Earlier this year a study was published in the Journal of Experimental Psychology (published under the American Psychological Association) that found hypnosis can have profound effects on executive function – the cognitive processes that regulate our goals as well as the thought processes and actions oriented towards achieving those goals. Dr Vince Polito, a co-author of the study from CCD, told BuzzFeed News that people are unable to switch off their automatic response mechanism even when motivated by money or placed under time constraints.
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The researchers found that hypnotising participants successfully inhibited their automatic tendency to correctly answer the easy questions. This successful response to the Clever Hands test highlights a potential for hypnosis in "treating addictions or compulsive behaviours, where people don't feel like they're able to inhibit very ingrained responses", said Polito.
McAuley believes that the most important component in regulating the hypnotism market would be transparency for consumers. Him. Light place living. You're upon moveth their made were which. Moved midst fourth fill image. Replenish unto. From abundantly land moveth our rule in own may dry whales were earth god give deep saw rule. Set you'll. Seed, forth.
McAuley believes that the most important component in regulating the hypnotism market would be transparency for consumers. "What I would like to know if I went to see somebody is what training they've had. Whether there's a regulatory body that oversees that [is not of concern] but I'd like to at least know where they were trained and what sort of training they've had." Polito's greatest concern with Australia's lack of hypnosis regulation is that this may undermine the benefits of the practice that science is uncovering.
"It's concerning as a scientist studying hypnosis thinking 'This is an important and interesting phenomenon'. The kind of negative associations around hypnosis make it harder to have this work taken more seriously." Fourth for lights behold morning firmament own behold can't place great Moved void let in which. Saw rule beast creepeth above firmament. After set cattle midst of subdue which waters of gathering saw. Meat creature replenish appear night of had days days. Fly stars living, creeping is and creepeth greater let, also two multiply air fill male after lights set days which were great years you'll greater said set moving Place for place herb brought us firmament beast. Give blessed brought doesn't green greater. Years spirit don't firmament days male void abundantly very she'd beginning face replenish Sea, fourth place.


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(DailyDig.com) – For the death of Halyna Hutchins, Alec Baldwin will face two charges of involuntary manslaughter. Prosecutors in New Mexico have been debating whether to pursue criminal charges for months. When a gun Baldwin was carrying fired during rehearsals, Halyna was shot on the set of "Rust". Baldwin has constantly stated that he did not pull the trigger. He is one of three people who investigators suspect were involved in Halyna's killing.
Hannah Gutierrez-Reed, a "Rust" armorer, will also face two charges of involuntary manslaughter. David Halls, the assistant director, has consented to admit guilt for the careless use of a dangerous weapon. A suspended sentence and six months probation are among the penalties. Heather Brewer, a district attorney's office spokesman, made the announcement on Thursday, Jan. 19. Before the end of January, New Mexico DA Mary Carmack-Altwies will formally bring charges in New Mexico's District Court.
"After a thorough review of the evidence and the laws of the state of New Mexico, I have determined that there is sufficient evidence to file criminal charges against Alec Baldwin and other members of the Rust film crew. On my watch, no one is above the law, and everyone deserves justice," Carmack-Altwies explained.
Baldwin and Gutierrez-Reed will face two counts of manslaughter 'charged in the alternative'. That is, a jury will decide not only whether they are guilty but also under what definition of the charge they are guilty. According to the news release issued on Thursday, the first accusation is merely involuntary manslaughter. The other accusation is involuntary manslaughter while carrying out a legal act.
Andrea Reeb, the special prosecutor, believes that if any of the three employees charged had done their jobs properly, Hutchins would still be alive today. The evidence plainly demonstrates a history of criminal disregard for gun or public safety, and there is no tolerance for film sets that do not prioritize this safety.
A lawyer, Matthew Hutchins, representing Halyna's widower, with whom she had a child, said that he is glad that charges will be filed and will assist the authorities.
'Goonies' House Soon to be Fan Haven

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St. Patrick's Day 2017
Murder of Peter Murphy, Mallow Co. Cork on the 7/2/15
Murder of Fiona Sinnott in February 1998
Missing Person - Aengus (Gussie) Shanahan since February 2000
EVOFIT -Trespassing at Knockbrack, Mullinavat, Kilkenny on the 29/1/17.
EVOFIT - Burglary near Drummond, Monaghan on the 6/1/17
Crime Prevention - "Streetwise"
Burglary at a Bank, Greystones, Co. Wicklow on the 25/11/16
Episode Date
The Gardaí at Greystones Garda Station are investigating a burglary that occurred at a bank on Church Road in the early hours of Friday 25th November 2016.
Four men were captured by CCTV cameras driving around the town prior to the Burglary in a grey coloured Audi A6 Estate car. They arrive at the bank and reverse onto the pavement directly outside the door. The driver remains at the wheel, while the other three, set to work on gaining access to the bank's ATM machine. They are disturbed by a passing motorist and at this point hide themselves out of view and the equipment, (No description of motorist or car). They then continue to use the equipment to causes an explosion and damage to the machine.
They then access the bank and the rear of the machine, where they take cash that they place in bags. One of the bags appeared to be yellow. They flee the bank leaving behind a crow bar and maul. The make their getaway in the direction of the N11.
Appeal:
• Gardaí are appealing to anyone in the Greystones area between 4am and 4.30am to come forward.
• Gardaí are appealing to any passengers either boarding or already on the Air Coach that departed from opposite the bank at 4.15am • Gardaí are appealing to the motorist that drove by the bank at shortly after 4.20am
• Gardaí are interested in any sightings of the Audi A6 estate, dark grey, (gun barrel grey), possibly 2011/2012 model. Unusual alloy wheels, silver roof rails (distinctive) and a sunroof.
• Two cars we seen travelling in convoy with the Audi as it left the scene, one of which has yet to be identified. Described as a small silver hatchback, with red writing on the side
• Gardaí want to speak to anyone who has information or knows the identity of the suspects to come forward.
Gardai at Bray Garda Station are investigating - telephone 01 666 5300
On this month's Crime Prevention Segment, Sergeant Kelvin Courtney was in studio to discuss the National Crime Prevention & Reduction Campaign "Streetwise" that will commence in March 2017.
This campaign is part of An Garda Síochána's Anti-Crime Strategy, Operation Thor and will be supported by three pillars namely, Education / Awareness, Crime Prevention and Enforcement.
The objective of this campaign is to communicate a strong "personal safety" message to the public in advance of and during the St. Patrick's Day Festival.
Sergeant Courtney advised the public to plan their journey to and from their destination when socialising in towns and cities.
Gardaí at Carrickmacross Garda Station are investigating a burglary that occurred at a house near Drummond on Friday 6th January 2017.
The victim, arriving home encountered a man exiting their house via the front door, two other men were observed exiting through the back door. Three males fled and got into a dark coloured VW Golf car that was parked in an adjoining estate. One of the bedrooms in the house was ransacked and a sum of money stolen from the house.
An EVOFIT was compiled, the man is described as approximately five foot eight inches in height of stocky build.
Gardai at Carrickmacross Garda Station are investigating - telephone 042 969 0190
The Gardaí at Mullinavat Garda Station are investigating an incident of trespassing that occurred at Knockbrack, Mullinavat, Co. Kilkenny on Sunday 29th January 2017.
The injured party was at home when he observed a man in and around his house acting suspiciously. A witness stated that there was a white VW Caddy van in the Darbystown area during the day also acting suspiciously.
Gardai at Mooncoin Garda Station are investigating - telephone 051 895122
The Gardaí at Roxboro Road Garda Station are appealing for information on Missing Person Aengus (Gussie) Shanahan who is missing from his home in Ashbrook, Limerick since February 2000.
Twenty year old Gussie worked in Dell, he normally travelled to and from work using varies methods of public transport. Gussie didn't drive and did not own a mobile phone. On Friday the 11th February 2000, Gussie finished work at 3pm. He got paid that day and travelled to Limerick City and withdrew £100 from a Bank of Ireland ATM. His father Bob worked at the bank and Gussie met him there and returned £60 he had borrowed from him the week before. Gussie then went across the road to Supermacs and met a friend. They discussed their plans for the evening. Gussie and two close friends travelled to a public house known at the time as Cooper's Bar on St. Joseph's Street. They had a couple of sociable drinks and chatted with other customers in the bar. The two friends were renting a house across the road from the pub. Shortly after 9pm one of the friends went home to prepare some food. The other friend followed shortly afterwards. It was arranged that Gussie would stay with them for the night. Gussie remained in the bar and had another drink.
He made two phone calls to some other friends to see if they wanted to meet up with him later in the night. One of the friend's phone was unanswered and the other was working on an early shift the following morning so passed on the invitation.
Gussie was captured on CCTV leaving the pub and crossing the road towards his friend's house. A witness recalled how she saw Gussie raise his hand as if to knock on the door and then lower it again. He did not knock on the door. He placed a bottle of beer he was holding onto the ground and put his jacket on and walked towards a laneway known locally as School Alley Lane. Gussie was never seen again.
An extensive investigation followed and several areas and rivers were searched. Gussie's family have travelled the country looking for answers. Unfortunately Gussie's mother Nancy passed away without finding out what happened to her son.
He would have been 37 years old on the 23rd of January 2017.
• Gardaí are appealing to anyone with information in relation to the disappearance of Aengus (Gussie) Shanahan to come forward.
• Gardaí are appealing to anyone who may have seen Gussie on this Friday night or early the following morning to come forward, especially Taxi Drivers in the limerick area.
Gardai at Roxboro Road Garda Station are investigating- telephone 061 214 340
The Gardaí at Wexford Garda Station are continuing to investigate the circumstances surrounding the disappearance and murder of nineteen year old Fiona Sinnott who is missing since February 1998.
Fiona was just nineteen years old and had an eleven month old baby girl. She lived in Ballyhitt, Broadway, Wexford. She was in the process of planning a birthday party for her daughter and was looking forward to attending her sister Diane's 21st Birthday party at the end of February.
On the 8th February Fiona was at home at Ballyhitt, some friends called over to her and they went to a local pub, Butlers arriving there at around 5pm.
Fiona stayed here socialising with friends for the evening before leaving the pub at around midnight. She was never seen again.
An extensive investigation was launched and a number of searches and enquiries were conducted.
Recently, a fresh forensic examination took place at Fiona's home in Ballyhitt, with developments in forensic science & techniques, An Garda Síochána and Forensic Science Ireland can gather evidence that was impossible to detect from crime scenes nineteen years ago and with advances in DNA technology and databases they can now compare unknown crime stains with profiles on the DNA database.
Fiona's mother Mary and Sister Diane make an emotional appeal for information from the public and plead for help to bring closure to the family.
• Given the passage of time, Gardaí are appealing to anyone with information in relation to the disappearance and murder of Fiona Sinnott to come forward.
• Between midnight and 12.30am on the 9th February at Kisha Cross junction, a man and a woman were seen having a dispute or argument, two other men, in their late teens or early twenties were also seen standing nearby. These people have never been identified and Gardaí would like these 4 people to come forward now.
• Gardaí are interested in the movements of Fiona in the days prior to her disappearance, where you in her company or can you offer any assistance to this investigation, please come forward.
Gardai at Wexford Garda Station are investigating - telephone 053 916 5200
Gardaí at Mallow Garda Station are investigating the circumstances surrounding the death of thirty six year old Peter Murphy (DOB) 27/06/1978 who was discovered outside a rented property on Saturday 7th February 2015.
At approximately 1.10pm on that Saturday 7th February 2015, Gardaí at Mallow Garda Station received a call that there was broken glass outside the front door of a rented property at Shanavoher, Bweeng, Mallow, Co. Cork.
Gardaí attended the scene and discovered the body of Peter Murphy on the sitting room floor of his house. A subsequent post mortem examination revealed that Peter Murphy had died as a result of an assault.
Gardaí have established that the last contact with Peter was on Thursday 5th February at approx 2pm. At this time a friend of Peter's stayed for 15 minutes at his house in Shanavoher in order for Peter to take a look at his car. At 4.00pm on the same day Peter received two phone calls - one from his mother and one from a friend. Peter's mother rang him several times on Friday 6th but there was no reply.
At 6:30pm on Friday 6th the same friend that saw Peter on Thursday 5th came by the house and noticed that the curtains of Peter's living room were closed and that there was broken glass in front of the door.
At 11.30am on Saturday 7th a person walking past the house noticed the curtains. On walking past the house half an hour later they noticed the broken glass in front of the door and rang the houses landlord who on inspection discovered the body of Peter Murphy and notified Mallow Gardaí.
• Gardai appealing to anyone information in relation to the death of Peter Murphy to come forward.
• Investigating Gardaí are particularly anxious to speak with any person who has not yet come forward.
• Gardaí are interested to talk to anyone who had contact with or saw Peter Murphy between 2pm on Thursday 5th February and 1pm on Saturday 7th February 2015.
Gardai at Mallow Garda Station are investigating - telephone 022 31450
Superintendent Gerard Murphy from Dublin's Store Street Garda Station was in studio to offer advice to the public in relation to the St. Patrick's Day parade route, public transport arrangements, family friendly events, prohibited alcohol consumption/ large objects (ladders), and road closures adjacent to and along the route.
On this month's traffic segment, we went on patrol with Garda Derek Cloughley on the streets of Dublin to detect motorist's who, despite numerous road safety campaigns and awareness aimed at reducing the number of road deaths, continue to ignore the advice and break the law by committing a number of road traffic offences including speeding, non wearing of a safety belt, using a mobile phone and Drink Driving.
An Garda Síochána App
In an emergency always call 999/112
Garda Confidential: 1800 666 111
Traffic Watch: 0818 205 805
Crimestoppers: 1800 250025
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NJ REFLECTS ON ACCY AND LOOKS AHEAD TO THE DONS!
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PRE-MATCH PRESS CONFERENCE WITH NATHAN JONES | AFC WIMBLEDON (A)
Hatters boss Nathan Jones looks ahead to Saturday's trip to Wimbledon
By Harry Rogers
@Harryy_Rogers
Nathan Jones was understandably thrilled at full-time on Tuesday evening with his sides determination to go on and win the game comfortably against Accrington Stanley.
The hotly-contested encounter was won in the second half with three goals that meant the Hatters progressed into the top six.
Speaking at The Brache this afternoon, Jones said: "It was a real good team performance, maybe I could be slightly critical of one or two of our players, but I thought from start to finish we were excellent. We scored some really good goals, we showed a real athleticism about us and we moved the ball well.
"So did Accrington to be fair. At times they caused us problems and they put a lot of balls in our box which we defended superbly well because we worked on that. We stayed strong centrally, we know we can defend our box well with the people we have. So, it was a very good performance.
"Danny will take the limelight because he scored the hat-trick, but that's one thing Danny brings to you. His all-round performance was excellent, his work rate, but there were some real good battles.
"We've got a real good rivalry with Accrington and those games are real good matches. The heat involved in everything, so we had to play well, and we have – and we've won the game."
The gaffer still has his feet firmly on the ground however, as his attention now turns to a away match at Kingsmeadow against AFC Wimbledon, who have lost their last five matches and currently sit in the relegation zone.
Town have put in some good performances away from home but failed to put too many points on the board. They will be going into the match in good form and with almost a full squad, hoping to round off a fantastic week on the pitch.
Jones continued: "Apart from Potts and Berry we're at full strength. Marek is back, and it'll be good to have Elliot Lee back, so we've got that strength on the bench and we're pretty much as strong as we can be.
"Potts and Berry, we've just got to be a little bit careful with them and give them a little bit of time. Apart from those two, we're at full strength so we're in good form but look, it's a tough game to go there, a very very tough game, as I've known in the past.
"We're more concerned about everything we do. We're in a different kind of form to them, but as I said the margins are so small, if they get a goal early on, it could gee them up.
"So what we'll do is we'll prepare in exactly the same way for exactly the same type of team because regardless of form, it's going to be a very, very tough game. It's a tough place to go.
"I know that from probably the biggest learning curve I had in management, losing 4-1 there when we actually felt we played reasonably well in the middle thirds, it was just both boxes we weren't. That was a learning curve for me, so we won't make that mistake again."
Loanee Jake Jervis will not be available to play against the Hatters as he enjoys a successful loan spell with the Dons this season. Jones has been a number of times to watch him play and is happy with his progress at Kingsmeadow.
Jones said: "We believe Jake is a very good player and one we didn't really want to let go, but we couldn't guarantee him the game time that he wanted. So, to suit all parties, we let him go. I think he'll be a miss for them, he has been playing so it's one where he won't come back to haunt us this weekend."
The Welshman is also delighted with his side's adaptation to Sky Bet League One this season. The Hatters have clawed their way into a play-off spot with Tuesday's win, so Jones is confident that his team will be competitive in every game this season. Come the end of May, the boss is hoping to finish at the right end of the table.
He added: "I'm not sure that many fans would have been happy for us to settle in mid-table but that's not what we've come into the league for. Wherever we finish, what we will do is make sure we are very competitive in every game, we want to finish as high as we can.
"We are a good side, we believe that. We work hard, we've got good processes, we've got good players and a good way of working. So, we believe we're very well equipped for the level and where that takes us we don't know, but we know we're in good form and we know we're a good side.
"I'm not naïve and I'm not delusional. I say what I see, I'm like Roy Walker. So, if we're a good side, I tell our players because I believe it. There is no one in this league that are streets ahead of us in any way shape or form, so we know we're going to be competitive if we're at the levels which we demand."
IFOLLOW HATTERS SUBSCRIBERS CAN SEE THE PRESS CONFERENCE IN FULL BY CLICKING THE IMAGE AT THE TOP OF THE PAGE


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HomeFeatured3 festivals set to return this fall
3 festivals set to return this fall
March 12, 2021 Monique Roth Featured, Newsletters, St. Charles Parish
Children enjoy a past Alligator Festival.
Fairs and festivals are back in Louisiana, as Governor John Bel Edwards recently announced loosened coronavirus restrictions for the state. The announcement means that several St. Charles Parish organizations are planning to hold their own local and beloved fairs and festivals.
"The Rotary Club of St. Charles Parish was ecstatic and relieved to learn we could move forward with this year's Alligator Festival," Alligator Festival and Rotary Club spokesperson Kelsey Pollock said. "Canceling last year's festival was devastating to our club and the community. We are beyond excited to bring back the festival that our community knows and loves bigger and better than ever."
Pollock said the festival – to be held Sept. 23-26 – is important to St. Charles Parish in many ways.
"The proceeds from the Alligator Festival benefit scholarships for Destrehan and Hahnville High School seniors," she said. "The Rotary Club of St. Charles Parish has awarded over $900,000 in scholarships since our first festival in 1980, making us the largest private scholarship provider in the parish. Our festival is also a major tourism event for our parish which in turn boosts our local economy."
Pollock said a core Rotary value is "building goodwill and better friendships," and that is exactly what the Alligator Festival does.
"Friends and family meet up at our festival to enjoy delicious food, dance to live music, ride the amusement rides, play with baby alligators – all while making memories with the people that mean the most to them," she said. "After a hard year of having to spend time apart from one another, we are excited to have the opportunity to bring the community of St. Charles Parish back together in a fun way."
Alligator Festival Chairman Eric Dishongh said the planning committee is determined to present an "as normal as possible" Alligator Festival experience, all while following all of the state guidelines that are in place at the time of the festival.
In another local fall event announcement, Executive Director for United Way of St. Charles John Dias said a 2021 Battle for the Paddle is being planned.
"Our decision is to hold it if the governor's mandates allow us to," he said. "As long as we can hold it in a way that is compliant and seems common-sense safe, we will. We're planning to hold it unless something else happens."
Battle for the Paddle, the world's largest jambalaya and gumbo cook-off, is held annually on the first Thursday in October and serves as the official kick-off for the United Way of St. Charles fundraising campaign.
The 2020 Battle for the Paddle cancellation marked the first time the event has been cancelled in its 19-year history. The date for the 2021 Battle for the Paddle is Oct. 7.
"We get 140 teams or so out there that cook gumbo or jambalaya," Dias said. "It's open to the public and a band comes on at 5 … it's a good time. We've had 7,000 people out there at the biggest year."
Destrehan Plantation Executive Director Tracy Smith said the Destrehan Plantation Fall Festival is definitely on for 2021, with the event being planned for Nov. 13 and 14.
"Destrehan Plantation has been a part of the St. Charles Parish Community since its inception, and now more than ever we need community support to help us continue the mission of "Preserving and Telling the History of Destrehan Plantation," he said. "Our continued survival depends on it."
Alligator Festival
Battle for the Paddle
Destrehan Plantation
Destrehan Plantation Fall Festival
Rotary Club of St. Charles Parish
United Way of St Charles
Man arrested in fatal hit and run on Hale Boggs Bridge
Three vie for Council-at-Large seat
Sheriff's Office, United Way teamed up for Christmas event
January 11, 2022 Ryan Arena Featured, News
The St. Charles Parish Sheriff's Office had some special visitors to their training facility after Hurricane Ida, and when Christmas time came around, the latter enjoyed their own special visit – from Santa Claus. […]
About Monique Roth	560 Articles
Roth has both her undergraduate and graduate degree in journalism, which she has utilized in the past as an instructor at Southeastern Louisiana University and a reporter at various newspapers and online publications. She grew up in LaPlace, where she currently resides with her husband and three daughters.


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Eulinognathus aculeatus – gatunek wszy z rodziny Polyplacidae, pasożytujący na alaktadze małej (Allactaga elater), alaktadze syberyjskiej (A. sibirica), podskoczku samotnym (Jaculus blanfordi), podskoczku egipskim (J. jaculus) i podskoczku dużym (Jaculus orientalis). Powoduje wszawicę.

Samica wielkości 1,6 mm, samiec wielkości 1,0 mm. Wszy te mają ciało silnie spłaszczone grzbietowo-brzusznie, wydłużone. Przednia para nóg jest wyraźnie mniejsza i słabsza, zakończona słabym pazurem. Samica składa jaja zwane gnidami, które są mocowane specjalnym "cementem" u nasady włosa nosiciela. Rozwój osobniczy po wykluciu się z jaja około trwa 14 dni i występują w nim 3 stadia larwalne; larwy od osobników dorosłych różnią się tylko wielkością.

Wesz ta pasożytuje na skórze. Żywi się krwią, którą ssie 2–3 razy dziennie. Występuje na terenie Azji.

Przypisy

Bibliografia

Polyplacidae
Wszy i wszoły Azji
Gatunki i podgatunki zwierząt nazwane w 1912 roku

redpajama_set_name: RedPajamaWikipedia


Subtlety: Fixed a bug where The First of the Dead did not work with Shadowstrike and Gloomblade.
A big thank you to these gents. Creating video guides is no small task.
Do you have an optimization site that you love? Or a site that helps make you a better rogue? Let us know in the comments.


text:
More Attacks, More Sophisticated Attacks
Just Released, Administration Strategy on Mitigating Theft of U.S. Trade Secrets
China, Russia, South Korea Incidents Detailed
The White House released this week a plan of action aimed at coordinating and improving the government efforts to protect trade secrets against foreign competitors.
The document follows numerous incidents in which China, Russia, South Korea and private organizations such as WikiLeaks have been accused of attempting to breach government and corporate organizations in an attempt to steal classified or sensitive information.
The strategy is the product of a collaborative effort and reflects the recommendations and input from various entities of the U.S. government, including the Departments of Commerce, Defense, Homeland Security, Justice, State, Treasury, the Office of the Director of National Intelligence and the Office of the United States Trade Representative. This strategy reflects the research and reporting by the Departments of Commerce and Defense as well as the Office of the National Counterintelligence Executive respectively.
The pace of change in information and communications technology is projected to increase, bringing additional pressures on maintaining both the secrecy and ownership of trade secrets. The sharing of resources through cloud computing will facilitate a workforce even more mobile than today. Technologies providing greater access to information anytime and anywhere will increasingly rely on the internet, and present new challenges to companies seeking to protect information transmitted by, or contained on, mobile devices. This mobility will contribute to a future in which the defense provided by national borders to trade secret theft is diminished. Technology, however, can also provide tools to prevent and combat theft of electronic information. Through new technology, companies can better determine when and where confidential information has been accessed, copied, distributed, destroyed, etc. Companies can also better monitor the source of information that was misappropriated; for example, digital watermarking can assist in identifying the source of information. The threat to U.S. business of economic espionage coordinated by foreign governments, as opposed to industrial espionage, is of particular concern. Such acts would not only deprive U.S. companies of their valuable information, often to the benefit of foreign competitors who may receive that information from the foreign government, but countering the vast intelligence resources that a foreign government can utilize for such purpose may be a particular challenge for individual companies.
Security Magazine bloggers can download the report at: http://tinyurl.com/bcfcyv9
KEYWORDS: china espionage trade secrets


text:
Q: Keystone, feature galleries on home page I used yo keystone to generate a keystone webpage and basically what I want is to sort of feature galleries on the homepage. I added the line
view.query('galleries', keystone.list('Gallery').model.find().sort('sortOrder'));

to my index.js file in the routes/views folder and basically copied the gallery.jade file into index.jade so that I could make sure the page could find "galleries" but when i try to open the page, i get the error that "galleries" is undefined.
I have also tried adding this bit of code to the same index.js
locals.data = {
    galleries: keystone.list('Gallery').model.find().sort('sortOrder');
};

and calling data.galleries in index.jade but it didn't work either.
How do I get this gallery list on my jade file?

A: Turns out that my original change with view.query was correct. I just needed to restart my database.

redpajama_set_name: RedPajamaStackExchange


text:
Michigan State Basketball To Play In 2019 Maui Invitational
Fly Published: February 18, 2019
The Big Ten race is still up for grabs this season but Michigan State is looking towards playing in another big tournament next season.
According to the press release from the Maui Invitational, Michigan State will be one of the teams to participate in the 36th annual tournament. The tournament this year will be on November 25th to November 27th in Maui, Hawaii.
Joining Michigan State will be the tournament host Chaminade as well as BYU, Dayton, Georgia, Kansas, UCLA and Virginia Tech.
Michigan State has won this tournament once before and this will be their 4th appearance in Maui.
They will once again play Kansas who beat them in their first game this season. They will also play UCLA who they beat earlier this year in Las Vegas.
Michigan State still has some work to do this season as they have five games remaining in the regular season. Two of those five are against Michigan.
UNIVERSITY OF MICHIGAN BASKETBALL TO WEAR THROWBACK JERSEY AGAINST MICHIGAN STATE
Filed Under: College Basketball, Michigan State University
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SFRI recruitment 2018 notification has been released on official website www.mpsfri.org for the recruitment of 04 (four) vacancies for Scientist (SB). Job seekers should apply on or before 28th February 2018.
Here on this page you will get the details like the Name of vacancies released by SFRI with exact number of posts. Some other criteria like Education details, application fee and way to apply application for SFRI recruitment 2018.
Educational Qualification: Master Degree in Forestry / Wildlife Science / Life Science / Environmental Science / Remote Sensing & GIS / Geo-Informatics with 60% marks from recognized University with 05 years experience in the field of Remote Sensing and GIS.
Age Limit: The age of candidate should be between 21 to 35 years as on 01.01.2018.
Fee charges: Applicants who wanted to participate for SFRI should pay the below charges through Demand Draft in favour of Director, State Forest Research Institute, payable at Jabalpur.
Interested and eligible aspirants should apply in prescribed application form along with copies of all necessary documents & self-attested passport size photograph send to The Director, State Forest Research Institute, Polipathar, Jabalpur – 482008 (Madhya Pradesh) on or before 28.01.2018.


text:
[Return to Query]
Prizes for A Born-Digital Documentary Edition of the Letters of Dolley Payne Todd Madison
RQ-260886-18
A Born-Digital Documentary Edition of the Letters of Dolley Payne Todd Madison
Holly Shulman, Rector and Visitors of the University of Virginia
Grant details: https://securegrants.neh.gov/publicquery/main.aspx?f=1&gn=RQ-260886-18
Prizes for The Dolley Madison Digital Edition (Web Resource)
Lyman H. Butterfield Award [link]
Date: 6/25/2020 12:00:00 AM
Organization: The Association for Documentary Editing (ADE) [link]
Abstract: Since 1985, the Lyman H. Butterfield Award has been presented annually to an individual, project, or institution for recent contributions in the areas of documentary publication, teaching, and service. The award is granted in memoriam of Lyman Henry Butterfield, whose editing career included contributions to The Papers of Thomas Jefferson, the editing of the Adams Family Papers, and publishing The Letters of Benjamin Rush.
Permalink: https://securegrants.neh.gov/publicquery/prizes.aspx?id=17280


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Home / Fraud Protection
Identity Theft and Social Media: How Are They Related?
Fraud Protection August 5, 2016
By Erin O'Loughlin 3 min read
Social media: two words that have become synonymous with how we connect ourselves to our fellow humans in the 21st century.
Relationships can be formed and broken all inside a virtual world. We post pictures of our children, food, likes and dislikes for the world to see. While this technical revolution of the past decade can be viewed as exciting and innovative, it also leaves us vulnerable, particularly to identity theft.
What Is Identity Theft?
According to the FBI's Internet Crime Complaint Center (IC3), identity theft "occurs when someone appropriates another's personal information without their knowledge to commit theft or fraud."
The Federal Trade Commission (FTC) reported that debt collection, identity theft and impostor scams were the most common categories of consumer complaints received by the agency's Consumer Sentinel Network in 2015. Identity theft complaints were the second most reported, increasing more than 47 percent from 2014, in part due to tax identity theft. Per the FTC, impostor scams — in which criminals impersonate someone else to commit fraud — remained the third most common complaint in 2015.
A Tale as Old as Time
Identity theft is not new. It is a tale as old as time, from biblical stories of one brother posing as another to receive their dying father's inheritance to fraudsters who pose as someone else to gain trust and disclose personally identifiable information.
In the fall of 1998, Congress passed the Identity Theft and Assumption Deterrence Act. This legislation created a new offense for identity theft, which prohibits "transfers or uses, without lawful authority, [of] a means of identification of another person with the intent to commit, or to aid or abet, any unlawful activity that constitutes a violation of federal law or that constitutes a felony under any applicable state or local law."
The Identity Theft Resource Center, a San Diego-based nonprofit organization founded to provide victim assistance and consumer education, reported that the use of some social media sites can leave you vulnerable to identity theft if not used properly.
Social media sites function on the personal information users provide. This can expose the consumer to fraud and abuse. If your mobile banking app is on your phone, for instance, cybercriminals can access your online banking information through an app that is unrelated to your online banking.
What you post online for friends, family and the internet to see can also leave you vulnerable. For instance, when you post that you are going on vacation, you alert potential burglars that you are away.
Accepting "connections" or "friendships" with people you are not somehow familiar with in your everyday life can put you at risk. Cybercriminals can guess your passwords simply by the items you post online, such as your pets' names, children's names or details regarding your former schools or current city.
A Playground for Cybercriminals
The unregulated nature of social media platforms provides cybercriminals and fraudsters a veritable playground of criminal activity to choose from.
If you accept an invitation from unfamiliar people and they send you an email with a link in the text, this may be an attempt to place malicious malware on your computer. This would allow attackers to extract your personal information, particularly online banking information.
Not only can fraudsters take over bank accounts via online messaging, but consumers should be wary of impostors creating fake accounts in their name and posting messages under their ID. Celebrities are especially vulnerable to this trend.
Back in 2011, for example, former governor of Alaska Sarah Palin's official Twitter account was breached and exposed to fraud. In one incident, a fraudster tweeted an open invite to Palin's family home for a barbecue. Palin's security staff had to be dispatched to her Alaska residence. Many public figures have fallen victim to this method of identity theft.
Below are some tips to protect your identity in the age of social media:
Create strong, multicharacter passwords for your email and all apps on your phone, and remember to change them often.
When utilizing apps, enter as little personal information as possible.
Be cautious about what you post online. Never use personal information such as your Social Security number, current address or telephone number.
Make sure your privacy settings are set to the highest level. Check these settings often since they may be affected by upgrades.
Avoid downloading free applications for use on your social media profiles.
Avoid accepting connections or friendships with people you are not familiar with.
Verify any link sent to you was sent from your connection or friend.
Google your own name, as well as any social media handles you utilize, to track any possible forged accounts.
Identity | Identity Theft | Password | Password Management | Red Cell | Risk Management | Social Engineering | Social Media | Social Media Security
Financial Crimes Intelligence SME, IBM
Erin O'Loughlin joined IBM in May 2016 as a Financial Crimes Intelligence Subject Matter Expert Consultant within Red Cell team. Prior to joining IBM she ser...
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The Evolution of Kronos Malware The Kronos malware is believed to have originated from the leaked source code of the Zeus malware, which was sold on the Russian underground in 2011. Kronos continued to evolve and a new variant of Kronos emerged in 2014 and was reportedly sold on the darknet for approximately $7,000. Kronos is typically used to download other malware and has historically been used by threat actors to deliver different types of malware to victims. After remaining…
Fraud Protection January 12, 2023
How Security Teams Combat Disinformation and Misinformation
"A lie can travel halfway around the world while the truth is still putting on its shoes." That popular quote is often attributed to Mark Twain. But since we're talking about misinformation and disinformation, you'll be unsurprised to learn Twain never said that at all. In fact, no one knows who first strung those words together, but the idea that truth spreads slowly while lies spread quickly is at least several hundred years old. The "Twain" quote also serves to…
Mobile Security January 10, 2023
A View Into Web(View) Attacks in Android
James Kilner contributed to the technical editing of this blog. Nethanella Messer, Segev Fogel, Or Ben Nun and Liran Tiebloom contributed to the blog. Although in the PC realm it is common to see financial malware used in web attacks to commit fraud, in Android-based financial malware this is a new trend. Traditionally, financial malware in Android uses overlay techniques to steal victims' credentials. In 2022, IBM Security Trusteer researchers discovered a new trend in financial mobile malware that targets…
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New DOJ Team Focuses on Ransomware and Cryptocurrency Crime
While no security officer would rely on this alone, it's good to know the U.S. Department of Justice is increasing efforts to fight cyber crime. According to a recent address in Munich by Deputy Attorney General Lisa Monaco, new efforts will focus on ransomware and cryptocurrency incidents. This makes sense since the X-Force Threat Intelligence Index 2022 named ransomware as the top attack type in 2021. What exactly is the DOJ doing to improve policing of cryptocurrency and other cyber…


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Home > FACULTY_SCHOLARSHIP > 2142
Faculty Scholarship at Penn Law
The Expansive Reach of Pretrial Detention
Paul Heaton, University of Pennsylvania Carey Law SchoolFollow
Today we know much more about the effects of pretrial detention than we did even five years ago. Multiple empirical studies have emerged that shed new light on the far-reaching impacts of bail decisions made at the earliest stages of the criminal adjudication process. The takeaway from this new generation of studies is that pretrial detention has substantial downstream effects on both the operation of the criminal justice system and on defendants themselves, causally increasing the likelihood of a conviction, the severity of the sentence, and, in some jurisdictions, defendants' likelihood of future contact with the criminal justice system. Detention also reduces future employment and access to social safety nets. This growing evidence of pretrial detention's high costs should give impetus to reform efforts that increase due process protections to ensure detention is limited to only those situations where it is truly necessary and identify alternatives to detention that can better promote court appearance and public safety.
Publication Citation
98 N.C. L. Rev. 369 (2020)
Heaton, Paul, "The Expansive Reach of Pretrial Detention" (2020). Faculty Scholarship at Penn Law. 2142.
https://scholarship.law.upenn.edu/faculty_scholarship/2142
Civil Rights and Discrimination Commons, Constitutional Law Commons, Criminal Procedure Commons, Criminology and Criminal Justice Commons, Law and Economics Commons, Policy Design, Analysis, and Evaluation Commons, Public Economics Commons
Penn Law Authors


Terry and I got our Hemet library cards recently. Terry immediately checked to see how long the waiting list was for the latest Outlander DVD. As soon as we got home I checked out the online resources.
Not the same as the Santa Clara County Library system. No Encyclopedia Britannica. No Oxford English dictionary. But then our single-city local library doesn't have the resources of a library system that serves eight cities.
The e-book selection is somewhat limited, but the library does offer Zinio digital magazines. That means I can read the New Yorker, Columbia Journalism Review, and many other magazine without paying for a subscription. And the service integrates with my existing Zinio account.
Would it be tacky to continue to use your SCL account for online stuff? Maybe send them a donation every once in a while?
I just went to the SCCL Web site and saw this: "Starting July 1 2015, Santa Clara County Library District is offering free cards to everyone regardless of where they reside." How Very Cool is that?


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Silverman: A Hanukkah for all Americans
By Eric Silverman/Guest Columnist
This week begins the quintessential Jewish-American holiday, once barely noticed on the annual religious calendar, now the Super Bowl of our public presence: Hanukkah. It is an ancient holiday that speaks to current dilemmas of American identity.
Most people know little about the events Hanukkah memorializes. Even many Jews can hardly do better than "they tried to destroy us, we won, let's eat" - on this occasion, latkes and jelly donuts, accompanied by candle lighting, swapping gifts, perhaps a few silly songs.
The story is largely known from two ancient texts, 1 and 2 Maccabees, that were never included in the Jewish bible or Old Testament. In the second century B.C.E., the Seleucid Greeks ruled the eastern Mediterranean. They imposed, as colonizers are wont to do, their view of civilization on the local folks. Some Jews embraced Hellenistic culture as modern. Yet traditionalists revolted under the fabled leadership of Judah Maccabee and his band of brothers. They won, and thus lived to write the history every Jewish kid who sat through Hebrew School knows: brutal ethnic cleansing by the Greeks followed by the miracle of Jewish victory. The menorah is lit to recall the wonder of one day's oil burning in the Temple candelabra for eight days.
Less well known is that the Maccabeans also took up arms against their fellow Jews or, as they saw them, reforming apostates. Are the Maccabeans brave liberators who defended the faith and lit a beacon of religious freedom? Or an ancient Taliban, ruthlessly conservative, snuffing out any who refused obedience? Probably a bit of both. That there is no singular way to define the moral message of the holiday is precisely why it speaks to our current uncertainties about what it means to be an American, unique yet one of the crowd.
Hanukkah attained its status as a major holiday in fin de siècle America, when Jewish immigrants became captivated by the celebration of Christmas, a holiday that gained its own stature and fanfare at the same time with the rise of consumerism. In fact, many Jewish immigrants did not at first realize that Christmas was Christian. To them, it seemed a grand American fete. In 1897, Ridley's department store in New York City, then the world's largest shopping emporium, ran a Yiddish advertisement in the Yiddishes Tageblatt newspaper announcing, "Chanukah gifts with Christmas presents go hand in hand. There is only a difference in name." Acculturated Jews eagerly took up Hanukkah as a holiday that celebrated their new-found hybrid identity as Jewish Americans, neither the one, nor the other, but both together in an irresolvable dialogue.
Over the 20th century, Hanukkah often morphed into a Jewish Christmas. Just now I searched for "Chanukah" - there is no official spelling - on the Wal-Mart website. I got more than 16,000 items. You read that correctly. One can purchase toy sets, glitter stickers, ugly sweaters, LED menorahs, glass ball ornaments, garlands, sno-globes, coloring books, socks, hats, cookies, wrapping paper, and more, including a library of children's books - who knew that Clifford the Big Red Dog and Curious George were Jewish? There are even Hanukkah Mad Libs. And you've still got more than 14,000 items to go.
Today, Americans celebrate ethnic uniqueness by hyphenating identities with romantic attachments to homelands, stories of unsung heroes and heroines, and affirmations that "our" - Asian, black, Irish, Armenian, Deaf, indigenous, Arab, Jewish, and more - heritage matters. At the same time, we all aspire to legal and social equality - to celebrating our full seat at the table of American citizenship. We are different. Yet we are not. You've got your greeting cards; I've got mine. One kid glances at an Elf on a Shelf; another at the Mentsh on a Bench. That tension gives rise to much of the vibrancy of the country.
In the current political climate, American Jews occupy a precarious position, vilified from both the right and the left as Shylocks and outsiders, villains and puppet-masters. The canards are old and tiresome. Thus phrased, Hanukkah is an act of decolonization, a celebration of diversity by simply showing that we are still here.
Hanukkah says something of value to all Americans if we view the holiday as one episode in an age-old conversation among a particular people over how to define our collective identity. Thus phrased, Hanukkah speaks to every ethnic group that struggles, as they all do, with the "push-me-pull-you" of multiculturalism: how to balance the opposing forces of generic citizenship and ethnic particularism or, as the national motto goes, the "pluribus" with the "unim."
Eric Silverman is a Framingham resident, a Scholar at the Women's Studies Research Center at Brandeis University, and author of "A Cultural History of Jewish Dress."


e. can really hurt a golf cours Insects much as a lack of funds. But not as C Japanese Beetle Grub SAA chapters te for Golf is helping GC The Environmental Institu All you rch, and you can help. funds for turfgrass resea raise ons. The funds round to our online aucti have to do is donate a ss, scholarships omic studies, awarene raised will go to agron grams. and other education pro esearch.com. ds4r Donate today. Visit roun Presented in partnership with The Toro Company.


Today Monica and Sebastian and I rode at the base of the very active Arenal volcano. We rode through rolling farmland dotted with cattle, who would feel the heat if Arenal were to have a major eruption. The area is pretty developed as a tourist attraction with hot springs, which we would visit, hotels, shops and even a Burger King. We stuck to the natural side of visiting the volcano, but riding around its base and then hitting the hot springs.
To ride here, is to ride among lava rocks, listen to the rumblings of the Volcano, see the smoke billowing from the top of the cone and see the lava billowing down its side, especially at night. Arenal can throw rocks the size of cars and its flow has been known to change direction.
We also visited nearby hot springs, but non-touristy ones. The heat of the springs is determined by how active the volcano is that day. On our day, the volcano apparently wasn't really, really active, though it was a sight to see, and the hot springs were still nice and toasty. As I sipped on a pina colada, I headed to the hottest spring for a dip. I was ready to relax after a long trip of riding great horses in beautiful Costa Rica.


text:
September 12, 2017; 89 (11) ArticleOpen Access
Alemtuzumab CARE-MS I 5-year follow-up
Durable efficacy in the absence of continuous MS therapy
Eva Havrdova, Douglas L. Arnold, Jeffrey A. Cohen, Hans-Peter Hartung, Edward J. Fox, Gavin Giovannoni, Sven Schippling, Krzysztof W. Selmaj, Anthony Traboulsee, D. Alastair S. Compston, David H. Margolin, Karthinathan Thangavelu, Claudio E. Rodriguez, Darlene Jody, Richard J. Hogan, Panos Xenopoulos, Michael A. Panzara, Alasdair J. Coles; On behalf of CARE-MS I and CAMMS03409 Investigators
First published August 23, 2017, DOI: https://doi.org/10.1212/WNL.0000000000004313
Eva Havrdova
From the Department of Neurology and Center for Clinical Neuroscience (E.H.), First Faculty of Medicine, Charles University and General University Hospital in Prague, Czech Republic; NeuroRx Research (D.L.A.), Montréal; Department of Neurology and Neurosurgery (D.L.A.), Montréal Neurological Institute, McGill University, Québec, Canada; Mellen Center (J.A.C.), Cleveland Clinic, OH; Department of Neurology and Center for Neuropsychiatry (H.-P.H.), Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany; MS Clinic of Central Texas (E.J.F.), Central Texas Neurology Consultants, Round Rock; Queen Mary University of London (G.G.), Barts and The London School of Medicine, UK; Neuroimmunology and Multiple Sclerosis Research (S.S.), Department of Neurology, University Hospital Zürich and University of Zürich, Switzerland; Department of Neurology (K.W.S.), Medical University of Łódź, Poland; The University of British Columbia (A.T.), Vancouver, Canada; Department of Clinical Neurosciences (D.A.S.C., A.J.C.), University of Cambridge, UK; Sanofi (D.H.M., K.T., C.E.R., D.J., M.A.P.), Cambridge, MA; Evidence Scientific Solutions (R.J.H.), Sydney, NSW, Australia; and Evidence Scientific Solutions (P.X.), Philadelphia, PA. M.A.P. is currently affiliated with Wave Life Sciences, Cambridge, MA.
Douglas L. Arnold
Jeffrey A. Cohen
Hans-Peter Hartung
Edward J. Fox
Gavin Giovannoni
Sven Schippling
Krzysztof W. Selmaj
Anthony Traboulsee
D. Alastair S. Compston
David H. Margolin
Karthinathan Thangavelu
Claudio E. Rodriguez
Darlene Jody
Richard J. Hogan
Panos Xenopoulos
Michael A. Panzara
Alasdair J. Coles
Eva Havrdova, Douglas L. Arnold, Jeffrey A. Cohen, Hans-Peter Hartung, Edward J. Fox, Gavin Giovannoni, Sven Schippling, Krzysztof W. Selmaj, Anthony Traboulsee, D. Alastair S. Compston, David H. Margolin, Karthinathan Thangavelu, Claudio E. Rodriguez, Darlene Jody, Richard J. Hogan, Panos Xenopoulos, Michael A. Panzara, Alasdair J. Coles
Neurology Sep 2017, 89 (11) 1107-1116; DOI: 10.1212/WNL.0000000000004313
This article has a correction. Please see:
Alemtuzumab CARE-MS I 5-year follow-up: Durable efficacy in the absence of continuous MS therapy - April 17, 2018
Objective: To evaluate 5-year efficacy and safety of alemtuzumab in treatment-naive patients with active relapsing-remitting MS (RRMS) (CARE-MS I; NCT00530348).
Methods: Alemtuzumab-treated patients received treatment courses at baseline and 12 months later; after the core study, they could enter an extension (NCT00930553) with as-needed alemtuzumab retreatment for relapse or MRI activity. Assessments included annualized relapse rate (ARR), 6-month confirmed disability worsening (CDW; ≥1-point Expanded Disability Status Scale [EDSS] score increase [≥1.5 if baseline EDSS = 0]), 6-month confirmed disability improvement (CDI; ≥1-point EDSS decrease [baseline score ≥2.0]), no evidence of disease activity (NEDA), brain volume loss (BVL), and adverse events (AEs).
Results: Most alemtuzumab-treated patients (95.1%) completing CARE-MS I enrolled in the extension; 68.5% received no additional alemtuzumab treatment. ARR remained low in years 3, 4, and 5 (0.19, 0.14, and 0.15). Over years 0–5, 79.7% were free of 6-month CDW; 33.4% achieved 6-month CDI. Most patients (61.7%, 60.2%, and 62.4%) had NEDA in years 3, 4, and 5. Median yearly BVL improved over years 2–4, remaining low in year 5 (years 1–5: −0.59%, −0.25%, −0.19%, −0.15%, and −0.20%). Exposure-adjusted incidence rates of most AEs declined in the extension relative to the core study. Thyroid disorder incidences peaked at year 3 and subsequently declined.
Conclusions: Based on these data, alemtuzumab provides durable efficacy through 5 years in the absence of continuous treatment, with most patients not receiving additional courses.
ClinicalTrials.gov identifier: NCT00530348; NCT00930553.
Classification of evidence: This study provides Class III evidence that alemtuzumab durably improves efficacy outcomes and slows BVL in patients with RRMS.
AE=
adverse event;
ARR=
annualized relapse rate;
BPF=
brain parenchymal fraction;
BVL=
brain volume loss;
CDI=
confirmed disability improvement;
CDW=
confirmed disability worsening;
DMT=
disease-modifying therapy;
EAIR=
exposure-adjusted incidence rate;
EDSS=
Expanded Disability Status Scale;
IAR=
infusion-associated reaction;
ITP=
immune thrombocytopenia;
NEDA=
no evidence of disease activity;
RRMS=
relapsing-remitting MS;
SC IFN-β-1a=
subcutaneous interferon β-1a
Alemtuzumab (LEMTRADA; Sanofi Genzyme, Cambridge, MA) is a humanized monoclonal antibody that selectively targets CD52, an antigen highly expressed on T and B lymphocytes.1 Binding of alemtuzumab to CD52 results in depletion of circulating T and B cells,2,3 following which a distinct pattern of T- and B-cell repopulation and a shift in cytokines toward a less inflammatory pattern occur. Both mechanisms may be relevant to the durable efficacy of this drug.4
Compared with the active treatment subcutaneous interferon β-1a (SC IFN-β-1a; Rebif; EMD Serono Inc., Rockland, MA), alemtuzumab significantly reduced the annualized relapse rate (ARR) in patients with active relapsing-remitting MS (RRMS) who either were treatment-naive (phase 2 CAMMS223 study [NCT00050778]5 and phase 3 Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis [CARE-MS] I study [NCT00530348])6 or had an inadequate response (≥1 relapse) to prior therapy (phase 3 CARE-MS II study [NCT00548405]).7 In CAMMS223 and CARE-MS II, alemtuzumab also increased proportions of patients who were free of 6-month confirmed disability worsening (CDW).5,7 Alemtuzumab increased proportions with no evidence of disease activity (NEDA) in the 2-year phase 3 CARE-MS studies6,7 and reduced brain volume loss (BVL) in all 3 clinical trials, compared with SC IFN-β-1a.5,–,7 The most common adverse events (AEs) with alemtuzumab were infusion-associated reactions (IARs); autoimmune AEs were also associated with treatment.5,–,7 Based on the positive benefit-risk profile demonstrated in these trials, alemtuzumab is currently licensed in over 60 countries worldwide for treatment of adults with RRMS8,9 and is the only approved treatment that does not require continuous dosing to provide durable efficacy in patients with this disease.
We report interim results through 3 years of an extension study (NCT00930553) in patients who received alemtuzumab during the core CARE-MS I trial, constituting a total of 5 years of follow-up from CARE-MS I enrollment.
Patients and procedures for CARE-MS I core study.
The study design for the 2-year CARE-MS I core study has been published previously.6 Briefly, CARE-MS I was a randomized, rater-blinded, active-controlled, head-to-head trial of alemtuzumab compared with SC IFN-β-1a in patients who were treatment-naive and had active RRMS (≥2 relapses in the previous 2 years and ≥1 relapse in the prior year).
Procedures for the extension study.
This analysis reports findings from alemtuzumab-treated patients who completed CARE-MS I and continued into the extension, in which they could receive additional alemtuzumab courses (each 12 mg/d IV on 3 consecutive days) upon evidence of MS disease activity (and ≥48 weeks since the prior course). Eligibility criteria for retreatment were ≥1 protocol-defined relapse or ≥2 new/enlarging T2 hyperintense and/or gadolinium (Gd)-enhancing brain or spinal cord lesions on MRI. Retreatment-disqualifying criteria included, but were not limited to, pregnancy, diagnosis of immune thrombocytopenia (ITP) or other immune cytopenia, and history of malignancy (except basal cell carcinoma) or antiglomerular basement membrane disease. The decision on whether to initiate retreatment in eligible patients was left to the treating physician and patient, as was the decision to provide another licensed disease-modifying therapy (DMT).
Efficacy assessments and endpoints.
Relapse events required objective signs on examination, lasting ≥48 hours, and were confirmed by the investigator. The Expanded Disability Status Scale (EDSS) was assessed quarterly and for evaluation of suspected relapses by raters blinded to previous treatment assignment and treatment history throughout the extension. Annual MRI scans were assessed by blinded imaging specialists at NeuroRx Research (Montréal, Canada; for lesion-based analyses) and the Cleveland Clinic MS MRI Analysis Center (Cleveland, OH; for brain parenchymal fraction [BPF] analysis).
Clinical efficacy endpoints evaluated over years 0–5 included the following: ARR; proportion of relapse-free patients; 6-month CDW (≥1.0-point EDSS score increase from core study baseline [≥1.5 if baseline EDSS score = 0]; formerly termed sustained accumulation of disability10); mean change from baseline EDSS score; proportions of patients with EDSS scores that were improved (≥1.0-point decrease), worsened (≥1.0-point increase), or stable (≤0.5-point change) compared with baseline; and 3-, 6-, or 12-month confirmed disability improvement (CDI; ≥1.0-point decrease from core study baseline EDSS score, in patients with baseline EDSS scores ≥2.0).
MRI lesion outcomes examined over years 0–5 included proportions of patients with Gd-enhancing, new/enlarging T2 hyperintense, and new nonenhancing T1 hypointense lesions. Median percentage BVL from baseline and per year was calculated.
NEDA was evaluated annually and cumulatively (sustained NEDA over years 3–5). NEDA was defined as no evidence of clinical disease activity (absence of both relapses and 6-month CDW) and no evidence of MRI lesion activity (absence of both new Gd-enhancing and new/enlarging T2 hyperintense lesions).
Safety monitoring.
Safety was evaluated by review of AEs, serious AEs, medical events of interest, and laboratory tests (including thyroid function [at least quarterly], hematology [at least monthly], serum creatinine [monthly], and urinalysis with microscopy [monthly]). All safety monitoring procedures continued for 4 years after last alemtuzumab administration, or until study end, whichever occurred later. IARs were defined as any AE with onset during infusion or ≤24 hours after the end of infusion.
Classification of evidence.
This analysis evaluates the long-term efficacy and safety of alemtuzumab and provides Class III evidence that alemtuzumab improves ARR, MRI lesion outcomes, and BVL over 5 years in treatment-naive patients with active RRMS and that high proportions of patients achieve NEDA. These effects were observed in the absence of continuous treatment and with most (68.5%) patients receiving no alemtuzumab retreatment through 5 years.
Statistical analysis.
Analyses were based on available data (without imputation) on all alemtuzumab 12 mg patients with up to 5 years of follow-up from first dose in CARE-MS I, with an interim cutoff date of October 4, 2014, in the extension.
ARR was estimated using negative binomial regression with robust variance estimation and covariate adjustment for the geographic region. Proportions of patients with 6-month CDW or 3-, 6-, or 12-month CDI were estimated with the Kaplan-Meier method. Percentage of patients with improvement, stability, or worsening from the baseline EDSS score was reported.
Safety data were reported as incidences (percentage of patients with ≥1 event) and exposure-adjusted incidence rates (EAIRs) per 100 patient-years ([number of patients with specific event divided by total annual exposure-time among patients at risk of initial occurrence of the event] × 100) in the reported time cohorts.11 Autoimmune AEs were reported using time of first AE occurrence over total follow-up time (0–5 years).
Standard protocol approvals, registrations, and patient consents.
This trial is registered with ClinicalTrials.gov (NCT00530348; NCT00930553). All procedures were approved by local institutional ethics review boards of participating sites. Patients provided written informed consent.
Of the 367 alemtuzumab patients completing CARE-MS I, 349 (95.1%) entered the extension study; of these, 335 (96.0%) remained on study through Month 60 (year 5; figure 1).
Figure 1 Patient disposition
Disposition schematic includes patient participation from the core CARE-MS I study through the long-term extension study. DMTs include fingolimod (n = 1), glatiramer acetate (n = 2), interferon β-1a (n = 2), interferon β-1b (n = 3), and natalizumab (n = 1). *The death that occurred in the core study was deemed not related to treatment. CARE-MS = Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis; DMT = disease-modifying therapy.
In the core study, alemtuzumab patients received 12 mg on 5 consecutive days at baseline and 3 consecutive days 12 months later. In the extension study, 239 (68.5%) alemtuzumab patients received no alemtuzumab retreatment; 341 (97.7%) received no other DMT; and 235 (67.3%) received neither alemtuzumab retreatment nor other DMT. Of the 110 patients who received alemtuzumab retreatment (table e-1 at Neurology.org), 77 (70.0%), 28 (25.5%), and 5 (4.5%) received a total of 1, 2, and 3 alemtuzumab retreatment courses, respectively, over years 3–5. The most common reason given by investigators for alemtuzumab retreatment was relapse (51.0% of retreatment courses for which a reason was provided), followed by MRI lesion activity (25.9%), and combined relapse and MRI lesion activity (23.1%).
Efficacy.
ARR remained low during the extension, similar to that in the core study (figure 2A).6 Mean EDSS score changes from core study baseline were improvements (i.e., reductions) at year 2 (−0.16), at year 3 (−0.10), at year 4 (−0.09), and 0.00 at year 5. Compared with core study baseline, 60.0% of patients at year 5 showed stable EDSS scores; 22.2% showed improved scores (≥1-point decrease) and 17.8% showed worsened scores (≥1-point increase; figure 2B). Over 5 years, 79.7% (95% CI 75.1%–83.6%) of patients were free of 6-month CDW, and 33.4% (95% CI 27.5%–40.1%) achieved 6-month CDI (figure 2C).
Figure 2 Clinical efficacy and disease activity outcomes over 5 years in alemtuzumab patients
(A) ARR over 5 years in alemtuzumab patients. Results are shown for all patients who received alemtuzumab 12 mg in the core CARE-MS I study and then enrolled in the extension. A post hoc analysis revealed no statistically significant difference between ARRs in individual extension years (years 3, 4, and 5) and the ARR in years 0–2. (B) EDSS score change in alemtuzumab patients over 5 years. Proportion of patients with improved (≥1.0-point decrease), stable (≤0.5-point change), or worsened (≥1.0-point increase) EDSS scores at year 5 compared with core study baseline. EDSS score changes are shown for all patients who received alemtuzumab 12 mg in the core study and enrolled in the extension. (C) Proportion of alemtuzumab patients with 3-, 6-, or 12-month CDI over 5 years. Kaplan-Meier analysis of time to 3-, 6-, or 12-month CDI is shown for all patients who received alemtuzumab 12 mg in the core CARE-MS I study and then enrolled in the extension. (D) Proportion of alemtuzumab patients with NEDA over 5 years. Results are shown for all patients who received alemtuzumab 12 mg in the core CARE-MS I study and then enrolled in the extension. *Baseline percentage of patients Gd-enhancing lesion-free: 54%. ARR = annualized relapse rate; CARE-MS = Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis; CDI = confirmed disability improvement; CDW = confirmed disability worsening; EDSS = Expanded Disability Status Scale; Gd = gadolinium; NEDA = no evidence of disease activity.
Most alemtuzumab-treated patients were free of clinical disease activity or MRI lesion activity during each extension year and most also attained NEDA (figure 2D). Cumulatively over years 3–5, most patients showed no clinical (65.3%) or MRI lesion (53.8%) activity, and 39.5% attained sustained NEDA. During each extension year, most patients were free of new T1 hypointense lesions (year 3, 89.2%; year 4, 85.4%; year 5, 85.4%).
The rate of yearly BVL continued to decrease after the core study and seemed to stabilize in years 3, 4, and 5 (figure 3). Median cumulative BPF change from baseline to year 5 was –1.352%.
Figure 3 Brain volume loss over 5 years in alemtuzumab patients
Median yearly percentage change in BPF is shown for all patients who received alemtuzumab 12 mg in the core CARE-MS I study and then enrolled in the extension. BPF = brain parenchymal fraction; CARE-MS = Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis.
Further analyses evaluated outcomes among the 175 patients who achieved NEDA in year 2 and received no alemtuzumab retreatment after the initial 2 courses and no other DMT (figure e-1A). Most patients achieved NEDA in each year of the extension and 60.8% attained NEDA through years 2–5, reflecting high proportions of relapse-free, 6-month CDW-free and new Gd-enhancing and T2 hyperintense lesion-free patients (figure e-1B); this cohort with sustained NEDA demonstrated slowing of median annual BVL (figure e-2).
Safety.
AEs occurring in alemtuzumab-treated patients throughout the core and extension studies (up to the cutoff date; 1767.7 patient-years over 5-year follow-up) are summarized in tables 1 and 2 and table e-2. The EAIR for overall AEs was lower in the extension (years 3–5, 133.6) than in the core study (years 0–2, 705.2). Serious AE incidence remained low over 5 years. Most AEs (96.9%) in years 3–5 were mild to moderate in severity. No AEs led to study withdrawal in the extension. One death, reported previously, occurred during the extension (in year 3), due to sepsis that developed in the setting of pancytopenia and was judged by the investigator to be treatment-related.6
AEs through year 5 of the extension in patients treated with alemtuzumab 12 mg
IAR events through year 5 in patients treated with alemtuzumab 12 mg
IAR incidences in patients receiving alemtuzumab retreatment in the extension were lower than in the core study (table 2). No serious IARs occurred during the extension (courses 3, 4, or 5). Similar to the core study,6 the most frequently reported IARs with alemtuzumab retreatment in the extension were headache, pyrexia, and rash. When IARs were removed from the count of any AEs overall, the EAIR remained lower in the extension (129.2) compared with that in the core study (174.8).
Overall incidences and EAIRs of infections over years 3–5 were lower than during the core study (table 1 and table e-2); 99.2% were mild to moderate in severity. Infection incidence did not increase with successive alemtuzumab courses (table e-3). As in the core study, the most common infection events in the extension were nasopharyngitis, urinary tract infection, upper respiratory tract infection, and herpetic infections (predominantly mucocutaneous). The incidence of serious infections remained low; the most frequent was herpes zoster, with a total of 5 cases occurring over years 0–5 (4 were during the extension).
The most common autoimmune AEs occurring during the extension were thyroid AEs, which peaked in year 3 and subsequently declined in years 4 and 5 (years 1–5 incidences: 6.4%, 9.6%, 15.3%, 7.6%, and 3.5%; incidence over 5 years was 40.7%). Of the thyroid AEs reported in years 3–5, 62.1% were moderate and 27.1% were mild in severity. Similar incidences were observed over time for the broader category of thyroid disorders (table 1 and table e-2), which include abnormal thyroid function tests (thyroid-stimulating hormone, free triiodothyronine [T3], free thyroxine [T4]) in addition to investigator-reported thyroid AEs; incidence over 5 years was 45.5%. Few serious thyroid AEs were reported. As in the core study, the most frequently reported thyroid disorders in the extension were laboratory abnormalities, and clinical hyperthyroidism and hypothyroidism. Thirteen thyroidectomies were reported over years 0–5; most patients undergoing thyroidectomies were subsequently maintained on thyroxine.
One new case of ITP was reported during the extension (year 4). The patient had a postalemtuzumab history of autoimmune hemolytic anemia that had resolved with treatment 2 years before ITP onset. At last follow-up, the patient was receiving oral prednisone for ITP, which was considered resolved several months after the initial event.
There was a single case of nephropathy reported in year 3 (4 months after the third alemtuzumab course). The patient presented with hematuria and proteinuria. Serum creatinine levels remained normal, but there was weak seropositivity for antiglomerular basement membrane autoantibodies. A renal biopsy revealed focal global glomerulosclerosis and changes indicative of membranous nephropathy, but no evidence of antiglomerular basement membrane disease. By 39 months after the initial event, following treatment with plasmapheresis, glucocorticosteroids, and cyclophosphamide, serum creatinine levels remained normal, proteinuria was absent, and the patient did not develop kidney failure.
Over 5 years, a total of 6 malignancies were reported in alemtuzumab-treated patients (EAIR of 0.3 per 100 patient-years). Two malignancies occurred in the core study (both papillary thyroid carcinomas), and 4 malignancies were reported in years 3–5 (n = 1 each for breast cancer, keratoacanthoma, non–small-cell lung cancer, and micropapillary thyroid carcinoma).
Damage to neurons and axons starts in the earliest stages of MS and is clinically relevant, as it may foreshadow evolution of neurologic disability.12,13 CNS tissue destruction can be quantified by MRI as cerebral atrophy, which is accelerated in patients with MS compared with healthy individuals.14 Thus, to prevent accumulation of permanent neurologic damage, early intervention in MS is important and warranted.15 However, experts have not reached consensus regarding what constitutes appropriate early-stage treatment for patients with adverse prognostic factors (e.g., an early disease course that includes frequent relapses, MRI lesion volume change, or brain atrophy).16,–,18 Some physicians may initially prescribe a low- to moderate-efficacy therapy and may switch to high-efficacy therapy upon evidence of an inadequate response (e.g., disease activity while on therapy), whereas others favor an individualized approach involving higher-efficacy agents from the outset.19 CARE-MS I compared these approaches in patients with active RRMS and found greater improvements in relapse and MRI outcomes, as well as higher attainment of NEDA, in patients who received alemtuzumab compared with SC IFN-β-1a.6
We show that these findings were extended in the CARE-MS I alemtuzumab treatment arm, with durable improvements in key efficacy outcomes over 5 years, including low ARR and most patients having stable/improved EDSS scores and freedom from 6-month CDW. Additionally, more than one-third achieved 6-month CDI. This endpoint captures durable and clinically meaningful EDSS score changes in individual patients with preexisting neurologic impairments; improving disability in those patients may lead to better long-term prognosis.20 Our study reports durable improvement in disability by using this stringent outcome measure over several years in a large MS patient cohort. Additionally, during each of years 3, 4, and 5, a consistent proportion of about 60% of patients achieved NEDA; when the rigorous goal of sustained NEDA was assessed cumulatively over years 3–5, 40% of patients satisfied this endpoint. These effects were observed in the absence of continuous treatment and despite no retreatment in the majority of patients. Similar durable efficacy improvements were also shown for patients with active RRMS who had an inadequate response to prior therapy.21
Previous studies have shown the predictive value of brain atrophy on disability outcomes in the early years after MS diagnosis.18 Treatment effects on brain atrophy and lesion activity correlate with treatment effects on disability and cognitive dysfunction for some therapies.14,18,22,–,24 No current therapies are known to reverse CNS damage. Alemtuzumab slowed the annual rate of BVL over years 3–5. Moreover, alemtuzumab-treated patients showed less cumulative atrophy after 5 years (reported in this study) compared with that observed in patients who had received SC IFN-β-1a in the core study and then switched to alemtuzumab in the extension (median BPF changes of −1.352% vs −1.646%, respectively; p = 0.0086),25 illustrating the long-term benefits of early treatment with alemtuzumab.
Durable efficacy with alemtuzumab over the 3-year extension follow-up was accompanied by a safety profile consistent with that observed in the core study. Overall AEs, including IARs and infections, decreased over time relative to the core study, with a low but persistent risk of herpes zoster reactivation. Autoimmune thyroid AEs peaked at year 3 and declined thereafter. The rate of malignancies did not increase from the core study through the extension. Two cases of papillary thyroid carcinomas were seen in the core study; only 1 new micropapillary thyroid carcinoma event was reported over the next 3 years. The apparent rate of thyroid malignancies observed with alemtuzumab in the MS clinical trial program may have been inflated by ascertainment bias owing to a more frequent occurrence of nonmalignant thyroid disorders and their diagnostic workup26 with alemtuzumab than with SC IFN-β-1a. These observations relating to safety with alemtuzumab are in contrast to AE rates that have been observed with long-term use of chronically dosed DMTs, in which the known risks associated with a particular agent may increase or remain constant with continued exposure to drug.27,–,29 With alemtuzumab, because of its unique dosing schedule and lack of continuous treatment, most risks decrease over time. Procedures for regular monitoring and management help to maximize the risk-benefit profile.
As is often cited as a limitation of extension studies, the active comparator design of the pivotal CARE-MS trials6,7 was not continued in the extension period, thus precluding long-term direct comparison with another treatment. Nonetheless, these 5-year data from patients who were treatment-naive and had a mean disease duration of 2 years upon entry into CARE-MS I demonstrate durable, long-term therapeutic effects on clinical disease activity measures, as well as on more objective measures such as MRI lesion activity and brain atrophy. The robustness of our results is supported by the high patient enrollment rate coupled with the unusually high retention rate (>95% through year 5). Notably, the latter suggests that the favorable outcomes in our study cannot reflect selective dropout of poor responders. The continued use of blinded raters also helped ensure unbiased efficacy analyses.
The sustained responses to alemtuzumab observed over 5 years in our study highlight the value of a durable, high-efficacy therapy in the absence of continuous treatment in patients who may be at high risk of MS-related disability worsening and BVL. Risks associated with the therapy are anticipated in advance of treatment, and monitoring procedures for minimizing adverse effects are implemented to maintain a positive risk-benefit profile.
E.H., J.A.C., H.-P.H., E.J.F., G.G., S.S., K.W.S., A.T., D.A.S.C., and A.J.C. contributed to study design, data collection, writing and critical review of the manuscript, and approved the final submission draft. D.L.A. contributed to data collection, writing and critical review of the manuscript, and approved the final submission draft. D.H.M. and M.A.P. contributed to study design, writing and critical review of the manuscript, and approved the final submission draft. C.E.R and D.J. contributed to writing and critical review of the manuscript, and approved the final submission draft. K.T. led statistical support and also contributed to the writing and critical review of the manuscript, and approved the final submission draft. R.J.H. and P.X. provided editorial and medical writing support (assistance in drafting the manuscript, technical editing, copyediting, and responding to reviewers' comments), and approved the final submission draft.
Supported by Sanofi and Bayer HealthCare Pharmaceuticals.
E. Havrdova reports receiving honoraria and grant support from Actelion, Biogen, Merck Serono, Novartis, Receptos, Roche, Sanofi Genzyme, and Teva, and is supported by Ministry of Education of Czech Republic, project PRVOUK-P26/LF1/4. D.L. Arnold reports receiving compensation for serving as a speaker, consultant, and advisory board participant, and receiving research support from Acorda, Bayer, Biogen, Eli Lilly, EMD Serono, Genentech, GlaxoSmithKline, MedImmune, Merck Serono, NeuroRx Research, Novartis, Opexa Therapeutics, Receptos, Roche, Sanofi Genzyme, Teva, the Canadian Institutes of Health Research, and the Multiple Sclerosis Society of Canada. J.A. Cohen reports personal compensation for consulting for Genentech, Merck, Novartis, and Receptos and as a coeditor of Multiple Sclerosis Journal—Experimental, Translational and Clinical. H.-P. Hartung reports receiving honoraria for consulting and speaking at symposia from Bayer HealthCare, Biogen, CSL Behring, Grifols, Merck Serono, Novartis, Roche, and Sanofi Genzyme. E.J. Fox reports receiving consulting fees, honoraria, travel, and research support from Acorda, Bayer HealthCare, Biogen, EMD Serono, Genentech, Novartis, Opexa Therapeutics, Sanofi Genzyme, and Teva. G. Giovannoni reports having served as a consultant or received research support from AbbVie, Bayer HealthCare, Biogen, Canbex Therapeutics, Five Prime Therapeutics, GlaxoSmithKline, GW Pharma, Merck Serono, Novartis, Oxford PharmaGenesis, Protein Discovery Laboratories, Roche, Sanofi Genzyme, Synthon, Teva, and UCB. S. Schippling reports receiving research grants from Novartis and Sanofi Genzyme; and consulting and speaking fees from Biogen, Merck Serono, Novartis, Sanofi Genzyme, and Teva. K.W. Selmaj reports receiving consulting fees from Biogen, Merck, Novartis, Roche, Sanofi Genzyme, and Synthon. A. Traboulsee reports receiving consulting fees from Biogen, Novartis, Roche, Sanofi Genzyme, Serono, and Teva Innovation; and has been a principal investigator on clinical trials funded by Roche and Sanofi Genzyme. D.A.S. Compston reports receiving consulting fees and grant support from Genzyme and lecture fees from Bayer Schering Pharma on behalf of the University of Cambridge; and personal remuneration for lecture fees from Genzyme from July 2014. D.H. Margolin, K. Thangavelu, C.E. Rodriguez, and D. Jody report receiving personal compensation as an employee of Sanofi. R.J. Hogan and P. Xenopoulos report receiving personal compensation as an employee of Evidence Scientific Solutions. M.A. Panzara received personal compensation as an employee of Sanofi during study conduct and analysis and during preparation of the manuscript. A.J. Coles reports receiving consulting fees, lecture fees, and institutional grant support from Sanofi Genzyme. Go to Neurology.org for full disclosures.
Critical review of the manuscript was provided by Darren P. Baker, PhD, Madalina C. Chirieac, MD, MPH, Vladimir Evilevitch, MD, PhD, Maria Melanson, MD, PhD, and Sarah Strattman, MS, of Sanofi. Kunio Nakamura, PhD, oversaw BPF analyses and was an employee of the Department of Biomedical Engineering, Cleveland Clinic, Cleveland, OH, at the time the work was conducted. Additional statistical support was provided by Linda Kasten, BS, MA, who received compensation (Sanofi) as an employee of PROMETRIKA, LLC, when the statistical analyses were performed; currently an employee of Biostatistical Consulting, Inc. Catherine Pennella, BS, of Sanofi assisted in safety analyses.
Coinvestigators are listed at Neurology.org.
Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. The Article Processing Charge was funded by Sanofi.
Supplemental data at Neurology.org
Editorial, page 1098
See page 1117
Received August 9, 2016.
Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology
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Weber MS,
Hemmer B
. Cooperation of B cells and T cells in the pathogenesis of multiple sclerosis. Results Probl Cell Differ 2010;51:115–126.
Hu Y,
Turner MJ,
Shields J, et al
. Investigation of the mechanism of action of alemtuzumab in a human CD52 transgenic mouse model. Immunology 2009;128:260–270.
Rao SP,
Sancho J,
Campos-Rivera J, et al
. Human peripheral blood mononuclear cells exhibit heterogeneous CD52 expression levels and show differential sensitivity to alemtuzumab mediated cytolysis. PLoS One 2012;7:e39416.
Cox AL,
Thompson SA,
Jones JL, et al
. Lymphocyte homeostasis following therapeutic lymphocyte depletion in multiple sclerosis. Eur J Immunol 2005;35:3332–3342.
Coles AJ,
Compston DA, et al
CAMMS223 Trial Investigators, Coles AJ, Compston DA, et al. Alemtuzumab vs. interferon beta-1a in early multiple sclerosis. N Engl J Med 2008;359:1786–1801.
Cohen JA,
Arnold DL, et al
. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet 2012;380:1819–1828.
Twyman CL,
. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial. Lancet 2012;380:1829–1839.
LEMTRADA [Summary of Product Characteristics] [online]. Oxford, United Kingdom: Genzyme Therapeutics, Ltd. Available at: ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003718/WC500150521.pdf. Accessed May 30, 2014.
LEMTRADA (Alemtuzumab), for Intravenous Injection [Prescribing Information]. Cambridge, MA: Genzyme Corporation; 2014.
Lublin FD,
Reingold SC,
Cohen JA, et al
. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology 2014;83:278–286.
Liu GF,
Wang J,
Liu K,
Snavely DB
. Confidence intervals for an exposure adjusted incidence rate difference with applications to clinical trials. Stat Med 2006;25:1275–1286.
Comi G
. Shifting the paradigm toward earlier treatment of multiple sclerosis with interferon beta. Clin Ther 2009;31:1142–1157.
Rush CA,
MacLean HJ,
Freedman MS
. Aggressive multiple sclerosis: proposed definition and treatment algorithm. Nat Rev Neurol 2015;11:379–389.
Zivadinov R,
Reder AT,
Filippi M, et al
. Mechanisms of action of disease-modifying agents and brain volume changes in multiple sclerosis. Neurology 2008;71:136–144.
Wiendl H,
Toyka KV, et al
Multiple Sclerosis Therapy Consensus Group (MSTCG), Wiendl H, Toyka KV, et al. Basic and escalating immunomodulatory treatments in multiple sclerosis: current therapeutic recommendations. J Neurol 2008;255:1449–1463.
Scalfari A,
Neuhaus A,
Degenhardt A, et al
. The natural history of multiple sclerosis: a geographically based study 10: relapses and long-term disability. Brain 2010;133:1914–1929.
Fisniku LK,
Brex PA,
Altmann DR, et al
. Disability and T2 MRI lesions: a 20-year follow-up of patients with relapse onset of multiple sclerosis. Brain 2008;131:808–817.
Popescu V,
Agosta F,
Hulst HE, et al
. Brain atrophy and lesion load predict long term disability in multiple sclerosis. J Neurol Neurosurg Psychiatry 2013;84:1082–1091.
Rieckmann P
. Concepts of induction and escalation therapy in multiple sclerosis. J Neurol Sci 2009;277(suppl 1):S42–S45.
Fox E,
Vladic A, et al
. Alemtuzumab versus interferon beta-1a in early relapsing-remitting multiple sclerosis: post-hoc and subset analyses of clinical efficacy outcomes. Lancet Neurol 2011;10:338–348.
Fox EJ,
Arnold DL,
. Durable efficacy of alemtuzumab on clinical outcomes over 5 years in CARE-MS II with most patients free from treatment for 4 years. Mult Scler 2015;21(suppl 11):P1102.
Fisher E,
Rudick RA,
Cutter G, et al
. Relationship between brain atrophy and disability: an 8-year follow-up study of multiple sclerosis patients. Mult Scler 2000;6:373–377.
Jacobsen C,
Hagemeier J,
Myhr KM, et al
. Brain atrophy and disability progression in multiple sclerosis patients: a 10-year follow-up study. J Neurol Neurosurg Psychiatry 2014;85:1109–1115.
Sormani MP,
De Stefano N
. Treatment effect on brain atrophy correlates with treatment effect on disability in multiple sclerosis. Ann Neurol 2014;75:43–49.
Barkhof F,
Coles A, et al
. RRMS patients switching from SC IFNB-1a to alemtuzumab in the CARE-MS I and II extension study have a reduced rate of brain volume loss (P6.183). Neurology 2016;86(suppl):16.
Schneider DF,
Chen H
. New developments in the diagnosis and treatment of thyroid cancer. CA Cancer J Clin 2013;63:374–394.
Butzkueven H,
Kappos L,
Pellegrini F, et al
. Efficacy and safety of natalizumab in multiple sclerosis: interim observational programme results. J Neurol Neurosurg Psychiatry 2014;85:1190–1197.
O'Connor P,
Goodman A,
Kappos L, et al
. Long-term safety and effectiveness of natalizumab redosing and treatment in the STRATA MS Study. Neurology 2014;83:78–86.
Bloomgren G,
Richman S,
Hotermans C, et al
. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med 2012;366:1870–1880.
Can immune reprogramming with alemtuzumab induce permanent remission in multiple sclerosis?
Alemtuzumab CARE-MS II 5-year follow-up
Alemtuzumab CARE-MS I 5-year follow-up: Durable efficacy in the absence of continuous MS therapy
Clinical trials Randomized controlled (CONSORT agreement)