily or 750 mg every 8 hours plus peginterferon alfa-2a and ribavirin for 12 weeks; patients were then treated with peginterferon alfa-2a and ribavirin alone for 12 weeks if their level of HCV RNA at week 4 was <25 IU/mL or for 36 weeks if their level was higher. The primary objective was to demonstrate noninferiority of telaprevir twice daily versus every 8 hours in producing a sustained virological response 12 weeks after the end of therapy (SVR12) (based on a -11% lower limit of the 95% lower confidence interval for the difference between groups). Results At baseline, of 740 patients, 85% had levels of HCV RNA ≥800,000 IU/mL, 28% had fibrosis (F3-F4), 14% had cirrhosis (F4), 57% were infected with HCV genotype 1a, and 71% had the non-CC IL28B genotype. Of patients who were treated with telaprevir twice daily, 74.3% achieved SVR12 compared with 72.8% of patients who were treated with telaprevir every 8 hours (difference in response, 1.5%; 95% confidence interval, -4.9% to 12.0%), so telaprevir twice daily is noninferior to telaprevir every 8 hours. All subgroups of patients who were treated with telaprevir twice daily versus those who were treated every 8 hours had similar rates of SVR12. The most frequent adverse events (AEs) in the telaprevir phase were fatigue (47%), pruritus (43%), anemia (42%), nausea (37%), rash (35%), and headache (26%); serious AEs were reported in 9% of patients. Rates of AEs and serious AEs were similar or slightly higher among patients treated with telaprevir every 8 hours. Conclusions Based on a phase 3 trial, telaprevir twice daily is noninferior to every 8 hours in producing SVR12, with similar levels of safety and tolerability. These results support use of telaprevir twice daily in patients with chronic HCV genotype 1 infection, including those with cirrhosis. ClinicalTrials.gov, Number: NCT0124176

Методичні вказівки для проведення практичних занять і організації самостійної роботи з навчальної дисципліни «Управління нерухомим майном» (для студентів 4 курсу денної і заочної форм навчання напряму підготовки 6.080101 – Геодезія, картографія та землеустрій).

Table S2. Week-4 simeprevir pharmacokinetic parameters after administration in (a) Panels 1–3 and (b) Panel 4. (DOCX 15 kb

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Bio-Based <i>Eucommia ulmoides</i> Gum Composites with High Electromagnetic Interference Shielding Performance

Herein, high-performance electromagnetic interference (EMI) shielding bio-based composites were prepared by using EUG (Eucommia ulmoides gum) with a crystalline structure as the matrix and carbon nanotube (CNT)/graphene nanoplatelet (GNP) hybrids as the conductive fillers. The morphology of the CNT/GNP hybrids in the CNT/GNP/EUG composites showed the uniform distribution of CNTs and GNPs in EUG, forming a denser filler network, which afforded improved conductivity and EMI shielding effect compared with pure EUG. Accordingly, EMI shielding effectiveness values of the CNT/GNP/EUG composites reached 42 dB in the X-band frequency range, meeting the EMI shielding requirements for commercial products. Electromagnetic waves were mainly absorbed via conduction losses, multiple reflections from interfaces and interfacial dipole relaxation losses. Moreover, the CNT/GNP/EUG composites exhibited attractive mechanical properties and high thermal stability. The combination of excellent EMI shielding performance and attractive mechanical properties render the as-prepared CNT/GNP/EUG composites attractive candidates for various applications

Pooled resistance analyses of darunavir once-daily regimens and formulations across 10 clinical studies of treatment-naïve and treatment-experienced patients with human immunodeficiency virus-1 infection

Background The efficacy and high barrier to resistance of darunavir have been demonstrated across diverse populations with HIV-1 infection. Objective To evaluate post-baseline resistance among patients in studies of once-daily (QD) darunavir-based regimens and formulations. Methods The analysis included treatment-naïve and virologically failing or suppressed patients from 10 phase 2/3 studies (48–192 weeks in duration) of boosted darunavir 800 mg QD-based regimens. Three were phase 3 studies of the QD darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg single-tablet regimen. Post-baseline resistance was evaluated upon protocol-defined virologic failure (PDVF). Resistance-associated mutations (RAMs) were identified using International Antiviral Society-USA mutation lists. Phenotypic analyses varied across studies. Results Overall, 250 of 3635 patients in the analysis met PDVF criteria; 205 had post-baseline genotypes/phenotypes. In total, four (0.1%) patients developed (or had identified) ≥1 darunavir and/or primary protease inhibitor (PI) RAM; only one (10 years, loss of phenotypic susceptibility to darunavir was only observed once in a PI-experienced patient and has never been observed in treatment-naïve patients, treatment-experienced PI-naïve patients, or treatment-experienced virologically suppressed patients

Rapid initiation of darunavir/cobicistat/emtricitabine/tenofovir alafenamide in acute and early HIV-1 infection: a DIAMOND subgroup analysis

Background: Treatment during acute or early human immunodeficiency virus (HIV)-1 infection is associated with immunologic and virologic benefits. Objective: To evaluate darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) efficacy/safety among patients with acute or early HIV-1 infection who rapidly initiate treatment. Methods: DIAMOND (ClinicalTrials.gov Identifier: NCT03227861), a phase 3 study, evaluated the efficacy/safety of D/C/F/TAF 800/150/200/10 mg in rapid initiation. Adults aged ≥18 years began D/C/F/TAF within 14 days of diagnosis, prior to the availability of screening/baseline laboratory results. In this subgroup analysis, virologic response (HIV-1 RNA <50 copies/mL) was assessed at Week 48 by intent-to-treat FDA snapshot (ITT-FDA snapshot) and observed (excluding patients with missing data) analyses in patients with acute (HIV-1 antibody negative and HIV-1 RNA positive/p24 positive) or early (HIV-1 antibody positive and suspected infection ≤6 months before screening/baseline) infection. Results: Among 109 patients, 13 had acute and 43 had early HIV-1 infection. High rates of virologic response were demonstrated at Week 48 by ITT-FDA snapshot (acute: 10/13 [76.9%]; early: 37/43 [86.0%]) and observed (acute: 10/11 [90.9%]; early: 37/38 [97.4%]) analyses. No patients discontinued or required regimen change due to baseline resistance or lack of efficacy, or developed protocol-defined virologic failure. Through Week 48, 7 (53.8%) acute and 22 (51.2%) early infection patients had a D/C/F/TAF-related adverse event (AE); none had a D/C/F/TAF-related grade 4 or serious AE. Conclusions: High rates of viral suppression during acute/early infection were achieved with D/C/F/TAF rapid initiation, no treatment-emergent resistant mutations were observed, and D/C/F/TAF was safe and well tolerated

Darunavir/cobicistat/emtricitabine/tenofovir alafenamide in treatment-na\uefve patients with HIV-1: subgroup analyses of the phase 3 AMBER study

Background: The once-daily, single-tablet regimen darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10\u2009mg is approved for the treatment of HIV-1 infection. The 48-week efficacy and safety of D/C/F/TAF versus darunavir/cobicistat\u2009+\u2009emtricitabine/tenofovir disoproxil fumarate (control) in treatment-na\uefve adults were demonstrated in the phase 3 AMBER study. Objective: To describe AMBER outcomes across patient subgroups based on demographic and clinical characteristics at baseline. Methods: AMBER patients had viral load (VL) 651000 copies/mL, CD4+ cell count &gt;50 cells/\ub5L, and genotypic susceptibility to darunavir, emtricitabine, and tenofovir. Primary endpoint was the proportion of patients with virologic response (VL &lt;50 copies/mL; FDA snapshot). Safety was assessed by adverse events, estimated glomerular filtration rate (cystatin C; eGFRcystC), and bone mineral density. Outcomes were assessed by age ( 64/&gt;50 years), gender, race (black/non-black), baseline VL ( 64/&gt;100,000 copies/mL), baseline CD4+ cell count (50 years and women, relative to their comparator groups, regardless of treatment arm (notably, sample sizes were small for patients &gt;50 years and women). Improvements in eGFRcystC and stable bone mineral density were observed with D/C/F/TAF overall, and results were generally consistent across subgroups. Conclusions: For treatment-na\uefve patients in AMBER, initiating therapy with the D/C/F/TAF single-tablet regimen was an effective and well-tolerated option, regardless of demographic or clinical characteristics