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Book review - Forever and a Day
Anthony Horowitz's prequel to Ian Fleming's Casino Royale, Forever and a Day (2018) starts with M making the observation, 'So, 007 is dead.' Of course it isn't James Bond who is deceased but the unnamed previous incumbent with that Double-O number. A neat touch, that.
This is Horowitz's second foray into the James Bond universe, having earlier treated us to Trigger Mortis (2015) – reviewed here
Where the earlier book took place in 1957, shortly after Goldfinger, this one takes us to early 1950s, the beginning of Bond's career as the new 007; there are only three Double-O men – 008, 0011 and 007, it seems; M deplored using sequential numbers (p4). M's Chief of Staff reveals that 007 was murdered in the south of France, in Marseille. He'd been investigating the Corsican underworld in the area. 'It seems that there was a woman involved.' To which M replies, 'There always is.' Dry humour, just the right note. The woman is called Madame 16 or Sixtine, a one-time worker at Bletchley Park and subsequently an agent in SOE. As 008 was still out of action (hospitalised) and 0011 was in Miami, it was deemed necessary to send the new 007 to dig around – James Bond.
Eventually, Bond finds himself in Monte Carlo, playing Vingt-et-un against Sixtine. An amusing aside when a croupier mutters, among other appropriate phrases, Carré, doubtless Horowitz's nod to John Le Carré. (p59) This scene is also an homage to Fleming's lengthy discourse in Casino Royale.
We're made privy to the origin of Bond's vodka martini being shaken, not stirred (p70); another nice touch. As for his cigarettes, he was introduced to Morlands' coffin nails in preference to his Du Maurier 'named after a minor British actor.' (p122) Finally, we see how Bond acquires his trade-mark gunmetal cigarette case, which also masterfully explains the book title. (p169)
There are two villains, Scipio a grossly overweight Corsican and rich industrialist Irwin Wolfe. Scipio delivers Bond a trenchant speech via a translator: '… the arrogance of the British. You are a tiny island with bad weather and bad food also but you still think you rule the world… you are becoming irrelevant…' (104) Maybe he was an early scriptwriter for the EU negotiators?
Inevitably, Bond is faced with grim 'torture', which is only to be expected. However, more than once he seems to escape through no guile of his own; I won't say more. This didn't spoil the book for me; I perhaps was hoping for more, which may be my failing.
Horowitz also adopts the Fleming style of chapter headings, often playing with words, among them Killing by Numbers, Russian Roulette, Not So Joliette, Shame Lady, Love in a Warm Climate, Pleasure… or Pain? and Death at Sunset.
Yet again he has captured the flavour and tone of Fleming while adding his own stamp to the proceedings. Initially,
I wasn't impressed by the title, Forever and a Day, but it makes complete sense now that I've read the book. It's also the title of a 1943 film.
The cover is excellent, the luxury yacht resembling a deadly bullet!
I ended my review of Trigger Mortis with the hope of seeing another Horowitz 007 novel, and despite a few caveats he has not disappointed. I look forward to the next.
Repetition. On page 33 we're told 'Bill Tanner, M's chief of staff and a man Bond knew well.'
Then on p35 we read: 'The two men knew each other well.' The editor should have spotted this, and a few other minor points below…
Clumsy wording: 'Bond was holding the envelope that he had found in his right hand.' (p49) At the bottom of p48 we know Bond is holding an envelope which he'd just found. Had he just found it in his right hand?
'Then he slumped to the ground.' (p49) This is in an apartment, so it should be 'floor' not 'ground'.
'… punctuated by a slither of silver moonlight.' (p144) I'd reckon that should be 'sliver'.
Consistency. At one point we have eyeglasses (p103), and at another spectacles (p54).
'His ankles were also secured to the legs of the solid wooden chair…' And yet further down the same page, 'Bond hadn't moved or opened his eyes. (p100) But he knows it's a solid wooden chair…? Okay, just maybe…
As Bond is ex-Royal Navy, and it's mostly his point of view, when he's aboard Wolfe's luxurious vessel, he wouldn't note 'submarine-style hatches' but simply hatches. (p140). Again, 'the letter R was printed on the wall one floor down.' (243) But these are bulkheads and decks, even if in a luxury ship!
Labels: #espionage, #spy, 007, Anthony Horowitz, Casino Royale, Ian Fleming, James Bond, Trigger Mortis
A Dance to the Music of Time (5 of 12)
The first four volumes of A Dance to the Music of Time are reviewed in earlier blogs.
Anthony Powell's 1960 novel Casanova's Chinese Restaurant begins in the late 1920s and is again narrated by Nick Jenkins, and reveals in flashback his first meetings with Mr Deacon (deceased in the previous book), Maclintick, Gossage, Carolo and Moreland. As before, there is little emotion in the narrative: 'I listened to what was being said without feeling…' (p29) – which could apply to the story so far, really.
His friends Maclintick, Moreland and Barnby are intent on going to Casanova's Chinese Restaurant. Apparently, 'there used to the New Casanova, where the cooking was Italian and the decoration French eighteenth century. Further up the street was the Amoy, called by some Sam's Chinese Restaurant. The New Casanova went into liquidation. Sam's bought it up and moved over their pots and pans and chopsticks, so now you can eat treasure rice, or bamboo shoots fried with pork ribbons, under panels depicting scenes from the career of the Great Lover.' (p32)
Powell's narrator doesn't involve the reader greatly in the scenes: 'Maclintick and Barnby ordered something unadventurous from the dishes available; under Moreland's guidance, I embarked upon one of the specialities of the house.' (p34) You have to wonder if Powell could actually name any Chinese dishes; and the phrase 'from the dishes available' seems superfluous, as would 'from the menu'.
Following from these reminiscences, we move to the 1930s and Nick reveals he has been married to Isobel, 'perhaps a year'. (p58) The scandal about Mrs Simpson and, ultimately, The Abdication, is the talk of the town.
Lady Warminster is quite a character. She was 'prone to fortune-tellers and those connected with divination. She was fond of retailing their startling predictions.' (p74) Echoes of Nick's Uncle Giles's friend Mrs Erdleigh! One of her statements about the novelist St John Clarke: 'I always think one ought to be grateful to an author if one has liked even a small bit of a book' (p75) is damning with faint praise indeed! By now, Clarke was 'forgotten by the critics but remembered fairly faithfully by the circulating libraries…' (p80)
Nick had lost touch with Widmerpool, primarily because his wife Isobel didn't care for the man. 'In any case I should never have gone out of my way to seek him, knowing, as one does with certain people, that the rhythm of life would sooner or later be bound to bring us together again.' (p101)
When we do meet Widmerpool, he is more pompous than ever: 'I regret to say that few, if any, of my school contemporaries struck me sufficiently favourably for me to go out of my way to employ their services… It is one of my principles in life to surround myself with persons whose conduct has satisfied me.' (p122) And clearly he is not prescient: 'Setting aside a European war, which I do not consider a strong probability in spite of certain disturbing features, I favour a reasoned optimism.' (p123)
Maclintick is a sad figure, with a marriage that doesn't work, he and his wife constantly arguing: '… for a moment I thought he was going to strike her; just as I had thought she might stick a dinner knife into him when I had been to their house…' (p148)
There is a rare stab of emotion, however: 'I suddenly felt horribly uncomfortable, as if ice-cold waer were dripping very gently, very slowly down my spine…' (p151) when reminded of his old love Priscilla.
The narrator excuses his lack of emotional commitment in part: '... it is doubtful whether an existing marriage can ever be described directly in the first person and convey a sense of reality… if one has cast objectivity aside, the difficulties of presenting marriage are inordinate… I thought of some of these things on the way to the nursing home.' (p96)
At the nursing home he meets Moreland and, of all people, Widmerpool. Here, Nick reveals to Moreland, an expectant father, that Isobel has just had a miscarriage. Moreland is not particularly sympathetic, bemoaning the fact that his wife Matilda's constant false alarms were likely to make him bankrupt. (p98) These were the days before the National Health Service.
There's a preponderance of names beginning with the letter 'M' – Moreland, Maclintick, Mona, Members, Milly, Magnus, Mildred (dumped girlfriend of Widmerpool), Mortimer, Matilda ( wife of Moreland)… Reminds me of the story 'The Empty House' in The Return of Sherlock Holmes: 'My collection of M's is a fine one…' (p20) Though perhaps in this book's case there's an overabundance of names beginning with that letter.
Next: 6 – The Kindly Ones.
Labels: #Novel, A Dance to the Music of Time, Anthony Powell, Casanova's Chinese Restaurant, Sherlock Holmes


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Red & White: The Three Dimensions of Cricket
10th March 2020 10th March 2020 Pankaj Khanna	0 Comments IPL, ODI, T20, T20I, Test Cricket
Is red-ball cricket better than white-ball cricket or is white-ball cricket superior form of the game? Indian national cricket team's Test specialist Cheteshwar Pujara sparked off a debate among cricket fans on social media about a month ago by saying he considers winning the ICC Test Championship a bigger achievement than winning the ODI or T20 World Cup. Pujara's statement left the cricket fans in splits- debating over which form of cricket is the best.
Test-Cricket
The cricket pundits have been calling Test cricket as the ultimate form of the game ever since the advent of limited overs version of the game. But with the rise of white ball bonanza, Test cricket is fighting to complete while crash-bang-wallop version of the game has been the crowd puller. Does it make Test cricket irrelevant? Absolutely NO! True cricket romantics still love the format as it really tests your skills, mental strength and character as a player- you have nowhere to hide. Five day cricket gives you so much time for everything- leave, defence and attack. It throws you in a coliseum where your limitations cannot be concealed. You need to have a very good technique as a batsmen to bat for long periods of time facing a hostile spell of bowling in tough conditions. Leaving the balls that should be left. Avoiding poking at deliveries outside the off-stump. Getting your feet moving to the pitch off the ball so that you can be on top of the ball. Playing the ball with the full face of the bat. Having your front shoulder in the right position. All of this counts to be a successful Test batsmen.
As a bowler you plan to outfox the batsmen by setting them up. Laying the trap and patiently waiting for them to fall for it. Bowling long spells. There are often mini battles inside the game with ferocious spells of individual brilliance, outcomes of which have an impact on overall result of the game. Away from all the noise of the scorecard, the game drifts along at a pace of its own and you have to play it session by session. Same game presents several different challenges- countering the early morning swing, tackling the fading light when the day is ending, surviving on a minefield of a pitch on fourth or a fifth day and starting the next day from zero even if you are batting on a hundred. As a captain you have to find answers to important questions such as, when to declare? Do you want to bat again? How much time do you need to get the opposition out in the fourth innings? It gives you an opportunity to escape with a draw if you can bat entire day to save the game. Only after toiling hard for days with numerous swings in fortunes you get to the outcome of the game. Test cricket needs to be preserved for so many flavors it offers in a single game and World Test Championship is a step in the right direction.
In modern era, T20 has fundamentally changed the way cricket is played. Young batsmen believe in building their game on attack instead of solid defence as that's the skillset required to be successful in this format of the game. It is an explosive format which encourages power hitters. Players like Andre Russell can change the complexion of a game in a matter of two overs. Create an impact like Yuvraj Singh did by hitting six sixes in an over of Stuart Broad in the inaugural T20 World Cup in 2007. The game is so fast that you need to be on your toes. There is no time to get your eye in as a batsmen- you have to get going from the first ball. It demands the players to be innovative and fearless in their thinking. As a result batsmen have been more inventive and have mastered the art of playing unorthodox shots such as switch hit and the scoop. There is a need for the batters to maximize the hitting zone to score more. Clearing the front leg and hitting through the line. Using your feet especially to the spinners to unsettle the bowler early on in their spell. All of this requires hours and hours of practice in the nets facing throw downs or the bowling machine.
T20 bowling is a different from other formats. In Test Match cricket you would want to bowl consistent line and length as a bowler but if you do the same in T20 cricket you will be pounded for runs. As a bowler you will be getting flat decks to bowl at, so you will need more variations- slower balls, yorkers, knuckle balls, wide-yorkers, slower bouncers and cutters. Bowlers should be able to read the batters body language and mind-set, to bowl a delivery which they are least expecting, which would be their best opportunity to contain them or get them out. A bowler's dilemma in T20 cricket is whether to bowl a wicket-taking delivery or a dot ball. They are more inclined on containment and waiting for the batters to make a mistake. Are quite content with giving away a single if that can prevent a boundary. If a big hitting batsmen is looking for boundaries and as a bowler if you can restrict them for just a single and send him down to non-striker's end, it would be considered a good outcome. Test bowler bowling a low full-toss on the batsmen's pads will be clipped in the on-side for a boundary. But the same delivery in T20 with fielders in the deep to prevent a boundary becomes a safe option. Change in a spinner's mind-set has been even more profound. Instead of giving the ball more flight, spinners have been found bowling darters- flatter and quicker. The more preferred skill among the spinners is the ability to turn the ball both ways to deceive the batters.
Fielding is of utmost importance in T20 cricket so the teams around the world generally prefer young legs in the field. Most matches are closely contested and go down to the wire. Margin of victory is generally narrow. Runs saved in the field are likely to have an impact on the outcome of the game. So it is extremely important for the fielders to be brilliant in the field when it comes to diving, hitting the stumps, sprinting, taking relay catches, doing underarm diving throws and taking running catches in the deep.
One-day Internationals
ODI cricket is similar to T20 in some ways but requires a different approach. If you are a batsmen batting in the top 3 it would be expected of you to provide your team a steady start and set the platform for the lower order to explode pretty much like a T20 game. Your approach should be that of controlled aggression so that you can hope to continue for a longer period of time. A new batsmen will have sufficient time to get their eye in while playing the balls on merit. No. 4 is crucial position to bat in ODI cricket where the batsmen will be expected to keep the scoreboard ticking in the middle overs, running hard between the wickets- converting the ones into twos and taking the game deep. A No. 4 batsmen will also need to be dynamic in his approach as there will be times when he will be coming into bat at 30-2 and there will be times when he will be coming into bat at 200-2, so they should have the ability to adapt to different situations and be able to shift gears as the inning progresses. ODI pace bowler would be required to bowl in the first power play and will need to bowl consistent line and length. Unlike T20s, batsmen generally take time to settle in so they would not need to bowl six different balls in an over. Spinners look to give the ball a bit more air- inviting the batsmen into a drive with the attempt to deceiving them with the flight. Death bowling would you quite similar to that in T20 cricket.
So to conclude- no format is superior then the other, each requires a set of skills to be successful. Each format has its own audience, while Test cricket excites ardent cricket fans, limited overs cricket attracts new cricket audiences. All three forms of the game can exist together. ICC and cricket boards around the world need to come together to balance the three and keep innovating.
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Kohli's men got no Grip: Team India's problem of butter-fingers in the field
14th February 2020 14th February 2020 Pankaj Khanna 0
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The Rishabh Pant Saga: Emergence, Rise and Fall of the Southpaw
6th February 2020 14th February 2020 Pankaj Khanna 0

redpajama_set_name: RedPajamaCommonCrawl


It's about mountain man John Colter and his solo journey into the wilderness during the winter of 1806-7.
Actually, that's not quite true – Colter headed upriver from the Knife River on August 23, 1806, with two other men, Joseph Dixon and Forest Hancock. After that not much is known.
Above you can see a look at the rivers of the Dakotas and Montana. That's an image I use when I write this story, and it's a tactic I use a lot, looking at maps and images and studying history to write novels.
I've written several historical novels already, and I'm pretty good at it now. The problem I run into with this book is that there are large swaths of time I don't know about. What's more, to cover that up, I'm making up a few things…though at least they involved historical characters.
For instance, who is my antagonist here? While the weather and the elements can be one, that doesn't make for a very exciting novel.
So why not the companions? There is a bit of that, but again, history gets in the way – we know Colter split with them by October or November and the two men eventually headed back east.
No, I need a real antagonist, someone that can go into the other novels, or at least bring forth an idea of conflict. And that's why I need an Indian.
I'm writing a Western, and for that I need Indians. For this story, I'll use the Arikara Indians.
We know that the Arikara lived along the Grande River in the 1700s from European explorers. We know that by the 1790s they were up to the Cannonball River and by 1804-6 were around the Knife River, which was the same general area the Mandan villages were at, which had about 3,000 Indians in them at the time.
Something else that we know is that Colter and Hancock left Dixon in a cave somewhere on the Yellowstone River over the winter, when the snows came.
John Colter trapped and spent the winter of 1806-7 along the Yellowstone River.
So it's a good bet that the three trappers stayed on the Yellowstone River and didn't do much on the larger Missouri. So as the river narrowed and split after the last of Lake Sacajawea, the men took the southern course, the left bend and their path through the winter was set.
But what about that bad guy? Imagine a Wes Studi-type that feels he's been wronged by these men, and that will stop at nothing to get them. Imagine something setting up our later encounters between Colter and the Blackfeet, which he's most known for.
That's what I'm doing with this book, and it starts out a bit slow, the tension builds and builds, and then when the dam breaks the excitement does not stop, like water rushing downriver that needs a release and won't get it until it comes flooding into it's grand finale and conclusion.
And what happens after that? I mean, we're not even up to Colter's run yet.
John Colter headed back down to the Platte River in the spring of 1807, where he ran into Manuel Lisa and George Drouillard.
We know that Colter ran into Manuel Lisa and George Drouillard heading back up river, and we know that happened around the mouth of the Platte River, at today's Omaha and quite a bit below one of the main areas of civilization at that time, Floyd's Bluff, which was where the first member of the Lewis and Clark Expedition died of disease in 1804.
It was a long journey after that winter spent out in the wild alone, and Colter never kept a journal and we just don't know what happened on that stretch of the river. With this new John Colter novel, however, we'll have one fun ride speculating.
I hope you'll enjoy "Colter's Winter" when I put it out next month – sign up to my email list to hear about it first.
Things kind of got sidetracked with this book...again. I started my 5th volume of Montana history and put this on the back burner.
Still, I'm getting a cover made for it now, and have some cool drafts of that to show. Stay tuned - this book will be out this spring.


Resemblances obtain not only between objects but between properties. Resemblances of the latter sort - in particular resemblances between quantitative properties - prove to be the downfall of a well-known theory of universals, namely the one presented by David Armstrong. This paper examines Armstrong's efforts to account for such resemblances within the framework of his theory and also explores several extensions of that theory. All of them fail.
In "Does Four-Dimensionalism Explain Coincidence" Mark Moyer argues that there is no reason to prefer the four-dimensionalist (or perdurantist) explanation of coincidence to the three-dimensionalist (or endurantist) explanation. I argue that Moyer's formulations of perdurantism and endurantism lead him to overlook the perdurantist's advantage. A more satisfactory formulation of these views reveals a puzzle of coincidence that Moyer does not consider, and the perdurantist's treatment of this puzzle is clearly preferable.


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Q: Python pdf2image: hide consoles I'm using pdf2image which uses poppler to convert PDF to images. However, when you use it in Python it opens a new console every time to convert a PDF. Is there a way to hide this console?
for file_name in os.listdir(path):
  if file_name.endswith('.pdf'):
    pages = convert_from_path(path + file_name, thread_count=4)
    idx = 1
    for page in pages:
      page.save(file_name + '-page-' + str(idx) + '.jpg', 'JPEG')
      idx += 1

A: Yes there is, but you might not like it. You have to modify the convert_from_path function a bit. Currently the function looks like:
import os
import re
import tempfile
import uuid

from io import BytesIO
from subprocess import Popen, PIPE
from PIL import Image

def convert_from_path(pdf_path, dpi=200, output_folder=None, first_page=None, last_page=None, fmt='ppm', thread_count=1, userpw=None):
    page_count = __page_count(pdf_path, userpw)

    if thread_count < 1:
        thread_count = 1

    if first_page is None:
        first_page = 1

    if last_page is None or last_page > page_count:
        last_page = page_count

    # Recalculate page count based on first and last page
    page_count = last_page - first_page + 1

    if thread_count > page_count:
        thread_count = page_count

    reminder = page_count % thread_count
    current_page = first_page
    processes = []
    for _ in range(thread_count):
        # A unique identifier for our files if the directory is not empty
        uid = str(uuid.uuid4())
        # Get the number of pages the thread will be processing
        thread_page_count = page_count // thread_count + int(reminder > 0)
        # Build the command accordingly
        args, parse_buffer_func = __build_command(['pdftoppm', '-r', str(dpi), pdf_path], output_folder, current_page, current_page + thread_page_count - 1, fmt, uid, userpw)
        # Update page values
        current_page = current_page + thread_page_count
        reminder -= int(reminder > 0)
        # Spawn the process and save its uuid
        processes.append((uid, Popen(args, stdout=PIPE, stderr=PIPE)))

    images = []
    for uid, proc in processes:
        data, _ = proc.communicate()

        if output_folder is not None:
            images += __load_from_output_folder(output_folder, uid)
        else:
            images += parse_buffer_func(data)

    return images

The line we are interested in is:
processes.append((uid, Popen(args, stdout=PIPE, stderr=PIPE)))

We need to explicitly tell Popen not to show the console windows like so:
startupinfo=None
if platform_name == 'Windows':
  # this startupinfo structure prevents a console window from popping up on Windows
  startupinfo = subprocess.STARTUPINFO()
  startupinfo.dwFlags |= subprocess.STARTF_USESHOWWINDOW
processes.append((uid, Popen(args, stdout=PIPE, stderr=PIPE, startupinfo=startupinfo)))

Some versions of python 2.7 might need to use:
 startupinfo=None
    if platform_name == 'Windows':
      # this startupinfo structure prevents a console window from popping up on Windows
      startupinfo = subprocess.STARTUPINFO()
      startupinfo.dwFlags |= subprocess._subprocess.STARTF_USESHOWWINDOW
    processes.append((uid, Popen(args, stdout=PIPE, stderr=PIPE, startupinfo=startupinfo)))

A: Additional information:
In order to hide the console window completely when running from a compiled executable in Windows, need to patch three functions in pdf2img.py in which Popen is called:

*

*convert_from_path()

*pdfinfo_from_path()

*_get_poppler_version()

For example, from:
Popen(command, env=env, stdout=PIPE, stderr=PIPE)
To:
Popen(command, env=env, stdout=PIPE, stderr=PIPE, creationflags=0x08000000)
I am using Python 3.8 in Windows, whereas 0x08000000 is the new subprocess.CREATE_NO_WINDOW flag in Python 3.7+

A: currently the code comes by default:
# Spawn the process and save its uuid
    startupinfo=None
    if platform.system() == 'Windows':
        # this startupinfo structure prevents a console window from popping up on Windows
        startupinfo = subprocess.STARTUPINFO()
        startupinfo.dwFlags |= subprocess.STARTF_USESHOWWINDOW
    processes.append(
        (thread_output_file, Popen(args, env=env, stdout=PIPE, stderr=PIPE, startupinfo=startupinfo))
    )

I've tried many things and the console keeps popping up

redpajama_set_name: RedPajamaStackExchange


text:
Community Police Oversight Commission
Application Deadline for Community Police Oversight Commission Initial Appointments is March 15 at 5 p.m.
February 23, 2021 February 23, 2021 News
PASADENA, Calif.—In October 2020, the City Council established a Community Police Oversight Commission (CPOC) by ordinance. The purpose of the commission is to enhance, develop, and strengthen community-police relations, and review and make recommendations regarding the ongoing operations of the Pasadena Police Department to the chief of police, city manager, and/or City Council. The City is now accepting applications for the initial nominations for appointment to the commission, with appointments to occur in the coming weeks. The application for those... continue reading »"Application Deadline for Community Police Oversight Commission Initial Appointments is March 15 at 5 p.m."
Community Police Oversight Commission, CPOC, Pasadena Police Department
City of Pasadena Seeks Independent Police Auditor
PASADENA, Calif.—The City of Pasadena is seeking to contract with an independent police auditor to advise the newly-created 11-member Community Police Oversight Commission. Eligible firms or individuals are encouraged to review the request for proposals for independent police auditor, which can be found at the City of Pasadena's vendor portal or the City Attorney's website. In order to review request for proposals, proposers must register on the PlanetBids website. There is no charge for registration. The independent police auditor will be... continue reading »"City of Pasadena Seeks Independent Police Auditor"
Community Police Oversight Commission, independent police auditor, Pasadena Police Department, request for proposals
Application for Community Police Oversight Commission Now Online
January 13, 2021 February 23, 2021 News
PASADENA, Calif.—In October 2020, the City Council established a Community Police Oversight Commission (CPOC) by ordinance. The purpose of the commission is to enhance, develop, and strengthen community-police relations, and review and make recommendations regarding the ongoing operations of the Pasadena Police Department to the chief of police, city manager, and/or City Council. The City is now accepting applications for the initial nominations for appointment to the commission, with appointments to occur in the coming weeks. The application for those... continue reading »"Application for Community Police Oversight Commission Now Online"


Earlier this season, we were introduced to the Biossance line of skincare products, and fell in love instantly. Biossance's key ingredient is squalane. The human body produces its own version (known as squalene), but the amount made and retained in the skin decreases over time. It peaks in our teens and then starts to decline in our 20's, leaving skin rough and dry.
We got the full rundown from Teresa Lo, Biossance's Senior Director of Marketing, and Nancy Leung, who is head of New Product Development & Innovation. The Berkeley, California based company uses innovative biotechnology to "make a positive impact on the world," and believes the category of skincare should be no exception, "because our standards for clean beauty are high, and our standards for ourselves are even higher." Using only the most trustworthy and powerful ingredients in their products, Biossance offers a large, truly comprehensive range of items from an EWG approved SPF (a difficult feat to achieve) to hydrating cleansing cloths that don't strip the face, to a retinol serum, and a fine squalane-packed facial mist that can be used with or without makeup.
While the Biossance brand is "very clinically based," Lo and Leung explain that "the goal is to deliver a terrific consumer experience." That, indeed, they have. With a product for every possible skincare need and meticulous dedication to quality and the environment, we just can't wait to see what they do next.
Shop Biossance's bestselling "hero" product: squalane + vitamin C rose oil, along with our other favorites from the brand.


Jamie Sowden: What Is Drinking With Anxiety Like?
What Is Drinking With Anxiety Like?
I thought that today I would do a post about anxiety and drinking because I always get quite a few questions/enquiries on it and I think that it will just be easier if I explain everything via this post then I can just point to the post when I get asked a question about it.
Credit to Michelle for taking this photo!
If you have been reading the blog for a while then you will know that I suffer from depression and anxiety and I openly talk about it on social media and on the blog and I have also mentioned quite a lot that I can't get drunk due to anxiety and it seems weird to anyone that I mention that to. The simple thing is that alcohol releases endorphines and slowly makes you see things a certain way which causes adrenaline which for most is a good thing but isn't for anyone with anxiety as it then causes a panic attack. My mind notices this and instead of going panic panic panic, you don't know whats happening, it decides to ride it out and just goes stay with it so I don't get drunk but I just notice where I am and whats going on around me a bit more. This normally means I'm the friend who shouldn't be looking after people but who ends up looking after people.
Honestly, being like this puts you off wanting to go out/drinking as you realise what the world turns into when the night sky is about but its also interesting at the same time.
Anyways, I thought that I would just kind of explain that a bit. I hope that you have found this post interesting and I hope that you come back for the next blog post!


text:
Q: Create multiple email-server names My email server has two domains and the email hostname for each of them is mail.domain1.com.
I'm attempting to remove the 'mail' in mail.domain1.com for domain 1 and set domain 2 to domain2.com.
So that the detailed email headers for email sent from domain 1 only mentions domain 1, and email sent from domain 2 only mentions domain 2. i.e.
Email sent from domain 1 will read:
Received: from domain1.com ([xxx.xxx.xxx.1])

And email sent from domain 2 will read:
Received: from domain2.com ([xxx.xxx.xxx.1])

Instead of:
Received: from mail.domain1.com ([xxx.xxx.xxx.1])

How would this be done?

A: It can't be done, because that line is added by the server that you sent the message to, and the name it uses is determined by the rDNS you setup.

A: It can be done in various ways. You can add fake headers to the message that indicate relaying instead of submission. Or even you can setup some kind of virtualization for hosts domain1.com and domain2.com so relaying will occur IRL.


These men and women made my world a better place. Myself and scores more like me. They touched hearts and spread love and it seems frighteningly unfair that they should exit this existence.
So what is an artist to do?
Take the inspiration and keep walking my road. Build art that will last beyond my timeline. Uplift, assist and give of my best. Live beyond logic. Take the pain of my mutilated heart and turn it into energy … energy and magic that other wounded hearts need.
This heals me, as well. Not being paralyzed by the grief. Each step along the road brings new experiences, so live … live another day, even if only to see what's next.
Lastly … touch. Help those that need healing. Break hearts that are too hard and show them how powerful compassion can be.
Grieve … get that done, it's important. Then celebrate. Celebrate their lives and how they affected yours. Life is not in vain. Love is not a punchline.
Superman. In the seventies, when I discovered comics, Supe was my go-to. Action comics, The Brave & the Bold, Justice League, Legion of Superheroes … if Kal-El was in it, I had to read it. My favorite stories were from a writer called Elliot S! Maggin. He understood Kal, Superman and Clark Kent. He displayed the subtleties and friction between those three men.
Maggin wrote several Superman novelization paperbacks. One of those I read over and over until it literally fell to pieces. It spoke to me in a way I didn't know was valuable until many years later. I'm thinking now that I realized the abuse I was under and the book helped me believe in me, but definitely under the surface.
It was called 'Miracle Monday'. There's a subplot about visitors from the future and battling a demon, but the meat of the story is the utter defeat of Superman. Not through overwhelming brute force, but psychologically. The main villain convinces Kal-El that he does not belong among the people of Earth. He destroys Superman emotionally.
Superman abandons Clark Kent and flies to the top of the world to live in solitude. Grieving and feeling sorry for himself, he opens his ears to the entire world, listening. After a moment, he discovers the perfect rhythmic song of the world. The footsteps of a man crossing the street in New York are in rhythm with a band rehearsing in a garage in London, and so on. Fascinated, he shifts to listen more intently. Rocks that he disturbs tumble into a gorge and fall in sync with a dancer in Mexico.
Superman realizes he is a part of the music of the planet and … well, you know. He's Superman.
All of that to say: So are you. You are a superhero to someone. Your very heartbeat is a part of the lives of the people around you.
Keep seeking truth. Keep breathing. You are a valuable part of us.
The past year has been draining. Emotionally, physically … I am seeking help in the form of professional counsel and friends.
The people I relied upon for inspiration have removed their support. I'm not asking for pity, I can see my own mistakes leading to their decision, and I do hope for forgiveness and love, in time. This depression has led to my business and art faltering. The responsibilities I have are suffering and I'm all but broke, financially.
I have been bearing my burdens and trying not to wear them on my sleeve. Tonight, I am peaceful, thanks in large part to a friend with a smile and food. Food for my mouth and for my spirit. I will overcome this, I will book the shows I need (in abundance) and I will make art direct from my green, magic heart. I will take care of those who need, and … I will do card tricks that may well change your world for the better.
I will. I have faith that, though my road is rocky, it is still MY ROAD.
Pray for me, readers. Pray for continued strength, patience and understanding.
I hope that there's love where you are.
My first fully public show of 2016 was for the Lili VonSchtupp's 'Monday Night Tease show. Five fantastic dancers. one hilarious host and me … and I did card tricks.
That's what I do, you know? The cards are my canvas.
The results are powerful. Tears, thank yous … lots of personal stories. My art … my craft genuinely touched people. We bonded and I made some amazing new friends. I want to perform this again and again.
Here is a small gallery of my portion of the show. I hope it speaks to you.
False rumors and gossip destroyed some precious relationships. I let myself and some dear people down with that whole contest thing. I sank into depression, got voluntary/ involuntarily taken in for suicide observation and came close to ruining my 'career'.
I learned and I grew. All of these things forged me deeper. I honestly believe that hardship is needed for real growth. So I'm thankful for my struggle.
I'm going to forgive myself. I'm going to hope for forgiveness from others. I'm going to work hard and I'm going to strive to spread a message of love with my mouth and with my actions.
I can't tell the future, but I'm going to stay on this path. No matter what.


Please visit https://www.flhsmv.gov/motor-vehicles-tags-titles/disabled-person-parking-permits/ for more information.
A new, more secure, driver license and ID card is now available. The new technology provides Floridians with the most secure over-the-counter driver license and ID card on the market today.


text:
<?php

namespace phpbb\console\command\db;

use phpbb\user;
use phpbb\db\migrator_output_handler_interface;
use Symfony\Component\Console\Output\OutputInterface;

class console_migrator_output_handler implements migrator_output_handler_interface
{
	/**
	 * User object.
	 *
	 * @var user
	 */
	private $user;

	/**
	 * Console output object.
	 *
	 * @var OutputInterface
	 */
	private $output;

	/**
	 * Constructor
	 *
	 * @param user				$user	User object
	 * @param OutputInterface	$output	Console output object
	 */
	public function __construct(user $user, OutputInterface $output)
	{
		$this->user = $user;
		$this->output = $output;
	}

	/**
	 * {@inheritdoc}
	 */
	public function write($message, $verbosity)
	{
		if ($verbosity <= $this->output->getVerbosity())
		{
			$translated_message = call_user_func_array(array($this->user, 'lang'), $message);

			if ($verbosity === migrator_output_handler_interface::VERBOSITY_NORMAL)
			{
				$translated_message = '<info>' . $translated_message . '</info>';
			}
			else if ($verbosity === migrator_output_handler_interface::VERBOSITY_VERBOSE)
			{
				$translated_message = '<comment>' . $translated_message . '</comment>';
			}

			$this->output->writeln($translated_message);
		}
	}
}

redpajama_set_name: RedPajamaGithub


text:
Q: Coding a reddit bot I want to create a reddit 'novelty' account bot to better my coding/scripting skills. Currently I just want to make a simple bot that searches new or rising links on reddit and looks at the comments in each thread. If the text matches some string of characters, the bot replies with a message.
I know this is a really general question, but I'm looking for tips on which scripting/programming language to use. I mainly have experience with Java and Selenium along with R and a little bit of batch. I am willing to learn a new language (i have a lot of free time). Also the goal of the bot isn't very difficult, so even if i had to learn a new language I don't think it would be all too difficult.

A: Most reddit bots are made with something called PRAW. You use Python when creating something with PRAW. Python shouldn't be too hard to learn if you know Java.


text:
(2013-2014 HR#29) Compensation Update for Confidential, PM, AP and RA / SRA Staff
HR#29, 2013 – 2014
To: Confidential, Professional & Managerial Staff, Advancement Professionals, Research Associates and Senior Research Associates; – See more at:
From: Angela Hildyard, Vice-President, Human Resources & Equity – See more at:
Cc: HR Divisional Offices; Principals, Deans, Academic Directors & Chairs – See more at:
Re: Compensation Update for Confidential, PM, AP and RA / SRA Staff
Further to my message of April 22, 2014, I am writing to update you on changes to your compensation. On June 12, Business Board approved compensation increases, and some benefit changes, for Confidential, Professional & Managerial (PM) Staff, Advancement Professionals (AP), Research Associates and Senior Research Associates (RA / SRA). The increases align with existing government legislation and are responsive to the University's current financial constraints.
Merit increase
Business Board approved the implementation of annual merit increases within each group's fixed merit envelope, consistent with the Province's current compensation restraint legislation. While the merit pay will be effective July 1, 2014, it will be implemented retroactively, in accordance with this year's annual process timelines in October.
The RA / SRA Performance Assessment process will launch later this week, please look for a separate memo outlining process instructions.
Across the Board (ATB) increase
Effective, July 1, 2014 the Across the Board (ATB) increase will be 0.5% for all Confidential, Professional & Managerial Staff, Advancement Professionals, Research Associates and Senior Research Associates. We are working to ensure that eligible employees will receive any applicable ATB increases in their July pay. Further processing instructions for Business Officers will be forthcoming.
Dependant Scholarship Program
Historically, this Dependant Scholarship program has required that applicants must have a minimum 80% average in their best six university or college-level high school courses. To align with the benefit currently available to faculty where the minimum requirement is a 75% average, effective July 1, 2014, this will also apply to eligible employee groups. Please refer to the Human Resources & Equity website for full details on the Dependant Scholarship Program.
In order to ensure the long-term sustainability of public sector-defined benefit pension plans, the Ontario Government expects that employee / employer current service contributions should be matched, that is at a 50 / 50 balance. With this as a primary objective the University will be proceeding with the July 2014 employee contribution increase that was approved in 2012. In addition, Business Board approved two further employee contributions for additional employee pension contributions for July of 2015 and 2016 as follows:
July 1, 2015 Increase of 0.45% / 0.55% from 6.80% / 8.40% to 7.25% / 8.95%
Should you have any questions about these compensation changes, please contact your HR Divisional Office.


text:
Government agency calls 'Redskins' offensive
Washington (CNN) – The heated debate over the Washington Redskins name has now moved beyond living rooms and corporate offices to the U.S. government itself, with one agency making an unequivocal ruling that the term "Redskins" is offensive slang.
The U.S. Patent and Trademark Office rejected an application to trademark the name "Redskins Hog Rind," writing that the term "Redskins" is "a derogatory slang term that refers to, and is considered offensive by, American Indians."
The agency cited five definitions from online dictionaries - from The Oxford Dictionary to Yahoo – that labeled the word as offensive or disparaging. In addition the agency pointed to news articles about Native American challenges to the Redskins name, including the policy of the National Congress of American Indians, which officially refers to the team as the "R*dskins" or "R Word".
The Redskins' senior vice president for communications, Tony Wyllie, told CNN the team is not commenting on the decision.
Federal law prohibits trademarking any term that may be immoral, scandalous or may disparage another person. To determine what crosses the line, the agency looks at two questions: 1) the term's likely meaning and use in the product's context and 2) whether the phrase disparages a specific group of people.
Thus, many words have been approved in some circumstances and rejected in others.
The term "squaw," for example, was ruled offensive when used for clothing and general retail but was approved for use with skiing equipment associated with "Squaw Valley." And the PTO rejected the use of "Khoran" for a brand of alcohol, something that the Islamic holy book, the Quran, considers sinful. Actor Damon Wayans' application for a clothing line called "Nigga" was rejected, as have been several applications to use even the phrase "the N word." But a group protesting the phrase was allowed to trademark "Abolish the 'N' word."
Likewise, the agency has permitted the term "redskin" when applied to potatoes or when directly applied to the football team, as in "The Redskins Broadcast Network."
But outside of such contexts, this decision labels the term as offensive.
James Bethel, the man applying for the "Redskins Hog Rind" trademark, can appeal the PTO's decision.
tom l
Yeah, govt isn't getting too involved I. Our lives........
I'm just waiting for the Thought Police next
January 8, 2014 09:34 pm at 9:34 pm |
What are people going to do when someone gets offended because they over hear a joke being discussed thats funny? Are they going to find that offensive to! By the way, all races talk about each other behind one anothers back and it's been going on for centuries.
January 8, 2014 10:29 pm at 10:29 pm |
And the New Orleans Saints team name is offensive to atheists. And the Golden State Warriors is offensive to me because it implies people from California are violent. While we are at it, the Buffalo Sabres is offensive because it implies a weapon, which is also offensive to me. And the Miami Hurricanes should not use 'hurricane' because of Katrina. And don't get me started on the Fighting Irish of Notre Dame.
Jesus H. Spaghetti Monster, how is this STILL a point of contention? This football team should be laughed out of the NFL, at least until they can grow a pair and admit when they've made a mistake (and correct said mistake). I don't understand how ANYONE who works for the Redskins organization goes to work in the morning feeling good about what they'll be doing that day. There is no difference...none...between the name Washington Redskins and a name like Washington Filthy Savages. How about the Baltimore Porch Monkeys? The Arizona Wet Backs? The New York Guinea Greaseballs? How about the newest expansion team, the New Hampshire Cracka-lacka Honkey Brigade? You know I'm right (and CNN moderators, you know I'm using those awful terms for dramatic effect to make a salient point, not as racist trolling), so why do we go CRAZY when the president of Chik-Fil-A says he doesn't like gay people (to the point of calling for that man's LIFE), but we don't say a WORD about a team who refuses to change their dated, backwards, disgusting, and blatantly racist team name?!
ThinkAgain - If you want Congress to actually do something FOR the American people, vote out the Repub/tea bag majority
Cue tea bag outrage at the guvment in three, two, one ...
There are more important things to think about than this. People without jobs. People without housing. People without food, living in the streets or under them. I'm sure the major interest of the majority of the people is the name of a sports team. Get real.
The federal government offends a large part of the population.
Political correctness is a disease in this country.
January 9, 2014 12:18 am at 12:18 am |
God, must be at war with the poor, otherwise crap like this wouldn't be an issue while so many are doing without. You'd think the politicians and people in the entertainment industry would grasp this fact, and put insignificant issues like this on the back burner until some real problems are taken care of.
January 9, 2014 01:59 am at 1:59 am |
Funny response. Some might argue that the agency's use of the term "American INDIANS" [caps added] is ALSO considered offensive since they aren't from India. Of course, I keep reading the constitution and simply cannot find the part that says we have the right not to ever be offended by anything anyone else says or does. Could someone tell me where that's written and why it doesn't conflict with the 1st amendment right of free speech?
Just change the mascot to a potato
Marie MD
The owner, little mr. big man snyder, will never do it. He owns, if not the world, this area or so he thinks.
This fool bought a house on the Potomac River and cut down trees that were protected since he coulen't see the river from the house and because he could. Did he get a fine? Of course not! I take it he didn't realize that the trees were there before he built his mansion?
Her also tried to sue a Post reporter for calling him for who he is. Not sure what happened, but the truth must hurt and he can't sue if it IS the true.


At about 1130 Eastern time, the airplane was destroyed following an in-flight fire and emergency landing. The flight instructor and private pilot-rated student were not injured. Visual conditions prevailed for the post-annual-inspection test flight. During engine start, the flight instructor noticed the fuel pressure gauge showed no pressure, but the engine started normally, ran normally and the airplane took off and climbed normally.


text:
The Scotland Epistles Football Magazine
Scotland Football Fanzine
It Shouldn't Happen to A Scotland Player / Manager / Supporter
Magazine Pictures and Posters
Match Day Photos
Match Programmes – Home
Match Programmes Away
Match Programmes Other
Miscellaneous Memorabilia
Pen Pics
Postcards etc.
Scotland Kits – Down the Years
Scotland Players – Abroad
Stadium Postcards
Ticket Stubs
About / Buy the Magazine
Contact to Contribute
Happy Birthday David Hopkin
David Hopkin will be 45 on August 21st. If you've read Scotland Epistles #3 you will know that being included in a World Cup card or sticker set does not mean you are going to the World Cup, such a fate befell Mr. Hopkin too. Of course given the photo they used, perhaps David who has been known to make the list of ugliest Premiership players ever, would have preferred to have been omitted.
And yet it looked good at one point, David had gotten himself into the Scotland team just at the right time. He was due to play for Scotland against Wales in late May 1997 but having scored the play off winner for Crystal Palace against Sheffield United at Wembley a couple of days before he called off for the game. However, Craig Brown did not hold it against him and a few days later on June 1st he made his debut in a friendly against Malta in Valetta. Scotland won 3-2 with two goals from Darren Jackson after an early goal for Christian Dailly. David would be substituted early in the second half with Scot Gemmill replacing him, this scenario would be repeated a week later in Minsk, Belarus, as Scotland scraped a one nil win with a Gary McAllister penalty to keep their World Cup hopes alive.
In the summer of 1997, David moved to Leeds United for £3.25million. He would also be named as team Captain under George Graham at Elland Road. David would win his third cap up at Pittodrie against as Scotland cruised to a 4-1 win with Hopkin coming on as a substitute in the 50th minute and making an instant impact with a goal four minutes later. His second and Scotland's fourth was a great individual effort, which made it seem as though David was going to be an important player for Scotland in years to come.
Alas, it was not to be as David had an indifferent start to his Leeds career, with injuries, suspension and regularly being substituted, all hindering his impact at Elland Road. He would only play one more game prior to the '98 World Cup, making a one minute appearance against France in November, 1997. The 2-1 defeat would be the start of Scotland going on their longest run without a win, in a run of 9 games that unfortunately included the whole of the World Cup in France. David would return 18 months later in March 1999, starting the infamous game against the Czech Republic at Parkhead, where Gary McAllister was booed by some sections of the Scotland support. Scotland would lose this Euro Championship qualifier 2-1 and McAllister announced his retirement shortly after.
Cap number six would come against Bosnia in Sarajevo in September '99 as a makeshift left back. Scotland won 2-1 with goals from Don Hutchison and Billy Dodds. His seventh and final cap came a month later, also against Bosnia at Ibrox, in his more recognised position in midfield as Scotland won one nil with a John Collins penalty.
And that was it for David, if only his Scotland career had progressed the way we hoped it would that night at Pittodrie, but it was not to be. Happy Birthday David Hopkin and thanks for those brief glittering moments all those years ago.
David Stuart
First posted on Facebook August 21st 2015
Text widget title
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Scottish Football Today Annual
The Denis Law book of Soccer No.2
Happy Birthday Willie Carr
Happy Birthday to Davie Holt
Happy Birthday to Scot Gemmill


Less than two weeks ago Team Gilmour received a wildcard entry to compete in the prestigious ISAF Nations Cup in Middelfart, Denmark. Many champions of the sport have won the Nations Cup including 2007 Americas Cup winning helmsman Ed Baird.
Team Gilmour is excited to be racing against some of the best match racers in the world. Up to 12 countries will be represented at the event; Australia, Singapore, Denmark, Norway, Canada, France, Brazil, Great Britain, Japan, Norway, Sweden and USA.
For the Nations Cup all team members are required to be nationals of the country they represent. For this event Team Gilmour will be made up of core team members; David Gilmour, Pete Nicholas and Luke Payne. We will also be joined by legendary GBR 49er sailor Ed Powys (World ranking 4th in the 49er class) and team legal adviser/Monsoon Cup bowman Alistair Marchesi.
The team has had some intense training on the DS37 and Match 28 yachts in Middelfart over the last two days, and are feeling confident in both type of boats going into the first days racing tomorrow.
The event format will see the 14 teams split into two pools, with one pool sailing the DS37's while the other race in the Match 28's and then swap for the next round robin.
The winner of each group will progress straight through to the semi-finals while the rest will race another repechage round robin for the final two places in the semis. Not only do we need to qualify for the semis, but we also need to be ahead of the other Australian team as only one team per nation are able to progress through.
There will also be an exciting exhibition match race on Thursday 8th between local skipper Nicolai Sehested and Crown Prince Frederik of Denmark (married to Aussie Princess Mary) who has a crew made up of Danish past Olympians.


text:
Mi SciELO
texto en Español
Similares en Google
Revista Española de Enfermedades Digestivas
Rev. esp. enferm. dig. vol.106 no.4 Madrid abr. 2014
Hepatotoxicity associated with statin use: Analysis of the cases included in the Spanish Hepatotoxicity Registry
Hepatotoxicidad asociada al consumo de estatinas: análisis de los casos incluidos en el Registro Español de Hepatotoxicidad
Emilia V. Perdices1, Inmaculada Medina-Cáliz1, Sofía Hernando1, Aida Ortega1, Francisca Martín-Ocaña1, José M. Navarro2, Gloria Peláez3, Agustín Castiella4, Hacibe Hallal5, Manuel Romero-Gómez6, Andrés González-Jiménez1, Mercedes Robles-Díaz1, M.a Isabel Lucena1 and Raúl J. Andrade1, on behalf of the Spanish Hepatotoxicity Registry
1UGC Digestive Diseases and Department of Pharmacology. Instituto de Investigación Biomédica de Málaga (IBIMA). Hospital Universitario "Virgen de la Victoria". School of Medicine. Universidad de Málaga. Málaga, Spain. Centro de Investigación Biomédica en Red de enfermedades hepáticas y digestivas (CIBERehd). Barcelona, Spain
2Gastroenterology Unit. Agencia Sanitaria Costa del Sol. Marbella, Málaga. Spain
3Gastroenterology Department. Hospital Torrecárdenas. Almería, Spain
4Gastroenterology Department. Hospital de Mendaro. Guipuzcoa, Spain
5Gastroenterology Department. Hospital Morales Meseguer. Murcia, Spain
6Gastroenterology Department. Hospital de Valme. Sevilla, Spain. CIBERehd
Objectives: The hepatotoxic potential of statins is controversial. The objectives of this study were to describe the relative frequency of hepatotoxicity caused by statins and the phenotypes found in Spain.
Patients and methods: The incidence of hepatotoxicity attributed to statins in the Spanish Hepatotoxicity Registry (REH) were studied and compared with those attributed to other drugs.
Results: Between April 1994 and August 2012, the REH included a total of 858 cases of which 47 (5.5 %) were attributed to statins. Of these, 16 were due to atorvastatin (34 %); 13 to simvastatin (27.7 %); 12 to fluvastatin (25.5 %); 4 to lovastatin (8.5 %) and 2 to pravastatin (4.3 %). Statins represented approximately half of the cardiovascular group which occupied 3.er place (10 %), after anti-infectious agents (37 %) and central nervous system drugs (14 %). The hepatocellular pattern was predominant, especially in the simvastatin group (85%), the cholestatic/mixed pattern was more frequent with fluvastatin (66 %) and had a similar distribution to atorvastatin. Patients with statin-induced toxicity were older (62 years versus 53 years, p < 0.001) and more often demonstrated an autoimmune hepatitis phenotype (8.5 % versus 1.4 %, p < 0.003).
Conclusions: Statins are not a common cause of hepatotoxicity in Spain. Atorvastatin is the statin involved in the greatest number of incidents. The liver injury pattern varies among the different statins. The hepatitis phenotype with autoimmune features appears to be a characteristic signature of statin-induced hepatotoxicity.
Key words: Hepatotoxicity. Statins. Atorvastatin. Causality. Autoimmunity.
Objetivos: el potencial hepatotóxico de las estatinas es controvertido. Los objetivos de este estudio fueron describir la frecuencia relativa de hepatotoxicidad por estatinas y los fenotipos de presentación en España.
Pacientes y métodos: se analizaron las incidencias de hepatotoxicidad atribuidas a estatinas en el Registro Español de Hepatotoxicidad (REH) y se compararon con las atribuidas a otros fármacos.
Resultados: entre abril de 1994 y agosto de 2012 se incluyeron en el REH un total 858 casos de los que 47 (5,5 %) se atribuyeron a estatinas. De ellos, 16 fueron por atorvastatina (34 %); 13 por simvastatina (27,7 %); 12 por fluvastatina (25,5 %); 4 por lovastatina (8,5 %) y 2 por pravastatina (4,3 %). Las estatinas representaban aproximadamente la mitad del grupo cardiovascular que ocupaba la 3.a posición (10 %), tras anti-infecciosos (37 %) y fármacos del sistema nervioso central (14 %). El patrón hepatocelular fue predominante, especialmente en el grupo de simvastatina (85 %), el colestático/mixto fue más frecuente con fluvastatina (66 %) y se distribuyó de manera similar con atorvastatina. Los pacientes con toxicidad por estatinas eran de edad más avanzada (62 años vs. 53 años, p < 0,001) y mostraban más frecuentemente un fenotipo de hepatitis autoinmune (8,5 % vs. 1,4 %, p < 0,003).
Conclusiones: las estatinas no son una causa frecuente de hepatotoxicidad en España. La atorvastatina es la estatina implicada en un mayor número de incidencias. El patrón de lesión hepática varía entre las distintas estatinas. El fenotipo de hepatitis con rasgos de autoinmunidad parece ser una firma característica de la hepatotoxicidad por estatinas.
Palabras clave: Hepatotoxicidad. Estatinas. Atorvastatina. Causalidad. Autoinmunidad.
Liver damage caused by drugs, herbal products or dietary supplements, also known as DILI (Drug Induced Liver Injury) is an adverse reaction that is generally unpredictable and is associated with many commonly used drugs that constitutes a significant cause of potentially severe acute and chronic liver damage (1). DILI is responsible for approximately 11 % of cases of acute liver failure cases in the US (2) and 13 % in Spain (3). Adverse liver reactions are also the primary cause of developmental interruptions, usage warnings and removal of drugs from the market (4). Statins are a group of drugs used widely for first line treatment to lower LDL cholesterol levels and for the primary and secondary prevention of cardiovascular events.
The hepatotoxic potential of statins continues to be controversial. Only a small proportion of patients who participated in clinical trials with statins experienced transaminase elevations. Elevations achieved at least 3 times the upper limit of normal in 0.1-2.7 % of cases (5). The risk of liver profile changes associated with statins seen in clinical trials is no greater in the placebo group when low or moderate dosages are used (< 40 mg/day), less than 1 %, and the rate reaches 3 % with high dosages (80 mg/day) (6). These elevations are rarely associated with clinically-expressed DILI (7). Despite the pharmacokinetic, lipophilic and metabolic differences among statins, they all appear to be capable of producing hepatotoxicity (8).
It is well known that the most common cause of mild alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevations in patients who use statins is non-alcoholic fatty liver (5). A widely-held belief was to consider patients with non-alcoholic fatty liver or other varieties of chronic liver disease to be at an increased risk of statin-induced DILI. However, statins are not only safe and effective in patients with fatty liver (9), they also improve underlying biochemical and histological alterations (5). In addition, other beneficial effects include decreased portal vein pressure and decreased risk of hepatocellular carcinoma in patients with diabetes (10,11).
Since coming on the market, the published cases on statin-induced hepatotoxicity have been scarce when considering the large number of consumers, making them still considered as safe and well tolerated (7).
We have performed this study using the Spanish Hepatotoxicity Registry in order to evaluate the relative importance of statin-induced hepatotoxicity in Spain as compared to other drugs, as well as the potential hepatotoxicity among them, and to describe the injury patterns and prognosis.
The data used were extracted from the Spanish Hepatotoxicity Registry founded in 1994 and coordinated by 2 of the authors (RJA and MIL). The REH includes more than 40 clinical units from around Spain (12) that use a uniform methodology for identifying cases and collecting information and their subsequent inclusion in the Registry. This methodology has previously been described in detail (12,13).
Patients in the registry were identified using a search according to type of statin. A structured protocol containing the following elements was used to collect the data (13): Relevant clinical data on the patient; risk factors for liver disease; regular treatment and start and duration of use of each of the drugs; temporal relationship between the start of medication use and the onset of symptoms and/or laboratory changes; temporal relationship between discontinuance of the suspected agent and recovery from liver dysfunction. In addition, other causes of liver disease were ruled out: Recent viral hepatitis A (HAVab IgM), B (HBVab IgM) or C (HCVab and RNA by PCR); autoimmune diseases [antinuclear antibodies (ANA), antimitochondrial antibodies and anti-smooth muscle antibodies (ASMA)] and biliary obstruction by imaging study (abdominal ultrasound or MR cholangiography). In the same manner, if the clinical context warranted, CMV, EBV, herpes virus infection and HEV infection were ruled out.
Causality was evaluated using clinical judgment and later evaluated by applying the scale proposed by the Council for International Organizations of Medical Sciences (CIOMS), also called the Roussel-Uclaff Causality Assessment Method (RUCAM) (14). Only those cases scored by the CIOMS scale as possible, probable or highly probable were included in the database.
Two successive liver injury definitions were used. The standard definition of liver damage formulated by the international consensus group in 1989: Increase of two times the upper limit of normal (ULN) in ALT or conjugated bilirubin; or the combination of the increase in aspartate aminotransferase (AST), AP and total bilirubin with one of these greater than twice the ULN (15). The liver damage criteria were redefined in 2011 by an expert group, raising the cut-off threshold for ALT or AST when these are elevated in an isolated manner ≥ 5 ULN. Also considered as criteria for liver damage in this consensus group were an AP ≥ 2 x ULN or the combination of an increase in ALT > 3 x ULN and total bilirubin > 2 x ULN (16). This last criteria complies with the Hy's Law, which predicts at least 10 % fulminant disease (4). The liver damage pattern was established based on the (ALT/ULN)/AP (ULN) ratio. In this way, if it was greater than 5 it was hepatocellular, lower than 2 cholestatic and between 2 and 5 mixed damage. The term chronic DILI is reserved for cases in which the damage persisted for more than one year (15).
DILI was defined as an autoimmune phenotype when it combined the presence of autoantibodies with histological findings suggestive or compatible with autoimmune hepatitis and/or an at-risk HLA serotype.
The data obtained were analysed using IBM SPSS Statistics Version 20. A descriptive analysis was done for the cases of statin-induced hepatotoxicity found in the registry and a comparative analysis was made with the remaining cases of hepatotoxicity. The Chi-squared parametric test was used for comparison of qualitative variables. The ANOVA or Kruskall-Wallis test was used for comparing qualitative variables with quantitative variables. Student's t test was used for comparison of quantitative variables. Differences were considered statistically significant if the p-value was less than 0.05.
Between 1994 and August 2012, 858 cases were included in the Spanish Hepatotoxicity Registry. Anti-infectious agents (36 %), CNS drugs (14 %) and cardiovascular drugs (10 %), including statins, are responsible for the majority of cases in the hepatotoxicity registry.
Of the 858 cases, 47 were attributed to statins and 811 to an agent other than a statin. The comparative demographic characteristics of the patient cohort are shown in table I. The mean age of presentation in the statin group was greater than the overall group (62 versus 53, p < 0.001). The mean latency, hospitalization rate, severity defined by the percentage of cases that meet Hy's Law and the mean resolution time was similar in both patient groups. About 25 % of the overall group had hypersensitivity phenomena, meaning fever, rash, eosinophilia, lymphopenia, autoantibodies and/or arthralgias, with these manifestations seen in 17 cases (36 %) from the statin group. Although the distribution of hepatocellular, cholestatic and mixed liver injury patterns was similar in both groups, AP values > ULN were more elevated in the statin group (2.96 versus 2.04, p < 0.007) and the average bilirubin levels was lower without achieving statistical significance (5.3 mg/dL versus 7.5 mg/dL, p < 0.06). The proportion of DILI cases with an autoimmune phenotype was significantly greater in the statin group (8.5 % versus 1.4 %, p < 0.003).
Of the 47 cases of statin-induced hepatotoxicity, 22 were men (47 %). The majority (72 %) took another medication concomitantly. However, 32 patients (68 %) had only been taking lipid-lowering treatment for 3 months. Jaundice was present in 25 patients (53 %) and presented in similar proportion in both genders. Nineteen per cent of cases complied with Hy's Law. Hospitalization resulted in 19 patients (40 %). The predominant liver damage pattern was hepatocellular, which occurred in 24 cases (51 %). Sixty-four per cent of patients had a CIOMS/RUCAM scale score between 6 and 8. The recovery time was within the first three months in 34 % of cases with a mean recovery time of 153 days. 19 % of patients (9 cases) had chronic damage. There were 2 deaths in the 47 cases reported but they were due to causes other than the liver damage caused by the suspected agent (Table II).
The distribution by type of statin was: 16 were due to atorvastatin (34 %); 13 to simvastatin (27.7 %); 12 to fluvastatin (25.5 %); 4 to lovastatin (8.5 %) and 2 to pravastatin (4.3 %). Six of these 47 cases met the liver damage criteria established by the International Consensus Group in 1989 (14). However, they did not achieve transaminase levels to meet the recent definition by Aithal et al. (15). Of these 6 cases, 3 were due to simvastatin, 2 to pravastatin and 1 to atorvastatin; 5 were women; the average ALT and AP levels compared to the ULN were 2.25 and 1.25 IU/L, respectively, and all had a CIOMS score equal to or greater than 6 (5 cases were probable and 1 highly probable). It should be noted that 2 of these episodes occurred in the same patient. Neither of the two episodes presented with jaundice or hypersensitivity phenomena and the liver profile normalized shortly after discontinuing the drug. The remaining cases met the most stringent criteria for lever injury currently used in the majority of studies (15).
Atorvastatin-induced hepatotoxicity
Sixteen cases of DILI attributed to this drug were identified. Of these, 10 were in men (63 %). Hypersensitivity phenomena occurred in 50 % of cases. Nine patients (56 %) had jaundice. The hepatocellular pattern was present in half of cases. The CIOMS/RUCAM score had a probable value in 69 % of cases. Of these 16 patients, 6 underwent liver biopsy and 4 of these showed eosinophils. Two of the cases were classified as drug-induced autoimmune hepatitis. One of these cases had levels of ANA + 1/640 and IgG levels of 25/7 g/L. The liver biopsy revealed differentiated areas of micronodular cirrhosis and signs of subfulminant hepatitis (suggestive of drug-induced toxicity versus autoimmune hepatitis). The liver profile continued to be altered one year after onset. In another case, liver biopsy was not done but the ANA was positive at a titer of 1/160, as well as HLA DR-3 with an HAI index of 13. The recovery time was 6 months in this patient. Ten month prior, pravastatin had been discontinued due to elevated transaminase levels.
Simvastatin-induced hepatotoxicity
Thirteen cases were found in the registry, 4 of which (31 %) were men. Jaundice was present in 6 patients (46 %). The hepatocellular pattern was clearly predominant in this group. Two patients in this group died of causes other than liver damage. One case was classified as drug-induced autoimmune hepatitis. This case had ANA titers of 1/1,280 and the biopsy revealed panlobular and portal-periportal hepatitis with intense lymphoplasmacyte infiltrate and pyknocytic necrosis, hepatocellular ballooning with rosette formation and hemosiderin deposits in the Kupffer cells. This patient was put on steroid treatment. The recovery time was 2 months.
Fluvastatin-induced hepatotoxicity
There were 12 cases of DILI associated with fluvastatin use in the registry at the time of analysis. Of these, 7 were men (58 %). The hepatocellular pattern was present in 33.3 % of cases. Liver biopsy was carried out in 4 cases. Only one of these revealed eosinophils. One case was classified as drug-induced autoimmune hepatitis with ANA titers of 1/640 and homozygous for HLA DR 3. The biopsy revealed periportal hepatitis with slight inflammatory activity and mild hemosiderosis. Treatment was started with corticosteroids 4 months after onset of the index episode which were tapered until complete discontinuation 16 months later. Azathioprine treatment was added 6 months after the index episode. The liver profile normalized 8 months after the index episode.
Lovastatin-induced hepatotoxicity
There were only 4 cases recorded in the registry. The 4 patients were women. Three of these had jaundice. None had hypersensitivity phenomena. The hepatocellular pattern was only present in one case. Liver biopsy was carried out in two patients and neither had eosinophils.
Pravastatin-induced hepatotoxicity
There were only 2 were registered, one from each gender. There was no jaundice. The 2 cases had a cholestatic/mixed pattern. Both recovered from the liver injury.
Statins are drugs used worldwide to control cholesterol levels in order to prevent cardiovascular events.
The use of lipid-lowering medications in Spain went from 18.9 DDD (defined daily doses, per inhabitant per day) in 2000 to 102.6 DDD in 2012, an increase of 442 %. Statins are the most widely used drugs, representing 89.3 % of lipid-lowering agents in 2012. The most widely-used drug during the study period was atorvastatin, which went from 3.8 DDD in 2000 to 42.8 DDD in 2012 (increase of 1,012 %). It should also be noted that simvastatin was the second most commonly used statin over the course of this period. The sum of atorvastatin and simvastatin represented 78.2 % of total statin consumption in 2012 (17).
Toxic liver injury is an adverse effect of many commonly used medications. A characteristic element of toxic hepatitis is that it may present with several phenotypes capable of resembling other liver diseases and because specific markers for hepatotoxicity are not still available, the diagnosis is based on a compatible chronology between drug intake and the appearance of the liver dysfunction as well as the exclusion of alternate causes (16). Hepatotoxicity registries constitute a useful tool for reinforcing detection of cases with quality information which increases guarantees on certainty and allow for analysis of large series of well-phenotyped cases (12), as well as collecting biological samples to carry out genotype and mechanistic studies (18). This study had the objective of establishing the frequency with which statins are involved in episodes of hepatotoxicity compared with other drugs and describing their clinical presentation phenotypes and severity. In order to do this, we analysed cases of hepatotoxicity attributed to statins in the REH, a registry that is not restricted to drugs or drug groups. As a result, this registry includes any suspected case of hepatotoxicity that participating investigators detect. This circumstance, while not allowing for incidence figures to be established since there was no data on the exposed population (denominator) nor was it likely that the total number of cases that occurred was actually collected (numerator) (just probably some of the more severe ones), enables to diagram the relative frequency of induction of liver damage from drugs and drug groups.
In this analysis, statins constituted 5.5 % of cases of hepatotoxicity in the REH. This represents approximately half of all drugs from the cardiovascular group, which at 10 % constituted 3rd place. These data show that although statins are not a common cause of hepatotoxicity in our area, their appearance is not exceedingly rare either. In fact, there is a large debate on whether or not statins are drugs with significant hepatotoxic potential. There are authors who suggest that the liver toxicity of statins is a myth and they argue that statin-induced acute liver failure is no greater than idiopathic causes (19,20). Nevertheless, of a series of 133 incidents of drug-induced liver failure (excluding paracetamol) from different hospitals in the US, 10 were attributed to statins either on an isolated basis or in combination with other drugs (3). It is interesting to note that in the recently published populational study on the incidence of DILI in Iceland, of the 96 cases identified prospectively over the course of 2 years, one statin (atorvastatin) was responsible for 2 incidents (2 %), placing it on the low end of drugs with the highest incidence. Resources from the national health system of Iceland were used in this study. This has a powerful database with information on the total number of subjects exposed to each drug in order to calculate the risk of hepatotoxicity with each medication entered, which in the case of atorvastatin was 1/3,696 patients treated, greater than that seen with diclofenac, a drug that is widely known for its hepatotoxic potential (21).
The higher frequency of cases caused by atorvastatin is also consistent with the findings from two recently published case series (7,22). Russo et al. (2009) (7) reviewed all of the cases of statin-induced hepatotoxicity published up to that time. They identified 40 cases from 26 different publications. For their part, Björnsson et al. performed a review of suspected cases of statin-induced adverse events report to the Swedish Adverse Drug Reaction Advisory Committee (SADRAC) between 1998 and 2010. The most common adverse reaction was DILI in 57 % of cases. They only included cases with aminotransferase levels greater than 5 above the ULN and/or twice the upper limit of normal for alkaline phosphatase, resulting in a total of 73 cases (22). The general characteristics of both series compared with the series analysed in the present study are shown in table III. A differential finding for statin-induced hepatotoxicity in our series is that it affected to subjects of more advanced age. This peculiarity was seen in the other series (7,22). However, it risky to conclude that advanced age increases the risk of hepatotoxicity caused by these compounds and a prescribing bias cannot be excluded due to the clinical context in which these drugs are normally used. The latency period was also highly variable and occasionally long, both in our series (with latency periods greater than 1 year in several cases up to 5 years on one occasion) and in the analysis by Russo et al. (from 5 days to 4 years). These prolonged latency periods occurred with atorvastatin in our series. In another recently published series, atorvastatin was also responsible for a case of hepatotoxicity after 2.5 years of treatment (23). A very prolonged latency period constitutes and argument against the responsibility of a given drug, making it difficult to attribute a liver injury to hepatotoxicity, in addition to involving a challenge from an etiopathogenic point of view.
Idiosyncratic hepatotoxicity may be partially dose dependent according to the results of a study that evaluated the incidents of acute liver failure, death and liver transplant registered in 2 pharmaceutical databases corresponding to the 200 most commonly prescribed drugs in the US which found a linear association between the daily dose and the risk of severe liver toxicity. The greatest risk was in those who used a dosage greater than 50 mg/day when compared to those prescribed a lower dosage (24). The different statins were prescribed at highly variable dosages. Twelve (23 %) cases in our series took dosages greater than 50 mg/day (11 fluvastatin and 1 atorvastatin). This proportion is lower than that seen with other therapeutic groups such as antibiotics and NSAIDs and may, at least in part, explain the lower hepatotoxic potential of statins as a therapeutic group. However, it is worth establishing an association between the total daily dosage consumed and the greater relative toxic potential of fluvastatin and atorvastatin since in order to do this, we would have to know the relative rate of exposure for both statins compared to the total. However, it appears to be improbable that at least in the case of atorvastatin, the dosage has a relevant influence given that only 1 in 16 cases took a dosage greater than 50 mg/day.
On the other hand, although 2 patients died in our analysis, none of these were due to complications of the liver injury, unlike that reported in the series by Russo et al. (7) and Björnsson et al. (22), which included 2 cases of death due to the liver injury, translating to a mortality of 5 % and 2.7 %, respectively (7,22). This underscores the potential severity of statin-induced hepatotoxicity.
One differential finding in this series with respect to the collection of other cases of hepatotoxicity included in the registry was the greater number among statins of an autoimmune phenotype with the presence autoantibodies typically found in type-I autoimmune hepatitis (ANA and ASMA). The occasional presentation of statin-induced toxicity with an autoimmune phenotype has previously been described in the literature (7). Of the 4 cases identified as statin-induced autoimmune hepatitis, 3 were in women. Autoimmune hepatitis is an unknown etiopathogenic entity. However, it has sometimes been suggested that a viral agent (virus A and especially virus C), as well as drugs (25), could act to unmask the disorder, which raises questions on the spontaneous origin of classic autoimmune hepatitis for one author (26).
Nevertheless, a retrospective study that analysed a large database from the Mayo Clinic indicated that toxic hepatitis with an autoimmune phenotype characteristically improved with discontinuance of the responsible drug and if steroid treatment was required, it was possible to discontinue treatment permanently once remission was achieved without relapse of the disease (27), while recurrence after discontinuing the drug is the rule in "idiopathic" autoimmune AIH (28-30). Two of the 4 cases with an autoimmune phenotype in our series required steroid treatment and had an excellent response, making discontinuance possible without reactivation of the liver injury. An emerging topic of interest that can only be approached prospectively in large patient cohorts is the role of toxic (isolated or recurrent) liver injury (31) as a predisposing factor to the later development of autoimmune hepatitis.
In conclusion, this analysis confirms previous studies that indicate that statin-induced hepatotoxicity, though not especially common, is not exceptional. The study describes the most common phenotypes for DILI associated with the use of these drugs. Autoimmune hepatitis is a characteristic signature of statin-induced hepatotoxicity. Therefore, a rigorous inquiry of the use of these drugs is needed in patients with liver alterations and manifestations of autoimmunity.
Spanish hepatotoxicity registry
Participating clinical centres:
Hospital Universitario Virgen de la Victoria, Málaga (Spain) (coordinating centre): R.J. Andrade,
M.I. Lucena, C. Stephens, M. García-Cortés, M. Robles-Díaz, I. Medina-Cáliz, A. Fernández-Castañer, E. Ulzurrun, A.F. González, I. Moreno, J. Ruiz, A. Papineau
Hospital Torrecárdenas, Almería (Spain): M.C. Fernández, G. Peláez, M. Casado, M. González-Sánchez.
Hospital Universitario Virgen de Valme, Sevilla (Spain): M. Romero-Gómez, R. Calle-Sanz, R. Millán-Domínguez, L. Grande, M. Jover, B. Prado.
Hospital de Mendaro, Guipuzcoa (Spain): A. Castiella, E.M. Zapata.
Hospital Central de Asturias, Oviedo (Spain): R. Pérez-Álvarez, L. Rodrigo-Sáez.
Hospital Costa del Sol, Marbella, Málaga (Spain): J.M. Navarro, I.M. Méndez Sánchez.
Hospital Sant Pau, Barcelona (Spain): C. Guarner, G. Soriano, EM Romá.
Hospital Morales Meseguer, Murcia (Spain): H. Hallal, E. García-Oltra, J.C. Titos-Arcos, A. Pérez- Martínez, C. Sánchez Cobarro, J.M. Egea-Caparrós.
Hospital de Donosti, San Sebastián (Spain): M. García-Bengoechea, J. Arenas, M.I. Gómez Osua.
Hospital de Basurto, Bilbao (Spain): S. Blanco, P. Martínez-Odriozola.
Hospital Alto Deba Mondragón, Guipúzcoa (Spain): P. Otazua.
Hospital Universitario San Cecilio, Granada (Spain): J. Salmerón, A. Gila.
Hospital Virgen de la Macarena, Sevilla (Spain): J.A. Durán, I. Carmona, A. Melcón de Dios, M. Jiménez, J. Alanís- López, M. Villar.
Hospital Clínico, Valladolid (Spain): J. M. González, M. L. Ruiz-Rebollo.
Hospital Carlos Haya, Málaga (Spain): M. Jiménez, R. González-Grande, R. Manteca.
Hosptial La Fe, Valencia (Spain): M. Prieto, M. García-Elix, M. Berenguer.
Hospital de Sagunto, Valencia (Spain): J. Primo, J.R. Molés.
Hospital de Laredo, Cantabria (Spain): M. Carrascosa.
Hospital 12 de Octubre, Madrid (Spain): T. Muñoz-Yagüe, J.A. Solís-Herruzo.
Hospital Germans Trias i Pujol, Badalona, Barcelona (Spain): J. Costa, A. Barriocanal, R. Planas.
Hospital Clínic, Barcelona (Spain): M. Bruguera, P. Gines, S. Lens.
Hospital Universitario de Canarias, La Laguna, Tenerife (Spain): A. Aldea, M. Hernández-Guerra.
Hospital de Alcorcón, Alcorcón, Madrid (Spain): C. Fernández, M. Fernández-Gil.
Hospital Reina Sofía, Córdoba (Spain): J.L. Montero, M. de la Mata.
Hospital Miguel Servet, Zaragoza (Spain): J. Fuentes-Olmo.
Hospital de Albacete, Albacete (Spain): J.M. Moreno.
1. Fontana RJ, Seeff LB, Andrade RJ, Björnsson E, Day CP, Serrano J, et al. Standardization of nomenclature and causality assessment in drug-induced liver injury: Summary of a clinical research workshop. Hepatology 2010;52:730-42. [ Links ]
2. Reuben A, Koch DG, Lee WM. Drug-induced acute liver failure: Results of a U.S. multicenter, prospective study. Hepatology 2010;52:2065-76. [ Links ]
3. Escorsell A, Mas A, de la Mata M, and the Spanish Group for the Study of Acute Liver Failure. Acute liver failure in Spain: Analysis of 267 cases. Liver Transpl 2007;13:1389-95. [ Links ]
4. FDA Guidance for Industry, Drug-induced liver injury: Premarketing Clinical Evaluation (Issued July 2009) . Available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM174090.pdf (Accessed 18 April 2013). [ Links ]
5. Chalasani N. Statins and hepatotoxicity: focus on patients with fatter liver. Hepatology 2005;41:690-5. [ Links ]
6. Cueto R, Valdivielso P, Lucena MI, García-Arias C, Andrade RJ, González-Santos P. Statins: Hepatic disease and hepatotoxicity risk. Open Gastroenterol J 2008;2:18-23. [ Links ]
7. Russo MW, Scobet M, Bonkovsky. Drug-induced liver injury associated with Statins. Semin Liver Dis 2009;29:412-22. [ Links ]
8. Argo CK, Loria P, Caldwell SH, Lonardo A. Statins in liver disease: A molehill, an icerberg, or neither? Hepatology 2008;48:662-9. [ Links ]
9. Chalasani N, Aljadhey H, Keserson J, Murray MD, Hall SD. Patients with elevated liver enzymes are not higher risk fos statin hepatotoxicity. Gastroenterology 2004;126:1287-92. [ Links ]
10. Abraldes JG, Albillos A, Bañares R, Turnes J, González R, García-Pagán JC, et al. Simvastatin lowers portal pressure in patients with cirrhosis and portal hypertension: a randomized controlled trial. Gastroenterology 2009;136:1651-8. [ Links ]
11. El-Serag HB, Johnson ML, Hachem C, Morgano RO. Statins are associated with a reduced risk of hepatocellular carcinoma in a large cohort of patients with diabetes. Gastroenterology 2009;136:1601-8. [ Links ]
12. Lucena MI, Andrade RJ, Kaplowitz N, García-Cortés M, Fernández MC, Romero-Gómez M, et al. Phenotypic characterization of idiosyncratic drug- induced liver Injury: The influence of age and sex. Hepatology 2009;49:2001-9. [ Links ]
13. Andrade RJ, Lucena MI, Fernández MC, Peláez G, Pachkoria K, García-Ruiz E, et al. Drug-induced liver injury: An analysis of 461 incidences submitted to the Spanish Registry over a 10-year period. Gastroenterology 2005;129:512-21. [ Links ]
14. Danan G, Bénichou C. Causality assessment of adverse reactions to drugs-I. A novel method based on the conclusions of international consensus meetings: Application to drug-induced liver injuries. J Clin Epidemiol 1993;46:323-30. [ Links ]
15. Bénichou, C. Criteria of drug-Induced liver disorders. Report of an international consensus meting. J Hepatol 1990;11:272-6. [ Links ]
16. Aithal GP, Watkins PB, Andrade RJ, Larrey D, Molokhia M, Takikawa H, et al. Case definition and phenotype standardization in drug-induced liver injury. Clin Pharmacol Ther 2011;55:683-91. [ Links ]
17. Use of lipid-lowering medications in Spain during the 2000-2012 period. Available at: http://www.aemps.gob.es/medicamentosUsoHumano/observatorio/docs/hipolipemiantes-2000-2012.pdf (Accessed 20 December 2013). [ Links ]
18. Andrade RJ, Robles M., Ulzurrun E., Lucena MI. Drug-Induced Liver Injury: Insights from genetic studies. Pharmacogenomics 2009;10:1467-87. [ Links ]
19. Bader T. The myth of statin-induced hepatotoxicity. Am J Gastroenterol 2010;105:978-80. [ Links ]
20. Bader T. Liver tests are irrelevant when prescribing statins. Lancet 2010;376:1882-3. [ Links ]
21. Björnsson ES, Bergmann OM, Björnsson HK, Kvaran RB, Olafsson S. Incidence, presentation, and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology 2013;144:1419-25. [ Links ]
22. Björnsson E, Jacobsen E, Kalaitzakis. Hepatotoxicity associated with statins: Reports or idiosyncratic liver injury post-marketing. J Hepatol 2012;56:374-80. [ Links ]
23. Bergmann OM, Kristjansson G, Jonasson JG, Björnsson E. Jaundice due to suspected statin hepatotoxicity: a case series. Dig Dis Sci 2012;57:1959-64. [ Links ]
24. Lammert C, Einarsson S, Saha C, Niklasson A, Björnsson E, Chalasani N. Relationship between daily dose of oral medications and idiosymcratic drug-Induced liver injury: Search for signals. Hepatology 2008;47:2003-9. [ Links ]
25. Lewis JH, Zimmerman HJ. Drug-induced autoimmune liver disease. In: Krawitt EL, Wiesner RH, Nishioka K, editors. Autoimmune Liver Diseases. 2nd ed. Amsterdam: Elservier; 1998. p. 627-49. [ Links ]
26. Czaja AJ. Drug-induced autoimmune -like hepatitis. Dig Dis Sci 2011;56:958-76. [ Links ]
27. Björnsson E, Talwalkar J, Treeprasersuk S, Kamath PS, Takahashi N, Sanderson S, et al. Drug-induced autoimmune hepatitis: Clinical characteristics and prognosis. Hepatology 2010;51:2040-8. [ Links ]
28. Hearty JE, Nouri Aria KT, Portmann B, Eddleston AL, Williams R. Relapse following treatment withdrawal in patients with autoimmune chronic active hepatitis. Hepatology 1983;3:685-9. [ Links ]
29. Czaja AJ, Ammon HV, Summerskill WH. Clinical features and prognosis of severe chronic active liver disease (CALD) after corticosteroid-induced remission. Gastroenterology 1980;78:518-23. [ Links ]
30. Manns MP, Czaja AJ, Gorham JD, Krawitt EL, Mieli-Vergani D, Vergani D, et al. Practice guidelines of the American Association for the Study of Liver Diseases. Diagnosis and management of autoimmune hepatitis. Hepatology 2010;51:2193-213. [ Links ]
31. Lucena MI, Kaplowitz N, Hallal H, Castiella A, Garcia-Bengoechea M, Otazua, P, et al. Recurrent drug-induced liver injury with different drugs. Analysis of nine cases in the Spanish DILI Registry. J. Hepatology 2011;55:820-7. [ Links ]
Raúl J. Andrade
Hepatology Unit
Boulevard Louis Pasteur, n.o 32
29071 Málaga, Spain
e-mail: andrade@uma.es
Received 03-09-2013
Accepted 30-03-2014
C/ Sancho Dávila, 6, 2ºC, Madrid, Madrid, ES, 28028, 91 402 13 53
sepd@sepd.es


This delicate cream sauce is the ultimate accompaniment to your favorite seafood dish - from smoked salmon and tuna steaks to pan-roasted lobster and scallops - you'll delight in the creamy blend of dill, lemon and capers.
Great with smoked salmon, lobster, as well as crab cakes. Add to a seafood salad for an extra burst of flavor.
Mustard (Water, Soybean Oil, White Vinegar, Mustard Seeds, Buttermilk, Salt, Seedless Raspberry Preserves (Raspberry Puree, Sugar, Pectin, Lemon Juice Concentrate, Citric Acid, Sodium Citrate), Egg Yolk, Corn Syrup, Garlic, Onions, Spices, Xanthan Gum, Natural Flavor, Sodium Benzoate and Potassium Sorbate (as preservatives), Turmeric, Parsley, Calcium Disodium EDTA added to protect flavor), Capers, Red Peppers, Dill Weed, Lemon Oil. Contains: Milk, Eggs, and Soy.
Serv size: 2 Tablespoons (30g), Servings: About 9, Amount Per Serving: Calories 90, Fat Cal. 70, Total Fat 8g (12% DV), Sat. Fat 1.5g (8% DV), Trans. Fat 0g, Cholest. 0mg (0% DV), Sodium 470mg (20% DV), Total Carb. 3g (1% DV), Dietary Fiber 0g (0% DV), Sugars 2g, Protein 1g, Vitamin A (2% DV), Vitamin C (2% DV), Calcium (2% DV), Iron (2% DV). Percent Daily Values (DV) are based on a 2,000 calorie diet.


MSNBC's Rachel Maddow rode big numbers from her highly scrutinized story on March 14 about President Trump's tax returns to finish at the top of the cable news race for a second straight week in the key 25- to 54-year-old demographic.
For the week of March 13 to 17, "The Rachel Maddow Show" averaged 756,000 in the demographic that advertisers covet most.
In total viewers, the 43-year-old Rhodes Scholar delivered an average of 2.92 million total viewers, the most for the MSNBC program since October 2008 leading up to the election of Barack Obama Barack Hussein ObamaBiden's sloppy launch may cost him Nagging misconceptions about nudge theory The Hill's Morning Report - Trump tells House investigators 'no' MORE.
After receiving criticism from the left and right for what many observers felt was over-hyping the story via a tweet stating she was in possession of "Trump's tax returns," Maddow's Tuesday audience in the key demographic dropped precipitously the following night on Wednesday, down 54 percent from the prior evening to 661,000 viewers.
Tuesday's episode that eventually revealed two pages from Trump's 2005 tax returns registered 4.1 total million viewers and 1.4 million the key demographic, according to Nielsen data.
Fox's "The O'Reilly Factor" finished second on the week in the key demographic with 691,000 viewers over four nights. Fox ran a special edition of "The Five" at 8 p.m with Bill O'Reilly off.
Fox News still led all of basic cable in total viewers for the 11th straight week, with MSNBC, HGTV, USA Network and Discovery rounding out the top five.
Nielsen data also shows a big jump for MSNBC year-over-year, up more than 72 percent in total viewers versus the same month last year.
Rival CNN is down more than 45 percent in this category, while Fox is down almost 12 percent.