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Chemical cremation offers green alternative for deceased
Oct. 10 A funeral home in Florida has become the first in the world to perform a Bio cremation, a new alternative for the disposal of dead bodies. Through Bio cremation, the body is fully decomposed in just four hours using an accelerated chemical reaction. Ben Gruber reports.
David Cadoret is mourning the death of his father. Richard Cadoret, or Pete as he was known to family and friends, died peacefully just a few days ago.
In his Will, Pete chose to be cremated. But when David went to the Anderson/McQeen funeral home,clover copy necklace van cleef, he was told he had another choice.
(SOUNDBITE) (English) DAVID CADORET, SON OF DECEASED, SAYING:
"I think I was a little bit surprised to have more than one choice. I didn't realise there was a second choice and choices are good."
Just this week, the funeral home became the first in the world to offer bio cremation a process where instead of being burned in a cremator, a body is immersed in a chemical bath and broken down by a process called Alkaline Hydrolysis.
Alkaline Hydrolysis is the natural chemical reaction that takes place when a body decomposes after burial. For the past four years bio cremation inventor, Sandy Sullivan, has been trying to speed that process up."Alkaline Hydrolysis breaks down tissue and you end up with bones, ash at the end of the day. We apply it in a different way. We increase the alkalinity using a chemical called potassium hydroxide and we increase the heat because it is a chemical reaction. The more heat the faster the reaction, so we achieve what nature achieves in hours rather than months or years."
Sullivan designed a machine he calls a "Resomator". He says the system automatically calculates the weight of the body and the amount of potassium hydroxide and water needed to break it down.
The chamber heats up to 170 degrees celsius (370 f) and after four hours, all that's left are bone fragments.
These are then processed in the same manner as traditionally cremated remains and placed in a container for the family of the deceased. The chemical solution goes down the drain like any other liquid.
John McQueen, the president of the funeral home is quick to point out that the solution does not contain acid, but the same alkali used in cosmetics and soap.
(SOUNDBITE) (English) JOHN MCQUEEN, PRESIDENT OF THE ANDERSON/MCQUEEN FUNERAL HOME, SAYING:
"Actually what goes into the waste water treatment system is probably cleaner than most things that go into the waste water treatment system from our house or hospitals or nursing homes or other places. The solution that is discharged into that system is a sterile based solution, so it is sterile, there is no DNA whatsoever because the process breaks down the body to the basic amino acids."
Steve Schaal runs Matthews cremation, the company distributing Resomators in America. He says the machines' eco friendly appeal will help make it a success.
(SOUNDBITE) (English) STEVE SCHAAL, PRESIDENT OF MATTHEW'S CREMATION, SAYING:
"What we believe is that the fact that we are reducing carbon output by 75 percent, a huge reduction in energy usage, we are just seeing this as a fantastic opportunity in which can provide our funeral clients a new environmental way that is attractive to consumers."
In the end,van cleef arpels knock off alhambra necklace, David Cadoret chose bio cremation. He says that while the eco friendly sales pitch was appealing, it wasn't the main reason his family chose the new process.
(SOUNDBITE) (English) DAVID CADORET, SON OF DECEASED, SAYING:
"He chose to be cremated, ok, the bottom line. There is only two options and one was just more appealing than the other. When we get his remains in the urn,van cleef knock off clover necklace, not a big deal but, it's not going to scorched."
David also believes this is what his father would have wanted to be part of something new,van cleef and arpels fake necklace, even at the very end.
Oct. 10 A funeral home in Florida has become the first in the world to perform a Bio cremation, a new alternative for the disposal of dead bodies. Through Bio cremation, the body is fully decomposed in just four hours using an accelerated chemical reaction. Ben Gruber reports.
David Cadoret is mourning the death of his father. Richard Cadoret, or Pete as he was known to family and friends, died peacefully just a few days ago.
In his Will, Pete chose to be cremated. But when David went to the Anderson/McQeen funeral home,clover copy necklace van cleef, he was told he had another choice.
(SOUNDBITE) (English) DAVID CADORET, SON OF DECEASED, SAYING:
"I think I was a little bit surprised to have more than one choice. I didn't realise there was a second choice and choices are good."
Just this week, the funeral home became the first in the world to offer bio cremation a process where instead of being burned in a cremator, a body is immersed in a chemical bath and broken down by a process called Alkaline Hydrolysis.
Alkaline Hydrolysis is the natural chemical reaction that takes place when a body decomposes after burial. For the past four years bio cremation inventor, Sandy Sullivan, has been trying to speed that process up."Alkaline Hydrolysis breaks down tissue and you end up with bones, ash at the end of the day. We apply it in a different way. We increase the alkalinity using a chemical called potassium hydroxide and we increase the heat because it is a chemical reaction. The more heat the faster the reaction, so we achieve what nature achieves in hours rather than months or years."
Sullivan designed a machine he calls a "Resomator". He says the system automatically calculates the weight of the body and the amount of potassium hydroxide and water needed to break it down.
The chamber heats up to 170 degrees celsius (370 f) and after four hours, all that's left are bone fragments.
These are then processed in the same manner as traditionally cremated remains and placed in a container for the family of the deceased. The chemical solution goes down the drain like any other liquid.
John McQueen, the president of the funeral home is quick to point out that the solution does not contain acid, but the same alkali used in cosmetics and soap.
(SOUNDBITE) (English) JOHN MCQUEEN, PRESIDENT OF THE ANDERSON/MCQUEEN FUNERAL HOME, SAYING:
"Actually what goes into the waste water treatment system is probably cleaner than most things that go into the waste water treatment system from our house or hospitals or nursing homes or other places. The solution that is discharged into that system is a sterile based solution, so it is sterile, there is no DNA whatsoever because the process breaks down the body to the basic amino acids."
Steve Schaal runs Matthews cremation, the company distributing Resomators in America. He says the machines' eco friendly appeal will help make it a success.
(SOUNDBITE) (English) STEVE SCHAAL, PRESIDENT OF MATTHEW'S CREMATION, SAYING:
"What we believe is that the fact that we are reducing carbon output by 75 percent, a huge reduction in energy usage, we are just seeing this as a fantastic opportunity in which can provide our funeral clients a new environmental way that is attractive to consumers."
In the end,van cleef arpels knock off alhambra necklace, David Cadoret chose bio cremation. He says that while the eco friendly sales pitch was appealing, it wasn't the main reason his family chose the new process.
(SOUNDBITE) (English) DAVID CADORET, SON OF DECEASED, SAYING:
"He chose to be cremated, ok, the bottom line. There is only two options and one was just more appealing than the other. When we get his remains in the urn,van cleef knock off clover necklace, not a big deal but, it's not going to scorched."
David also believes this is what his father would have wanted to be part of something new,van cleef and arpels fake necklace, even at the very end.
An Exclusive Selection of the Best Dessert Wines to End a Meal
The absolutely enthralling aroma, the sparkling color, and the simply splendid taste is what defines the quintessential wines. The reds,van cleef and arpels clover copy necklace, the whites, and the dry ones! All have their own niche in the gourmet cuisine,van cleef necklace replica wholesale, while eating as well as the preparation of food. But which are the ones that go well with desserts? Join me as I try and explore which are the best dessert wines.
There are basically 2 categories of dessert wines. One is the fortified wine and the other is unfortified wine. The former ones are those, which are the port type from Portugal and other port style wines from different regions. These are, for instance, sherry and madeira. All these wines have spirits added to them, post fermentation, for kicking the alcohol content and sweetness a bit. On the contrary, the unfortified wines, like ice wines and Sauternes get their flavor from high alcohol content, on account of the yet to be fermented juice being concentrated through several methods. The temperature at which fortified wines are served is room temperature or a bit chilled. Ice wines on the other hand, are served chilled. Some of the best ones are enlisted below.
A sparkling golden wine, grapes for any type of late harvest wines like this are left on the vine for a longer period of time, as compared to table wines. This is done to create optimum ripeness and sweetness. Often a dessert in itself, this drink teams up amazingly well with cheese and fruit based desserts. Along with that, any dessert preparation involving cream, vanilla, and nuts pairs well with this drink.
Inniskillin Vidal Icewine 2006
Ice wines from this extremely famous winery Inniskillin, from Canada's Ontario region are a hit. Vidal blanc and Riesling from this winery are excellent to go with desserts. It is one of the premier wineries of Canada.
Talk of wines for chocolate and vintage Port,clover knock off necklace van cleef, Late Harvest Zinfandel, Lustau Muscat Sherry "Emlin," Recioto Amarone are a few of the best wines in this category. Simple dark chocolate is excellent to be paired with Cognac.
Saracco Moscato d'Asti 2006 (Italy)
This wine is one of the unique ones, and it is one of the semi sparkling wine. It is remarkably lighter and sweeter in flavor, and palate feel. This is a perfect partner for cheesecakes and the likes.
Brickish red in color, Churchill's 10 Year Tawny Port from Portugal is another wine that has a sweet, nutty aroma. Tawny port can be teamed up with a range of desserts, ranging from tiramisu to pecan pie to chocolate truffles, cheesecake,van cleef alhambra knock off necklace, and perhaps, a few main course items.
Amongst Pinot Gris, King Estate Domaine vin Glace Pinot is an exquisite Oregon ice wine. It has an amazing taste, as it is heavily concentrated in layers of honey. It can act as the dessert itself! It doesn't need to be paired with any other dessert!
From the beautiful locales of Italy's Piedmont region, this is a sparkling red wine with a sweet and subtle taste, flavored with raspberry and juicy strawberry. Wherever there are fresh fruit desserts and chocolate based desserts, this wine has to be there!
The absolutely enthralling aroma, the sparkling color, and the simply splendid taste is what defines the quintessential wines. The reds,van cleef and arpels clover copy necklace, the whites, and the dry ones! All have their own niche in the gourmet cuisine,van cleef necklace replica wholesale, while eating as well as the preparation of food. But which are the ones that go well with desserts? Join me as I try and explore which are the best dessert wines.
There are basically 2 categories of dessert wines. One is the fortified wine and the other is unfortified wine. The former ones are those, which are the port type from Portugal and other port style wines from different regions. These are, for instance, sherry and madeira. All these wines have spirits added to them, post fermentation, for kicking the alcohol content and sweetness a bit. On the contrary, the unfortified wines, like ice wines and Sauternes get their flavor from high alcohol content, on account of the yet to be fermented juice being concentrated through several methods. The temperature at which fortified wines are served is room temperature or a bit chilled. Ice wines on the other hand, are served chilled. Some of the best ones are enlisted below.
A sparkling golden wine, grapes for any type of late harvest wines like this are left on the vine for a longer period of time, as compared to table wines. This is done to create optimum ripeness and sweetness. Often a dessert in itself, this drink teams up amazingly well with cheese and fruit based desserts. Along with that, any dessert preparation involving cream, vanilla, and nuts pairs well with this drink.
Inniskillin Vidal Icewine 2006
Ice wines from this extremely famous winery Inniskillin, from Canada's Ontario region are a hit. Vidal blanc and Riesling from this winery are excellent to go with desserts. It is one of the premier wineries of Canada.
Talk of wines for chocolate and vintage Port,clover knock off necklace van cleef, Late Harvest Zinfandel, Lustau Muscat Sherry "Emlin," Recioto Amarone are a few of the best wines in this category. Simple dark chocolate is excellent to be paired with Cognac.
Saracco Moscato d'Asti 2006 (Italy)
This wine is one of the unique ones, and it is one of the semi sparkling wine. It is remarkably lighter and sweeter in flavor, and palate feel. This is a perfect partner for cheesecakes and the likes.
Brickish red in color, Churchill's 10 Year Tawny Port from Portugal is another wine that has a sweet, nutty aroma. Tawny port can be teamed up with a range of desserts, ranging from tiramisu to pecan pie to chocolate truffles, cheesecake,van cleef alhambra knock off necklace, and perhaps, a few main course items.
Amongst Pinot Gris, King Estate Domaine vin Glace Pinot is an exquisite Oregon ice wine. It has an amazing taste, as it is heavily concentrated in layers of honey. It can act as the dessert itself! It doesn't need to be paired with any other dessert!
From the beautiful locales of Italy's Piedmont region, this is a sparkling red wine with a sweet and subtle taste, flavored with raspberry and juicy strawberry. Wherever there are fresh fruit desserts and chocolate based desserts, this wine has to be there!
A Matter Of Justice 1,clover copy necklace van cleef
And beyond the ups and downs of life, there were times when nothing mattered more than the grimace of pleasure wandering the noblest features of my face as some voice in a sleek and solemn emphasis intoned the excellence of my name.
More than once, for that exclusive reason, I presume, I've been considered as a friend.
No,van cleef flower fake necklace, I'm not a complicated man. My intimacy is among the simplest ones. I pay my duties and also lean a hand when it's needed. That is, no one can blame on me for being what they expect me to be: the summun of a static when someone needs to reassure the quantities which may constitutes a mere and circumstantial reality.
True it is, there are many people looking at me with anger, with an academical contempt, but. Alas! They also have a place by my side.
True it is, that they resist being caught by flattery; aware of this, with pejorative sighs,van cleef clover knock off necklace, they put aside the temptation to considerer themselves with the importance granted to them by the vulgar for exalting their assertions as unique and perhaps ultimate truths.
Yes,van cleef and arpels fake butterfly necklace, they refuse to the sinful pleasure of Hybris. No shapeless world for them or equalitities only based on the Epic or the drama of the contrast.
Countless times I've heard them declaim that these attitudes are the ones which change the world!
I do not think so; and I shall not allow anyone to become a martyr.
A man must preserve his convictions from a civilized integrity, without extreme implications; and whether they were good or wrong, only history will consider.
I wish I could explain it in the conspicuous preface of a treatise on Ethic. I think I deserve it.
But my daily work does not allow me to develop the issue in a more expansive way. It is known that reality is more practical. There are always decisions and attitudes which need to be taken. And what people may say is an irrelevant fact which only leads to a little more than a childish argument.
Our decision are those which strenghten the systems!
Only to sum up I'll declare that, as a judge, I must ignore any perspective involving sentimentalism or emotional alterations. Can not hesitate.
The look of a convict is something that escapes from any attempt of weighting. I'm not certain if all of them, the defendants, are aware of the power I possess over their misarable lives.
In general they're condemned by me.
Allow me to add that Justice, in its abstract significance, has hardly something to do with my business. On behalf of the worthy community i represent, I need to be practical, summary, brief.
Yes, I can admit that my task is inspiring fear.
I don't even look into the offenders' eyes. I just down mines when they get to the courtroom, imploring for mercy. Most of them are usually guilty of witchcraft, blasphemy, heresy and others issues. More than once I've notice they start shaking just at the sight of me. My colleages claim that no one can generate this effect but me.
For the rest, I think it is time to say that an unfavorable verdict in my Court means the Capital Punishment.
And beyond the ups and downs of life, there were times when nothing mattered more than the grimace of pleasure wandering the noblest features of my face as some voice in a sleek and solemn emphasis intoned the excellence of my name.
More than once, for that exclusive reason, I presume, I've been considered as a friend.
No,van cleef flower fake necklace, I'm not a complicated man. My intimacy is among the simplest ones. I pay my duties and also lean a hand when it's needed. That is, no one can blame on me for being what they expect me to be: the summun of a static when someone needs to reassure the quantities which may constitutes a mere and circumstantial reality.
True it is, there are many people looking at me with anger, with an academical contempt, but. Alas! They also have a place by my side.
True it is, that they resist being caught by flattery; aware of this, with pejorative sighs,van cleef clover knock off necklace, they put aside the temptation to considerer themselves with the importance granted to them by the vulgar for exalting their assertions as unique and perhaps ultimate truths.
Yes,van cleef and arpels fake butterfly necklace, they refuse to the sinful pleasure of Hybris. No shapeless world for them or equalitities only based on the Epic or the drama of the contrast.
Countless times I've heard them declaim that these attitudes are the ones which change the world!
I do not think so; and I shall not allow anyone to become a martyr.
A man must preserve his convictions from a civilized integrity, without extreme implications; and whether they were good or wrong, only history will consider.
I wish I could explain it in the conspicuous preface of a treatise on Ethic. I think I deserve it.
But my daily work does not allow me to develop the issue in a more expansive way. It is known that reality is more practical. There are always decisions and attitudes which need to be taken. And what people may say is an irrelevant fact which only leads to a little more than a childish argument.
Our decision are those which strenghten the systems!
Only to sum up I'll declare that, as a judge, I must ignore any perspective involving sentimentalism or emotional alterations. Can not hesitate.
The look of a convict is something that escapes from any attempt of weighting. I'm not certain if all of them, the defendants, are aware of the power I possess over their misarable lives.
In general they're condemned by me.
Allow me to add that Justice, in its abstract significance, has hardly something to do with my business. On behalf of the worthy community i represent, I need to be practical, summary, brief.
Yes, I can admit that my task is inspiring fear.
I don't even look into the offenders' eyes. I just down mines when they get to the courtroom, imploring for mercy. Most of them are usually guilty of witchcraft, blasphemy, heresy and others issues. More than once I've notice they start shaking just at the sight of me. My colleages claim that no one can generate this effect but me.
For the rest, I think it is time to say that an unfavorable verdict in my Court means the Capital Punishment.
Around Australia pilgrimage for family of six,van cleef necklace alhambra replica
Pulling out of the driveway with their four children and a hand painted retro caravan in tow, Annie and Rohan Williams felt the weight of the world lift from their shoulders.
They said goodbye to their routines for a year to travel around Australia.
It was to be a year without work pressures, school deadlines, sport or music lessons as the family of six left their home and pets, including a wombat, for life on the open road.
Rohan Williams, a GP at a busy medical clinic at Berri in the South Australian Riverland, said the trip planning was stepped up when he became immobilised with a sore back.
"I decided there were things we needed to do and maybe we should get on and do them now,clover necklace brand replica, while we could," he said.
Their four girls, Nadia, 12, Georgia, 11, Amelia, 9 and Laura, 8, were still in primary school and their parents felt the timing was right.
"We wanted to do the whole around Australia thing, we also wanted to break off all the shackles of life rather than just go on a holiday," Mr Williams said.
The trip started with the drive and boat trip to Tasmania and then the family headed west and clockwise around Australia.
One of the few commitments was a promise to catch up with friends in Darwin.
"Literally as we drove off on the first night . I remember saying to Annie that I feel like the weight of the world was lifting off," Mr Williams said.
"I felt like we owed nobody anything, that we were just free."
Their retro caravan had a refurbished interior and was hand painted with flowers and rainbows by their children's school friends.
"Our plans basically started with a caravan even before we had the car, so it was a bit backward," Annie Williams said.
"The caravan's been a bit of a scream as we were travelling around. It attracted lots and lots of attention, lots of people took photographs of it.
"Part way around the caravan fell apart, the chassis snapped in half . but we were lucky it was on the last night we needed it in Brisbane. It kind of added to the adventure and the stories, it was quite funny in the end."
Getting by with little
Another challenge was to fit everything into the small van.
"Fitting our whole life in there was impressive I think," Mr Williams said.
"What was even more impressive I think was when we came home and realised how few clothes we managed to get by on for over a year and then looking at all of the packed up bags of clothes left behind and thinking 'Do we really need all of this stuff that we have?'"
The four children were home schooled for the year but the family admits formal lessons took a back seat to sightseeing and the adventure of being on the road.
"Initially when I was planning it I thought I had to be very organised and have lots of schooling and make sure the kids did lots of work and that changed really quickly," Annie Williams said.
"I realised it was more about spending time together as a family.
"They kept their journals up to date every day and [did] a few school projects, but the trip really wasn't about school, it was about spending time together."
She said the family members had found how much they enjoyed each other's company.
Now getting home to work, school and routine has taken some adjustment.
The girls are back at school but the transition has felt hard for their parents,van cleef necklace clover replica.
Annie Williams is back at work with the Riverland Division of General Practice and her husband has accepted a fly in fly out medical placement at a mine at Queensland.
"I think it's almost a transition to real life, because it doesn't feel like work in some ways because I'm spending a couple of weeks at work and then I'm home for a couple of weeks," he said of the mining site work.
Annie Williams said she would do it all again,van cleef heart necklace replica, but admitted it was unlikely the family would ever get the opportunity to leave their busy lives behind for an entire year.
Pulling out of the driveway with their four children and a hand painted retro caravan in tow, Annie and Rohan Williams felt the weight of the world lift from their shoulders.
They said goodbye to their routines for a year to travel around Australia.
It was to be a year without work pressures, school deadlines, sport or music lessons as the family of six left their home and pets, including a wombat, for life on the open road.
Rohan Williams, a GP at a busy medical clinic at Berri in the South Australian Riverland, said the trip planning was stepped up when he became immobilised with a sore back.
"I decided there were things we needed to do and maybe we should get on and do them now,clover necklace brand replica, while we could," he said.
Their four girls, Nadia, 12, Georgia, 11, Amelia, 9 and Laura, 8, were still in primary school and their parents felt the timing was right.
"We wanted to do the whole around Australia thing, we also wanted to break off all the shackles of life rather than just go on a holiday," Mr Williams said.
The trip started with the drive and boat trip to Tasmania and then the family headed west and clockwise around Australia.
One of the few commitments was a promise to catch up with friends in Darwin.
"Literally as we drove off on the first night . I remember saying to Annie that I feel like the weight of the world was lifting off," Mr Williams said.
"I felt like we owed nobody anything, that we were just free."
Their retro caravan had a refurbished interior and was hand painted with flowers and rainbows by their children's school friends.
"Our plans basically started with a caravan even before we had the car, so it was a bit backward," Annie Williams said.
"The caravan's been a bit of a scream as we were travelling around. It attracted lots and lots of attention, lots of people took photographs of it.
"Part way around the caravan fell apart, the chassis snapped in half . but we were lucky it was on the last night we needed it in Brisbane. It kind of added to the adventure and the stories, it was quite funny in the end."
Getting by with little
Another challenge was to fit everything into the small van.
"Fitting our whole life in there was impressive I think," Mr Williams said.
"What was even more impressive I think was when we came home and realised how few clothes we managed to get by on for over a year and then looking at all of the packed up bags of clothes left behind and thinking 'Do we really need all of this stuff that we have?'"
The four children were home schooled for the year but the family admits formal lessons took a back seat to sightseeing and the adventure of being on the road.
"Initially when I was planning it I thought I had to be very organised and have lots of schooling and make sure the kids did lots of work and that changed really quickly," Annie Williams said.
"I realised it was more about spending time together as a family.
"They kept their journals up to date every day and [did] a few school projects, but the trip really wasn't about school, it was about spending time together."
She said the family members had found how much they enjoyed each other's company.
Now getting home to work, school and routine has taken some adjustment.
The girls are back at school but the transition has felt hard for their parents,van cleef necklace clover replica.
Annie Williams is back at work with the Riverland Division of General Practice and her husband has accepted a fly in fly out medical placement at a mine at Queensland.
"I think it's almost a transition to real life, because it doesn't feel like work in some ways because I'm spending a couple of weeks at work and then I'm home for a couple of weeks," he said of the mining site work.
Annie Williams said she would do it all again,van cleef heart necklace replica, but admitted it was unlikely the family would ever get the opportunity to leave their busy lives behind for an entire year.
argenx NV ARGX
Mr. Tim Van Hauwermeiren is Chief Executive Officer of arGEN X BV. Tim has 18 years of business development and operational management experience within the biotech and consumer goods sectors. During which time he has played a key role in a number of fund raisings, IPO and the negotiation of a number of major licensing deals. Prior to becoming CEO of arGEN X, he was senior Business Development Manager at Ablynx NV where we was part of the team that negotiated a $265 million research development deal with Boehringer Ingelheim in 2007. Prior to joining Ablynx, Tim held various management positions with the Procter Gamble Company in R and Business Development,van cleef fleurette necklace replica, where he conceived and developed several new products. Among those was a healthcare innovation which won the United Nations ICC World Business Award in 2004. Tim holds a Master of Science degree in Bio engineering from the University of Gent (Belgium) and received general management training at INSEAD and The Vlerick School of Management (Executive MBA).
Mr. Mr. Castaldi has 27 years of international financial executive management experience, including 18 years in the biopharmaceutical industry. Before joining arGEN X,van cleef pendant necklace replica, Mr. Castaldi was CFO from 1998 to 2013 at Nicox, a Euronext listed biotech company. At Nicox, he was a member of the Executive committee and participated in all the financings of the company since its IPO in November 1999. From 2008 to 2012 he also served as board member and chairman of the audit committee of Hybrigenics, a French biopharmaceutical company specialized in oncology and listed on Euronext. Prior to this he was CFO at Safety Kleen Corporation, a US based environmental waste company,tiffany s necklace replica, where he was responsible for operations in France and Belgium. From 1989 through 1997, he was CFO in charge of French and German operations, at My Kinda Town plc, a European leisure company. During that period, he was involved in the 1994 flotation of that company on the London Stock Exchange. From 1986 through 1989, he was employed as Financial Analyst at the Research and Development Centre, located in Sophia Antipolis, of Cordis Corporation, a US based company specialized in bio surgical instrumentation. He graduated in Finance,van cleef arpel alhambra necklace replica, Accountancy and Administration from the University of Nice in 1986.
Ms. Debbie has been active in the antibody engineering field since the 1980s. She brings to arGEN X more than 30 years of corporate and business development experience with small and large biotech companies focused on biopharmaceuticals. She established her Business Development career at Cambridge Antibody Technology (now MedImmune), where she had management responsibility for technology, intellectual property and product out licensing, corporate equity, co development and cross license agreements. She was responsible for the 1999 license agreement with Human Genome Sciences that led to the discovery of the monoclonal antibody drug BENLYSTA (belimumab), now approved for the treatment of systemic lupus erythematosus. Prior to joining arGEN X, Debbie acted for eight years as an independent consultant to around 25 emerging biotech companies, providing strategic management and business development support.
Dr. Michael Saunders is Senior Director, Targets Programs of arGEN X BV. He has twenty years of small molecule and biological drug discovery experience from both pharmaceutical and biotechnology, spanning several therapeutic areas. He has experience in target selection, project leadership, and project management. He holds a Doctoral degree from University of North Carolina in United States, a Bachelor of Arts in natural sciences from Cambridge University in United Kingdom, and an Executive Master's in Business Administration from ESSEC business school in Germany.
Dr. Alain Thibault serves as Chief Medical Officer of arGEN X BV. He has clinical development experience in oncology, both in the United States and Europe. Prior to joining arGEN X, he was therapeutic area head of Oncology at Regeneron Pharmaceuticals where he was responsible for clinical development, product strategy and portfolio management, as well as coordination of the collaboration with Sanofi to develop fully human antibody products for multiple cancer indications. He previously held senior research positions at Johnson Johnson and Hoffman La Roche before joining Regeneron. Dr. Thibault holds a Doctorate of Medicine from the McGill University (Canada).
Dr. John de Koning is Member of the Supervisory Board of arGEN X BV. Dr. de Koning is Partner at LSP (Life Sciences Partners), an independent European investment firm, providing financing to private and public life science companies. He serves or has served on the supervisory boards of arGEN X, BMEYE (acquired by Edwards Lifesciences), Innovative Biosensors Inc., Merus, Pronota, Prosensa, and Skyline Diagnostics. Dr. de Koning has a Master's degree in Molecular Biology from the University of Utrecht and a PhD in Oncology from the Erasmus University of Rotterdam.
Dr. David L. Lacey is Member of the Supervisory Board of arGEN X BV. He moved from academia to an industry setting when he joined Amgen. During the last five years of his tenure he assumed the head of Discovery Research (> 1200 FTEs) for Amgen. In this capacity, he charted the course and motivated a diverse senior team of scientific leaders from different disciplines as well as engaging and managing a diverse stakeholder network. At any given time there were over 100 actively managed preclinical projects across four therapeutic areas: hematology/oncology, inflammation, metabolic disorders, and neuroscience.
Dr. Bruno Montanari is Member of the Supervisory Board of arGEN X BV. He is a Director at Omnes Capital's Life Sciences Venture Capital team, which he joined in January 2010. He began his career in 1999 in London as an Investment Banker in the Healthcare Groups of Deutsche Bank and Merrill Lynch, later joining the venture capital community first with CDP Capital and then Atlas Venture, responsible for several European portfolio companies in the biotech and medtech areas as board member or observer.
Dr. Harrold van Berlingen is Member of the Supervisory Board of arGEN X BV. He is the Managing Director and Founder of Thuja Capital. He headed the life sciences effort of AlpInvest Partners managing a portfolio of over 30 companies, prior to founding Thuja Capital in 2006. Dr. van Barlingen joined AlpInvest Partners in 2001, from the Boston Consulting Group (BCG), where he worked as a consultant in management and strategy. Before BCG, he was acting head of the continental activities of the Lewin Group (a Quintiles subsidiary), an internationally active firm specialized in the field of health economics.
Mr. Tim Van Hauwermeiren is Chief Executive Officer of arGEN X BV. Tim has 18 years of business development and operational management experience within the biotech and consumer goods sectors. During which time he has played a key role in a number of fund raisings, IPO and the negotiation of a number of major licensing deals. Prior to becoming CEO of arGEN X, he was senior Business Development Manager at Ablynx NV where we was part of the team that negotiated a $265 million research development deal with Boehringer Ingelheim in 2007. Prior to joining Ablynx, Tim held various management positions with the Procter Gamble Company in R and Business Development,van cleef fleurette necklace replica, where he conceived and developed several new products. Among those was a healthcare innovation which won the United Nations ICC World Business Award in 2004. Tim holds a Master of Science degree in Bio engineering from the University of Gent (Belgium) and received general management training at INSEAD and The Vlerick School of Management (Executive MBA).
Mr. Mr. Castaldi has 27 years of international financial executive management experience, including 18 years in the biopharmaceutical industry. Before joining arGEN X,van cleef pendant necklace replica, Mr. Castaldi was CFO from 1998 to 2013 at Nicox, a Euronext listed biotech company. At Nicox, he was a member of the Executive committee and participated in all the financings of the company since its IPO in November 1999. From 2008 to 2012 he also served as board member and chairman of the audit committee of Hybrigenics, a French biopharmaceutical company specialized in oncology and listed on Euronext. Prior to this he was CFO at Safety Kleen Corporation, a US based environmental waste company,tiffany s necklace replica, where he was responsible for operations in France and Belgium. From 1989 through 1997, he was CFO in charge of French and German operations, at My Kinda Town plc, a European leisure company. During that period, he was involved in the 1994 flotation of that company on the London Stock Exchange. From 1986 through 1989, he was employed as Financial Analyst at the Research and Development Centre, located in Sophia Antipolis, of Cordis Corporation, a US based company specialized in bio surgical instrumentation. He graduated in Finance,van cleef arpel alhambra necklace replica, Accountancy and Administration from the University of Nice in 1986.
Ms. Debbie has been active in the antibody engineering field since the 1980s. She brings to arGEN X more than 30 years of corporate and business development experience with small and large biotech companies focused on biopharmaceuticals. She established her Business Development career at Cambridge Antibody Technology (now MedImmune), where she had management responsibility for technology, intellectual property and product out licensing, corporate equity, co development and cross license agreements. She was responsible for the 1999 license agreement with Human Genome Sciences that led to the discovery of the monoclonal antibody drug BENLYSTA (belimumab), now approved for the treatment of systemic lupus erythematosus. Prior to joining arGEN X, Debbie acted for eight years as an independent consultant to around 25 emerging biotech companies, providing strategic management and business development support.
Dr. Michael Saunders is Senior Director, Targets Programs of arGEN X BV. He has twenty years of small molecule and biological drug discovery experience from both pharmaceutical and biotechnology, spanning several therapeutic areas. He has experience in target selection, project leadership, and project management. He holds a Doctoral degree from University of North Carolina in United States, a Bachelor of Arts in natural sciences from Cambridge University in United Kingdom, and an Executive Master's in Business Administration from ESSEC business school in Germany.
Dr. Alain Thibault serves as Chief Medical Officer of arGEN X BV. He has clinical development experience in oncology, both in the United States and Europe. Prior to joining arGEN X, he was therapeutic area head of Oncology at Regeneron Pharmaceuticals where he was responsible for clinical development, product strategy and portfolio management, as well as coordination of the collaboration with Sanofi to develop fully human antibody products for multiple cancer indications. He previously held senior research positions at Johnson Johnson and Hoffman La Roche before joining Regeneron. Dr. Thibault holds a Doctorate of Medicine from the McGill University (Canada).
Dr. John de Koning is Member of the Supervisory Board of arGEN X BV. Dr. de Koning is Partner at LSP (Life Sciences Partners), an independent European investment firm, providing financing to private and public life science companies. He serves or has served on the supervisory boards of arGEN X, BMEYE (acquired by Edwards Lifesciences), Innovative Biosensors Inc., Merus, Pronota, Prosensa, and Skyline Diagnostics. Dr. de Koning has a Master's degree in Molecular Biology from the University of Utrecht and a PhD in Oncology from the Erasmus University of Rotterdam.
Dr. David L. Lacey is Member of the Supervisory Board of arGEN X BV. He moved from academia to an industry setting when he joined Amgen. During the last five years of his tenure he assumed the head of Discovery Research (> 1200 FTEs) for Amgen. In this capacity, he charted the course and motivated a diverse senior team of scientific leaders from different disciplines as well as engaging and managing a diverse stakeholder network. At any given time there were over 100 actively managed preclinical projects across four therapeutic areas: hematology/oncology, inflammation, metabolic disorders, and neuroscience.
Dr. Bruno Montanari is Member of the Supervisory Board of arGEN X BV. He is a Director at Omnes Capital's Life Sciences Venture Capital team, which he joined in January 2010. He began his career in 1999 in London as an Investment Banker in the Healthcare Groups of Deutsche Bank and Merrill Lynch, later joining the venture capital community first with CDP Capital and then Atlas Venture, responsible for several European portfolio companies in the biotech and medtech areas as board member or observer.
Dr. Harrold van Berlingen is Member of the Supervisory Board of arGEN X BV. He is the Managing Director and Founder of Thuja Capital. He headed the life sciences effort of AlpInvest Partners managing a portfolio of over 30 companies, prior to founding Thuja Capital in 2006. Dr. van Barlingen joined AlpInvest Partners in 2001, from the Boston Consulting Group (BCG), where he worked as a consultant in management and strategy. Before BCG, he was acting head of the continental activities of the Lewin Group (a Quintiles subsidiary), an internationally active firm specialized in the field of health economics.
Boost for traditional Chinese medicine
DESPITE advances in Western medicine, traditional Chinese medication is gaining acceptance in local government hospitals,van cleef small necklace replica, said Perak MCA organising secretary Dr Mah Hang Soon.
Dr Mah, who represented MCA secretary general Datuk Seri Ong Ka Chuan,van cleef and arpels heart necklace replica, said such forums were important to encourage traditional healers, or sinseh,van cleef and arpels alhambra diamond necklace replica, to share their knowledge.
He noted that since the international forum commenced in 1998, over 1,000 working papers in the fields of orthopaedic medicine has been presented.
This would help upgrade the level of treatment in this field, said Dr Mah.
He pointed out that the civilisations of the mighty Babylonians, Incans and the Mayans had since vanished.
But I think the reason that the Chinese and Indian nations are able to survive thousands of years is due to the strength and power of their traditional medicine,van cleef black onyx necklace replica, he added.
DESPITE advances in Western medicine, traditional Chinese medication is gaining acceptance in local government hospitals,van cleef small necklace replica, said Perak MCA organising secretary Dr Mah Hang Soon.
Dr Mah, who represented MCA secretary general Datuk Seri Ong Ka Chuan,van cleef and arpels heart necklace replica, said such forums were important to encourage traditional healers, or sinseh,van cleef and arpels alhambra diamond necklace replica, to share their knowledge.
He noted that since the international forum commenced in 1998, over 1,000 working papers in the fields of orthopaedic medicine has been presented.
This would help upgrade the level of treatment in this field, said Dr Mah.
He pointed out that the civilisations of the mighty Babylonians, Incans and the Mayans had since vanished.
But I think the reason that the Chinese and Indian nations are able to survive thousands of years is due to the strength and power of their traditional medicine,van cleef black onyx necklace replica, he added.
Cats smash Crows in pre
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Nine pointers: Geelong: P Chapman T Varcoe. Adelaide: S Kerridge.
Goals: Geelong: S Kersten 3 B Smedts 2 J Bartel 2 J Murdoch 2 M Duncan 2 A Mackie G Horlin Smith J Kelly M Blicavs T Hunt. Adelaide: P Dangerfield 3 B Martin G Johncock J Porplyzia N van Berlo R Douglas.
Umpires: Scott Jeffery, Nicholas Foot, Andrew Talbot
Venue: Skilled Stadium
Old hands Harry Taylor and Jimmy Bartel piloted an experimental Geelong line up to a commanding 63 point victory over disappointing Adelaide in the pre season Cup clash at Simonds Stadium.
Taylor was impassable in defence for the Cats, completely blanketing Crows spearhead Taylor Walker while amassing a game high 31 possessions.
Varcoe was limited to just one game in 2012 because of a serious foot injury,bracelet alhambra replica van cleef.
In contrast there was little to get enthused about for Crows coach Brenton Sanderson, less than three weeks out from the Crows' season opener against Essendon.
Adelaide went with a near full strength lineup on Saturday, with midfielder Rory Sloane and last year's Rising Star winner Daniel Talia among their few notable absentees.
Powerhouse Patrick Dangerfield was a rare shining light with three goals.
The home side had the match well in hand when they led by by 42 points at quarter time having begun the match kicking with the aid of a strong breeze.
Geelong took no risks with star utility Paul Chapman, substituting him out of the game at quarter time after he landed heavily in a marking contest.
The Cats return to Simonds Stadium next Saturday for a pre season Cup clash against North Melbourne while the Crows host Carlton at AAMI Stadium on Friday night.
ADELAIDE 0.2.0 0.5,van cleef and arpels alhambra replica bracelet.4 0,van cleef bracelet knock off alhambra.6,bracelet fake van cleef and arpels.4 1.8.6 (63)
Nine pointers: Geelong: P Chapman T Varcoe. Adelaide: S Kerridge.
Goals: Geelong: S Kersten 3 B Smedts 2 J Bartel 2 J Murdoch 2 M Duncan 2 A Mackie G Horlin Smith J Kelly M Blicavs T Hunt. Adelaide: P Dangerfield 3 B Martin G Johncock J Porplyzia N van Berlo R Douglas.
Umpires: Scott Jeffery, Nicholas Foot, Andrew Talbot
Venue: Skilled Stadium
Old hands Harry Taylor and Jimmy Bartel piloted an experimental Geelong line up to a commanding 63 point victory over disappointing Adelaide in the pre season Cup clash at Simonds Stadium.
Taylor was impassable in defence for the Cats, completely blanketing Crows spearhead Taylor Walker while amassing a game high 31 possessions.
Varcoe was limited to just one game in 2012 because of a serious foot injury,bracelet alhambra replica van cleef.
In contrast there was little to get enthused about for Crows coach Brenton Sanderson, less than three weeks out from the Crows' season opener against Essendon.
Adelaide went with a near full strength lineup on Saturday, with midfielder Rory Sloane and last year's Rising Star winner Daniel Talia among their few notable absentees.
Powerhouse Patrick Dangerfield was a rare shining light with three goals.
The home side had the match well in hand when they led by by 42 points at quarter time having begun the match kicking with the aid of a strong breeze.
Geelong took no risks with star utility Paul Chapman, substituting him out of the game at quarter time after he landed heavily in a marking contest.
The Cats return to Simonds Stadium next Saturday for a pre season Cup clash against North Melbourne while the Crows host Carlton at AAMI Stadium on Friday night.
at the heart of Feng Shui
In my previous articles I have explained the origin and the philosophy of the authentic Feng Shui. Now is the time to go into the core of the theory and see how Feng Shui really works.
At the heart of everything Feng Shui, and moreover in all Chinese metaphysics, there is the theory of the Qi. The Qi is the life force: called prana, pneuma, ki, etc. in other cultures. It surrounds us,van cleef and arpels clover knock off bracelet, and it is both internal and external.
Without Qi, there is no life; and where there is life there is Qi! If you remember the old Star Wars movies (the good ones) when Yoda talked about the that penetrates everything and is everywhere, he was talking about the Qi! Wisdom where you least expect it one hand, acupuncture, Chinese medicine or Qigong techniques, to name a few, are working on the flow of internal Qi. On the other hand,van cleef & arpels replica bracelet, Feng Shui and Chinese oracles deal with the external Qi the one the affects us through our environment, or through the will of Heaven (luck we can tap in with the use of Chinese oracles).
Now it is time to move to the next level, which is the five elements theory.
Knowing that there is a universal energy is a good thing. However knowing the pattern of this energy is a more advanced step. This is where the theory of the five elements comes into the picture.
elements is a rough translation a more accurate one would be the phases of the Qi. They have to be understood as five aspects the Qi takes in our physical world. They are water, wood, fire, earth and metal. Their characteristics are as follows:
The elements are the BASE of all Chinese metaphysics. No matter how complicated a formula is, how advanced a Feng Shui solution is, they always relate back to the five elements.
Now the mistake of a very superficial Feng Shui, like the western version of the Ba Zhai (or 8 mansions), is to assume that as the elements are coming from such directions you can simply enhance all of them by putting corresponding artefacts in their specific corners. This approach doesn take you very far for several reasons:
1. The eight mains sectors are subdivided into 24 sub sectors, called the 24 mountains. The flux of energy based on this mapping is much more subtle. For example one of the directions in the North sector, called Ren (North 1), contains the fire element even if in a water sector
2. By enhancing everything you enhance nothing! Let draw a comparison. The dish you have cooked is way too salted. You then decide to double the proportions you have used to cover the salt, but you still double the salt amount as well. Do you think you will end up with a less salty result?
Those energies are already here. Trying to boost all sectors in your house does not convert it in any way it just put everything on the next level of Such an approach is particularly detrimental for businesses. A business relates to one or two elements,van cleef knock off alhambra bracelet, and the conversion has to be done based on those elements only. For example the hospitality industry relates to the water element. A successful conversion will enhance the metal and water element to create a natural money flow and a customer appeal. Trying to strengthen other elements like wood or fire for that business would be very counterproductive.
4. There is no proper Feng Shui if it is not connected to the people. Treating a house by itself has no effect; the cure is the link between the house and the people who live in it.
Through the BaZi (4 pillars), a Feng Shui master can understand which of the five elements each person can take. The house conversion will then be based on the supporting elements of the chart only. This is really a tailor made approach a bit like determining what body type, what allergies and what illness someone has before choosing the appropriate holistic treatment.
The trick is also to determine what really influences each element. For example putting a lot of metallic furniture in a room is not going to transform it in a metal room; however using a conversion through colours, based on the directional Qi received by the room, will do it. A metal direction is therefore stronger than a metal artefact fact about the elements.
Now fasten your seatbelts. The theory of five elements is easy to understand; however the applications are truly mind blowing and surprising,van cleef and arpels knock off bracelets! The elements have many layers to them.
For example, the elements represent physical directions and locations this is the first step. They also represent colours, and material another aspect we have seen. However the elements are also a timing factor.
In the Chinese calendar, a year is divided in 24 sub seasons all combinations of elemental Qi. The same concept of element equals timing applies to the Ba Zi. The four pillars of a chart are the year, the month, the day and the time of birth. Each pillar is a combination of a stem and branch: a and a Qi. They all have an element and a polarity (Yin metal or Yang Fire for example). The complete chart picture draws the elemental affinity of a person: a strong fire person will for example favour earth and metal to balance the fire in their chart.
Remember that the elements are also related to physical location. This is how Feng Shui works: the same symbol is an energy that is part of you (in your chart) but also a precise space in your living place. This is how you can trigger powerful changes of action reaction through the interactions of the five elements there are much more to the elements but we will see that in our next article.
In my previous articles I have explained the origin and the philosophy of the authentic Feng Shui. Now is the time to go into the core of the theory and see how Feng Shui really works.
At the heart of everything Feng Shui, and moreover in all Chinese metaphysics, there is the theory of the Qi. The Qi is the life force: called prana, pneuma, ki, etc. in other cultures. It surrounds us,van cleef and arpels clover knock off bracelet, and it is both internal and external.
Without Qi, there is no life; and where there is life there is Qi! If you remember the old Star Wars movies (the good ones) when Yoda talked about the that penetrates everything and is everywhere, he was talking about the Qi! Wisdom where you least expect it one hand, acupuncture, Chinese medicine or Qigong techniques, to name a few, are working on the flow of internal Qi. On the other hand,van cleef & arpels replica bracelet, Feng Shui and Chinese oracles deal with the external Qi the one the affects us through our environment, or through the will of Heaven (luck we can tap in with the use of Chinese oracles).
Now it is time to move to the next level, which is the five elements theory.
Knowing that there is a universal energy is a good thing. However knowing the pattern of this energy is a more advanced step. This is where the theory of the five elements comes into the picture.
elements is a rough translation a more accurate one would be the phases of the Qi. They have to be understood as five aspects the Qi takes in our physical world. They are water, wood, fire, earth and metal. Their characteristics are as follows:
The elements are the BASE of all Chinese metaphysics. No matter how complicated a formula is, how advanced a Feng Shui solution is, they always relate back to the five elements.
Now the mistake of a very superficial Feng Shui, like the western version of the Ba Zhai (or 8 mansions), is to assume that as the elements are coming from such directions you can simply enhance all of them by putting corresponding artefacts in their specific corners. This approach doesn take you very far for several reasons:
1. The eight mains sectors are subdivided into 24 sub sectors, called the 24 mountains. The flux of energy based on this mapping is much more subtle. For example one of the directions in the North sector, called Ren (North 1), contains the fire element even if in a water sector
2. By enhancing everything you enhance nothing! Let draw a comparison. The dish you have cooked is way too salted. You then decide to double the proportions you have used to cover the salt, but you still double the salt amount as well. Do you think you will end up with a less salty result?
Those energies are already here. Trying to boost all sectors in your house does not convert it in any way it just put everything on the next level of Such an approach is particularly detrimental for businesses. A business relates to one or two elements,van cleef knock off alhambra bracelet, and the conversion has to be done based on those elements only. For example the hospitality industry relates to the water element. A successful conversion will enhance the metal and water element to create a natural money flow and a customer appeal. Trying to strengthen other elements like wood or fire for that business would be very counterproductive.
4. There is no proper Feng Shui if it is not connected to the people. Treating a house by itself has no effect; the cure is the link between the house and the people who live in it.
Through the BaZi (4 pillars), a Feng Shui master can understand which of the five elements each person can take. The house conversion will then be based on the supporting elements of the chart only. This is really a tailor made approach a bit like determining what body type, what allergies and what illness someone has before choosing the appropriate holistic treatment.
The trick is also to determine what really influences each element. For example putting a lot of metallic furniture in a room is not going to transform it in a metal room; however using a conversion through colours, based on the directional Qi received by the room, will do it. A metal direction is therefore stronger than a metal artefact fact about the elements.
Now fasten your seatbelts. The theory of five elements is easy to understand; however the applications are truly mind blowing and surprising,van cleef and arpels knock off bracelets! The elements have many layers to them.
For example, the elements represent physical directions and locations this is the first step. They also represent colours, and material another aspect we have seen. However the elements are also a timing factor.
In the Chinese calendar, a year is divided in 24 sub seasons all combinations of elemental Qi. The same concept of element equals timing applies to the Ba Zi. The four pillars of a chart are the year, the month, the day and the time of birth. Each pillar is a combination of a stem and branch: a and a Qi. They all have an element and a polarity (Yin metal or Yang Fire for example). The complete chart picture draws the elemental affinity of a person: a strong fire person will for example favour earth and metal to balance the fire in their chart.
Remember that the elements are also related to physical location. This is how Feng Shui works: the same symbol is an energy that is part of you (in your chart) but also a precise space in your living place. This is how you can trigger powerful changes of action reaction through the interactions of the five elements there are much more to the elements but we will see that in our next article.
BBC crew caught up in volcano blast
Etna is one of the most active volcanoes in the world. That makes it a big draw not only for the scientists who want to understand better how these mountains work,van cleef and arpels clover knock off bracelet, but also for tourists who want to be amazed by a spectacular show of fire.
But you do not just wander up the mountain. If you're a reporter, you go with an experienced science team; if you're a tourist, you go with guides who are familiar with the sights and sounds that spell danger.
But even so,van cleef fake rose gold bracelet, a volcano can often do something that catches everyone by surprise.
In this case a flow of lava ran into snow, producing superheated steam that sent fragments of rock flying in all directions. Everyone counts themselves lucky to have escaped with just cuts and bruises.
Rebecca Morelle's team was on site filming for a report about advances in volcano monitoring,van cleef knock off alhambra bracelet. What happened illustrates just how much we still need to learn about these mountains,alhambra knock off bracelet van cleef.
Etna is one of the most active volcanoes in the world. That makes it a big draw not only for the scientists who want to understand better how these mountains work,van cleef and arpels clover knock off bracelet, but also for tourists who want to be amazed by a spectacular show of fire.
But you do not just wander up the mountain. If you're a reporter, you go with an experienced science team; if you're a tourist, you go with guides who are familiar with the sights and sounds that spell danger.
But even so,van cleef fake rose gold bracelet, a volcano can often do something that catches everyone by surprise.
In this case a flow of lava ran into snow, producing superheated steam that sent fragments of rock flying in all directions. Everyone counts themselves lucky to have escaped with just cuts and bruises.
Rebecca Morelle's team was on site filming for a report about advances in volcano monitoring,van cleef knock off alhambra bracelet. What happened illustrates just how much we still need to learn about these mountains,alhambra knock off bracelet van cleef.
analysis of 230 cohort studies with 3
AbstractObjectiveTo conduct a systematic review and meta analysis of cohort studies of body mass index (BMI) and the risk of all cause mortality, and to clarify the shape and the nadir of the dose response curve, and the influence on the results of confounding from smoking, weight loss associated with disease, and preclinical disease.Data synthesisSummary relative risks were calculated with random effects models. Non linear associations were explored with fractional polynomial models.Results230 cohort studies (207 publications) were included. The analysis of never smokers included 53 cohort studies (44 risk estimates) with >738144 deaths and >9976077 participants. The analysis of all participants included 228 cohort studies (198 risk estimates) with >3744722 deaths among 30233329 participants. The summary relative risk for a 5 unit increment in BMI was 1.18 (95% confidence interval 1.15 to 1.21; I2=95%, n=44) among never smokers, 1.21 (1.18 to 1.25; I2=93%, n=25) among healthy never smokers, 1.27 (1.21 to 1.33; I2=89%, n=11) among healthy never smokers with exclusion of early follow up, and 1.05 (1.04 to 1.07; I2=97%, n=198) among all participants. There was a J shaped dose response relation in never smokers (Pnon linearityConclusionOverweight and obesity is associated with increased risk of all cause mortality and the nadir of the curve was observed at BMI 23 24 among never smokers, 22 23 among healthy never smokers, and 20 22 with longer durations of follow up. The increased risk of mortality observed in underweight people could at least partly be caused by residual confounding from prediagnostic disease. Lack of exclusion of ever smokers, people with prevalent and preclinical disease, and early follow up could bias the results towards a more U shaped association.IntroductionThe prevalence of overweight and obesity has increased rapidly over the past decades throughout the world.1 This has raised serious public health concerns because of the association between overweight and obesity and increased risk of a wide range of chronic diseases, including cardiovascular diseases,2 type 2 diabetes,3 several types of cancer,4 5 6 7 8 gallbladder disease,imitation f��erie de van cleef & arpels,9 gout,10 osteoarthritis,11 and several other conditions, 11 12 13 as well as all cause mortality.2 14Though many studies have shown an increased risk of all cause mortality with greater adiposity as measured by body mass index (BMI),15 16 17 18 19 20 21 22 23 24 questions remain about the shape of the dose response relation. Several large scale prospective studies15 16 17 18 19 20 21 22 23 24 and pooled analyses (each with 900000 to 1.46 million participants)2 14 25 have reported increased risk of all cause mortality with greater BMI, and most of these found the lowest risk among participants with BMI in the range of 20 or 22.5 to 24.9. A large meta analysis of 97 cohort studies with 2.88 million participants and 270000 deaths, which used the WHO cut off points for overweight and obesity, however, found summary hazard ratios of 0.94 (95% confidence interval 0.90 to 0.97), 0.97 (0.90 to 1.04), and 1.34 (1.21 to 1.47) for a BMI of 25 26 That review, however, had several limitations for example,van cleef joaillerie replique, it excluded several large and some smaller studies including >5.4 million participants and >1.1 million deaths that used more refined categorisations of BMI than the WHO categorisations.15 16 18 19 20 24 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 Thus more deaths and participants were excluded than included in the analysis, and questions have been raised with regard to the validity of the findings.55 In addition, a large number of additional cohorts were either missed by the search or excluded from the analysis,56 57 58 59 60 61 62 63 64 65 and at least 53 additional studies have since been published, including >2.3 million deaths and >21.6 million participants.23 24 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 An updated analysis is therefore warranted.It is well known that smoking strongly increases risk of mortality and many specific causes of death,116 117 and there is therefore a great potential for residual confounding by smoking as it is typically also associated with lower weight.118 Indeed, many studies have reported a different shape of the dose response relation between BMI and mortality when the analysis is restricted to people who have never smoked or in comparisons between smokers and never smokers,2 14 15 16 17 18 19 20 21 22 24 77 but this was not adequately dealt with in the previous meta analysis.26 Furthermore, confounding by prevalent or undiagnosed illness could also have biased the results. It is well known that many chronic diseases (which increase the risk of death) lead to weight loss.119 Weight loss can precede a diagnosis of disease by many years and because of such preclinical weight loss the associations between low BMI and increased mortality might at least partly be caused by confounding by preclinical disease.120 Such bias might be avoided by the exclusion of people with prevalent disease at baseline, by exclusion of the early follow up period of the studies, and by stratifying studies by duration of follow up, but the most recent meta analysis did not conduct such subgroup or sensitivity analyses.26For these reasons we conducted a systematic review and dose response meta analysis of published cohort studies to clarify the strength and the shape of the dose response relation between BMI and all cause mortality,van cleef and arple replique, the potential confounding effects of smoking, and whether prevalent disease, exclusion of early follow up, or stratification by duration of follow up, or the quality of the studies influenced the association between BMI and all cause mortality. We used fractional polynomial models to assess the association between BMI and mortality, and this allowed for inclusion of all relevant studies reporting results for three or more categories of BMI and not only those reporting results using the WHO criteria for categorisation of BMI.MethodsSearch strategy and inclusion criteriaWe searched PubMed and Embase up to 23 September 2015 for eligible studies (DA, AS), using wide search terms (appendix 1). We followed standard criteria for conducting and reporting meta analyses.121 In addition, we searched the reference lists of a previous meta analysis26 for further studies. Study quality was assessed with the Newcastle Ottawa scale.122Patient involvementNo patients were involved in setting the research question or the outcome measures, nor were they involved in developing plans for design, or implementation of the study. No patients were asked to advise on interpretation or writing up of results. There are no plans to disseminate the results of the research to study participants or the relevant patient community.Study selectionWe included cohort studies of the association between BMI and risk of all cause mortality published in English language and excluded abstract only publications and grey literature. In each publication, adjusted relative risk estimates (hazard ratios or risk ratios) for three or more BMI categories had to be available, either with the 95% confidence intervals or with the information to calculate them. The dose response analysis, a quantitative measure of the exposure (BMI), also had to be available. Studies from populations living in the community were included, while studies that included only patients (for example, those with diabetes, stroke, heart disease, and cancer), nursing home residents, and disabled people were excluded. When multiple publications were published from the same study, in general we used the publication with the largest number of deaths. Exceptions to this rule were made when publications with smaller number of deaths provided more detailed analyses with restriction to never smokers, healthy people, and/or exclusion of early follow up than the publications with larger number of deaths. In the analysis of never smokers, the definition of never smokers was strict so we did not include data from studies that combined never smokers and former smokers who had quit for a long duration. When more detailed analyses (restricted to never smokers or other subgroups) were published in an overlapping publication but not in the publication used for the main analysis we used the information from the overlapping publication in the specific analysis, but each study was included only once in each analysis. Studies that reported only a continuous linear risk estimate were excluded as there is evidence that the association between BMI and mortality is non linear. A list of the excluded studies and reasons for exclusion is provided in table A in appendix 2.Statistical methodsWe used a random effects model to calculate summary relative risks and 95% confidence intervals for a 5 unit increment in BMI.123 For the primary analysis we used the model from each study that had the greatest degree of control for potential confounding, with the exception of studies that also adjusted mutually between BMI and waist circumference and waist to hip ratio or that adjusted for potentially intermediate variables such as diabetes, hypertension, and serum cholesterol, for which we used the multivariate model without such adjustment if available. If the alternative model was adjusted only for age and the multivariate model included other confounders as well, we chose the multivariate model with intermediates. We estimated the average of the natural logarithm of the relative risks and weighted the relative risk from each study according to the method of DerSimonian and Laird.123 A two tailed PWe used the method described by Greenland and Longnecker124 for the linear dose response analysis of BMI and mortality and calculated study specific slopes (linear trends) and 95% confidence intervals from the natural logs of the reported relative risks and confidence intervals across categories of BMI. When the reference category was not the lowest category (because, for example, of power issues) we excluded the categories below the reference category for the linear dose response analysis to model the association between higher BMI and mortality. The mean or median BMI level in each category was assigned to the corresponding relative risk for each study, and for studies that reported the exposures in ranges we used the midpoint of the upper and the lower cut off point. When upper and lower categories were open ended or had extreme upper or lower values, we used the width of the adjacent category to calculate an upper or lower bound. When studies reported analyses by the WHO categories of overweight and obesity we used a BMI of 15 as a lower bound for the underweight category (125 We determined the best fitting second order fractional polynomial regression model, defined as the one with the lowest deviance. A likelihood ratio test assessed the difference between the non linear and linear models to test for non linearity.125 For the non linear dose response analysis we included all categories of BMI (even the underweight categories) to model the association between BMI and mortality across the full BMI range and used the method of Hamling and colleagues to convert risk estimates when the lowest category was not the reference category.126 The analyses were re scaled so the reference category was a BMI of 23, which seemed to be the nadir of the curve among never smokers, so there was no loss of statistical power from these re calculations. The fractional polynomial method estimated a dose response curve for each study across the BMI values observed in the whole dataset (which was extrapolated across the full BMI range for studies with a limited BMI range), so all studies contributed to the pooled risk estimates across the full BMI range. The dose response curves for each of the individual studies were then pooled into an overall dose response curve, which are the curves showed in the non linear figures. The relative risk estimates in the tables were based on the non linear figures but show risk estimates for selected BMI values.We conducted subgroup and meta regression analyses to investigate potential sources of heterogeneity and heterogeneity between studies quantitatively assessed by the Q test and I2.127 Small study effects, such as publication bias, were assessed by inspection of the funnel plots for asymmetry and with Egger's test128 and Begg's test,129 with the results considered to indicate small study effects when P26 and in smokers in secondary analyses. Further subgroup analyses were conducted by sex, method of assessment of weight and height, duration of follow up, geographical location, number of deaths, study quality and adjustment for confounders, adjustment for mediators, and restriction to studies with appropriate adjustment for age, smoking, alcohol, and physical activity, but without adjustment for prevalent disease or intermediate factors. Because we did not have access to the original data and because not every study excluded early follow up we also conducted analyses stratified by duration of follow up to investigate the influence of undiagnosed disease on the results. As the number of deaths increases with increasing duration of follow up, the early follow up (when participants with undiagnosed disease most likely would have died) will account for a smaller and smaller proportion of the total deaths the longer the duration of follow up is. As preclinical weight loss can precede the diagnosis of disease by many years, stratification by duration of follow up can allow for assessments of the longer term impact of confounding by undiagnosed disease. We used Stata, version 12.0 (Stata Corp, College Station, TX) for the statistical analyses.ResultsFrom a total of 112173 records identified by the search we included 207 publications16 17 18 19 20 21 22 23 24 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 with 230 cohort studies including >3748549 deaths among 30361918 participants in the meta analysis of BMI and risk of all cause mortality (table B in appendix 2; fig 1). Table 1 summarises the main characteristics (number of studies, cases, and participants, geographical location, study size, and mean or median duration of follow up) of the studies included in the analysis of never smokers and among all participants. Some publications reported on or included data from more than one study (which were analysed as one combined dataset); one publication included data from nine studies,138 and another publication included eight cohort studies that were combined in one analysis,16 one publication reported results from six studies that were combined,95 five publications reported results from three studies that were combined,74 140 142 150 178 four publications reported results from two studies,163 170 189 191 which were included in the analysis. Four publications reported on men and women separately from the same two studies.30 31 131 132 Two duplicate publications were included only in subgroup analyses by sex229 235 as the main article provided only results for both sexes combined140 or because the duplicate publication had a longer follow up.235 That publication was not used for the main analysis as it reported only on women, while the main publication reported on both men and women.166 One publication was included only in the analysis of African Americans237 as the main publication reported results from the full population.17Fig 1 chart of study selection in systematic review and non linear dose response meta analysis of BMI and all cause mortalityThere was no heterogeneity in the analyses among never smokers when we stratified by sex, and, although there was heterogeneity when we stratified analyses of all participants by sex, this seemed to be due to no association among the studies of men and women combined, and when analysis was restricted to studies in either men or women there was no heterogeneity (tables C, D, and F in appendix 2, fig I in appendix 3). Although there was evidence of heterogeneity by geographical location in the linear dose response analysis of all participants (P=0.04), with a significant positive association observed only for Europe and North America (table F in appendix 2), there was no heterogeneity by geographical location in never smokers (P=0.91) and positive associations were observed in European, North American, Australian, and Asian studies (table C in appendix 2), although slight variations in the risk estimates from the non linear dose response analyses were observed (table H in appendix 2, fig J in appendix 3). There was evidence of heterogeneity between studies when we stratified by study quality scores in the analysis of all participants (P=0.03), with a significant association among studies with high study quality scores but not among the studies with medium study quality scores (table F in appendix 2). The non linearity was also more pronounced among the studies with medium study quality compared with the studies of high study quality (table I in appendix 2, figs K and L in appendix 3). There was, however, no heterogeneity by study quality scores in the subgroup analyses of never smokers (table C in appendix 2, figs M and N in appendix 3). There was evidence of heterogeneity when we stratified studies by the number of deaths in the analysis of all participants (PThe positive association between BMI and all cause mortality among never smokers persisted in subgroup analyses defined by sex, assessment of anthropometric measures, geographical location, number of deaths, and adjustment for confounding factors including age, education, alcohol, physical activity, height, dietary pattern, and intake of fat, fruit, and vegetables. There was little evidence of heterogeneity between any of these subgroups with meta regression analyses (table C in appendix 2). We observed no association among the few studies that adjusted for potential intermediate factors (diabetes, hypertension, cholesterol). In general, heterogeneity was high in most of the subgroup analyses.In the analysis of all participants there was no evidence of heterogeneity when we stratified studies by adjustment for age, education, socioeconomic status, alcohol, smoking status, pack years, years since quitting, physical activity, height, dietary pattern, fat intake, or fruit and vegetable intake. There was heterogeneity among studies when we stratified by adjustment for number of cigarettes smoked a day (PWhen we stratified studies by potential intermediates, there was heterogeneity by whether studies adjusted for diabetes, with no association among studies with such adjustment (table F in appendix 2). Although the test for heterogeneity was not significant, there was also no association among studies with adjustment for systolic blood pressure and hypertension. There was also heterogeneity by adjustment for prevalent coronary heart disease (P=0.003), stroke (P=0.07),van cleefs & arpels replique, and prevalent cancer (P=0.03), with no association among studies with such adjustment (table F in appendix 2). Although the test for heterogeneity between subgroups was not signi
AbstractObjectiveTo conduct a systematic review and meta analysis of cohort studies of body mass index (BMI) and the risk of all cause mortality, and to clarify the shape and the nadir of the dose response curve, and the influence on the results of confounding from smoking, weight loss associated with disease, and preclinical disease.Data synthesisSummary relative risks were calculated with random effects models. Non linear associations were explored with fractional polynomial models.Results230 cohort studies (207 publications) were included. The analysis of never smokers included 53 cohort studies (44 risk estimates) with >738144 deaths and >9976077 participants. The analysis of all participants included 228 cohort studies (198 risk estimates) with >3744722 deaths among 30233329 participants. The summary relative risk for a 5 unit increment in BMI was 1.18 (95% confidence interval 1.15 to 1.21; I2=95%, n=44) among never smokers, 1.21 (1.18 to 1.25; I2=93%, n=25) among healthy never smokers, 1.27 (1.21 to 1.33; I2=89%, n=11) among healthy never smokers with exclusion of early follow up, and 1.05 (1.04 to 1.07; I2=97%, n=198) among all participants. There was a J shaped dose response relation in never smokers (Pnon linearityConclusionOverweight and obesity is associated with increased risk of all cause mortality and the nadir of the curve was observed at BMI 23 24 among never smokers, 22 23 among healthy never smokers, and 20 22 with longer durations of follow up. The increased risk of mortality observed in underweight people could at least partly be caused by residual confounding from prediagnostic disease. Lack of exclusion of ever smokers, people with prevalent and preclinical disease, and early follow up could bias the results towards a more U shaped association.IntroductionThe prevalence of overweight and obesity has increased rapidly over the past decades throughout the world.1 This has raised serious public health concerns because of the association between overweight and obesity and increased risk of a wide range of chronic diseases, including cardiovascular diseases,2 type 2 diabetes,3 several types of cancer,4 5 6 7 8 gallbladder disease,imitation f��erie de van cleef & arpels,9 gout,10 osteoarthritis,11 and several other conditions, 11 12 13 as well as all cause mortality.2 14Though many studies have shown an increased risk of all cause mortality with greater adiposity as measured by body mass index (BMI),15 16 17 18 19 20 21 22 23 24 questions remain about the shape of the dose response relation. Several large scale prospective studies15 16 17 18 19 20 21 22 23 24 and pooled analyses (each with 900000 to 1.46 million participants)2 14 25 have reported increased risk of all cause mortality with greater BMI, and most of these found the lowest risk among participants with BMI in the range of 20 or 22.5 to 24.9. A large meta analysis of 97 cohort studies with 2.88 million participants and 270000 deaths, which used the WHO cut off points for overweight and obesity, however, found summary hazard ratios of 0.94 (95% confidence interval 0.90 to 0.97), 0.97 (0.90 to 1.04), and 1.34 (1.21 to 1.47) for a BMI of 25 26 That review, however, had several limitations for example,van cleef joaillerie replique, it excluded several large and some smaller studies including >5.4 million participants and >1.1 million deaths that used more refined categorisations of BMI than the WHO categorisations.15 16 18 19 20 24 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 Thus more deaths and participants were excluded than included in the analysis, and questions have been raised with regard to the validity of the findings.55 In addition, a large number of additional cohorts were either missed by the search or excluded from the analysis,56 57 58 59 60 61 62 63 64 65 and at least 53 additional studies have since been published, including >2.3 million deaths and >21.6 million participants.23 24 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 An updated analysis is therefore warranted.It is well known that smoking strongly increases risk of mortality and many specific causes of death,116 117 and there is therefore a great potential for residual confounding by smoking as it is typically also associated with lower weight.118 Indeed, many studies have reported a different shape of the dose response relation between BMI and mortality when the analysis is restricted to people who have never smoked or in comparisons between smokers and never smokers,2 14 15 16 17 18 19 20 21 22 24 77 but this was not adequately dealt with in the previous meta analysis.26 Furthermore, confounding by prevalent or undiagnosed illness could also have biased the results. It is well known that many chronic diseases (which increase the risk of death) lead to weight loss.119 Weight loss can precede a diagnosis of disease by many years and because of such preclinical weight loss the associations between low BMI and increased mortality might at least partly be caused by confounding by preclinical disease.120 Such bias might be avoided by the exclusion of people with prevalent disease at baseline, by exclusion of the early follow up period of the studies, and by stratifying studies by duration of follow up, but the most recent meta analysis did not conduct such subgroup or sensitivity analyses.26For these reasons we conducted a systematic review and dose response meta analysis of published cohort studies to clarify the strength and the shape of the dose response relation between BMI and all cause mortality,van cleef and arple replique, the potential confounding effects of smoking, and whether prevalent disease, exclusion of early follow up, or stratification by duration of follow up, or the quality of the studies influenced the association between BMI and all cause mortality. We used fractional polynomial models to assess the association between BMI and mortality, and this allowed for inclusion of all relevant studies reporting results for three or more categories of BMI and not only those reporting results using the WHO criteria for categorisation of BMI.MethodsSearch strategy and inclusion criteriaWe searched PubMed and Embase up to 23 September 2015 for eligible studies (DA, AS), using wide search terms (appendix 1). We followed standard criteria for conducting and reporting meta analyses.121 In addition, we searched the reference lists of a previous meta analysis26 for further studies. Study quality was assessed with the Newcastle Ottawa scale.122Patient involvementNo patients were involved in setting the research question or the outcome measures, nor were they involved in developing plans for design, or implementation of the study. No patients were asked to advise on interpretation or writing up of results. There are no plans to disseminate the results of the research to study participants or the relevant patient community.Study selectionWe included cohort studies of the association between BMI and risk of all cause mortality published in English language and excluded abstract only publications and grey literature. In each publication, adjusted relative risk estimates (hazard ratios or risk ratios) for three or more BMI categories had to be available, either with the 95% confidence intervals or with the information to calculate them. The dose response analysis, a quantitative measure of the exposure (BMI), also had to be available. Studies from populations living in the community were included, while studies that included only patients (for example, those with diabetes, stroke, heart disease, and cancer), nursing home residents, and disabled people were excluded. When multiple publications were published from the same study, in general we used the publication with the largest number of deaths. Exceptions to this rule were made when publications with smaller number of deaths provided more detailed analyses with restriction to never smokers, healthy people, and/or exclusion of early follow up than the publications with larger number of deaths. In the analysis of never smokers, the definition of never smokers was strict so we did not include data from studies that combined never smokers and former smokers who had quit for a long duration. When more detailed analyses (restricted to never smokers or other subgroups) were published in an overlapping publication but not in the publication used for the main analysis we used the information from the overlapping publication in the specific analysis, but each study was included only once in each analysis. Studies that reported only a continuous linear risk estimate were excluded as there is evidence that the association between BMI and mortality is non linear. A list of the excluded studies and reasons for exclusion is provided in table A in appendix 2.Statistical methodsWe used a random effects model to calculate summary relative risks and 95% confidence intervals for a 5 unit increment in BMI.123 For the primary analysis we used the model from each study that had the greatest degree of control for potential confounding, with the exception of studies that also adjusted mutually between BMI and waist circumference and waist to hip ratio or that adjusted for potentially intermediate variables such as diabetes, hypertension, and serum cholesterol, for which we used the multivariate model without such adjustment if available. If the alternative model was adjusted only for age and the multivariate model included other confounders as well, we chose the multivariate model with intermediates. We estimated the average of the natural logarithm of the relative risks and weighted the relative risk from each study according to the method of DerSimonian and Laird.123 A two tailed PWe used the method described by Greenland and Longnecker124 for the linear dose response analysis of BMI and mortality and calculated study specific slopes (linear trends) and 95% confidence intervals from the natural logs of the reported relative risks and confidence intervals across categories of BMI. When the reference category was not the lowest category (because, for example, of power issues) we excluded the categories below the reference category for the linear dose response analysis to model the association between higher BMI and mortality. The mean or median BMI level in each category was assigned to the corresponding relative risk for each study, and for studies that reported the exposures in ranges we used the midpoint of the upper and the lower cut off point. When upper and lower categories were open ended or had extreme upper or lower values, we used the width of the adjacent category to calculate an upper or lower bound. When studies reported analyses by the WHO categories of overweight and obesity we used a BMI of 15 as a lower bound for the underweight category (125 We determined the best fitting second order fractional polynomial regression model, defined as the one with the lowest deviance. A likelihood ratio test assessed the difference between the non linear and linear models to test for non linearity.125 For the non linear dose response analysis we included all categories of BMI (even the underweight categories) to model the association between BMI and mortality across the full BMI range and used the method of Hamling and colleagues to convert risk estimates when the lowest category was not the reference category.126 The analyses were re scaled so the reference category was a BMI of 23, which seemed to be the nadir of the curve among never smokers, so there was no loss of statistical power from these re calculations. The fractional polynomial method estimated a dose response curve for each study across the BMI values observed in the whole dataset (which was extrapolated across the full BMI range for studies with a limited BMI range), so all studies contributed to the pooled risk estimates across the full BMI range. The dose response curves for each of the individual studies were then pooled into an overall dose response curve, which are the curves showed in the non linear figures. The relative risk estimates in the tables were based on the non linear figures but show risk estimates for selected BMI values.We conducted subgroup and meta regression analyses to investigate potential sources of heterogeneity and heterogeneity between studies quantitatively assessed by the Q test and I2.127 Small study effects, such as publication bias, were assessed by inspection of the funnel plots for asymmetry and with Egger's test128 and Begg's test,129 with the results considered to indicate small study effects when P26 and in smokers in secondary analyses. Further subgroup analyses were conducted by sex, method of assessment of weight and height, duration of follow up, geographical location, number of deaths, study quality and adjustment for confounders, adjustment for mediators, and restriction to studies with appropriate adjustment for age, smoking, alcohol, and physical activity, but without adjustment for prevalent disease or intermediate factors. Because we did not have access to the original data and because not every study excluded early follow up we also conducted analyses stratified by duration of follow up to investigate the influence of undiagnosed disease on the results. As the number of deaths increases with increasing duration of follow up, the early follow up (when participants with undiagnosed disease most likely would have died) will account for a smaller and smaller proportion of the total deaths the longer the duration of follow up is. As preclinical weight loss can precede the diagnosis of disease by many years, stratification by duration of follow up can allow for assessments of the longer term impact of confounding by undiagnosed disease. We used Stata, version 12.0 (Stata Corp, College Station, TX) for the statistical analyses.ResultsFrom a total of 112173 records identified by the search we included 207 publications16 17 18 19 20 21 22 23 24 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 with 230 cohort studies including >3748549 deaths among 30361918 participants in the meta analysis of BMI and risk of all cause mortality (table B in appendix 2; fig 1). Table 1 summarises the main characteristics (number of studies, cases, and participants, geographical location, study size, and mean or median duration of follow up) of the studies included in the analysis of never smokers and among all participants. Some publications reported on or included data from more than one study (which were analysed as one combined dataset); one publication included data from nine studies,138 and another publication included eight cohort studies that were combined in one analysis,16 one publication reported results from six studies that were combined,95 five publications reported results from three studies that were combined,74 140 142 150 178 four publications reported results from two studies,163 170 189 191 which were included in the analysis. Four publications reported on men and women separately from the same two studies.30 31 131 132 Two duplicate publications were included only in subgroup analyses by sex229 235 as the main article provided only results for both sexes combined140 or because the duplicate publication had a longer follow up.235 That publication was not used for the main analysis as it reported only on women, while the main publication reported on both men and women.166 One publication was included only in the analysis of African Americans237 as the main publication reported results from the full population.17Fig 1 chart of study selection in systematic review and non linear dose response meta analysis of BMI and all cause mortalityThere was no heterogeneity in the analyses among never smokers when we stratified by sex, and, although there was heterogeneity when we stratified analyses of all participants by sex, this seemed to be due to no association among the studies of men and women combined, and when analysis was restricted to studies in either men or women there was no heterogeneity (tables C, D, and F in appendix 2, fig I in appendix 3). Although there was evidence of heterogeneity by geographical location in the linear dose response analysis of all participants (P=0.04), with a significant positive association observed only for Europe and North America (table F in appendix 2), there was no heterogeneity by geographical location in never smokers (P=0.91) and positive associations were observed in European, North American, Australian, and Asian studies (table C in appendix 2), although slight variations in the risk estimates from the non linear dose response analyses were observed (table H in appendix 2, fig J in appendix 3). There was evidence of heterogeneity between studies when we stratified by study quality scores in the analysis of all participants (P=0.03), with a significant association among studies with high study quality scores but not among the studies with medium study quality scores (table F in appendix 2). The non linearity was also more pronounced among the studies with medium study quality compared with the studies of high study quality (table I in appendix 2, figs K and L in appendix 3). There was, however, no heterogeneity by study quality scores in the subgroup analyses of never smokers (table C in appendix 2, figs M and N in appendix 3). There was evidence of heterogeneity when we stratified studies by the number of deaths in the analysis of all participants (PThe positive association between BMI and all cause mortality among never smokers persisted in subgroup analyses defined by sex, assessment of anthropometric measures, geographical location, number of deaths, and adjustment for confounding factors including age, education, alcohol, physical activity, height, dietary pattern, and intake of fat, fruit, and vegetables. There was little evidence of heterogeneity between any of these subgroups with meta regression analyses (table C in appendix 2). We observed no association among the few studies that adjusted for potential intermediate factors (diabetes, hypertension, cholesterol). In general, heterogeneity was high in most of the subgroup analyses.In the analysis of all participants there was no evidence of heterogeneity when we stratified studies by adjustment for age, education, socioeconomic status, alcohol, smoking status, pack years, years since quitting, physical activity, height, dietary pattern, fat intake, or fruit and vegetable intake. There was heterogeneity among studies when we stratified by adjustment for number of cigarettes smoked a day (PWhen we stratified studies by potential intermediates, there was heterogeneity by whether studies adjusted for diabetes, with no association among studies with such adjustment (table F in appendix 2). Although the test for heterogeneity was not significant, there was also no association among studies with adjustment for systolic blood pressure and hypertension. There was also heterogeneity by adjustment for prevalent coronary heart disease (P=0.003), stroke (P=0.07),van cleefs & arpels replique, and prevalent cancer (P=0.03), with no association among studies with such adjustment (table F in appendix 2). Although the test for heterogeneity between subgroups was not signi