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The free trial period is 3 days. The paid version is $0.97 USD(97 cents) per month. To start the free trial or the paid version. Click on the license icon in the Netflix's video pages. Click on the [Reload license] button in the window. For more details -netflixdualsub-license/ver.2.1.8 November 11, 2023The Chrome Web Store category has expanded. We've changed it to the appropriate category.ver.2.1.8 March 20, 2023Migrated to the new Google sign-in from deprecated legacy Google Sign-inver.2.1.0 November 23, 2022Migrated this Chrome extension from Manifest V2 to Manifest V3ver.1.21.32 September 19, 2022Changed the manifestver.1.21.25 March 5, 2022Improved the performancever.1.21.24 February 24, 2022Changed the descriptionsver.1.21.19 October 9, 2021Fixed the UIver.1.21.11 July 7, 2021Changed license descriptionsver.1.21.9 January 7, 2021Changed license descriptionsver.1.21.8 December 2, 2020Google has announced that the payment service of the Chrome Web Store will end. The subscription of Chrome Web Store will not renew automatically after February 1, 2021. Please use Stripe's payment platform instead of Chrome Web Store.ver.1.21.4 April 25, 2020Fixed a bug of all available subtitles weren't displayed.ver.1.21.3 April 3, 2020Added features.ver.1.20.3 Dec 31, 2019Added features.ver.1.20.0 Dec 5, 2019Fixed the critical issue. 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Added a feature that Display the similar phrases and the translated phrases when hovering the mouse over the word.ver.1.14.0 April 19, 2019Added a feature that Favorite playback rate. The default value is set to 0.8x. Press [K] key to set. 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The next phrase is [H]ver.1.6.0 February 02, 2019Added a feature that Double-click the icon or press the [N] button twice to rewind to the previous phrase.ver.1.5.0 January 29, 2019Added all subtitles and dubbing to the menu if it's availableFixed bug that occasionally subtitles are not displayedver.1.4.2 January 28, 2019Added Furigana(ふりがな) to Japanese subtitlesver.1.4.1 January 26, 2019Fixed Japanese subtitles issuever.1.3.0 January 24, 2019Changed image based subtitles to text based subtitles. We can select on the subtitles with a mouse cursor.ver.1.2.2 January 22, 2019Fixed the issue caused by other Chrome extensions.ver.1.2.1 January 19, 2019Fixed the issue caused by the internal update of Netflix.ver.1.2.0 December 16, 2018Added a feature that saving the subtitle settings then loading the previous settingsAdded the overlay is not displayed while pausing a videoChanged the keyboard shortcuts. Pause or play to [V]. Hide the control bar and the overlay to [C]ver.1.1.4 November 21, 2018Fixed the subtitle menu for the new UIver.1.1.3 August 18, 2018Fixed the list of subtitle menuver.1.1.2 August 7, 2018Fixed the new player UIver.1.1.1 July 27, 2018Fixed the player controller functionver.1.1.0 July 24, 2018Added keyboard shortcuts for the playback ratever.1.0.5 July 2, 2018Fixed subtitles move up at one video frame when hiding the control barver.1.0.4 July 1, 2018Fixed overlapping subtitles on specific videos

DIAN scientists used this observational data for two main purposes. They built a mathematical disease-progression model to serve as a quantitative framework for treatment trials in this form of AD. They also tap this observational data to supplement the placebo dataset of DIAN-TU treatment trials so that fewer mutation carriers have to be on placebo during a multiyear trial. (The odds of being on placebo deters people from committing to long clinical trials.)

Preparations for an ongoing platform of successive DIAN-TU drug trials started nine years ago (Dec 2011 conference news). It engaged families the world over, together with pharma and other companies, academics and their site staff, funders, and other stakeholders, in an intensive public-private partnership. This PPP has thus far planned a series of seven drug arms, of which the solanezumab and gantenerumab treatment arms are the first two. The third arm, of the BACE inhibitor atabecestat, stopped in 2018 due to side effects, and arms four to seven will test drugs targeting tau and attempt primary prevention, respectively.

Seven Years. Over its long course, the first trial in dominantly inherited AD switched from a biomarker to a cognitive outcome trial, and escalated doses of both study drugs. [Courtesy of DIAN-TU.]

On the primary endpoint, neither treatment group did significantly better than placebo by year four, the last time point at which cognitive and biomarkers were both assessed. (At year five, cognitive but not biomarker data were assessed, and the groups were smaller due to the dropouts.) Overall, both placebo and drug arms declined.

Part of the problem with the trial data arises from the disease-progression model. It constitutes the statistical construct for analysis of the primary endpoint data in both trial arms. The model was fitted to the DIAN-obs data. To compensate for limitations inherent in running treatment trials in this rare disease, the model made assumptions, for example that performance on all tests would decline, or that variance would be constant across presymptomatic and symptomatic participants, and also about when symptoms would likely start.

Biomarkers to the Rescue?
The U-turn toward hope came with the biomarker analysis. The near-total completion rate of assessments in this trial generated a plethora of fluid and imaging data. At AAT-AD/PD, Bateman first presented prespecified analyses of each drug arm compared with placebo. As was expected, gantenerumab showed target engagement via a statistically significant reduction on PiB PET. At 0.64 SUVR, this reduction was large, and similar to the reduction previously reported for high-dose gantenerumab in a LOAD open-label extension (Dec 2019 conference news).

On downstream disease-modification markers, FDG PET and thickness of the precuneus, an early affected part of the cortex, were not significantly different in the combined asymptomatic/symptomatic groups with either antibody. Bateman did not report tau PET data at AAT-AD/PD because DIAN-TU added this marker midway through the trial, hence has few scans taken at baseline for comparison.

In CSF, the Aβ42/40 ratio was up significantly, and CSF total tau and CSF pTau181 were down by nearly a third. These three changes all indicate a reversal toward normal levels, and came in at p values of below 0.001. CSF neurofilament light chain (NfL) showed less increase on gantenerumab than placebo, at p=0.024.

How about solanezumab? It also engaged its primary target, as evidenced by a steep increase of total CSF Aβ42; however, of the downstream markers, only CSF NfL was significantly different between drug and placebo, and its change pointed toward worsening on drug, with p=0.017. CSF total tau and pTau181 did not budge.

As was the case for the cognitive data, breaking open the PiB data by presymptomatic and symptomatic groups revealed just how different they were at the start of the trial. Unlike for the cognitive readouts, however, both presymptomatic and symptomatic participants responded to gantenerumab with amyloid reduction. Expressed in centiloids, presymptomatic carriers started out near 30; those on placebo added some 10 centiloids, whereas those gantenerumab lost 10, for a difference of 20 centiloids. Symptomatic carriers started out around 85 centiloids; placebo recipients went up above 100 and gantenerumab recipients down to about 65. Mutation noncarriers posted zero centiloids throughout the trial.

The bigger surprise was the strength of the data on downstream markers. At AAT-AD/PD, Bateman showed that both tau measures reversed direction toward normal in people on gantenerumab, posting at least 30 percent difference between drug and placebo by year four. In people on placebo, both total tau and p-tau181 rose year-on-year from baseline; on drug, both decreased year-on-year. In noncarriers, total and p-181 tau stayed unchanged. Commentators agreed that these changes are large and likely biologically significant. Neurofilament light chain, considered a generic indicator of active neurodegeneration, rose more in carriers on placebo than on gantenerumab but stayed largely stable in noncarriers, for a group difference of 10.8 percent. Additional downstream markers remain to be analyzed for differences by disease stage.