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External validity as seen from other quantitative social sciences - and the gaps in our practice
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First a bit of a conceptual framework. Let's think about the assessment of external validity as an assessment of how well the impact estimate (based on the trial sample) predicts the impact of the same intervention implemented at scale in the target population. In short we care about Δ, which we define as the difference in the average treatment effect between the estimate from the trial and what would be obtained in the population. If there is no difference – if the impact evaluation is fully externally valid – then Δ = 0. Yet Δ can be non-zero due to differences in characteristics between the sample and the population, if such characteristics also mediate the treatment impact. Δ may also be non-zero due to differences in program implementation between small-scale and at-scale. More formally we can decompose Δ into its constituent components:
Δ =Δ_xo + Δ_xu + Δ_io + Δ_iu + interaction terms
Where Δxo and Δxu are the differences in observed and unobserved characteristics between the trial population and the target population, and Δio and Δiu are the differences in observed and unobserved implementation factors between trial and at-scale. For any one impact evaluation to be readily generalizable, we would hope for all of these delta terms to be zero or close to it. But what if they aren't?
A paper by Olsen, Orr, Bell, and Stuart doesn't attempt to answer this question directly, but does seek to clarify the conditions under which Δ will be non-zero. They model external validity bias as a product of three factors:
- the degree of variance in impact across sites in the population of interest
- the coefficient of variation in the inclusion probability of sites across the population of interest
- the correlation between site specific impact and site inclusion probabilities in the population
A recent paper by Cole and Stuart explores techniques to extrapolate trial estimates to a larger population. Specifically the two researchers standardize the observed results of one of the first ARV trials in the U.S. to a broader specified target population – the population of all HIV positive U.S. residents. The original trial found clear mortality reductions from ARV therapy but this original RCT of 1150 patients was largely older, whiter, and better educated than the overall population of HIV positive individuals.
To adjust the trial results so that the impact reflects the broader population, the researchers require values in this target population for the key characteristics that mediate the treatment effect but also vary between the study and target population. In this study, the characteristics considered are sex, race, and age. The conditional probabilities of selection in the trial sample are then estimated as a function of these characteristics, and used to reweight the estimated trial effect in order to reflect the target population. This process still finds overall mortality reductions but a 12% lower effect than found in the trial.
Similar to the above, a paper by Stuart, Cole, Bradshaw, and Leaf uses propensity scores to quantify the difference between trial participants and the target population. Once this is done, the scores can be used to either match or weight control group outcomes to the population in order to assess how well these control group outcomes track the outcomes actually observed in the population. They use an example of a school-based intervention in the U.S.
In order to apply this approach there must be sufficient overlap in the propensity scores for the sample and target population – no method can help extrapolate trial results to a segment of the population if that segment is not observed at all in the trial. One measure of similarity between sample and population is simply the difference in the mean propensity score. While there is no magic threshold, differences of .25 standard deviations in mean propensity scores suggest that a large amount of extrapolation, perhaps unsubstantiated by the data, would be necessary.
Note that all of these papers discuss the importance of the study sample being sufficiently similar to the target population in order to ensure externally valid estimates. If this is not the case then perhaps these impact estimates can be corrected through re-weighting. As such these are all attempts to extrapolate impact estimates to a population when Δxo is non-zero. So this speaks to the importance for impact evaluations to comprehensively measure key mediating characteristics that also may vary respect to the target population. Doing so in a comprehensive fashion also reduces the potential importance of the Δxu term as fewer factors will be unobserved.
But what about the implementation factors, i.e. the Δio term? I couldn't yet find anything that deals with implementation differences in a quantitative fashion. This is not for lack of recognition of the problem. For example the Stuart et al. paper, which evaluates a school program, mentions that relatively little is known about the school-level moderators of the program impact. Some possible key moderators they mention include the schools organizational capacity to implement the program, the principal's support for the program, and the institutional motivations for participating in the program. However factors such as these were not assessed, and in fact it's not clear how to best to measure them.
It is fairly clear however that, with respect to implementation factors, the external validity work is severely underdeveloped – for most studies there is no discussion of which implementation aspects matter the most and, from among these, which of them can be accurately measured. This is a major gap in our evaluative practice and a ripe area for future work.
So some take away messages from this review, as well as the handful of papers in econ that explore this topic:
- To estimate possible bias from Δxo, follow an approach similar to explorations of internal validity bias by comparing characteristics of study sites to target population
- Where divergences exist, perhaps extrapolations can be improved by re-weighting
- Ensure a sufficient number of sites whenever possible, and either select them randomly or, if you must select purposively, do so with goal of broader representation
- Devote additional effort and resources to recruiting sites that initially resist inclusion
- Think hard about factors of implementation that vary between the trial and scale versions of the intervention, and develop suitable quantitative measures where possible
Join the Conversation
I like your decomposition of the average treatment effect between the estimate from the trial and what would be obtained in the population. Of course, writing it that way immediately suggests that one could manipulate Δ_io so as to offset the effect of Δ_xo. But first we have to understand how Δ_io and Δ_xo work...
Stefano, thanks very much for the comment, and I agree with the possibility you suggest, although that implies a high level of project self-knowledge. I think we also definitely agree that we need to measure the relevant Δ_io and Δ_xo - we don't even do that yet very well....
Sorry Jed, even your mathematical model is no match to the dynamics of external environments in which development interventions operate. Simply put, the existing tools and techniques used in ex-post development evaluations these days are no match to the dynamics of external environments. No wonder why managers of development interventions are hesitant to use ex-post development evaluation reports' recommendations. I have the impression that given such dynamics, development evaluation reports are already obsolete as soon as they are created. They are good for 'post-mortem analysis' rather than cure the 'disease' while the development intervention is still 'alive'.
Hi Jed, further to my comment on your previous post I thought I would just add a link to my ABCDE paper here for those who are interested in the above ideas in more detail:
(earlier version here: http://opensaldru.uct.ac.za/handle/11090/691)


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I'm a little late in getting this out, but I just wanted to thank Geneabloggers (and especially Gini) for profiling me in the "Let Me Introduce You" posting on Monday. I was so surprised and thrilled when Gini contacted me about this and I think she did an amazing job with the article.
I would definitely encourage anyone blogging about genealogy-related topics to join the Geneabloggers community if they have not already done so!

subset: commoncrawl


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Let us hold unswervingly to the hope we profess, for he who promised is faithful. And let us consider how we may spur one another on toward love and good deeds, not giving up meeting together, as some are in the habit of doing, but encouraging one another … If we deliberately keep on sinning after we have received the knowledge of the truth, no sacrifice for sins is left, but only a fearful expectation of judgment and of raging fire that will consume the enemies of God. (Hebrews 10.23-27)
Andy and Red were up against it; they had their backs to the wall. They'd recently learned that one of their best friends, Brooks, had killed himself. Hopeless, he had hung himself.
And though neither Andy or Red ever mentioned the word, hope is what they were talking about. Specifically, what a person does – and does not do – as a result of having hope, or not having it, in their life.
The difference between them was that though both were imprisoned, only one of them was imprisoned in mind. As Andy saw it, the only thing keeping him from freedom was made out of stone. Red? He was so shackled the only thing left for him was to find the will to use a rope. Just like Brooks.
But Andy? Andy had hope. And so, he scratched his way out through stone walls and filth. How he perceived his future powerfully impacted what he chose to do with his present. He chose to hope, and so he chose to do. And so, stone walls wouldn't – couldn't – contain him.
"It comes down to a simple choice, really: get busy living or get busy dying!"
You probably recall that scene from the movie The Shawshank Redemption. This month is that movie's twentieth anniversary (hard to believe, isn't it). And so, let me ask you …
What do you believe? About your future? About hope? And what you're to be about in the here and now?
Do you have hope? Vibrant, living hope? A hope you simply cannot leave behind? A hope that spurs you on to do what you can with today? For your own blessing and the blessing of others?
If you know Jesus Christ – truly know him – you don't merely have hope. You know him as your hope. He is your hope. He is your all. Every day. He is what gives your life meaning.
You could no more turn your back on him and walk away from him than Andy Dufresne could have given up his dream to live in a place with no memory of all wrong and his daily toil to get there.
Know this kind of hope; come to know Jesus Christ. Know him as your Lord – as your daily hope – and he will be your Savior. Take on his mind and ways, and he will become your way to freedom. In this life, and in the one beyond. For no walls, made of stone or perception, can restrain him. Or you in your life with him.
Choose him. Choose life. Every day of your life. For today. For the sake of your future. For him.
It will make all the difference in your life. And in the lives of many a Red Redding.
Get busy living.


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Sexy new drugs have appeared ahead of schedule on drugstore shelves and with much fanfare. Gilead Sciences, gained approval for Truvada, a combination pill of Viread plus Emtriva. GlaxoSmithKline (GSK), have combined Epivir and Ziagen to a one pill Epzicom. Patients often ask how pharmaceutical companies come up with their unusual names of the various drugs. This time there's an answer! Epzicom is named for the acronym for EPivir plus ZIagen COMbo and Truvada was named for TRUe once-A-DAy. Both products have differing qualities and features. This article will discuss each from various standpoints.
In Epzicom, the components Epivir and Ziagen are well known as antiretroviral agents from the nucleoside reverse transcriptase (NRTI) class. Epivir (lamivudine) was first approved in November 1995 and Ziagen (abacavir) in December of 1998. Both have long track records of use, originally administered as twice-daily drugs.
In Truvada's ingredients, Viread (tenofovir DF) was uniquely developed as the first nucleotide and is administered as a one pill, once daily; it was observed to be uniquely effective against Epivir-resistant virus. Approval of Emtriva (emtricitabine) followed last year, another once-a-day pill. Emtriva (emtricitabine) is a nucleoside analog that is similar to 3TC (Epivir) with advantages of having favorable pharmacokinetic (PK) profile (for discussion on PK, see below) that permits once-daily dosing and its' potency was a little stronger than Epivir. In HIV-infected volunteers, 200 mg once daily of Emtriva compared with twice-daily 3TC 150 mg showed a more potent viral load drop after 11 days of treatment (-1.7 compared to -1.45 log10 c/ml; 6th CROI, 1999).
All four drugs, Epivir, Emtriva, Viread and Ziagen are generally very well tolerated having low side effect profiles. All four have low propensity to cause lipodystrophy, compared to other antiviral agents. Unique to this group however, Ziagen can cause a severe allergic response called a hypersensitivity reaction (HSR).
Ziagen HSR is a systemic allergic reaction often manifesting as flu-like symptoms. When it takes place, it is associated with at least two of various side effects occurring simultaneously including: skin rash, fever, body aches, malaise, headaches, abdominal symptoms, shortness of breath. One should know that this HSR only occurs in 5-9% of patients starting Ziagen and usually occurs within the first two-three weeks of treatment. Once a person experiences this HSR, they can never attempt taking Ziagen again. Because Ziagen is a component of Epzicom, the vigilance regarding HSR is also needed with Epzicom.
Both pharmaceutical companies would like physicians to choose their products for newly diagnosed and antiretroviral experienced patients. Consider the mounting competition in the marketplace for companies involved in the development of HIV drugs. Now that there are several once-daily antivirals, competition is heating up and companies are vying for market share and leadership. Experienced physicians following the progress and research regarding these agents should understand the scientific attributes of each and tailor regimens to specific individual patient needs.
Blood Levels
In scientific parlance, pharmacokinetics (PK) refers to the way a drug is metabolized in the blood. A favorable PK generally refers to the blood longevity levels of antiviral drugs: medications should be sufficiently potent and be present long enough in the blood and cells to allow for enough medication to provide powerful antiviral effect without causing overwhelming toxicity, while maintaining easy dosing schedules.
Different PK considerations must be taken into account for the nucleoside reverse transcriptase inhibitor (NRTI) class because these agents are phosphorylated intracellularly (chemically altered within the cell) to become active. Thus, a drug effect is dependent on dose, plasma (blood) half-life, rate of intracellular phosphorylation and intracellular half-life.
When first approved, Viread and Emtriva were both developed and approved to be administered once-daily, in contrast to Epivir and Ziagen which were originally developed and administered twice per day. As newer techniques to study cellular half-lives were used (PBMCs, as opposed to cancer cells) the actual PKs of Epivir and Ziagen became better understood. These recent studies of the pharmacokinetic properties and clinical efficacy made it possible to consider reducing dosing frequency of Epivir and Ziagen (abacavir) to once daily.
As illustrated in Table 1 below, Ziagen's (abacavir) active drug metabolite (carbovir triphosphate) has an intracellular half-life (longevity within the cell) of 12 to 19 hours, while its serum half-life (blood longevity) is only 1.5 hours. Epivir has an intracellular half-life of the active (phosphorylated) forms of 11 to 16 hours; its activity in plasma is only 3-6 hours. Both components of Truvada have much longer longevity, however. Viread (Tenofovir) has an intracellular half life (intracellular longevity) of more than 60 hours and serum half life being at 17 hours; Emtriva (emtricitabine) intracellularly is 39 hours and serum half life is 10 hours. Patients being human, may miss dosing by several hours from time to time. Drugs with longer half lives, while remaining longer within body cells may be more forgiving and less apt to promote resistance.
Importantly, the clinical research supports once-daily dosing of Ziagen (abacavir) and Epivir. One recent clinical study of naive patients (patients not previously treated) evaluated once-daily administrations of both Epivir and Ziagen combined with Sustiva (efavirenz). The Ziagen/Epivir once-daily arm was randomly compared to Ziagen administered twice daily for 48 weeks. (ZODIAC -- CNA30021, 43rd ICAAC, Sept 2003). Both groups of patients had identical antiviral benefit with no increased side effects observed in the once-daily group.
In contrast, preliminary results from a recent trial (study 934) may have also illustrated how PK and tolerability can impact on treatment success. This study compared the components of Truvada, Viread plus Epivir once daily, to treatment with twice-daily Combivir or AZT plus Epivir. AZT's intracellular half life is very short and only 3 hours; its plasma half life is 1.1 hour. Preliminary data at 24 weeks showed superiority in the Viread/Emtriva once daily vs. Combivir (88% vs. 80% had viral loads <400 copies). All study patients in both arms were also treated with Sustiva.
Once a Day Keeps the Doctor Away
Adherence is another way of describing the habit of taking all medication doses as prescribed. Good adherence is required to achieve the best therapeutic results. However, adherence can be influenced by life style, dosing and side effects. Treatments need to correspond to individual patient needs. Thus, new formulations like Truvada and Epzicom are indeed a welcome addition to our treatment landscape and should add to overall convenience for both new patients starting on treatment as well as experienced patients. In other words, one hopes and expects that these new additions will improve adherence for many individuals.
Moreover, a clinical study demonstrated once-daily dosing of HAART was better than multi-dosed treatment and was presented at the 10th CROI in 2003 (Molina JM et al). Individuals who had suppressed viral load levels were switched randomly to a new once-daily regimen of emtricitabine (Emtriva), didanosine (ddI-EC), and efavirenz (Sustiva) versus continuation of their old multi-dose protease inhibitor regimens. There was a significant difference favoring the once-daily arm, as 95% vs. 87%, once daily vs. protease inhibitor arms, had undetectable viral loads below 50 copies. The once-daily regimen resulted in improvements in adherence. As more data from large randomized trials become available, once-daily HAART may demonstrate better durability in treatment throughout.
Combining these agents into one pill provide the practicality of lower bill burden and ease of administration. In contrast, pushing individuals to once-daily drug regimens may have other implications. Agents that do not provide full coverage for 24 hours and missing doses while on a once-daily HAART can potentially be a danger for subtherapeutic blood levels during delayed dosing. As an example, in twice-daily regimens, one missed dose a week translates to one out of 14 doses or 8% missed. One missed dose of once-a-day regimen equals missed for a complete 24 hour period or 15% missed. In this situation, more time without antiviral coverage means suboptimal viral suppression. This usually results in lowered antiretroviral plasma (blood) levels leading to development of resistant strains.
Despite the missed dosing drawback, it is generally agreed that once-daily dosing is more practical and patient friendly; ultimately it should improve durability through better adherence. Because there are other factors that influence adherence, seasoned HIV physicians understand that there is no magical answer for all patients.
Resistance and Controversies Regarding Drug Sequencing
There exists much controversy regarding the sequencing of these drugs. When we refer to sequencing we are describing a chess game. When making each move on the chess board, one needs to keep in mind your partners next move against you, and your own next move following. Likewise, choosing an antiviral regimen mandates an awareness of potential resistance later and a plan for the next treatment options ahead. Resistance and sequencing is complicated and there is much we are still learning. Thus starting a regimen containing Epzicom or Truvada, planning for the next treatment options down the road is important.
Various mutations are associated with resistance to specific antiviral agents. For example, mutations such as the M184V is associated with Epivir resistance and K65R can be associated with Ziagen, ddI and /or Viread. If Epivir resistance develops during treatment with Epzicom (M184V mutation), then later treatment with Viread continues to remain a treatment option. However, if Epzicom selects for the L74V mutant, a recent study showed this to potentially result in the eventual emergence of the K65R which can potentially block an option for later treatment with Viread.
During phase 2 and 3 trials (studies 902 & 907), Viread was given to highly treatment experienced patients. The infrequent presence of K65R was associated with only low grade resistance to Viread. The few patients during these trials who had this mutation also had a history of Ziagen or ddI treatment (previously), which was implicated as the cause of the K65R. Moreover, the K65R mutation is associated with a low-grade resistance to ddI and Ziagen, and moderate resistance to Epivir. In a real world clinic, resistance to Viread occurs relatively infrequently and patients who have the K65R often respond to Viread treatment (and is often sensitive by phenotypic testing).
To make things more complicated, if a patient takes Truvada and develops both K65R and M184V, there is the potential to eliminate later options for treatment with Ziagen and Epzicom. However, if one developed resistance with Combivir or AZT, the mutations are generally of the TAMS variety or thymidine-associated mutations. This also blocks one's potential options with Viread later on as well as other agents.
Thus one can see how complicated drug sequencing becomes, especially when newer treatments come to market. We usually don't have all the answers at first.
The arrival of the two new formulations, combinations of two NRTIs each, have made it simpler for patients. There are still some unanswered questions and clinicians debate about which drug combinations of nukes, non-nukes, protease inhibitors and boosted protease inhibitors are best suited for starting patients when beginning therapy. Many patient specific particulars need to be considered and many details such as pharmacokinetics, resistance and sequencing all need to be measured. The availability of both Epzicom and Truvada are another step in the right direction towards improving HIV treatment. Both can be combined with other single dosed antivirals to construct true once-daily regimens. They can also be combined with other dosing regimens to reduce pill burden. Furthermore, a recent press release announced that Bristol-Myers-Squibb, Gilead Sciences and Merck have announced plans to develop a fixed-dose combination pill of three antivirals.
Daniel S. Berger, M.D., is Medical Director of Chicago's largest private HIV treatment and research center, NorthStar Healthcare and Clinical Assistant Professor of Medicine at the University of Illinois at Chicago. He serves as medical consultant and columnist for Positively Aware and serves on the HIV Medical Issues Committee for the Illinois AIDS Drug Assistance Program, the Board of Directors for the AIDS Foundation of Chicago and the Editorial Board of Contagion, Reports, Cases, and Commentaries in HIV and Infectious Disease Research_. Dr. Berger can be reached at firstname.lastname@example.com or (773) 296-2400._


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5 Rhythms Dance
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Beginners are welcome, No experience is necessary. This is a lovely community of dancers age range 20's-70's. Welcome to come and try out a class to see if it is for you. There are no steps to learn and no way to get it right nor wrong!
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Abbeydale Park Rackets and Fitness Club offers squash and racketball for all standards, beginners to national champions. Light and airy fitness suite. Also holds classes in aerobics, zumba, pilates, yoga, spin bikes and circuit training. Squash and Racketball Has teams in Yorkshire League and the…
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Speaking about the new [lastfm]Bon Jovi[/lastfm] Greatest Hits Collection, frontman Jon Bon Jovi noted, "Music marks milestones in all our lives. These songs have stood the test of time and they remind us all where we came from, even as we keep our eyes towards the future." In a two and a half decade career filled with many, many milestones, [lastfm]Bon Jovi[/lastfm] has established itself as one of the iconic American rock bands. If you were ever in doubt of that, or are simply looking for a the end-all of [lastfm]Bon Jovi[/lastfm] Greatest Hits albums, look no further than Bon Jovi's Greatest Hits: Ultimate Collection.
Things get off to a fast start with tracks from one of the group's biggest albums, 1986's Slippery When Wet. Stadium anthems like "You Give Love a Bad Name," "Living on a Prayer," and "Wanted Dead or Alive" are the kind of songs that made the album the top seller of 1987 and established [lastfm]Bon Jovi[/lastfm] as the biggest name in New Jersey rock'n'roll since [lastfm]Bruce Springsteen[/lastfm].
From there, the collection takes us through the rest of the group's monster hits like "It's My Life" as well as fan favorites such as "Bed of Roses" and "Blood on Blood." In addition, there are four brand-new songs recorded specifically for this compilation: "The More Things Change," "No Apologies," "This Is Love, This Is Life", and "What Do You Got?" The inclusion of these tracks next to classics like "Runaway" (the song that started it all for the band) show not only how far Bon Jovi has come, but that the guys still haven't lost their edge.
To take a trip down memory lane, check out the original video for "Runaway" below:
1 Livin' On A Prayer
2 You Give Love a Bad Name
3 Runaway
4 Bad Medicine
5 Born to Be My Baby
6 I'll Be There For You
7 Lay Your Hands On Me
8 It's My Life
9 Always
10 Wanted Dead or Alive
11 Blaze of Glory
12 Who Says You Can't Go Home (duet featuring Jennifer Nettles)
13 Have a Nice Day
14 We Weren't Born to Follow
15 What Do You Got? * New Song
16 No Apologies * New Song
1 In These Arms
2 Someday I'll Be Saturday Night
3 Lost Highway
4 Keep The Faith
5 When We Were Beautiful
6 Bed of Roses
7 This Ain't a Love Song
8 These Days
9 (You Want to) Make a Memory
10 Blood on Blood
11 This is Love This is Life
12 The More Things Change
If you like what you hear, check out Bon Jovi Greatest Hits – The Ultimate Collection available now at iTunes and Amazon.
Watch Bon Jovi perform a free Live on Letterman concert webcast Nov. 9 at 8pm ET (5pm PT).


text:
Kaplan-Meier analysis is for the event rate of the combined primary end point in patients with and without high on-treatment platelet reactivity as measured by multiple platelet function tests. LTA indicates light transmittance aggregometry; ADP, adenosine diphosphate.
Odds ratios are for the combined primary end point by quintiles of on-treatment platelet reactivity according to multiple platelet function assays. Error bars indicate 95% confidence intervals. Cumulative Kaplan-Meier time-to-aperture-closure plot in patients with and without the combined primary end point according to the PFA-100 system and INNOVANCE PFA. Quintiles for light transmittance aggregometry 5 μmol/L ADP (1, ≤27.1%; 2, >27.1%-36.6%; 3, >36.6%-44.1%; 4, >44.1%-52.1%; 5, >52.1%-78.6%), light transmittance aggregometry 20 μmol/L ADP (1, ≤45.4%; 2, >45.4%-56.0%; 3, >56.0%-63.9%; 4, >63.9%-70.7%; 5, >70.7%-96.6%), Plateletworks (1, ≤36.4%; 2, >36.4%-66.5%; 3, >66.5%-82.5%; 4, >82.5%-93.8%; 5, >93.8%-100%), reaction units using the VerifyNow P2Y12 test (1, ≤146; 2, >146-198; 3, >198-235; 4, >235-276; 5, >276-413), % surface coverage using the IMPACT-R test (1, ≤3.9%; 2, >3.9%-6.7%; 3, >6.7%-9.6%; 4, >9.6%-13.2%; 5, >13.2%-30.7%), and the IMPACT-R ADP (1, 20.5%->5.4%; 2, 5.4%->3.2%; 3, 3.2%->2.2%; 4, 2.2%->1.3%; 5, ≤1.3%).
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Breet NJ, van Werkum JW, Bouman HJ, et al. Comparison of Platelet Function Tests in Predicting Clinical Outcome in Patients Undergoing Coronary Stent Implantation. JAMA. 2010;303(8):754–762. doi:10.1001/jama.2010.181
© 2019
Author Affiliations: Departments of Cardiology (Drs Breet, van Werkum, Kelder, Bal, van der Heyden, Rensing, Suttorp, and ten Berg and Ms Bouman), Clinical Chemistry (Drs Ruven and Hackeng), and Clinical Pharmacy (Drs Deneer and Harmsze), St Antonius Hospital; and St Antonius Center for Platelet Function Research (Drs Breet, van Werkum, Kelder, Deneer, Harmsze, Hackeng, and ten Berg and Ms Bouman), Nieuwegein, the Netherlands.
Context High on-treatment platelet reactivity is associated with atherothrombotic events following coronary stent implantation.
Objective To evaluate the capability of multiple platelet function tests to predict clinical outcome.
Design, Setting, and Patients Prospective, observational, single-center cohort study of 1069 consecutive patients taking clopidogrel undergoing elective coronary stent implantation between December 2005 and December 2007. On-treatment platelet reactivity was measured in parallel by light transmittance aggregometry, VerifyNow P2Y12 and Plateletworks assays, and the IMPACT-R and the platelet function analysis system (PFA-100) (with the Dade PFA collagen/adenosine diphosphate [ADP] cartridge and Innovance PFA P2Y). Cut-off values for high on-treatment platelet reactivity were established by receiver operating characteristic curve analysis.
Main Outcome Measurement The primary end point was defined as a composite of all-cause death, nonfatal acute myocardial infarction, stent thrombosis, and ischemic stroke. The primary safety end point included TIMI (Thrombolysis In Myocardial Infarction) criteria major and minor bleeding.
Results At 1-year follow-up, the primary end point occurred more frequently in patients with high on-treatment platelet reactivity when assessed by light transmittance aggregometry (11.7%; 95% confidence interval [CI], 8.9%-15.0% vs 6.0%; 95% CI, 4.2%-8.2%; P < .001), VerifyNow (13.3%; 95% CI, 10.2%-17.0% vs 5.7%; 95% CI, 4.1%-7.8%; P < .001) and Plateletworks (12.6%; 95% CI, 8.8%-17.2% vs 6.1%; 95% CI, 3.8%-9.2%; P = .005), which also had modest ability to discriminate between patients having and not having a primary event: light transmittance aggregometry (area under the curve [AUC], 0.63; 95% CI, 0.58-0.68), VerifyNow (AUC, 0.62; 95% CI, 0.57-0.67), and Plateletworks (AUC, 0.61; 95% CI, 0.53-0.69). The IMPACT-R, Dade PFA collagen/ADP, and Innovance PFA P2Y were unable to discriminate between patients with and without primary end point at 1-year follow-up (all AUCs included 0.50 in the CI). None of the tests identified patients at risk for bleeding.
Conclusions Of the platelet function tests assessed, only light transmittance aggregometry, VerifyNow, and Plateletworks were significantly associated with the primary end point. However, the predictive accuracy of these tests was only modest. None of the tests provided accurate prognostic information to identify low-risk patients at higher risk of bleeding following stent implantation.
Trial Registration clinicaltrials.gov Identifier: NCT00352014
Dual antiplatelet therapy with aspirin and clopidogrel reduces atherothrombotic complications in patients undergoing percutaneous coronary intervention (PCI) with stenting.1,2 However, the individual response to dual antiplatelet therapy is not uniform, and consistent findings across multiple investigations support the association between a lower degree of platelet inhibition, a high on-treatment platelet reactivity, and the occurrence of atherothrombotic events.3-10
The major drawbacks of these previous investigations are the relatively small sample size of the studied populations and the fact that on-treatment platelet reactivity was evaluated by only 1 platelet function test per study. There is currently no consensus regarding the most appropriate method to quantify the magnitude of on-treatment platelet reactivity. Therefore, the aim of The Popular Study (Do Platelet Function Assays Predict Clinical Outcomes in Clopidogrel-Pretreated Patients Undergoing Elective PCI) was to evaluate the ability of multiple platelet function tests in predicting atherothrombotic events, including stent thrombosis, in clopidogrel-pretreated patients undergoing PCI with stent implantation.
Consecutive patients with established coronary artery disease scheduled for elective PCI with stent implantation were included in this study. All patients received optimal clopidogrel treatment (defined as a maintenance of 75 mg/d therapy for >5 days or a loading dose of 300 mg ≥24 hours before PCI or 600 mg ≥4 hours before PCI) and aspirin (80-100 mg/d ≥10 days) unless they were receiving long-term anticoagulation with warfarins. According to our institutional practice, all patients (after receiving drug-eluting and bare-metal stenting) were treated with clopidogrel for at least 1 year since 2003. Clopidogrel and aspirin maintenance doses were 75 mg and 80 to 100 mg daily, respectively. Higher maintenance doses were not used. Adherence to antiplatelet medication was routinely assessed by outpatient visits at 6 weeks, 3 months, and 1 year and also verified by pharmacy refill data.
All interventions were performed according to current guidelines11 and the choice of stent type and periprocedural use of glycoprotein IIb/IIIa inhibitors was left to the operator's discretion, but the latter were always administered after blood collection. Patients using concomitant medication known to affect platelet function other than aspirin (ie, nonsteroidal anti-inflammatory agents, dipyramidole, upstream glycoprotein IIb/IIIa inhibitors) and patients with a known platelet function disorder or a whole blood platelet count of less than 150 × 103/μL were excluded. Written informed consent was obtained before PCI. All data were prospectively collected and entered into a central database. Clinical follow-up was obtained by additional telephone contact to all patients at 30 days and 12 months and verified using source documents from medical records from the referring hospitals.
The study was conducted according to the principles of the Declaration of Helsinki and the laws and regulations applicable in the Netherlands. The local institutional review board (Verenigde Commissies Mensgebonden Onderzoek) approved the study.
The primary end point of Popular was defined as a composite of all-cause death, nonfatal myocardial infarction (the occurrence of ischemic symptoms and a spontaneous troponin T value [ie, not periprocedural or postprocedural] or creatine kinase myocardial >the upper limit of normal), stent thrombosis (according to Academic Research Consortium criteria12), and ischemic stroke (focal loss of neurologic function caused by an ischemic event). The primary safety end point was defined as major or minor bleeding according to the modified Thrombolysis In Myocardial Infarction (TIMI) Study Group criteria.13
Exploratory end points included elective target vessel revascularization (revascularization of the vessel treated at the time of inclusion in the study), elective nontarget vessel revascularization (revascularization of a vessel different from the one treated at the time of enrollment), and hospitalization for ischemia (hospitalization with ischemic symptoms, ie, evidence for ischemia on electrocardiogram but without elevated cardiac markers).
An independent committee with blinding for platelet function data adjudicated all end points through review of medical record source documents.
Before heparinization, whole blood samples were drawn from the femoral or radial artery sheath into 3.2% citrate tubes for light transmittance aggregometry and for testing using IMPACT-R (Matis Medical Inc, Beersel, Belgium). Testing with VerifyNow P2Y12 (Accumetrics, San Diego, California) was performed using Greiner tubes, according to the manufacturer's test protocol. For the platelet function analysis system (PFA-100; Siemens Healthcare Diagnostics Products GmbH, Marburg, Germany), 3.8% buffered citrated blood was used according to the manufacturer's test protocol. Blood samples for whole blood count were drawn into tubes containing K3-EDTA and tubes containing diphenylalanyl-L-prolyl-L-arginine chloromethyl ketone (PPACK [50 μmol/L]) to perform testing with the Plateletworks (Helena Laboratories, Beaumont, Texas).
The magnitude of on-treatment platelet reactivity was quantified using the platelet function tests in parallel: light transmittance aggregometry with adenosine diphosphate (ADP) 5 and 20 μmol/L as the agonist, the VerifyNow P2Y12 assay, the Plateletworks assay using ADP tubes, the IMPACT-R assay (with and without ADP prestimulation), and the Dade PFA collagen/ADP test cartridge (PFA-100 system). Halfway through the study, the final prototype of the novel Innovance PFA P2Y PFA-100 system became available for performance evaluation. Except for the Innovance PFA P2Y, which is still under development at time of this publication, all platelet function tests were commercially available at the start of the study. All platelet function measurements were performed within 2 hours after blood collection. A detailed description of the platelet function tests is summarized in supplementary material (eAppendix).14-18
Sample size calculation was based on the ISAR-REACT I trial,19 which included a cohort with similar selection criteria and the same treatment strategy. Therefore, we assumed an incidence of the primary end point of 6%. The study was designed on the basis of the superiority principle to have 80% power to observe an incidence of the primary end point in patients exhibiting high on-treatment platelet reactivity of 10% and 4% in patients without high on-treatment platelet reactivity. On this basis, 380 patients were needed in each group. To compensate for loss to follow-up, we aimed for a population of 800 as measured with each test.
Continuous variables are presented as mean plus or minus SD. Categorical data are reported as frequencies (percentages). Categorical variables were compared using the χ2 test. Normally distributed continuous variables were compared with a 2-sided unpaired t test. Since the PFA-100 system confines detection of a closure time to a 300-second window, and because the majority of patients receiving adequate antiplatelet therapy exhibit nonclosure according to Innovance PFA P2Y, the results of the PFA-100 system are depicted as a Kaplan-Meier time-to-aperture-closure plot and a log-rank test was used.
To evaluate a platelet function assay's ability to distinguish between patients with and without primary end point at 1-year follow-up, a receiver operating characteristic (ROC) curve analysis was calculated for each test. The optimal cut-off level was calculated by determining the smallest distance between the ROC curve and the upper left corner of the graph. Patients above the optimal cut-off level were considered to exhibit high on-treatment platelet reactivity. Survival analysis for patients with and without high on-treatment platelet reactivity, according to the ROC of the specific test, was performed using the Kaplan-Meier method and the differences between groups were assessed by the log-rank test. The measure of effect was the odds ratio (OR) and estimated from a logistic regression analysis. A second ROC curve analysis was performed based on the 1-year primary safety end point combining TIMI major and minor bleeding.
Logistic regression modeling was used to identify independent correlates of the primary end point and to adjust for potential confounders (classic cardiovascular risk factors, renal failure, left ventricular ejection fraction <45%, total stent length, number of lesions treated, amount of stents implanted, bifurcation lesions, comedication [including use of clopidogrel loading dose, warfarins, proton pump inhibitors, calcium channel blockers, statins, or glycoprotein IIb/IIIa inhibitors], laboratory parameters [hemoglobin, platelet count, and mean platelet volume], left anterior descending coronary artery, or graft-stenting). All univariate variables with a P value <.10 were included in multivariate analysis. Whether a variable had additional contribution to a logistic regression model without that variable was tested with the likelihood ratio test. The Hosmer-Lemeshow goodness-of-fit test was performed to assess the adequacy of the model. All statistical analyses were performed with R (version 2.9, http://www.r-project.org) and a 2-tailed P value <.05 was considered significant.
In total, 1328 consecutive patients were invited to participate in the study with 21 (1.6%) refusing to participate. Another 238 patients were initially included in the study but since no stent was implanted, they were also excluded (eg, patients underwent only balloon angioplasty or a fractional flow reserve measurement demonstrating nonischemic coronary disease), resulting in a population of 1069 consecutive patients. Owing to irregularities in platelet assay supply, particularly in the supply of the Plateletworks as well as technical failure in a minority of platelet function tests, not all platelet function assays were performed in every patient. As a consequence, light transmittance aggregometry was performed in 1049 patients with 5 μmol/L ADP and in 1051 patients with 20 μmol/L ADP; the VerifyNow P2Y12 cartridge was used in 1052 patients; the Plateletworks assay in 606 patients; and the IMPACT-R in 910 patients without prestimulation and in 905 with ADP prestimulation. The PFA COL/ADP was performed in 812 patients and Innovance PFA P2Y in 588 patients.
Baseline characteristics of the cohort are depicted in Table 1. Baseline characteristics of the subpopulations according to the tests performed are summarized in eTable 1, demonstrating that the subpopulations tested were well balanced (except for white blood cell counts, P = .04; all P values were >.85). All patients received optimal clopidogrel pretreatment, 50.6% received a maintenance dose of 75 mg daily therapy for more than 5 days, 41.6% received a loading dose of 300 mg at least 24 hours before PCI, and 8.3% received a loading dose of 600 mg at least 4 hours before PCI. There were 995 patients (89.4%) who received 80 to 100 mg aspirin daily for more than 10 days.
Clinical outcome at 12 months was available for 1067 (99.8%) patients. Adherence for clopidogrel was 95.2% after 6 months and 82.1% after 1 year. During 1-year follow-up, a total of 18 patients died (1.7%), 64 patients had nonfatal acute myocardial infarction (6.0%), 13 presented with definite stent thrombosis (1.2%), and 14 patients experienced nonfatal ischemic stroke (1.3%). Three possible stent thromboses occurred (0.3%) and no probable stent thromboses were found. A total of 55 patients (5.1%) presented with bleeding: 33 TIMI-major (3.1%) and 24 TIMI-minor bleeding (2.2%).
Receiver operating characteristic curve analysis demonstrated that light transmittance aggregometry (both 5 μmol/L ADP and 20 μmol/L), the VerifyNow P2Y12 cartridge, and the Plateletworks assay were able to distinguish between patients with and without ischemic events at 1-year follow-up. Conversely, neither the IMPACT-R with and without ADP prestimulation nor the PFA collagen/ADP or Innovance PFA P2Y were able to discriminate between patients with and without postprocedural events. Table 2 displays the area under the curve (AUC) and optimal cut-off value for every test. eFigure 1 depicts the optimal cut-off values per test and the percentages of patients exhibiting high on-treatment platelet reactivity according to the test. Baseline characteristics for every test, for patients with and without high on-treatment platelet reactivity, are depicted in eTable 2, showing significant differences between the 2 groups.
Logistic regression modeling was used to identify independent predictors for the primary end point. The model included on-treatment platelet reactivity according to the various tests as a categorical variable (patients with vs without high on-treatment platelet reactivity using the cut-off defined with the ROC analysis) and multiple potential confounders. Independent predictors of 1-year primary end point were age (calculated for an increase of 10 years [OR, 1.22; 95% confidence interval {CI}, 0.97-1.51; P = .08]), hypertension (OR, 2.50; 95% CI, 1.30-4.82; P = .006), hypercholesterolemia (OR, 0.57; 95% CI, 0.33-0.98; P = .04), left ventricular ejection fraction of less than 45% (OR, 1.83; 95% CI, 1.07-3.11; P = .06), and a prior coronary artery bypass grafting (OR, 1.91; 95% CI, 0.96-3.81; P = .06). Procedural factors independently predicting the primary end point were total stent length (OR, 0.97; 95% CI, 0.94-1.00; P = .05), number of lesions treated (OR, 1.92; 95% CI, 1.10-3.39; P = .02), number of stents implanted (OR, 2.4; 95% CI, 1.38-4.30; P = .002), left anterior descending artery stenting (OR, 1.79; 95% CI, 1.11-2.88; P = .017) or graft stenting (OR, 2.88; 95% CI, 1.00-8.32; P = .049), stenting a bifurcation lesion (OR, 5.43; 95% CI, 1.91-15.45; P = .002), and a clopidogrel loading dose (OR, 1.73; 95% CI, 2.73-1.09; P = .02). The remaining variables included for multivariate analysis were not found to be independent correlates of the primary end point (P > .10) and were not included in the model.
The addition of high on-treatment platelet reactivity to this statistical model revealed that high on-treatment platelet reactivity as measured with light transmittance aggregometry (both 5 μmol/L ADP and 20 μmol/L), the VerifyNow-P2Y12 cartridge, and the Plateletworks assay significantly improved the AUC. Likewise, the likelihood ratio test demonstrated that high on-treatment platelet reactivity, according to these tests, provided an additional contribution to the model (Table 2). The goodness-of-fit test demonstrated that the predicting model was adequate (all P values >.10). On the contrary, the AUC did not improve when high on-treatment platelet reactivity as measured with IMPACT-R (with and without ADP prestimulation) or the PFA test cartridges (PFA COL/ADP and Innovance PFA P2Y) were added to the model.
At 1-year follow-up, the primary end point occurred more frequently in patients with high on-treatment platelet reactivity compared with patients without high on-treatment platelet reactivity, when platelet function was evaluated with light transmittance aggregometry (11.7% [95% CI, 8.9%-15.0%] vs 6.0% [95% CI, 4.2%-8.2%]; P < .001 using 5 μmol/L ADP and 12.0% vs 6.2%; P = .001 using 20 μmol/L ADP, respectively), the VerifyNow P2Y12 assay (13.3% [95% CI, 10.2%-17.0%] vs 5.7% [95% CI, 4.1%-7.8%]; P < .001), and the Plateletworks assay (12.6% [95% CI, 8.8%-17.2%] vs 6.1% [95% CI, 3.8%-9.2%]; P = .005). One-year follow-up for patients with and without high on-treatment platelet reactivity according to each platelet function test is depicted in Table 3 and Table 4.
The survival rate free from the primary end point was significantly lower in patients with high on-treatment platelet reactivity when measured with light transmittance aggregometry 5 μmol/L ADP and 20 μmol/L ADP, VerifyNow, Plateletworks, and Innovance PFA P2Y as compared with patients without high on-treatment platelet reactivity, whereas no significant relation was detected when platelet function was assessed by the IMPACT-R (both with and without prestimulation) or by the PFA collagen/ADP (Figure 1).
The occurrence of the primary end point was also compared when groups were divided in quintiles according to on-treatment platelet reactivity (Figure 2). Patients in the higher quintiles according to the light transmittance aggregometry 5 μmol/L ADP and 20 μmol/L ADP and the VerifyNow P2Y12 assay were at significantly higher risk for the primary end point. In contrast, no significant difference in the occurrence of the primary end point was observed between quintiles as measured with the IMPACT-R tests and Plateletworks. Since the PFA-100 system confines detection of a closure time to a 300-second window, the results of both PFA cartridges are depicted as time-to-aperture-closure Kaplan-Meier curves. Closure times as measured by the PFA COL/ADP were not significantly different between patients with and without a primary end point.
A second ROC analysis demonstrated that none of the performed tests were able to discriminate between patients with and without bleeding (all AUCs included 0.50 in the CI). Stratification by quintiles based on on-treatment platelet reactivity demonstrated no significant difference in the occurrence of bleeding between the quintiles (eFigure 2). In addition, no significant increase in bleeding was observed in the lowest quintile of patients compared with quintiles 2 to 5. A third ROC analysis further demonstrated that the platelet function tests were not able to predict postdischarge (>48 hours) minor or major bleedings (all AUCs included 0.50 in the CI).
High on-treatment platelet reactivity, when assessed by light transmittance aggregometry (both 5 μmol/L and 20 μmol/L ADP), VerifyNow P2Y12 assay, and Plateletworks, was significantly associated with atherothrombotic events. In contrast, the shear stress-based tests IMPACT-R (with and without ADP prestimulation) and the Dade PFA-100 system (the collagen/ADP and Innovance PFA P2Y) did not show an association with outcome.
The criterion standard light transmittance aggregometry has been the most widely used technique and has clearly demonstrated the relationship between high on-treatment platelet reactivity and subsequent atherothrombotic events.4-6 Popular found an optimal diagnostic cut-off level discriminating patients with atherothrombotic events from those without, similar to that found by Gurbel et al.4 However, light transmittance aggregometry is not suitable for routine use in clinical practice due to the poor reproducibility, the long sample processing time, and the need for specialized technicians. Therefore, several new, more easy-to-use platelet function tests have been introduced. Our study revealed that the VerifyNow P2Y12 cartridge is capable of identifying patients who are at risk for atherothrombotic events after undergoing PCI. Our optimal diagnostic cut-off value of 236 P2Y12 reaction units is consistent with that reported in previous reports.7,8,20 We demonstrated a relation between the Plateletworks ADP assay and clinical outcome and established an optimal cut-off value. Plateletworks ADP had the largest increase in predictive value of all evaluated tests. However, rapid performance (within 10 minutes after blood withdrawal) of this assay is required since the ADP-induced platelet aggregates disaggregate after this time point, resulting in an unreliable test result as described in eAppendix .16 Therefore, the use of the Plateletworks in routine clinical practice might be limited.
We reported performance data of the prototype Innovance PFA P2Y, which in its final design became available halfway through the inclusion period. Although the sample size has insufficient statistical power, the survival analysis demonstrated a lower incidence of the primary end point in patients without high on-treatment platelet reactivity.
In light of the Popular data, should high on-treatment platelet reactivity be used as a prognostic marker in clinical practice? Despite growing evidence that high on-treatment platelet reactivity is associated with adverse clinical outcome, platelet function testing is not widely implemented in clinical practice due to a lack of consensus on the optimal method and on the optimal cut-off values of the different tests to identify patients at higher risk. Popular provides additional evidence, including optimal cut-off values, that 3 tests might be used (light transmittance aggregometry, VerifyNow, and Plateletworks). However, other risk factors such as diabetes mellitus and poor left ventricular function have also been demonstrated to predict atherothrombotic events poststent implantation.21-24 Furthermore, these same risk factors have been shown to be associated with high on-treatment platelet reactivity25,26 and thus, high on-treatment platelet reactivity is probably a composite of several of these risk factors as well as the response to antiplatelet therapy.
In Popular, high on-treatment platelet reactivity added to the overall risk model. The modest contribution of high on-treatment platelet reactivity might be attributed to its relatively low-risk population, excluding higher-risk patients (ie, ST-elevation myocardial infarction). The greater importance of high on-treatment platelet reactivity in patients at higher risk has been demonstrated by Marcucci et al and Sibbing et al.7,9
Despite numerous data on the association between high on-treatment platelet reactivity and adverse outcome, there are only preliminary data concerning the benefit of tailoring therapy based on the results of platelet function testing.27 Therefore, the correct treatment, if any, of high on-treatment platelet reactivity remains unknown pending the completion of currently ongoing clinical trials: the GRAVITAS (NCT00645918), the DANTE (NCT00774475), the ARCTIC (NCT00827411), as well as the TRIGGER-PCI (NCT00910299), which may reveal whether individualized antiplatelet treatment based on platelet function testing improves outcome. Until then, clinical practice should not be guided by (point-of-care) platelet function testing.
Some issues merit careful consideration. First, the sample size of Innovance PFA P2Y was too small to have sufficient statistical power to detect the relationship between high on-treatment platelet reactivity and clinical outcome. Second, not all currently available platelet function tests were included with additional tests including the Multiplate (Dynabyte Informationssysteme GmbH, Munich, Germany), the thromboelastograph, and the flowcytometric vasodilator–stimulated phosphoprotein (VASP) analysis. However, at the start of our inclusion, the Multiplate and the platelet assay for the thromboelastograph were not available. Furthermore, the published results with the VASP assay were mainly preliminary and did not provide a solid base for choosing VASP as one of the platelet function tests. Third, patients received 3 different, but adequate, clopidogrel dosing strategies. Previous studies have demonstrated differences in the effect on platelet reactivity of these 3 dosing regimens. However, these 3 regimens are current clinical practices and our study therefore reflects the clinical relevance of monitoring platelet function in daily practice.
In conclusion, of the platelet function tests assessed, only light transmittance aggregometry, VerifyNow, and Plateletworks were significantly associated with the primary end point. However, the predictability of these 3 tests was only modest. None of the tests provided accurate prognostic information to identify patients at higher risk of bleeding. Thus, Popular does not support the use of platelet function testing to guide clinical practice in a low-risk population of patients undergoing elective PCI.
Corresponding Author: Jurriën M. ten Berg, MD, PhD, Department of Cardiology, St Antonius Hospital, PO Box 2500, 3435 CM Nieuwegein, the Netherlands (email@example.com).
Author Contributions: Dr ten Berg had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: van Werkum, Ruven, Deneer, Harmsze, Hackeng, ten Berg.
Acquisition of data: Breet, van Werkum, Bouman, Harmsze.
Analysis and interpretation of data: Breet, van Werkum, Bouman, Kelder, Ruven, Bal, Deneer, van der Heyden, Rensing, Suttorp, Hackeng, ten Berg.
Drafting of the manuscript: Breet, van Werkum, Hackeng, ten Berg.
Critical revision of the manuscript for important intellectual content: Breet, van Werkum, Bouman, Kelder, Ruven, Bal, Deneer, Harmsze, van der Heyden, Rensing, Suttorp, Hackeng, ten Berg.
Statistical analysis: Breet, van Werkum, Kelder.
Obtained funding: van Werkum, Hackeng, ten Berg.
Administrative, technical, or material support: van Werkum, Bouman, Ruven, Deneer, Harmsze, Hackeng, ten Berg.
Study supervision: van Werkum, Ruven, Bal, Deneer, van der Heyden, Rensing, Suttorp, Hackeng, ten Berg.
Financial Disclosures: Dr van Werkum reports receipt of speakers bureau fees from Accumetrics and Siemens; and providing consultancy services for The Medicines Company. Dr ten Berg reports receipt of speakers bureau fees from Sanofi-Aventis, Lilly and Co, Bristol-Myers Squibb, and Merck and Co, Inc; and providing consultancy services for Sanofi-Aventis, Eli Lilly, Schering-Plough, and GlaxoSmithKline. The other authors reported no disclosures.
Funding/Support: Siemens Healthcare Diagnostics provided the Dade PFA Collagen/ADP Test Cartridge and Innovance PFA P2Y without charge.
Role of the Sponsor: Siemens Healthcare Diagnostics was not involved in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript.
Previous Presentation: This study was presented as a late-breaking clinical trial at the American Heart Association Scientific Sessions, Orlando, Florida, November 14-18, 2009.
Additional Contributions: Innovance PFA P2Y is under development at the time of this publication and not available for sale.
We thank the independent committee that adjudicated all events: B. M. Swinkels, MD, St Antonius Hospital, Nieuwegein; W. Dewilde, MD, Catharina Hospital, Eindhoven; and F. W. A. Verheugt, MD, PhD, University Medical Center St Radboud, Nijmegen, the Netherlands. These individuals did not receive compensation in association with their work on this article.
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Sony is holding a 'PlayStation Meeting 2013' event in New York today where it is expected to announce the PS4. You can watch the event live here: PS4 launch: live. UPDATE: see our story - PS4 launching Holidays 2013 full details. See also: PS4 price in UK; how much will the PlayStation 4 cost?
The PS4 will be the firm's new gaming console to replace the popular PlayStation 3. The device comes shortly after Nintendo launched the Wii U and perhaps more importantly before Microsoft reveals the next generation of its Xbox typically known as the Xbox 720.
See also: PS4 event E3 2013: live video stream.
Sony's PlayStation meeting will take place later today at 6pm New York time (11pm UK time) so the wait is nearly over to find out the details of the highly anticipated PS4.
See also: How to watch PlayStation Meeting 2013: new PlayStation 4 launch
The original PlayStation was launch in Japan back in 1994 and was followed up by the PlayStation 2 in 2000 and the PlayStation 3 launched in 2006. All six year gaps but no PS4 appeared last year.
Sony's last PlayStation Meeting, held in 2011, was for the handheld PS Vita, so it's extremely likely that today's is for the PS4.
PS4: Specifications
Rumoured specifications for the PlayStation 4 include an AMDx64 CPU and an AMD Southern Island GPU. This means it will be capable of a 4096 x 2160 image while 3D games can be played in 1080p - the PS3 can only manage 3D games at a resolution of 720p.
We've heard that the PS4 won't be backwards compatible with old games, like most consoles. However, a recent rumour suggests that users will be able to stream PS3 games online.
Microsoft Kinect styled movement-based gaming is supposedly going to be a standard feature on the PS4. Developer PlayStation kits come with 4GB of RAM but the consumer console will apparently pack 8GB of RAM.
Below is a leaked image of what could be the PS4 controller complete with a PS Vita style touchpad in the middle. The light on top suggests a PlayStation Move sensor and there's also a suggestion the that a microphone built-in will allow for Siri-like voice control.
PS4: Release date
Although the PS4 will probably be announced today, it's unlikely to hit the shops for a number of months. Sony will probably launch it in Japan, and possible the US, in time for Christmas but it may not arrive in Europe until afterwards.
PS4: Price
It's anyone's guess as to how much the PS4 will cost and there may be different versions at different price points. Based on various rumours a good starting point is around the £300 mark. We'll have to wait and see.
There will be likely different bundles of the console sold with different games included.
Follow Chris Martin and @PCAdvisor on Twitter.
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Washington, D.C. (June 26, 2012) — Pharmaceutical Research and Manufacturers of America (PhRMA) President and CEO John J. Castellani issued the following statement today regarding reauthorization of the Prescription Drug User Fee Act (PDUFA):
"Today's Senate passage of S. 3187, the Food and Drug Administration (FDA) Safety and Innovation Act of 2012, is the culmination of a multi-year effort on the part of biopharmaceutical companies, FDA, Congress, and stakeholders that featured unprecedented collaboration, public input, and bipartisanship.
"On behalf of the more than 650,000 employees of America's biopharmaceutical companies, I enthusiastically thank Chairman Harkin, Ranking Member Enzi, Chairman Upton, Ranking Member Waxman, and members of both the Senate and House Committees for their dedication to a bipartisan, collaborative process. The final bill will enhance the efficiency of FDA's human drug review program, and will help bring safe, effective, and innovative medicines to patients in a timely manner.
"The result of this process is evident in the permanent reauthorization of the Best Pharmaceuticals for Children Act and Pediatric Research Equity Act, which will improve medical care for children by driving research to create innovative medicines for use in pediatric patients. Bipartisan support for these programs was led by Senator Reed, Senator Alexander, Senator Murray, Senator Roberts, Representative Rogers, Representative Eshoo and Representative Markey.
"Congress also made significant policy changes that will help alleviate drug shortages and improve the integrity of the pharmaceutical supply chain.
"We look forward to continue working with Senators Burr and Bennet, as well as other stakeholders in the domestic supply chain, to complete work on track-and-trace legislation this year."
The Pharmaceutical Research and Manufacturers of America (PhRMA) represents the country's leading pharmaceutical research and biotechnology companies, which are devoted to inventing medicines that allow patients to live longer, healthier, and more productive lives. PhRMA companies are leading the way in the search for new cures. PhRMA members alone invested an estimated $49.5 billion in 2011 in discovering and developing new medicines.
Find PhRMA Online:
- Website – http://www.phrma.org
- facebook – www.facebook.com/PhRMA
- Blog – www.phrma.org/catalyst
- Twitter – www.Twitter.com/PhRMA and www.Twitter.com/PhRMApress
- YouTube – www.youtube.com/PhRMApress
- E-News Alerts – www.phrma.org/updates
For information on how innovative medicines save lives, visit: http://www.innovation.org
For information on the Partnership for Prescription Assistance, visit: http://www.pparx.org
For information on ensuring the flow of medicines during public health emergencies, visit http://www.rxresponse.org


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DarkOne said:
Well hello there. Before we get into the main meat of this news post I'd like to list a few things happening right now on the sites that we are aware of, that we don't need you to tell us about or confirm, or reconfirm, that will be fixed soon. I say soon, we've been working 14 hours straight, from 9am to 11pm and while the main conversion is complete there's still work to do which will be pushed into Tuesday day (i.e. we're going to bed soon!). Anyway, here's the list, and if you comment on this news post bringing up these points it means you didn't actually read this news post before commenting and that you, sir, deserve a turd sandwich:
- Apparent slowness on all sites or pages not loading at all with 500-504 errors. Sometimes at random, sometimes all the time. This is because our new server setup and configuration needs lots of testing and tweaking with the new load put on it. It should go away over the coming days. Good news for us is it's not database related. First time this year.
- Not all the file servers are up and operational yet. The ones that are up might be slow, or not working at all, due to this fact.
- Issues with some Premium Memberships not working. Unsure whether this is on the sites (can't replicate this issue on my end) or in NMM (can replicate this issue on my end, Premium Members not being recognised in NMM). Feel free to share feedback on this one to help me troubleshoot (obligatory turd sandwich is waived in this instance).
- A few broken links. I know about the forum button link and the "More from this uploader" link. Any others feel free to share.
And now, to the meat of the news...
Our maintenance work is now completed on all sites and I can now happily announce the completion of my plans to centralise the Nexus into one database and open up the site to mods for all PC games.
The overall premise of this update is to centralise the management and presentation of game files across all the games we support while still maintaining that drilled-down, focused aspect of browsing individual Nexus sites for individual games. I understand that some users only visit the Nexus to get files for a single game and I also understand that some users use various different Nexus sites and also have files and images on multiple different Nexus sites. I didn't want to remove the more personal Nexus browsing experience you get when browsing a Nexus site for a specific game but I did want to offer the option to users to very quickly and easily find files for multiple different games very quickly and easily without having to switch between sites, or even pages.
Perhaps more exciting is the fact we have updated our file upload wizard and now accept files for any and all games on the PC platform. As part of my wish to support modding in totality I wanted to open up the Nexus so it could be used by all mod authors out there, irrespective of whether we support the game currently or not. As a mod author it's actually extremely simple to add a file for a game we don't currently support and there's very little extra work involved. The process is as follows:
- Go to our file upload wizard on nexusmods.com
- The very first step, Step 1, is where you choose what game your file is for
- If the game already exists simply select it from the drop-down menu
- If the game does not exist enter the name of the game
- Continue with the file upload wizard as per before
Note: this step is made simpler if you use the file upload wizard from a specific Nexus site, e.g. if you use the file upload wizard on Skyrim Nexus then step 1 is completed for you with Skyrim pre-selected.
The game addition phase is a manual one which requires an administrator to confirm the submittal of your suggested game to the database. This means until an administrator confirms your game suggestion your file won't be visible on the sites. While adding this bottleneck is a bit counter to how we've done things up until now I'm sure you'll agree it could become an organisational nightmare if the game adding process was automatic. It's simply there to allow me time to add the game box art and ensure that people haven't uploaded different files for the same game under different names, e.g. C&C3, Command & Conquer 3, Command And Conquer 3, CNC3 and so on. In such an event I can merge all the files in all those games under one name and ensure everything isn't a mess before publishing the game on the network. However, you can still create your entire file page including uploading your images and files and submit your file so that as soon as the game is approved by an admin it will be instantly published along with the site. That means you don't have to suggest a game, wait for it to be approved, and then submit your file. You do it all at once and then simply wait for me to approve the game, at which point your file will become available.
Once a new game is approved a new Nexus site is automatically created and added into the pool of games to browse in the file database and our game list. For all intents and purposes once the game is approved you've just created an entirely new Nexus site in seconds. Minecraft Nexus? You can do that. The Sims Nexus? Yep. GTA Nexus? Uh huh. I no longer dictate what games the Nexus supports, the mod authors do.
Any new Nexus site created by this new system will use a generic design under the original Nexus orange and grey colour scheme (the Oblivion colour scheme) with no background image. You can tell what Nexus site you're currently browsing in many different ways. Established Nexus sites have unique colour schemes and unique background images that really make them stand out, but all Nexus sites have the name of the game in the top-left hand corner of the site below the Nexus logo. It's my hope and intention to create unique colour schemes and background images for any games that reach a certain level of activity. In my mind that level of activity is around about the 30 files uploaded mark. Once 30 files have been added to a specific Nexus site I'll create a unique background and colour scheme for it.
With this update we've also changed the addresses/URL's used and we've moved away from the subdomain system of separating Nexus sites (e.g. skyrim.nexusmods.com, oblivion.nexusmods.com, etc.). I know this is annoying for some of you who like to ensure you're using the latest links but we really did think it through and, with this update, the benefits of changing from a subdomain system far outweigh the annoyance of the change. We've been careful to ensure any old links to your files will still work with the new system; they should seamlessly redirect to the new URL, but I do understand the frustration of having to change links, just please know it was in our best interests, and ultimately, yours (it's all to do with search engine optimisation). All new Nexus sites will not have a subdomain attached to them. If you're noticing that redirects from the old URL to the new URL are not working then please let me know and I'll get it fixed up as soon as possible.
We've updated the NexusMods.com homepage accordingly to become the central hub for finding all the games we support and even accessing all the files across all the games from one single page. From NexusMods.com you can find any file for any game on any Nexus site from the files page. This page is exactly the same as the file page on individual Nexus sites only you can broaden your browsing range from a single game to all games. If you prefer to browse for files from specific Nexus sites then you can still do that (indeed, the Nexus sites remain pretty much unchanged with this update), and you can also access our game list to see a list of all the games the Nexus currently supports.
As part of this work we've centralised our database into one single database. Originally each Nexus site used a different database. 18 games, 18 databases. We've now merged all the databases into one. This provides practical functionality to the sites, for example if you've uploaded files or images across multiple different Nexus sites you can now manage all of them from a single page or, in keeping with my wish to maintain a more personal approach, you can continue to go to each individual Nexus site and maintain your files for individual games from there. Your file management pages have a form field at the top that lets you filter between all the games you've uploaded files for which provides quick and easy access. Similarly the centralisation also allows us to present a unified listing of all your files and images on your profile page for everyone to see. Once again, filter options are available that allow users to see what files you've uploaded for specific games.
While originally only Skyrim was using our new Cloud setup we've now moved every site on to the Cloud. While this might create a few days of instability as we re-tune all the settings and config for the increased load on the nodes it is the next step in our efforts to increase the reliability of the network which I'm sure you'll agree (and if you don't you're being silly) has improved over the past couple of months compared to the past few years. It's still not perfect by any means but we are getting there and this work is a step towards the ultimate goal of 100% uptime and 100% reliability. Liken it to surgery; relatively brief times of pain for much longer term benefits and gain.
Having said that this centralisation work is the combination of thousands of hours of work and while we've tried to test it all as much as possible I think logic (and past experience) dictates that there are going to be niggling issues and, potentially, bugs. We'll be working overtime to ensure we fix any bugs as soon as we find out about them and, once again, we're relying on you guys to let us know when you find something amiss or not working properly. We can only fix what we know about.
It's important to understand that this update is laying the groundwork to future improvement. It's not the end, it's simply the beginning of a new era, a new foundation for Nexus Mods from which we'll be working from. This year has been all about two things. Improving the reliability of the network and opening up the network to files for all PC games. In the new year we'll build on both of those objectives and we'll be switching our focus away from these two big projects into a lot of smaller, more functional updates and improvements which we haven't really focused on this year at all. It's difficult to say "the best is yet to come" but I honestly believe it. What you see before you right now is a foundation. Next year we want to build on it and improve on it based on your feedback to us and we've positioned ourselves accordingly.
FYI Nexus have also change its domain prefix from <TES game>.nexusmods.com/ to http://www.nexusmods.com/<TES game>/?.


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It's not in every case simple to design the loft room, so you are going to require an arrangement before you start. You will have slanting roofs to manage just as stairs that need to mix in with the stylistic theme. With a splendid arrangement, you can have a wonderful room that everybody will need to remain in.
Hardwood flooring is the most widely recognized ground surface for upper room rooms. You can total the look of the room by putting geometric mats down on the floor. Try not to add botanical mats to the upper room since it influences the space to appear to be excessively little and jumbled. Rather utilize strong shading floor coverings made of cotton since cotton is delicate and agreeable. Place one on each side of your bed and at the foot of the bed.
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Rather than a storeroom entryway on the storage room, you have to put a shade for an entryway. A shade can be produced using brilliant material and will save money on the room. You don't need the additional room it takes to open the wardrobe entryway. You can change the drape in your storage room each time you change your stylistic layout. Take a stab at making the window ornament from a splendid white shading or a yellow shading rather than a dim strong shading.
You can enrich whatever is left of the room as indicated by your preference for stylistic layout. You can put two seats that sit next to each other at a point toward one another and put a minor table between them. Keep the room straightforward and don't include excessively furniture.
The most imperative piece of brightening the upper room is to make sense of where you need the bed to be put. At that point, you can beautify whatever is left of the room around the bed. A standout amongst the most wide recognized spots to put the bed was on one side of the loft rather than amidst the room. The loft won't have a ton of room, and putting the bed amidst the floor will naturally influence the space to appear to be much littler then what it truly is.
Lighting is likewise critical. Since the territory is little in size, you have to light up it up by setting enough lighting in the room. You require a little light on the table between the two seats. Place track lighting over a work area and at the bed. You can change these lights as needs are.
Rather than a full-size dresser or department, you might need to settle on a wardrobe in the corner and use bushels that are fixed with organizing material. You can either make these or you can get them effectively made.
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Priyanka Chopra was born on July 18, 1982 in Jamshedpur, Jharkhand in India to Dr. Ashok (father) and Dr. Madhu (mother) Chopra.
Since her father was a doctor in the Indian army, they spent a lot of time moving around, so she lived in many places growing up, such as Jamshedpur, Delhi, Pune, Lucknow, Massachusetts, and Iowa, among other locations. While in Boston, she participated in many charitable activities, theatre productions, and song and dance activities. She returned to India to finish high school and during this time, she won a local beauty pageant, "May Queen." She registered for classes at Jai Hind College, but left shortly after once she decided to head into the world of glamor, taking part in the Femina Miss India contest. This contest actually came to her as a surprise, since her mother sent pictures of her to the contest without her knowing. Upon being called to participate in the contest, she was encouraged by her father and decided to go for it. She came in second place in the contest and went on to the Miss World Pageant. Wowing the judges, she took home the title of Miss World 2000. "When I became Miss World, I couldn't believe I had won it. I used to sleep with my crown on because I thought someone would steal it. In a minute the world changed for me." She spent a year travelling the world with the Miss World organization and eventually made the decision to become an actress Chopra kicked off her acting career in 2002 film, Thamizhan with the role of Priya, the love interest of the protagonist. The film received decent reviews, but Chopra's character was seen as falling a little short. She followed up with her Bollywood debut in the film, The Hero: Love Story of a Spy (2003). The film did well in the box office, but was not received as well by critics. Chopra however, was received better than she was in Thamizhan, earning herself good reviews. Also in 2003, she starred in Andaaz as another love interest. This film also did well in the box office in addition to earning her a Filmfare Best Female Debut Award as well as a nomination for Filmfare Best Supporting Actress Award. 2004 started off a little rough for her, with some films that did poorly in the box office, but redeemed herself with her role in the film, Mujhse Shaadi Karogi, a romantic comedy that ended up being the third-highest grossing film of the year. But what really helped her break through was her role in the film, Aitraaz, a thriller in which she plays a villainous role. She received much praise from critics for this role as well as earning a Filmfare Award for Best Performance in a Negative Role. 2005 was an average year for her with six films being released, four of which didn't do so well, and the other two being modestly successful. Despite the modest to poor performance of these films, Chopra was still noticed for her roles by critics and viewers for her passionate performances and her gorgeous looks. 2006 was a better year for her, starring films such as Krrish and Don, which became blockbusters in India as well as receiving praise around the world. 2007 and 2008 were not so kind to Chopra with many unsuccessful films that not only flopped in the box office, but also garnered negative reviews of her performances. However, she managed to turn out two successful films in 2008: Fashion and Dostana, which both were received well in the box office as well as with critics for her performance and looks. In 2009 Chopra became the first actress in cinema history to play 12 distinct roles in the same film, What's Your Raashee? The film was a financial and critical flop, but Chopra's performance didn't go unnoticed, as critics praised her ability to play so many different characters. During the following years, she went on to star in other films, some that did well, and others that didn't. These films included Pyaar Impossible! (2010), 7 Khoon Maaf (2011), and Don 2 (2011), among others. In 2012, Chopra became the first Bollywood star to sign with the Creative Artists Agency (CAA), a well known entertainment and sports agency based in Los Angeles, which will help her with her career in Hollywood. In September 2012 Chopra appeared in Barfi ! as an autistic girl who falls in love with a deaf and mute boy. The film was a hit with critics, and Chopra received praise from critics across the board for what was considered to be her best performance yet. The film has been chosen as India's official entry for the 85th Academy Awards in February 2013. Chopra is very proud of her accomplishments to date, but also very humble, stating, "I don't come from a film background. I haven't learned anything about films or film-making. But I have a thirst to know everything about my profession. I want to learn about cinematography, about editing, about music recordings, about post-production. So when people in the know talk, I willingly listen. Also, I'm not scared of working 20 hours a day."She has also worked on her singing through the years, and in 2011 she signed with Universal Music Group and DesiHits. She has been working on her debut album, going back and forth between India and Los Angeles. It's set to be released in December 2012. She is currently single, but hopes to be married some day; "I thoroughly believe in the institution of marriage, but there's a long way to go before I get married. Right now I want to concentrate on my career."
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Slacker who came in from the cold
Think you're a loser just because you dropped out of high school and never finished the military training you began?
Think you're a dud just because you work as a security guard even though you dreamed of becoming a global savior?
Story Continued Below
Well, don't beat yourself up. You, too, can become an international super spy like Edward Snowden.
Snowden, 29 and possessing all the qualifications to become a grocery bagger, instead gets hired by the National Security Agency as a security guard, after dropping out of high school and the Army.
( PHOTOS: 10 famous whistleblowers)
This naturally brings him to the attention of the Central Intelligence Agency, which hires him and sends him to Geneva, Switzerland, with diplomatic cover and a high security clearance.
With all that on his résumé, he gets scooped up by defense contractor colossus Booz Allen Hamilton, which assigns him to work at an NSA facility in Hawaii for a reported $200,000 per year. This allows Snowden to rent a house near the beach for him and his girlfriend.
Not that Snowden wasn't carefully vetted. Booz Allen, which was paid 1.3 billion U.S. tax dollars in the last fiscal year to safeguard U.S. intelligence secrets, issued a statement Sunday: "Booz Allen can confirm that Edward Snowden, 29, has been an employee of our firm for less than three months, assigned to a team in Hawaii. News reports that this individual has claimed to have leaked classified information are shocking. …"
He worked there less than three months? A guy with hardly any qualifications is earning $200,000 a year with access to classified information after less than three months?
Is this the American dream or what?
Some would think this is not a bad life for a guy who has been a total slacker. But this is not what Edward Snowden thinks. He has still not saved the world nor become an international celebrity.
So first he leaks classified information that reveals our government is collecting information on all phone calls made on the Verizon network and then leaks classified info that reveals the government collects Internet data on foreigners from companies like Google and Facebook.
The U.S. government has two contradictory responses to the leaks. First, it says, the stuff Snowden has leaked is no big deal and the media are guilty of "hyperbole" in their reporting on it.
On the other hand, according to Director of National Intelligence James Clapper, "For me, it is literally — not figuratively — literally gut wrenching to see this happen because of the huge, grave damage it does to our intelligence capabilities."
So take your pick.
In any case, Snowden flees the United States to a luxury hotel in — wait for it — China.


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this is a discussion within the Full Disclosure Community Forum; The Fourth Kind is an American science fiction thriller that was released in 2009. Set in Nome, Alaska, the story is based on the mysterious disappearances of 24 people in Nome from the 1960s through to 2004. According to Box ...
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The Real Story Behind Nome, Alaska: Missing People or Alien Abductions?
The Fourth Kind is an American science fiction thriller that was released in 2009. Set in Nome, Alaska, the story is based on the mysterious disappearances of 24 people in Nome from the 1960s through to 2004.
According to Box Office Mojo, The Fourth Kind was a box office hit, making $47.46 million worldwide, from an estimated $10 million budget. (1)
Despite enjoying considerable box office success, The Forth Kind was panned by critics with some deeming it has being insensitive to the families of the missing victims. (2).
In an analysis of The Forth Kind, Rotten Tomatoes, a website devoted to reviews, information and film news, summed the film up as follows:
While it boasts a handful of shocks, The Forth Kind is hokey and clumsy and makes its close encounters seem eerily mundane.
Nome Alaska Missing People Truth vs. Fiction
The true part of the story is as follows.
In 2005, FBI homicide detectives did in fact investigate the mysterious disappearance of 24 people that had taken place in Nome between the 1960s and 2004, which caused locals to initially think there was a serial killer involved.
According to the Anchorage Daily News, most of the victims were native men who had travelled to Nome from surrounding villages. The FBI determined there was no real reason to suspect a serial killer and instead came up with the explanation that, Excessive alcohol consumption and a harsh winter climate, were to blame for the disappearances. (4)
However, The Forth Kind is based on a conspiracy theory from the movie producers as to why those people went missing from Nome, and that they were actually abducted by aliens.
The footage in the film that shows hypnotherapy sessions taking place between Dr. Abigail Tyler, played by Milla Jovovich, and the patients who claimed they had been abducted. The movie was dubbed as being, the most disturbing evidence of alien abduction ever documented. (5)
Between the FBI dismissing the Nome missing peoples case as being due to excessive alcohol and a harsh winter climate, and movie producers cashing in on the story by producing a fabricated tale about alien abduction, it is hardly surprising that the families of those who disappeared are upset about the lack of case closure.
UFO Sightings in Nome Alaska
Being located on the very edge of the continent, local UFO watchers feel a special kinship with Nome. And according to Huliq.com, there are regular UFO sightings in the Nome region throughout the year, with ufologists thinking this may be a region for a sort of command centre for alien life on Earth. (6)
Despite the so-called UFO sightings that regularly take place in Nome, proof that the alien explanation behind the Nome missing people was fabricated was made in 2009 when Universal Pictures, the company that made The Forth Kind, had to pay a settlement for creating fake news accounts to promote the so-called documentary film.
A report made by Fox News stated that Universal Pictures agreed to $20,000 to the Alaska Press Club to settle complaints that fake news archives were used to promote the movie. (7)
According to the report, Universal Pictures had created a series of fabricated online news articles to promote the alien-abduction movie, and the articles posted had the appearance of coming from real Alaska newspapers.
These fake news reports included an obituary and news story allegedly taken from the Fairbanks Daily News-Miner, about the death of one of the movies leading characters, Dr. William Tyler. Besides being forced to pay $20,000 in compensation, Universal was also required to remove the fake news articles from the Internet. (8)
The problem at that point is that the damage had already been done. The originals had gone viral, and there were many thousands of believers that continued to believe the story was real, even though the fake evidence had been removed from the Internet.
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Re: The Real Story Behind Nome, Alaska: Missing People or Alien Abductions?
I just cued the movie up on Netflix. I may watch it tonight.
I'm hooked on Being Human (American version) right now but I may slip this flick in.
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Re: The Real Story Behind Nome, Alaska: Missing People or Alien Abductions?
Time to rewatch...
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Re: The Real Story Behind Nome, Alaska: Missing People or Alien Abductions?
Time to watch. I just got Netflix.
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