A cross-jurisdictional comparison on residential waste collection rates during earlier waves of COVID-19.

There is currently a lack of studies on residential waste collection during COVID-19 in North America. SARIMA models were developed to predict residential waste collection rates (RWCR) across four North American jurisdictions before and during the pandemic. Unlike waste disposal rates, RWCR is relatively less sensitive to the changes in COVID-19 regulatory policies and administrative measures, making RWCR more appropriate for cross-jurisdictional comparisons. It is hypothesized that the use of RWCR in forecasting models will help us to better understand the residential waste generation behaviors in North America. Both SARIMA models performed satisfactorily in predicting Regina's RWCR. The SARIMA DCV model's performance is noticeably better during COVID-19, with a 15.7% lower RMSE than that of the benchmark model (SARIMA BCV). The skewness of overprediction ratios was noticeably different between jurisdictions, and modeling errors were generally lower in less populated cities. Conflicting behavioral changes might have altered the residential waste generation characteristics and recycling behaviors differently across the jurisdictions. Overall, SARIMA DCV performed better in the Canadian jurisdiction than in U.S. jurisdictions, likely due to the model's bias on a less variable input dataset. The use of RWCR in forecasting models helps us to better understand the residential waste generation behaviors in North America and better prepare us for a future global pandemic.

Generate Analysis-Ready Data for Real-world Evidence: Tutorial for Harnessing Electronic Health Records With Advanced Informatic Technologies.

Although randomized controlled trials (RCTs) are the gold standard for establishing the efficacy and safety of a medical treatment, real-world evidence (RWE) generated from real-world data has been vital in postapproval monitoring and is being promoted for the regulatory process of experimental therapies. An emerging source of real-world data is electronic health records (EHRs), which contain detailed information on patient care in both structured (eg, diagnosis codes) and unstructured (eg, clinical notes and images) forms. Despite the granularity of the data available in EHRs, the critical variables required to reliably assess the relationship between a treatment and clinical outcome are challenging to extract. To address this fundamental challenge and accelerate the reliable use of EHRs for RWE, we introduce an integrated data curation and modeling pipeline consisting of 4 modules that leverage recent advances in natural language processing, computational phenotyping, and causal modeling techniques with noisy data. Module 1 consists of techniques for data harmonization. We use natural language processing to recognize clinical variables from RCT design documents and map the extracted variables to EHR features with description matching and knowledge networks. Module 2 then develops techniques for cohort construction using advanced phenotyping algorithms to both identify patients with diseases of interest and define the treatment arms. Module 3 introduces methods for variable curation, including a list of existing tools to extract baseline variables from different sources (eg, codified, free text, and medical imaging) and end points of various types (eg, death, binary, temporal, and numerical). Finally, module 4 presents validation and robust modeling methods, and we propose a strategy to create gold-standard labels for EHR variables of interest to validate data curation quality and perform subsequent causal modeling for RWE. In addition to the workflow proposed in our pipeline, we also develop a reporting guideline for RWE that covers the necessary information to facilitate transparent reporting and reproducibility of results. Moreover, our pipeline is highly data driven, enhancing study data with a rich variety of publicly available information and knowledge sources. We also showcase our pipeline and provide guidance on the deployment of relevant tools by revisiting the emulation of the Clinical Outcomes of Surgical Therapy Study Group Trial on laparoscopy-assisted colectomy versus open colectomy in patients with early-stage colon cancer. We also draw on existing literature on EHR emulation of RCTs together with our own studies with the Mass General Brigham EHR.

Exploring the use of sodium caseinate-assisted responsive separation for the treatment of washing effluents in shoreline oil spill response.

The produced effluents after shoreline washing contain a certain number of oil droplets and further treatment is necessary. In this study, the innocuous, widely available, and biodegradable sodium caseinate (NaCas) was deployed to capture oil pollutants from oily wastewater. Oil droplets can be effectively and rapidly captured by NaCas and subsequently removed after pH-triggered separation, producing a clean supernatant with low turbidity. The removal efficiency was enhanced by increasing NaCas concentration and separation time. The salinity inhibited the oil removal by increasing the interfacial tension of NaCas and reducing their sorption sites caused by the large particle size. Humic acid negatively influenced the oil separation performance of NaCas because of the competitive sorption and enhanced repulsion force between oil and NaCas. In addition, the increasing temperature was found to augment the oil removal. Factorial analysis revealed the individual factors and two-factor interactions that had significant effects on oil removal. Biotoxicity experiments proved that NaCas can fully offset the inhibitory effect of oil on the photosynthesis of algae and thus promote algae growth. Two post-treatment methods, namely thermal treatment, and biodegradation, can be used for the post-treatment of NaCas/oil precipitation residues. The use of NaCas-assisted responsive separation in the treatment of washing effluents can help achieve a sustainable shoreline oil spill response.

A pH-responsive phosphoprotein washing fluid for the removal of phenanthrene from contaminated peat moss in the cold region.

Oil pollution is one of the major environmental concerns in the petroleum industry. In this study, a cheap food-grade sodium caseinate (NaCas) was used as a pH-responsive washing fluid in the remediation of phenanthrene (PHE) affected peat moss. The effects of environmental factors on the removal of PHE were systematically investigated. The results showed that increasing NaCas concentration and washing temperature improved the PHE mobilization, while high salinity and humic acid dosage displayed a negative effect. The factorial analysis revealed that three individual factors and two interactions exhibited significant effects on the washing performance. Due to the pH-responsive property of NaCas, the turbidity, total organic carbon (TOC), and chemical oxygen demand (COD) of the washing effluent were remarkably reduced by simply adjusting the solution acidity, improving the practical application of such a washing method. Significantly, the toxicity modeling proved that NaCas can reduce the binding energy between PHE and superoxide dismutase (SOD) of the selected marine organism, and thus relieve the toxicity of PHE to the organisms. Given these advantages, NaCas-assisted washing can be a viable option for the remediation of contaminated peat moss.

Exploring the characteristics, performance, and mechanisms of a magnetic-mediated washing fluid for the cleanup of oiled beach sand.

In the present study, an innovative, environmentally benign recyclable, and magnetically mediated surface washing fluid based on water-dispersible magnetite nanoparticles has been designed and investigated for the cleanup of oiled beach sand. The characterization results showed that the as-prepared magnetite nanoparticles had a spherical morphology with an average diameter of around 250 nm and the particle surface was successfully functionalized with carboxyl groups. The magnetite nanoparticles could be easily re-dispersed by lightly shaking the dispersion after withdrawing the magnet. In addition, prolonging the magnetic field strength and response time promoted the oil recovery from the washing effluent. Thermodynamic modeling was applied to theoretically elucidate the mechanism and the results were in alignment with the experimental findings. Four mechanisms were identified to likely affect surface washing performance. The magnetic fluid had a relatively low operation cost and good reusability for a number of multiple cycles. In terms of other operational limitations, it was noted that washing performance declined as clay (kaolinite) concentrations and salinity values increased. Based on these findings, the proposed stable, low-cost magnetite fluid formulation warrants further investigation as the basis for an operational system for the cleanup of sand beaches contaminated by oil spills.

Health-related Quality of Life Analysis from KEYNOTE-426: Pembrolizumab plus Axitinib Versus Sunitinib for Advanced Renal Cell Carcinoma.

BACKGROUND: In the phase 3 KEYNOTE-426 (NCT02853331) trial, pembrolizumab + axitinib demonstrated improvement in overall survival, progression-free survival, and objective response rate over sunitinib monotherapy for advanced renal cell carcinoma (RCC). OBJECTIVE: To evaluate health-related quality of life (HRQoL) in KEYNOTE-426. DESIGN, SETTING, AND PARTICIPANTS: A total of 861 patients were randomly assigned to receive pembrolizumab + axitinib (n = 432) or sunitinib (n = 429). HRQoL data were available for 429 patients treated with pembrolizumab + axitinib and 423 patients treated with sunitinib. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: HRQoL end points were measured using the European Organisation for the Research and Treatment of Cancer Core (EORTC) Quality of Life Questionnaire (QLQ-C30), EQ-5D visual analog rating scale (VAS), and Functional Assessment of Cancer Therapy Kidney Cancer Symptom Index-Disease-Related Symptoms (FKSI-DRS) questionnaires. RESULTS AND LIMITATIONS: Better or not different overall improvement rates from baseline between pembrolizumab + axitinib and sunitinib were observed for the FKSI-DRS (-0.79% improvement vs sunitinib; 95% confidence interval [CI] -7.2 to 5.6), QLQ-C30 (7.5% improvement vs sunitinib; 95% CI 1.0-14), and EQ-5D VAS (9.9% improvement vs sunitinib; 95% CI 3.2-17). For time to confirmed deterioration (TTcD) and time to first deterioration (TTfD), no differences were observed between arms for the QLQ-C30 (TTcD hazard ratio [HR] 1.0; 95% CI 0.82-1.3; TTfD HR 0.82; 95% CI 0.69-0.97) and EQ-5D VAS (TTcD HR 1.1; 95% CI 0.87-1.3; TTfD HR 0.98; 95% CI 0.83-1.2). TTfD was not different between treatment arms (HR 1.1; 95% CI 0.95-1.3) for the FKSI-DRS, but TTcD favored sunitinib (HR 1.4; 95% CI 1.1-1.7). Patients were assessed during the off-treatment period for sunitinib, which may have underestimated the negative impact of sunitinib on HRQoL. CONCLUSIONS: Overall, patient-reported outcome scales showed that results between the pembrolizumab + axitinib and sunitinib arms were not different, with the exception of TTcD by the FKSI-DRS. PATIENT SUMMARY: Compared with sunitinib, pembrolizumab + axitinib delays disease progression and extends survival, while HRQoL outcomes were not different between groups.

Two-level approaches to missing data in longitudinal trials with daily patient-reported outcomes.

In longitudinal clinical trials with daily patient-reported outcomes, the analysis endpoints are often defined as the averaged daily diary outcomes in a treatment cycle (such as a month or a week). Conventional methods often deal with missing data at the cycle level by imputing the average, and the cycle average is treated as missing if the number of days with available outcomes in the treatment cycle is less than a certain number. This was the method used for a case study of a phase 3 clinical trial evaluating a treatment for insomnia with daily patient-reported outcomes. Such methods may introduce bias. Motivated by this, we propose methods to impute missing daily outcomes in this paper. Specifically, we define a two-level missing pattern for clinical trials with daily patient-reported outcomes, and propose two-level methods to impute missing data at daily base. Other than the standard methods by multiple imputations, we derive analytic formulas for the proposed two-level methods to reduce computational intensity and improve the estimates of variances. The proposed two-level methods provide more powerful approaches to estimate the treatment difference compared to the conventional cycle-level methods, which are evaluated by theoretical development and simulation studies. In addition, the methods are applied to the motivating phase 3 trial evaluating a treatment for insomnia with daily patient-reported outcomes.

Periodic benefit-risk assessment using Bayesian stochastic multi-criteria acceptability analysis.

Benefit-risk (BR) assessment is essential to ensure the best decisions are made for a medical product in the clinical development process, regulatory marketing authorization, post-market surveillance, and coverage and reimbursement decisions. One challenge of BR assessment in practice is that the benefit and risk profile may keep evolving while new evidence is accumulating. Regulators and the International Conference on Harmonization (ICH) recommend performing periodic benefit-risk evaluation report (PBRER) through the product's lifecycle. In this paper, we propose a general statistical framework for periodic benefit-risk assessment, in which Bayesian meta-analysis and stochastic multi-criteria acceptability analysis (SMAA) will be combined to synthesize the accumulating evidence. The proposed approach allows us to compare the acceptability of different drugs dynamically and effectively and accounts for the uncertainty of clinical measurements and imprecise or incomplete preference information of decision makers. We apply our approaches to two real examples in a post-hoc way for illustration purpose. The proposed method may easily be modified for other pre and post market settings, and thus be an important complement to the current structured benefit-risk assessment (sBRA) framework to improve the transparent and consistency of the decision-making process.

Safety and efficacy of a fixed-dose combination regimen of grazoprevir, ruzasvir, and uprifosbuvir with or without ribavirin in participants with and without cirrhosis with chronic hepatitis C virus genotype 1, 2, or 3 infection (C-CREST-1 and C-CREST-2, part B): two randomised, phase 2, open-label trials.

BACKGROUND: There is a need for hepatitis C virus (HCV) therapies with excellent efficacy across genotypes and in diverse populations. Part A of the C-CREST-1 and C-CREST-2 trials led to the selection of a three-drug regimen of grazoprevir (MK-5172; an HCV NS3/4A protease inhibitor; 100 mg/day) plus ruzasvir (MK-8408; an NS5A inhibitor; 60 mg/day) plus uprifosbuvir (MK-3682; an HCV NS5B polymerase inhibitor; 450 mg/day). Part B of the studies tested this combination as a single formulation in different treatment durations in a broader population. METHODS: Part B of these randomised, phase 2, open-label clinical trials enrolled individuals from 15 countries who were chronically infected with HCV genotypes 1-6 (HCV RNA ≥10 000 IU/mL) with or without compensated cirrhosis. Those with genotype 1, genotype 2, genotype 4, or genotype 6 were treatment-naive; those with genotype 3 could be treatment-naive or treatment-experienced with pegylated interferon and ribavirin. Randomisation occurred centrally using an interactive voice response system and integrated web response system. Participants were randomly assigned to receive treatment for 8, 12, or 16 weeks with a fixed-dose combination of grazoprevir, ruzasvir, and uprifosbuvir with or without ribavirin. The primary endpoint was the proportion of participants achieving sustained virological response 12 weeks after the end of all study therapy (SVR12), defined as HCV RNA less than the lower limit of quantification (either target detected unquantifiable or target not detected [<15 IU/mL]). The trials are registered at ClinicalTrials.gov, numbers NCT02332707 and NCT02332720. FINDINGS: 676 participants were randomly assigned between Feb 18, 2015, and Aug 16, 2016. In all 675 participants who received at least one dose of study drug (full analysis set), SVR12 for the 8-week regimen of grazoprevir, ruzasvir, and uprifosbuvir with and without ribavirin was achieved in 39 (93% [95% CI 81-99]) of 42 participants with genotype 1a, 45 (98% [88-100]) of 46 with genotype 1b, 54 (86% [75-93]) of 63 with genotype 2, 98 (95% [89-98]) of 103 with genotype 3, and seven (100% [59-100]) of seven participants with genotype 4. SVR12 for the 12-week regimen with and without ribavirin was achieved in 87 (99% [95% CI 94-100]) of 88 participants with genotype 1, 61 (98% [91-100]) of 62 with genotype 2, and four (100% [40-100]) of four with genotype 6. Among participants with cirrhosis who were infected with genotype 3, SVR12 for the 12-week regimen with and without ribavirin was achieved in 28 (97% [95% CI 82-100]) of 29 of those who were treatment-naive and 29 (100% [88-100]) of 29 who were treatment-experienced. SVR12 for the 16-week regimen with and without ribavirin was achieved in 26 (100% [95% CI 87-100]) of 26 participants with genotype 2 infection and 72 (96% [89-99]) of 75 participants with genotype 3 infection. The most common adverse events were headache (143 [22%] of 664), fatigue (129 [19%] of 664), and nausea (83 [13%] of 664). 16 (2%) of 664 participants had serious adverse events. INTERPRETATION: The combined regimen of grazoprevir (100 mg/day), ruzasvir (60 mg/day), and uprifosbuvir (450 mg/day) has the potential to provide a simplified treatment for HCV that is effective and well tolerated in most individuals infected with HCV, as well as a shorter duration of treatment in many individuals. FUNDING: Merck & Co, Inc.

Safety and efficacy of an 8-week regimen of grazoprevir plus ruzasvir plus uprifosbuvir compared with grazoprevir plus elbasvir plus uprifosbuvir in participants without cirrhosis infected with hepatitis C virus genotypes 1, 2, or 3 (C-CREST-1 and C-CREST-2, part A): two randomised, phase 2, open-label trials.

BACKGROUND: New hepatitis C virus (HCV) therapies with pan-genotypic efficacy are needed. The goals of part A of C-CREST-1 and C-CREST-2 were to compare the efficacies of two doses (300 mg or 450 mg once daily) of uprifosbuvir (MK-3682; NS5B inhibitor) in an 8-week regimen combined with grazoprevir (NS3/4A inhibitor; 100 mg once daily) and an NS5A inhibitor, either elbasvir (50 mg once daily) or ruzasvir (MK-8408; 60 mg once daily), and to evaluate the safety and tolerability of these combination regimens in individuals infected with genotypes 1, 2, or 3. METHODS: Part A of these phase 2, randomised, multicentre, open-label, clinical trials enrolled participants from 11 countries, aged 18 years or older, chronically infected with HCV genotypes 1, 2, or 3, with HCV RNA of at least 10 000 IU/mL, without evidence of cirrhosis, who had not received previous treatment for HCV infection. Within each HCV genotype, participants were randomly assigned (1:1:1:1) with a block size of 4, to open-label treatment to one of four treatment groups: grazoprevir (100 mg/day) plus ruzasvir (60 mg/day) plus uprifosbuvir (300 mg/day); grazoprevir (100 mg/day) plus ruzasvir (60 mg/day) plus uprifosbuvir (450 mg/day); grazoprevir (100 mg/day) plus elbasvir (50 mg/day) plus uprifosbuvir (300 mg/day); or grazoprevir (100 mg/day) plus elbasvir (50 mg/day) plus uprifosbuvir (450 mg/day), according to a computer-generated allocation schedule. Randomisation was centrally implemented using an interactive voice response system and integrated web response system. The primary endpoint was the proportion of participants achieving sustained virological response at 12 weeks (SVR12; HCV RNA less than the lower limit of quantitation at 12 weeks after the end of all study therapy) in the per-protocol analysis set, which included all participants who were randomised and received at least one dose of study drug. The trials are registered with ClinicalTrials.gov, numbers NCT02332707 and NCT02332720. FINDINGS: 241 participants were randomised between Feb 18, 2015, and March 16, 2015. 240 participants completed 8 weeks of treatment and reached follow-up 12 weeks after the end of treatment. Of the four regimens, grazoprevir plus ruzasvir plus uprifosbuvir 450 mg had the most consistently high SVR12 (>90%) for participants infected with genotype 1 (21 [91%] of 23), genotype 2 (15 [94%] of 16), and genotype 3 (20 [91%] of 22). In particular, among those with genotype 2 infection, the grazoprevir plus ruzasvir plus uprifosbuvir 450 mg regimen had a higher SVR12 (15 [94%] of 16) than the grazoprevir plus ruzasvir plus uprifosbuvir 300 mg regimen (ten [71%] of 14), grazoprevir plus elbasvir plus uprifosbuvir 300 mg regimen (11 [69%] of 16), or grazoprevir plus elbasvir plus uprifosbuvir 450 mg regimen (nine [60%] of 15). Overall, the most common adverse events were headache (55 [23%] of 240), fatigue (47 [20%] of 240), and nausea (32 [13%] of 240). Two (<1%) of 240 participants had serious adverse events (pharyngeal abscess and keratitis), which were not considered drug related by the respective investigators. INTERPRETATION: These results support further evaluation of the three-drug direct-acting antiviral agent regimen of grazoprevir 100 mg plus ruzasvir 60 mg plus uprifosbuvir 450 mg among a more diverse HCV-infected population, including those with compensated cirrhosis, previous treatment with an interferon-containing regimen, and HCV-HIV co-infection. FUNDING: Merck & Co, Inc.

Grazoprevir plus elbasvir in treatment-naive and treatment-experienced patients with hepatitis C virus genotype 1 infection and stage 4-5 chronic kidney disease (the C-SURFER study): a combination phase 3 study.

BACKGROUND: Chronic hepatitis C virus (HCV) infection in patients with stage 4-5 chronic kidney disease increases the risk of death and renal graft failure, yet patients with hepatitis C and chronic kidney disease have few treatment options. This study assesses an all-oral, ribavirin-free regimen in patients with HCV genotype 1 infection and stage 4-5 chronic kidney disease. METHODS: In this phase 3 randomised study of safety and observational study of efficacy, patients with HCV genotype 1 infection and chronic kidney disease (stage 4-5 with or without haemodialysis dependence) were randomly assigned to receive grazoprevir (100 mg, NS3/4A protease inhibitor) and elbasvir (50 mg, NS5A inhibitor; immediate treatment group) or placebo (deferred treatment group) once daily for 12 weeks. Randomisation was done centrally with an interactive voice response system. An additional cohort of patients who were not randomised received the same regimen open-label and underwent intensive pharmacokinetic sampling. The primary efficacy outcome was a non-randomised comparison of sustained virological response at 12 weeks (SVR12) after the end of therapy for the combined immediate treatment group and the pharmacokinetic population with a historical control. The primary safety outcome was a randomised comparison between the immediate treatment group and the deferred treatment group. After 4 weeks of follow-up (study week 16), unmasking occurred and patients in the deferred treatment group received grazoprevir and elbasvir. The primary efficacy hypothesis was tested at a two-sided significance level (type I error) of 0·05 using an exact test for a binomial proportion. Safety event rates were compared between immediate treatment and deferred treatment groups using the stratified Miettinen and Nurminen method with baseline dialysis status as the strata. The study is registered at ClinicalTrials.gov, number NCT02092350. FINDINGS: 224 patients were randomly assigned to the immediate treatment group with grazoprevir and elbasvir (n=111) or the deferred treatment group (n=113), and 11 were assigned to the intensive pharmacokinetic population. Overall, 179 (76%) were haemodialysis-dependent, 122 (52%) had HCV genotype 1a infection, 189 (80%) were HCV treatment-naive, 14 (6%) were cirrhotic, and 108 (46%) were African American. Of the 122 patients receiving grazoprevir and elbasvir, six were excluded from the primary efficacy analysis for non-virological reasons (death, lost-to-follow-up [n=2], non-compliance, patient withdrawal, and withdrawal by physician for violent behaviour). No patients in the combined immediate treatment group and intensive pharmacokinetic population and five (4%) in the deferred treatment group discontinued because of an adverse event. Most common adverse events were headache, nausea, and fatigue, occurring at similar frequencies in patients receiving active and placebo drugs. SVR12 in the combined immediate treatment group and intensive pharmacokinetic population was 99% (95% CI 95·3-100·0; 115/116), with one relapse 12 weeks after end of treatment when compared with a historical control of 45%, based on meta-analyses of interferon-based regimens used in clinical trials of patients infected with HCV who are on haemodialysis. INTERPRETATION: Once-daily grazoprevir and elbasvir for 12 weeks had a low rate of adverse events and was effective in patients infected with HCV genotype 1 and stage 4-5 chronic kidney disease. FUNDING: Merck Sharp & Dohme Corp.

Grazoprevir-Elbasvir Combination Therapy for Treatment-Naive Cirrhotic and Noncirrhotic Patients With Chronic Hepatitis C Virus Genotype 1, 4, or 6 Infection: A Randomized Trial.

BACKGROUND: Novel interferon- and ribavirin-free regimens are needed to treat hepatitis C virus (HCV) infection. OBJECTIVE: To evaluate the safety and efficacy of grazoprevir (NS3/4A protease inhibitor) and elbasvir (NS5A inhibitor) in treatment-naive patients. DESIGN: Randomized, blinded, placebo-controlled trial. (ClinicalTrials.gov: NCT02105467). SETTING: 60 centers in the United States, Europe, Australia, Scandinavia, and Asia. PATIENTS: Cirrhotic and noncirrhotic treatment-naive adults with genotype 1, 4, or 6 infection. INTERVENTION: Oral, once-daily, fixed-dose grazoprevir 100 mg/elbasvir 50 mg for 12 weeks, stratified by fibrosis and genotype. Patients were randomly assigned 3:1 to immediate or deferred therapy. MEASUREMENTS: Proportion of patients in the immediate-treatment group achieving unquantifiable HCV RNA 12 weeks after treatment (SVR12); adverse events in both groups. RESULTS: Among 421 participants, 194 (46%) were women, 157 (37%) were nonwhite, 382 (91%) had genotype 1 infection, and 92 (22%) had cirrhosis. Of 316 patients receiving immediate treatment, 299 of 316 (95% [95% CI, 92% to 97%]) achieved SVR12, including 144 of 157 (92% [CI, 86% to 96%]) with genotype 1a, 129 of 131 (99% [CI, 95% to 100%]) with genotype 1b, 18 of 18 (100% [CI, 82% to 100%]) with genotype 4, 8 of 10 (80% [CI, 44% to 98%]) with genotype 6, 68 of 70 (97% [CI, 90% to 100%]) with cirrhosis, and 231 of 246 (94% [CI, 90% to 97%]) without cirrhosis. Virologic failure occurred in 13 patients (4%), including 1 case of breakthrough infection and 12 relapses, and was associated with baseline NS5A polymorphisms and emergent NS3 or NS5A variants or both. Serious adverse events occurred in 9 (2.8%) and 3 (2.9%) patients in the active and placebo groups, respectively (difference <0.05 percentage point [CI, -5.4 to 3.1 percentage points]); none were considered drug related. The most common adverse events in the active group were headache (17%), fatigue (16%), and nausea (9%). LIMITATION: The study lacked an active-comparator control group and included relatively few genotype 4 and 6 infections. CONCLUSION: Grazoprevir-elbasvir achieved high SVR12 rates in treatment-naive cirrhotic and noncirrhotic patients with genotype 1, 4, or 6 infection. This once-daily, all-oral, fixed-combination regimen represents a potent new therapeutic option for chronic HCV infection. PRIMARY FUNDING SOURCE: Merck & Co.

Activation tagging, an efficient tool for functional analysis of the rice genome.

Over the past 6 years, we have generated about 50,000 individual transgenic rice plants by an Agrobacterium-mediated transformation approach with the pER38 activation tagging vector. The vector contains tandemly arranged double 35S enhancers next to the right border of T-DNA. Expression analysis by reverse transcription-PCR indicates that the activation efficiency is high if the genes are located within 7 kb of the inserted double 35S enhancers. Comparative field phenotyping of part of the activation tagging and enhancer trapping populations in two generations (6,000 and 6,400 lines, respectively, in the T(0) generation, and 36,000 and 32,000 lines, respectively, in the T(1) generation) identified about four hundred dominant mutants. Characterization of a dominant mutant with a large leaf angle (M107) suggests that this mutant phenotype is caused by enhanced expression of CYP724B1/D11. The activation tagging pool described in this paper is a valuable alternative tool for functional analysis of the rice genome.

Linkage analyses of rheumatoid arthritis and related quantitative phenotypes: the GAW15 experience.

The group that formed on the theme of linkage analyses of rheumatoid arthritis RA and related phenotypes (Group 10) in the Genetic Analysis Workshop 15 comprised 18 sets of investigators. Two data sets were available: one was a real set provided by the North American Rheumatoid Arthritis Consortium and collaborators in Canada, France (European Consortium Of Rheumatoid Arthritis Families) and the UK; the other was a simulated data set modelled after the real data set. Whereas a majority of the investigators analyzed the RA affection status as a binary phenotype, a few contributions considered data on correlated quantitative traits such as anti-cyclic citrullinated peptide and rheumatoid factor-immunoglobulin M. The different investigators applied a wide spectrum of linkage methods. As expected, most methods could identify the human leukocyfeantigen region on chromosome 6 as a major genetic factor for RA. In addition, some novel chromosomal regions provided significant evidence of linkage in multiple contributions in the group. In this report, we discuss the different strategies explored by the different investigators with the common goal of improving the power to detect linkage.

A likelihood-based procedure for obtaining confidence intervals of disease loci with general pedigree data.

We proposed a confidence interval method for disease gene localization by testing every position on each chromosome of interest for its possibility of being a disease locus and including those not rejected into the interval. Three test statistics were proposed to perform the tests, including one based on LOD and two generalized likelihood ratio tests with or without model averaging (GLRT/MA and GLRT). For the statistic based on LOD, an integrated procedure was proposed with an adaptive and an importance sampling component. We also proposed asymptotic approaches based on GLRT and GLRT/MA as alternatives that are much more efficient computationally but depends on the reliability of the limiting distributions. Besides its efficiency, the asymptotic procedure based on GLRT/MA also takes model uncertainty into consideration. Applications of these methods to the Genetic Analysis Workshop 15 (GAW15) rheumatoid arthritis data from the French population gave results that successfully captured the well recognized susceptibility gene HLA*DRB1 to a less than 6 cM, 99% confidence interval with the two asymptotic approaches.

Comparisons of methods for linkage analysis and haplotype reconstruction using extended pedigree data.

We compare and contrast the performance of SIMPLE, a Monte Carlo based software, with that of several other methods for linkage and haplotype analyses, focusing on the simulated data from the New York City population. First, a whole-genome scan study based on the microsatellite markers was performed using GENEHUNTER. Because GENEHUNTER had to drop individuals for many of the pedigrees, we performed a follow-up study focusing on several regions of interest using SIMPLE, which can handle all pedigrees in their entirety. Second, 3 haplotyping programs, including that in SIMPLE, were used to reconstruct haplotypic configurations in pedigrees. SIMPLE emerges clearly as a preferred tool, as it can handle large pedigrees and produces haplotypic configurations without double recombinant haplotypes. For this study, we had knowledge of the simulating models at the time we performed the analysis.