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By employing Mindlin’s Form II gradient elasticity theory (strain gradient elasticity theory), we investigate the SH surface wave propagating in a strain-gradient layered half-space. The dispersion equation of the SH surface wave is derived analytically. For the general case where both the surface layer and the half-space are strain-gradient elastic materials, the dispersion equation involves 10 material constants. The dispersion equation of the general case can degenerate to that of several special cases by dropping some material parameters. The existence regions of the dispersion curves are discussed in detail. The effects of strain-gradient elastic constants on the dispersion curves are examined. It is seen that the features of SH surface waves in strain-gradient elastic materials are much richer than those in classical elastic materials. Ministry of Education (MOE) The authors would like to thank the financial support from Singapore Ministry of Education Academic Research Fund Tier 1 (RG185/18). Jianmin Long also acknowledges the support from the National Natural Science Foundation of China (11702081) and the Fundamental Research Funds for the Central Universities, Hohai University (2019B08714).

Introduction Some direct-acting antiviral regimens for hepatitis C virus (HCV) infection pose safety or efficacy concerns if coadministered with drugs containing ethinyl estradiol. The present analysis was conducted to examine the impact of concomitant oral contraceptive pills (OCP) or hormone replacement therapy (HRT) during treatment with elbasvir (EBR)/grazoprevir (GZR) in women with HCV genotype (GT)1 or GT4 infection. Methods This is a post hoc, integrated retrospective analysis of female participants with HCV GT1 or GT4 infection who received EBR 50 mg/GZR 100 mg once daily for 12 weeks in phase 2/3 clinical trials. The primary end point was sustained virologic response at 12 weeks after therapy completion (SVR12). For this analysis, participants were stratified according to whether they received OCP or HRT during the original treatment study. Results A total of 1,022 women with HCV GT1 or GT4 infection were included (receiving OCP/HRT, n=81; not receiving OCP/HRT, n=941). Most participants receiving OCP/HRT were treatment-naive (79%), noncirrhotic (91.4%), and aged >35 years (71.6%). SVR12 rates were similar in women receiving OCP/HRT and those not receiving OCP/HRT (95.1% vs 96.3%). SVR12 rates remained high across all subgroups within the population receiving OCP/HRT: SVR12 rates were 94.6%, 100%, and 100% in participants with GT1a, GT1b, and GT4 infection, and all women aged 18-35 years achieved SVR (21/21). Treatment-related adverse events occurred in 40.7% (33/81) and 30.1% (283/941) of women receiving and those not receiving OCP/HRT, respectively. Conclusion The efficacy and safety of EBR/GZR administered for 12 weeks was similar in women receiving OCP/HRT and those not on OCP/HRT. These data indicate that EBR/GZR can be safely used for the treatment of HCV GT1 or GT4 infection in women receiving concomitant OCP/HRT.

In this paper, we present an unconditional stable linear high-order finite difference scheme for three dimensional Allen–Cahn equation. This scheme, which is based on a backward differentiation scheme combined with a fourth-order compact finite difference formula, is second order accurate in time and fourth order accurate in space. A linearly stabilized splitting scheme is used to remove the restriction of time step. We prove the unconditional stability of our proposed method in analysis. A fast and efficient linear multigrid solver is employed to solve the resulting discrete system. We perform various numerical experiments to confirm the high-order accuracy, unconditional stability and efficiency of our proposed method. In particular, we show two applications of our proposed method: triply-periodic minimal surface and volume inpainting.

Background Mucosal melanoma is an aggressive melanoma with poor prognosis. We assessed efficacy of pembrolizumab in patients with advanced mucosal melanoma in KEYNOTE-001 (NCT01295827), −002 (NCT01704287), and −006 (NCT01866319). Methods Patients received pembrolizumab 2 mg/kg every 3 weeks (Q3W) or 10 mg/kg Q2W or Q3W. Response was assessed by independent central review per RECIST v1.1. Results 1567 patients were treated and 84 (5%) had mucosal melanoma. Fifty-one of 84 were ipilimumab-naive. In patients with mucosal melanoma, the objective response rate (ORR) was 19% (95% CI 11–29%), with median duration of response (DOR) of 27.6 months (range 1.1 + to 27.6). Median progression-free survival (PFS) was 2.8 months (95% CI 2.7–2.8), with median overall survival (OS) of 11.3 months (7.7–16.6). ORR was 22% (95% CI 11–35%) and 15% (95% CI 5–32%) in ipilimumab-naive and ipilimumab-treated patients. Conclusion Pembrolizumab provides durable antitumour activity in patients with advanced mucosal melanoma regardless of prior ipilimumab.

Elevated progesterone levels on the day of trigger negatively impact the outcome of assisted reproductive technique (ART) treatment and forced ovarian stimulation might be a cause of progesterone elevation during ovarian stimulation. To analyze the impact of forced and prolonged stimulation on the progesterone elevation, this data analysis from the Ensure study compared hormonal stimulation with corifollitropin alpha (CFA)-only with CFA plus recombinant (rec) follicle-stimulating hormone (FSH) after day 8 (CFA-plus group) of ovarian stimulation. In the Ensure study, 268 patients underwent ovarian stimulation with 100 µg CFA and 128 patients with recombinant FSH. A total of 35 patients (13.1%) from the CFA-arm received the hCG trigger after stimulation with CFA-only, 233 patients (86.9%) needed additional rec FSH from day 8 onwards to meet the criteria for trigger. Progesterone levels0.8 ng/ml on the trigger day occurred in 90 patients (38.6%) from the CFA plus FSH group and only in one patient (2.8%) in the CFA-only group (p .001). The ongoing pregnancy rate (OPR) was 31.4% (11/35) for patients in the CFA-only group and 24.5% (57/233) for patients CFA-plus group with additional recFSH after day 8 (p = .378). This set of data demonstrates that prolongation of stimulation in combination with intense stimulation leads to a statistically significant increased incidence of progesterone elevation on the day of trigger.摘要 诱发当天孕酮水平升高对辅助生殖技术（ART）的结果产生负面影响, 强的卵巢刺激可能是卵巢刺激过程中孕酮过早升高的原因。为了分析强的和长时间刺激对孕酮升高的影响, 来自Ensure研究的数据对卵巢刺激第8天后单用卵泡刺激素a进行刺激（CFA组）、与用CFA+重组（rec）卵泡刺激素（FSH）进行激素刺激（ CFA-plus组）进行了分析比较。在Ensure研究中, 268名患者接受了100μg CFA的卵巢刺激, 128名患者接受了重组FSH的卵巢刺激。来自CFA组的总共35名患者（13.1％）在单用CFA刺激后接受hCG诱发, 233名患者（86.9％）从第8天开始需要额外的rec FSH以满足诱发标准。CFA-plus组的90名患者（38.6％）和CFA组中仅一名患者（2.8％）出现了诱发日的孕酮水平0.8 ng/ml（p.001）。CFA组的持续妊娠率（OPR）为31.4％（11/35）, 在第8天后增加rec FSH的CFA-plus组的持续妊娠率（OPR）为24.5％（57/233）（p = .378）。这组数据表明, 刺激时间延长与强烈刺激相结合, 导致触发当天孕酮升高的发生率显著增加, 具有统计学意义。.

The sizes of most asperities on actual rough surfaces range from nanometers to microns. Recent investigations reveal that surface tension plays an important role in micro-/nano-sized contact. Therefore, in this paper, we address the influence of surface tension on the elastic contact of rough surfaces. Nayak's model is employed to describe rough surface with stochastic distribution of both heights and curvatures. As a fundament, we present the general relations of contact area and load as the function of indent depth for a single micro-/nano-sized asperity by accounting for surface tension. Based on the refined relations, we derive the general relations concerned in the contact of rough surfaces. Compared with the conventional multi-asperity contact models based on the Hertzian contact theory, the existence of surface tension decreases the real contact area and requires higher load to generate a given indent depth. It is found that the area of intimate contact is still approximately proportional to the external load, but the proportionality depends on the surface tension.

Surface tension plays a significant role in micro- and nanoindentation tests. Based on the solution of a concentrated force acting on an elastic half-plane with surface tension, the two-dimensional indentations of an elastic half-plane by a cylindrical indenter, a wedge indenter and a flat-ended indenter are formulated, and by employing the Gauss–Chebyshev quadrature formula, the corresponding singular integral equations are numerically solved. For each indentation, the analytic solutions of two limit cases considering only bulk elasticity or surface tension are derived. Then through simple combinations of the results of two limit cases, the analytic relations between load and contact half-width or indent depth are formulated for the general case, and compared with the numerical results. The analytic relations established in this paper facilitate better characterization of mechanical properties of materials by micro/nanoindentation tests.

In the present paper, the nanoindentation of an elastic half-space by a conical indenter is investigated with the influence of surface tension. Based on the solution of a point force acting on an elastic half-space with surface tension, the singular integral equation of this problem is formulated and is then solved numerically by using the Gauss–Chebyshev quadrature formula. Surface tension flattens the pressure distribution in the contact region. Compared to the result of the classical elasticity model, surface tension evidently decreases the normal displacement on the surface of the half-space. The explicit relations between load and contact radius, and between load and indent depth are derived, which are helpful to characterize the mechanical properties of the materials in nanoindentation.

Surface layers with microstructures are widely used in many engineering fields. The mechanical behavior of microstructures in solids can be described by gradient elasticity theories. [One of them is the couple stress theory (Mindlin and Tiersten in Arch. Ration. Mech. Anal. 11:415–448, 1962).] In the present paper, we study the in-plane surface wave propagating in a classical elastic half-space covered by a surface layer described by the couple stress theory. We firstly develop the full solution for the above configuration. Since our primary objective is to introduce the couple stress theory (or strain-gradient elasticity theory) into the surface elasticity model (Gurtin and Murdoch in Arch. Ration. Mech. Anal. 57:291–323, 1975), we are particularly interested in the case that the surface layer is very thin. Therefore, as our second step, by employing the Kirchhoff thin plate model, we establish the surface elasticity model considering couple stresses and derive the isotropic surface elasticity solution of the present problem. Thirdly, by employing the second-order strain-gradient model (Aifantis in Int. J. Eng. Sci. 30:1279–1299, 1992), we derive the dispersion equation of the surface wave for the case that the microstructure length scale is larger than the layer thickness. The last two solutions are compared with the full solution numerically for the lowest mode of the surface wave. It should be pointed out that the present study involves multi-field knowledge of surface waves, couple stress theory, and surface elasticity theory. Ministry of Education (MOE) The authors would like to thank the financial support from Singapore Ministry of Education Academic Research Fund Tier 1 (RG185/18). Jianmin Long also acknowledges the supports from the National Natural Science Foundation of China (11702081) and the Open Project of State Key Laboratory for Strength and Vibration of Mechanical Structures, Xi’an Jiaotong University (SV2017-KF-19).

Background: In the United States, the number of new cases of hepatitis C virus infection has risen in recent years, driven largely by transmission among young white adults in their 20s and 30s. Herein, we report an integrated analysis of participants with hepatitis C virus infection aged ≤35 years from 12 phase II/III clinical trials of elbasvir/grazoprevir. Methods: Treatment-naive and -experienced adults with hepatitis C virus genotype 1 or 4 infection received elbasvir (50 mg/day)/grazoprevir (100 mg/day) for 12 weeks without ribavirin. Analyses were stratified according to participant age (≤35 years vs >35 years). The primary endpoint was sustained virologic response (hepatitis C virus RNA Results: Sustained virologic response was achieved by 98.9% (271/274) of participants aged ≤35 years and by 96.9% (2093/2160) aged >35 years. Three participants aged ≤35 years with genotype 1b infection relapsed. Eight participants with genotype 1a infection and baseline non-structural protein 5 A resistance-associated substitutions achieved sustained virologic response. Similarly, all 85 participants aged ≤35 years with genotype 1a infection and no baseline non-structural protein 5 A resistance-associated substitutions achieved sustained virologic response. Safety was favorable, with the incidence of drug-related adverse events similar in younger and older participants (30.1% vs 30.6%). One participant (0.4%) aged ≤35 years and 15 participants (0.7%) aged >35 years discontinued treatment owing to adverse events. Conclusions: Elbasvir/grazoprevir for 12 weeks was safe and highly effective in participants aged ≤35 years with hepatitis C virus genotype 1 or 4 infection.

Christophe Hézode,1 Paul Kwo,2 Jan Sperl,3 Peggy Hwang,4 Jianmin Long,4 Rohit Talwani,4 Michael N Robertson,4 Barbara A Haber4 1Service d’Hépatologie, Hôpital Henri-Mondor, AP-HP, Université Paris-Est, INSERM U955, Créteil, France; 2Division of Gastroenterology/Hepatology, Department of Medicine, Stanford University School of Medicine, Palo Alto, CA, USA; 3Department of Hepatogastroenterology, Institut Klinické a Experimentální Medicíny (IKEM), Prague, Czech Republic; 4Department of Infectious Disease, Merck & Co., Inc., Kenilworth, NJ, USACorrespondence: Christophe HézodeService d’Hepatologie, Hôpital Henri Mondor, 51, avenue du Maréchal de Lattre de Tassigny, Créteil 94010, FranceTel +33 14 981 2111Email christophe.hezode@aphp.frIntroduction: Some direct-acting antiviral regimens for hepatitis C virus (HCV) infection pose safety or efficacy concerns if coadministered with drugs containing ethinyl estradiol. The present analysis was conducted to examine the impact of concomitant oral contraceptive pills (OCP) or hormone replacement therapy (HRT) during treatment with elbasvir (EBR)/grazoprevir (GZR) in women with HCV genotype (GT)1 or GT4 infection.Methods: This is a post hoc, integrated retrospective analysis of female participants with HCV GT1 or GT4 infection who received EBR 50mg/GZR 100mg once daily for 12weeks in phase 2/3 clinical trials. The primary end point was sustained virologic response at 12weeks after therapy completion (SVR12). For this analysis, participants were stratified according to whether they received OCP or HRT during the original treatment study.Results: A total of 1,022 women with HCV GT1 or GT4 infection were included (receiving OCP/HRT, n=81; not receiving OCP/HRT, n=941). Most participants receiving OCP/HRT were treatment-naive (79%), noncirrhotic (91.4%), and aged >35years (71.6%). SVR12 rates were similar in women receiving OCP/HRT and those not receiving OCP/HRT (95.1% vs 96.3%). SVR12 rates remained high across all subgroups within the population receiving OCP/HRT: SVR12 rates were 94.6%, 100%, and 100% in participants with GT1a, GT1b, and GT4 infection, and all women aged 18–35years achieved SVR (21/21). Treatment-related adverse events occurred in 40.7% (33/81) and 30.1% (283/941) of women receiving and those not receiving OCP/HRT, respectively.Conclusion: The efficacy and safety of EBR/GZR administered for 12weeks was similar in women receiving OCP/HRT and those not on OCP/HRT. These data indicate that EBR/GZR can be safely used for the treatment of HCV GT1 or GT4 infection in women receiving concomitant OCP/HRT.Keywords: clinical trial, ethinyl estradiol, levonorgestrel, NS5A inhibitor, NS3/4A protease inhibitor

When contact radius reduces to micro or nano scale, the influence of surface tension becomes important. In this paper, we summarize some of our works in this subject. Based on the solution of a point force acting on an elastic half space with surface tension, we consider the indentation on an elastic half space by rigid cylinder and sphere, respectively. The explicit relations of load depending on contact radius and indent depth are presented. Through a finite element approach accounting for surface energy, we verify the equivalence of the compression of an elastic sphere and the indentation of a half space, even with the presence of surface tension. Furthermore, we address the influence of surface tension on adhesive contact, and give the explicit expressions of contact radius and indent depth. These works are useful to accurately characterize the contact problems at micro and nano scale.

In the present paper, the adhesive contact between a rigid sphere and a compliant elastic substrate with surface tension is analyzed. Using the minimum potential energy principle and considering both the effects of surface tension and adhesion, explicit solutions are obtained for the contact radius and the indent depth for the case without external loading. It is found that surface tension evidently alters the pressure distribution in the contact region and tends to decrease both the contact radius and the indent depth. The present model establishes a bridge between the JKR model for adhesive contact problems and the Young-Laplace's law of surface tension.

Physical aging widely exists in amorphous polymers, which refers to the nonequilibrium structure of amorphous polymers evolving towards the equilibrium state. Aging can significantly influence the thermomechanical properties and subsequently the macroscopic response of polymers. In our recent work, we performed a series of uniaxial compression tests on amorphous thermoplastic poly(ethyleneterephthalate)-glycol (PETG) subject to different annealing temperature and time. The results showed that both annealing time and temperature have a significant influence on the yield strength. Here we apply a two-temperature continuum model to simulate the stress response of PETG with different thermal treatments. The model employs the effective temperature as a variable to characterize the nonequilibrium state. The physical aging is characterized by the evolution of the effective temperature. The effective temperature is also coupled with the viscoplastic deformation to describe strain softening induced by mechanical rejuvenation. The simulation results can reasonably reproduce the main experimental observations with some discrepancies. The possible reasons for the discrepancies between experiments and simulations are also critically analyzed. The theory is also used to simulate the response of amorphous glassy polymers in the creep and strain-rate-switching tests. The model successfully captures the important features of experimental observations in the literature.

Ceftolozane/tazobactam is approved for treatment of complicated intra-abdominal infection (cIAI) and complicated urinary tract infection (cUTI) with renal function-based dose adjustment. Given that creatinine clearance, body weight and sex are highly correlated in severely/morbidly obese patients, this study investigated whether approved dosing regimens for ceftolozane/tazobactam are appropriate in severely/morbidly obese patients based on simulated pharmacokinetic/pharmacodynamic target attainment, with confirmation from observed clinical outcomes data from the phase 3 clinical development programme. Using a previously published population pharmacokinetic model, 1000 patients were randomly sampled from an internal pooled database of 201 severely/morbidly obese patients (BMI ≥ 35 kg/m2) and were used for Monte Carlo simulation to test whether the labelled dose regimens can achieve ≥90% probability of a target of 32.2% (1-log kill) time above free ceftolozane concentration against pathogens at an MIC up to 8 mg/L. Clinical outcomes data for severely/morbidly obese patients with cIAI or cUTI from pivotal phase 3 studies were summarised to calculate clinical and composite cure rates as a complimentary support. With the approved renal function-based dosing regimens, >90% target attainment of bactericidal activity was achieved at MICs up to 8 mg/L in the simulated severely/morbidly obese patients with cIAI or cUTI, similar to target attainment in non-obese patients and further confirmed by phase 3 outcomes where cure rates in severely/morbidly obese patients and non-obese patients are similar. Approved dosing regimens of ceftolozane/tazobactam, adjusted according to renal function, can achieve adequate target attainment and high clinical cure rates in severely/morbidly obese patients with cIAI or cUTI.

The conventional contact mechanics does not account for surface tension; however, it is important for micro- or nanosized contacts. In the present paper, the influences of surface tension on the indentations of an elastic half-space by a rigid sphere, cone, and flat-ended cylinder are investigated, and the corresponding singular integral equations are formulated. Due to the complicated structure of the integral kernel, it is difficult to obtain their analytical solutions. By using the Gauss–Chebyshev quadrature formula, the integral equations are solved numerically first. Then, for each indenter, the analytical solutions of two limit cases considering only the bulk elasticity or surface tension are presented. It is interesting to find that, through a simple combination of the solutions of two limit cases and fitting the direct numerical results, the dependence of load on contact radius or indent depth for general case can be given explicitly. The results incorporate the contribution of surface tension in contact mechanics and are helpful to understand contact phenomena at micro- and nanoscale.

Two novel methods for image feature extraction based on fractional differentiation are presented in this paper. The first method is the feature extraction of fusing multi-direction CRONE operators. In this method, the fractional differential CRONE mask is generalized to eight directions at first for extracting image features; then the extracted features are tested by the statistic method and fused by the gradient ratio, so that the outlines of the objects in the image are obtained. In order to extract the detail feature information in the image effectively, the second method, the ‘S+Z’ extraction combined with the space-filling curves, is presented. By introducing the space-filling curves, the ‘S’ curve and the ‘Z’ curve, and making full use of the neighborhood information of image pixels, the detailed features of the objects in the image are obtained. The experiment results show that our methods can obtain satisfactory image features.

The interaction of asperities plays an important role in the contact of rough surfaces. This paper develops a self-consistent contact model, in which the effect of asperity interaction is accounted for by applying the mean pressure around a representative asperity. Based on the Boussinesq’s solution of a point force acting on an elastic half-plane, the problem is transformed into a singular integral equation. Using the Gauss–Legendre quadrature formula, we solve the integral equation numerically. The results demonstrate that when the ratio between the real contact area and the nominal one is small, the effect of asperity interaction is negligible and the present mode coincides with the Greenwood–Williamson model. However, when the area ratio gets larger, the interaction of asperities becomes prominent. For a given ratio between the real contact area to the nominal one, the self-consistent contact model predicts a higher load than the Greenwood–Williamson model, in agreement with relevant experimental results.

Interferon alfa has been used to treat chronic hepatitis C virus (HCV) infection since the early 1990s and remains the backbone of many treatment regimens involving HCV protease inhibitors [1–3]. Interferon alfa, however, has many side effects, including cytopenias [1]. When patients are treated with one of the long-acting, pegylated formulations of interferon, pegylated interferon (peg-IFN) alfa-2a, or peg-IFN alfa-2b, in combination with ribavirin (RBV) for up to 48 weeks, the incidence of severe neutropenia, defined as an absolute neutrophil count (ANC) of 3000) and the breadth of data collected, the Individualized Dosing Efficacy vs Flat Dosing to Assess Optimal Pegylated Interferon Therapy (IDEAL) study provides a unique opportunity to evaluate the incidence of and risk factors associated with acute infections among patients receiving HCV treatment with peg-IFN/RBV, with an emphasis on understanding the relationship between treatment-induced cytopenias and infection [15].

Background: 76 academic and 42 community-based US centers participated in the IDEAL study, providing an opportunity to evaluate various metrics of quality and site performance in this large multicenter study. Methods: 3070 treatment-naive, HCV genotype 1 infected patients received peg interferon (PEG) alfa-2b 1.5 or 1 µg/kg/wk plus ribavirin (RBV) 800-1400 mg/d or PEG alfa-2a 180 µg/wk plus RBV 1000-1200 mg/d for up to 48 weeks. We retrospectively evaluated rates of screen failure, completion, and discontinuation of treatment and follow-up, treatment adherence, and virologic response by site type. Results: Of 4469 subjects screened, 63% and 37% were in academic and community centers, respectively. Screen failure rates were similar (30-32%). Of the 1905 (62%) and 1165 (38%) patients treated in academic and community centers, respectively, baseline characteristics were comparable, except more African Americans (21% vs 15%) were treated at academic centers, and more Hispanics were treated at community centers (10% vs 5%) (Table). End-of-treatment (EOT) response, relapse, and sustained virologic response (SVR) rates in academic and community centers did not differ. 9% of patients in academic and 12% in community centers achieved rapid virologic response (undetectable HCV RNA at week 4); 39% and 42% achieved complete early virologic response (undetectable HCV RNA at week 12). Adherence to ≥80% of PEG and RBV dosing for ≥80% assigned duration was also similar (46% in academic and 47% in community centers). 54% of patients in both academic and community centers completed treatment; there were similar discontinuation rates for treatment failure and adverse events. Conclusions: No differences in adherence, incidence of adverse events, rates of discontinuation, on-treatment virologic response, and SVR were found when comparing academic and community sites. This large trial further supports that outcomes for patients are largely similar when comparing academic versus community based treatment for chronic hepatitis C.

For micro/nanosized contact problems, the influence of surface tension becomes prominent. Based on the solution of a point force acting on an elastic half space with surface tension, we formulate the contact between a rigid ellipsoid and an elastic substrate. The corresponding singular integral equation is solved numerically by using the Gauss–Chebyshev quadrature formula. When the size of contact region is comparable with the elastocapillary length, surface tension significantly alters the distribution of contact pressure and decreases the contact area and indent depth, compared to the classical Hertzian prediction. We generalize the explicit expression of the equivalent contact radius, the indent depth, and the eccentricity of contact ellipse with respect to the external load, which provides the fundament for analyzing nanoindentation tests and contact of rough surfaces.

Background: Vicriviroc, an investigational CCR5 antagonist, demonstrated short-term safety and antiretroviral activity. Methods: Phase 2, double-blind, randomized study of vicriviroc in treatment-experienced subjects with CCR5-using HIV-1. Vicriviroc (5, 10, or 15 mg) or placebo was added to a failing regimen with optimization of background antiretroviral medications at day 14. Subjects experiencing virologic failure and subjects completing 48 weeks were offered open-label vicriviroc. Results: One hundred eighteen subjects were randomized. Virologic failure (

The two-stage sample size re-estimation procedure developed previously in the literature (e.g.,Shih, 1992; Gould and Shih, 1992) treats the blinded data from a randomized clinical trial as a sample from a mixture of two normal distributions of equal variances.This paper investigates the procedure when being applied to the situations where the variances are unequal and blocking effects by clinical centers are present.We show by simulations that in both situations the re-estimation procedure is still capable to update the sample size properly for attaining the required power and preserving the type-1 error at the nominal level.

Drug resistance represents a new challenge to the fast-evolving therapy of chronic hepatitis C virus (HCV) [1–4]. Virologic failure during treatment with directly acting antiviral agents is often accompanied by the emergence of resistance-associated variants (RAVs) [5, 6]. The error-prone HCV RNA-polymerase generates quasi-species of genetically related viruses harboring minor genomic differences [7]. Polymorphic variants associated with decreased susceptibility to some drugs are likely already circulating at low levels in many patients, even before exposure to directly acting antiviral agents [8–11]. Resistance-associated variants may then become the dominant species under selective drug pressure when viral replication is inadequately suppressed [12, 13]. Boceprevir is a NS3/4A-protease inhibitor approved for treatment of HCV genotype-1 infection in combination with peginterferon-α/ribavirin (P/R). Boceprevir RAVs were (1) initially discovered in the NS3-protease gene after in vitro selection using HCV-replicon cell lines and (2) presumptively confirmed by sequencing the protease gene from viruses emerging in HCV-infected patients coincident with virologic failure on triple therapy with boceprevir plus P/R [4, 5]. These variants were subsequently shown to confer varying degrees of decreased susceptibility to boceprevir when introduced as amino acid substitutions into the recombinant NS3-protease enzyme or wild-type replicons. The common mutants have been mapped to their positions in the 3-dimensional structure of the NS3-protease active site and correlated with their effects on the enzymatic properties of the NS3/4A-protease and the magnitude of resistance conferred in replicon assays. Although RAVs have been well characterized in vitro, their full therapeutic ramifications are still inadequately understood [1, 3, 13–15]. The objective of the current pooled analysis of the clinical trial database was to assess the impact of preexisting variants on treatment outcomes in subjects treated with boceprevir plus P/R. The primary question was if or when did detection of RAVs at baseline predict a high likelihood of treatment failure. In particular, we sought to determine whether baseline RAVs at levels detectable by population sequencing (∼20% of circulating quasi-species) were associated with treatment failure and whether interferon-responsiveness was a critical cofactor in any relationship between baseline RAVs and SVR. Although the current analysis focused on boceprevir, these data can help inform how baseline variants might impact the efficacy of newer antiviral regimens, including or exclusively consisting of directly acting agents against HCV.

OBJECTIVE The primary objectives of this study were to evaluate the safety, tolerability, and antiviral activity of pegylated interferon-alpha (PegIntron) in HIV-1 treatment-experienced patients failing their current antiretroviral regimen. DESIGN This was a phase II, multicenter, randomized, double-blind, placebo-controlled study. METHODS Patients were randomized to receive either weekly subcutaneous PegIntron 0.5, 1.0, 1.5, or 3 microg/kg or placebo added to their failing antiretroviral regimen for the first 4 weeks of study. Individuals who achieved more than 0.5 log10 reduction in HIV RNA at week 4 were allowed to continue study medication with optimization of their antiretroviral therapy for an additional 24 weeks. RESULTS In the 259 patients included in the intent-to-treat analysis, changes in plasma HIV RNA from baseline to week 4 were -0.25 (P > 0.5), -0.46 (P = 0.024), -0.39 (P = 0.008), -0.53 (P 0.5) log10 copies/ml in the 0.5, 1.0, 1.5, and 3.0 microg/kg and placebo arms, respectively. No significant changes were seen in CD4 T-cell parameters in any of the treatment or control arms. Adverse events (most commonly fever, flu-like symptoms, other constitutional symptoms, and psychiatric symptoms) resulted in discontinuation of study medication in 13, 17, 16, 28, and 2% of patients in the 0.5, 1.0, 1.5, 3.0 microg/kg, and placebo group, respectively. CONCLUSION The demonstration of significant antiviral activity in a heavily pretreated patient population with acceptable toxicity and only weekly dosing makes PegIntron a potentially valuable therapy for patients with HIV infection that warrants further investigation in a broader population of patients.

Background. Vicriviroc (VCV) is a CCR5 antagonist with nanomolar activity against human immunodeficiency virus (HIV) replication in vitro and in vivo. We report the results of a phase II dose-finding study of VCV plus dual nucleoside reverse-transcriptase inhibitors (NRTIs) in the treatment-naive HIV-1‐infected subjects. Methods. This study was a randomized, double-blind, placebo-controlled trial that began with a 14-day comparisonof3dosagesofVCVwithplacebointreatment-naivesubjectsinfectedwithCCR5-usingHIV-1.After14days of monotherapy, lamivudine/zidovudine was added to the VCV arms; subjects receiving placebo were treated with efavirenz and lamivudine/zidovudine; the planned treatment duration was 48 weeks. Results. Ninety-two subjects enrolled. After 14 days of once-daily monotherapy, the mean viral loads decreased frombaselinevaluesby0.07log10copies/mLintheplaceboarm,0.93log10copies/mLintheVCV25mgarm,1.18log10 copies/mL in the VCV 50 mg arm, and 1.34 log10 copies/mL in the VCV 75 mg arm (P .001 foreach VCV arm vs. the placebo arm). The combination-therapy portion of the study was stopped because of increased rates of virologic failureintheVCV25mg/dayarm(relativehazard[RH],21.6;95%confidenceinterval[CI],2.8‐168.9)andtheVCV 50 mg/day arm (RH, 11.7; 95% CI, 1.5‐92.9), compared with that in the control arm. Conclusions. VCV administered with dual NRTIs in treatment-naive subjects with HIV-1 infection had increased rates of virologic failure, compared with efavirenz plus dual NRTIs. No treatment-limiting toxicity was observed. Study of higher doses of VCV as part of combination therapy is warranted. Increasing rates of resistance, long-term metabolic and end-organ toxicities are driving factors in the develop

AIM: To evaluate addition of boceprevir to peginterferon/ribavirin (PR) in Russian patients with chronic hepatitis C virus (HCV). METHODS: Treatment-naive (TN) and treatment-experienced (TE) patients (who had failed prior treatment with PR for ≥ 12 wk) with chronic HCV genotype 1 infection were enrolled in this placebo-controlled, double-blind study. All patients initially received PR for 4 wk. Patients randomized to control treatment then received PR for an additional 44 wk. TN patients randomized to triple therapy received boceprevir (800 mg three times daily) plus PR for 24 wk and then further therapy according to treatment week 8 (TW8) HCV RNA levels. TE patients received boceprevir plus PR for 32 wk and then further therapy according to TW8 HCV RNA levels. Treatment was discontinued for TN patients with detectable HCV RNA at TW24 and TE patients with detectable HCV RNA at TW12 because of futility. The primary efficacy end point was sustained virologic response (SVR) defined as undetectable HCV RNA 24 wk after completing all study therapy. RESULTS: SVR was 74.8% in the boceprevir plus PR arm compared with 46.2% in the control arm, with a stratification-adjusted treatment difference of 29.2% (95%CI: 16.4-41.5; P < 0.0001). Rates of SVR were higher in the boceprevir arm in both TN and TE patient groups (TN 78.4% vs 56.3%; TE 69.4% vs 30.0%). Within TE patients, the rates of SVR were higher with boceprevir plus PR compared with PR, regardless of treatment failure type (null responder, partial responder, and relapser). Most patients receiving boceprevir plus PR in both TN (86%) and TE (71%) populations were eligible for reduced treatment duration. Anemia was increased in patients receiving boceprevir plus PR vs PR alone (47.2% vs 24.4%); there was a corresponding increase in ribavirin dose reduction and erythropoietin use. Among patients receiving boceprevir plus PR, SVR rates were similar in patients with anemia (< 10 g/dL) and those without anemia (71.2% vs 77.4%). CONCLUSION: Regulatory approval has been obtained for boceprevir plus PR in Russian patients with HCV genotype 1 infection based on the results of this study.

A project is defined as the collection of activities (or events) {a, b,…} among which a precedence relation a ≺ b is defined. It is supposed to be transitive, i.e., if a ≺ b and b ≺c then a ≺c. Any project can be depicted as a directed network, where the directed arcs represent the activities. Without restricting generality, we may assume that there is exactly one node such that no arc leads into it and there is exactly one node such that no arc goes out of it. These two nodes will be called original and terminal nodes, respectively.

Background We investigated the frequency of RAVs among patients failing to achieve SVR in two clinical trials. We also investigated the impact of interferon responsiveness on RAVs and specific baseline RAVs relationship with boceprevir treatment failure. Methods Data are from 1020 patients enrolled into either SPRINT-2 or RESPOND-2; patients received a 4-week PR lead-in prior to receiving boceprevir or placebo. RAVs were analyzed via population-based sequence analysis of the NS3 protease gene (success rate of >90% at a virus level of ≥10,000 IU/mL) Results The high SVR rate in patients who received boceprevir resulted in a low rate of RAVs; 7% was detected at baseline in all patients, which rose to 15% after treatment. However, RAVs were detected in 53% of patients that failed to achieve SVR, which declined to 22.8% 6–14 months following cessation of boceprevir therapy. Baseline RAVs alone were not predictive of virologic outcome; poor interferon responsiveness was highly predictive of non-SVR. RAVs were more frequently detected in poor interferon responders. Conclusions We detected no association between the presence of baseline amino acid variants at boceprevir resistance-associated loci and outcome in the context of good IFN response.

In the present paper, we consider a two-dimensional contact problem of a rigid cylinder indenting on an elastic half space with surface tension. Based on the solution of a point force acting on a substrate with surface tension, we derive the singular integral equation of this problem. By using the Guass–Chebyshev quadrature formula, the integral equation is solved numerically to illuminate the influence of surface tension on the contact response. It is found that when the contact width is comparable with the ratio of surface tension to elastic modulus, surface tension significantly alters the pressure distribution in the contact region and the contact width. Compared to that of the classical Hertzian contact, the existence of surface tension decreases the displacements on the half plane and yields a continuous slope of normal stress and displacements across the contact fringe. In addition, it predicts the increase of hardness as the radius of indent cylinder decreasing. The obtained results are useful for the measurement of mechanical properties of materials based on the indentation technique.