Generalizing the per-protocol treatment effect: The case of ACTG A5095

Background Intention-to-treat comparisons of randomized trials provide asymptotically consistent estimators of the effect of treatment assignment, without regard to compliance. However, decision makers often wish to know the effect of a per-protocol comparison. Moreover, decision makers may also wish to know the effect of treatment assignment or treatment protocol in a user-specified target population other than the sample in which the trial was fielded. Here, we aimed to generalize results from the ACTG A5095 trial to the US recently HIV-diagnosed target population. Methods We first replicated the published conventional intention-to-treat estimate (2-year risk difference and hazard ratio) comparing a four-drug antiretroviral regimen to a three-drug regimen in the A5095 trial. We then estimated the intention-to-treat effect that accounted for informative dropout and the per-protocol effect that additionally accounted for protocol deviations by constructing inverse probability weights. Furthermore, we employed inverse odds of sampling weights to generalize both intention-to-treat and per-protocol effects to a target population comprising US individuals with HIV diagnosed during 2008–2014. Results Of 761 subjects in the analysis, 82 dropouts (36 in the three-drug arm and 46 in the four-drug arm) and 59 protocol deviations (25 in the three-drug arm and 34 in the four-drug arm) occurred during the first 2 years of follow-up. A total of 169 subjects incurred virologic failure or death. The 2-year risks were similar both in the trial and in the US HIV-diagnosed target population for estimates from the conventional intention-to-treat, dropout-weighted intention-to-treat, and per-protocol analyses. In the US target population, the 2-year conventional intention-to-treat risk difference (unit: %) for virologic failure or death comparing the four-drug arm to the three-drug arm was −0.4 (95% confidence interval: −6.2, 5.1), while the hazard ratio was 0.97 (95% confidence interval: 0.70, 1.34); the 2-year risk difference was −0.9 (95% confidence interval: −6.9, 5.3) for the dropout-weighted intention-to-treat comparison (hazard ratio = 0.95, 95% confidence interval: 0.68, 1.32) and −0.7 (95% confidence interval: −6.7, 5.5) for the per-protocol comparison (hazard ratio = 0.96, 95% confidence interval: 0.69, 1.34). Conclusion No benefit of four-drug antiretroviral regimen over three-drug regimen was found from the conventional intention-to-treat, dropout-weighted intention-to-treat or per-protocol estimates in the trial sample or target population

Assessment and improvement of the Plasmodium yoelii yoelii genome annotation through comparative analysis

Motivation: The sequencing of the Plasmodium yoelii genome, a model rodent malaria parasite, has greatly facilitated research for the development of new drug and vaccine candidates against malaria. Unfortunately, only preliminary gene models were annotated on the partially sequenced genome, mostly by in silico gene prediction, and there has been no major improvement of the annotation since 2002

Grain refinement of magnesium alloys: a review of recent research, theoretical developments and their application

This paper builds on the ‘‘Grain Refinement of Mg Alloys’’ published in 2005 and reviews the grain refinement research onMg alloys that has been undertaken since then with an emphasis on the theoretical and analytical methods that have been developed. Consideration of recent research results and current theoretical knowledge has highlighted two important factors that affect an alloy’s as-cast grain size. The first factor applies to commercial Mg-Al alloys where it is concluded that impurity and minor elements such as Fe and Mn have a substantially negative impact on grain size because, in combination with Al, intermetallic phases can be formed that tend to poison the more potent native or deliberately added nucleant particles present in the melt. This factor appears to explain the contradictory experimental outcomes reported in the literature and suggests that the search for a more potent and reliable grain refining technology may need to take a different approach. The second factor applies to all alloys and is related to the role of constitutional supercooling which, on the one hand, promotes grain nucleation and, on the other hand, forms a nucleation-free zone preventing further nucleation within this zone, consequently limiting the grain refinement achievable, particularly in low solute-containing alloys. Strategies to reduce the negative impact of these two factors are discussed. Further, the Interdependence model has been shown to apply to a broad range of casting methods from slow cooling gravity die casting to fast cooling high pressure die casting and dynamic methods such as ultrasonic treatment

Construction status and prospects of the Hyper-Kamiokande project

The Hyper-Kamiokande project is a 258-kton Water Cherenkov together with a 1.3-MW high-intensity neutrino beam from the Japan Proton Accelerator Research Complex (J-PARC). The inner detector with 186-kton fiducial volume is viewed by 20-inch photomultiplier tubes (PMTs) and multi-PMT modules, and thereby provides state-of-the-art of Cherenkov ring reconstruction with thresholds in the range of few MeVs. The project is expected to lead to precision neutrino oscillation studies, especially neutrino CP violation, nucleon decay searches, and low energy neutrino astronomy. In 2020, the project was officially approved and construction of the far detector was started at Kamioka. In 2021, the excavation of the access tunnel and initial mass production of the newly developed 20-inch PMTs was also started. In this paper, we present a basic overview of the project and the latest updates on the construction status of the project, which is expected to commence operation in 2027

Prospects for neutrino astrophysics with Hyper-Kamiokande

Hyper-Kamiokande is a multi-purpose next generation neutrino experiment. The detector is a two-layered cylindrical shape ultra-pure water tank, with its height of 64 m and diameter of 71 m. The inner detector will be surrounded by tens of thousands of twenty-inch photosensors and multi-PMT modules to detect water Cherenkov radiation due to the charged particles and provide our fiducial volume of 188 kt. This detection technique is established by Kamiokande and Super-Kamiokande. As the successor of these experiments, Hyper-K will be located deep underground, 600 m below Mt. Tochibora at Kamioka in Japan to reduce cosmic-ray backgrounds. Besides our physics program with accelerator neutrino, atmospheric neutrino and proton decay, neutrino astrophysics is an important research topic for Hyper-K. With its fruitful physics research programs, Hyper-K will play a critical role in the next neutrino physics frontier. It will also provide important information via astrophysical neutrino measurements, i.e., solar neutrino, supernova burst neutrinos and supernova relic neutrino. Here, we will discuss the physics potential of Hyper-K neutrino astrophysics

A spatiotemporal statistical model of the risk factors of human cases of H5N1 avian influenza in South-east Asian countries and China

Objectives: This article aims to quantify the risk factors associated with the human cases of H5N1 avian influenza in South-east Asian countries and China; a dangerous region for this disease that has the potential for a pandemic outbreak. Study design: A statistical model with time and spatial dimensions was built to capture the international spread patterns of this disease. Methods: The grid search method was used to fit the model with 2004-2006 data. The grid search approach is a simple procedure that allows the fit of any function to data. Results: This study found that: (1) when the number of domestic H5N1 human cases increases by one person in a certain time period, the chance that the country will have a human case in the next period increases by 22.10%; (2) when the number of human cases in a neighbouring country increases by one person in a certain time period, the chance that the country will have a human case in the next period increases by 1.62%; (3) when the number of avian cases in a neighbouring country increases by one, the chance that the country will have a human case increases by 0.02%; (4) as the human population increases by one unit. the chance that the country will have a human case increases by 0.10%; (5) when the quantity of imported poultry increases by 1000 metric tons, the chance that the country will have a human case increases by 0.03%; (6) when the outbreak of the disease among domestic birds increases by one, the chance that the country will have a human case increases by 0.19%; and finally (7) when the number of birds destroyed increases by 1000, the chance that the country will have a human case decreases by 0.30%. Conclusions: These findings shed new light on the spatiotemporal characteristics of the epidemic, and thus need to be taken into consideration in interdisciplinary and scientific discussion of the disease. (C) 2008 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved

A spatiotemporal statistical model of the risk factors of human cases of H5N1 avian influenza in South-east Asian countries and China

Objectives: This article aims to quantify the risk factors associated with the human cases of H5N1 avian influenza in South-east Asian countries and China; a dangerous region for this disease that has the potential for a pandemic outbreak. Study design: A statistical model with time and spatial dimensions was built to capture the international spread patterns of this disease. Methods: The grid search method was used to fit the model with 2004-2006 data. The grid search approach is a simple procedure that allows the fit of any function to data. Results: This study found that: (1) when the number of domestic H5N1 human cases increases by one person in a certain time period, the chance that the country will have a human case in the next period increases by 22.10%; (2) when the number of human cases in a neighbouring country increases by one person in a certain time period, the chance that the country will have a human case in the next period increases by 1.62%; (3) when the number of avian cases in a neighbouring country increases by one, the chance that the country will have a human case increases by 0.02%; (4) as the human population increases by one unit. the chance that the country will have a human case increases by 0.10%; (5) when the quantity of imported poultry increases by 1000 metric tons, the chance that the country will have a human case increases by 0.03%; (6) when the outbreak of the disease among domestic birds increases by one, the chance that the country will have a human case increases by 0.19%; and finally (7) when the number of birds destroyed increases by 1000, the chance that the country will have a human case decreases by 0.30%. Conclusions: These findings shed new light on the spatiotemporal characteristics of the epidemic, and thus need to be taken into consideration in interdisciplinary and scientific discussion of the disease. (C) 2008 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved