COSTA MESA?? The legal battle over the City Council's outsourcing plan has cost the city more than $400,000 ? almost doubling the total legal fees so far this fiscal year ? and there's no end in sight.
High-level attorney firm Jones Day has charged the city $390,701 at $495 an hour to handle a lawsuit from the Costa Mesa City Employees Association that seeks to stop the City Council's plan to lay off more than 200 of its workers. Employees allege that the council acted illegally in its pursuit to explore the viability of outsourcing city services.
After the trial begins in April, an unknown number of motions and appeals could be filed, potentially drawing out the process ? and attorney fees along with it.
Residents and union leaders have voiced concern at meetings and public forums that the seemingly limitless cost of the lawsuit could exceed the savings the council hopes to attain from outsourcing.
The city could not put a dollar limit in its contract with Jones Day, which is mounting a "vigorous" legal defense, city spokesman Bill Lobdell said.
"In litigation, you can't have a cap because when you hit that cap what are you going to do?" Lobdell said. "When you're being sued, there's no choice."
The city's total legal fees through November amount to $1.05 million. Jones Day has not billed the city for work done in December and January.
The city has also paid $18,286 to Jones and Mayer, the attorney firm the city contracts for general legal counsel, for costs regarding the litigation since it started last year.
"We don't budget for being sued by our employees," said Councilman Jim Righeimer, the catalyst behind the outsourcing plan and the proposed city charter.
"Nobody wants to pay for litigation," he said. "But the citizens of the community aren't going to want the council to just roll over if it's getting sued by its employees and not do what it was elected to do, which was get the city's finances in order."
The funds used to pay for the city's legal defense come from a self-insurance fund, up to $2 million set aside from the general fund by the city for potential settlements, litigation and other legal issues, Lobdell said.
While the council's goal in outsourcing is to save money on future pension expenses, critics have questioned the plan's net savings after all the legal bills are paid.
"We wouldn't have to go to court if they would have followed the law," said Jennifer Muir, spokeswoman for the Orange County Employees Association. "Taxpayers should be furious because this is just a waste. Instead (the council majority) wanted to make a political statement in Costa Mesa."
Muir said the city is paying 400 percent more on the lawsuit than what the association is paying, but would not provide an exact amount.
"We're no where near what the city is paying to advance this outsourcing scheme," she said.
The city does not yet have a complete figure reflecting the total potential savings from outsourcing. Once city staff completes an analysis of bids received on 19 city services, a clearer picture of the potential savings will emerge.
On jail services alone, Righeimer said, the city could save $600,000 a year if it contracted out. Staff recently completed interviews with an organization that responded to a request for proposal on jail operations.
Councilwoman Wendy Leece, who has opposed the outsourcing process from the beginning, said the $400,000 legal bill could have been avoided if the city had asked its employees to pay more toward their retirement before the process began.
"All these legal fees would have been unnecessary if we had gone back to the table and met with our general employees to achieve more savings and talk about efficiencies in outsourcing," Leece said.
Contact: Andrea Boyle Tippett aboyle@udel.edu 302-831-1421 University of Delaware
A cheetah running in its natural environment is an elegant, fluid display of biomechanics. What if robots could run the same way, and be deployed for search and rescue operations in areas where conventional vehicles cannot go?
According to University of Delaware assistant professor Ioannis Poulakakis, a large fraction of the Earth's surface remains inaccessible to conventional wheeled or tracked vehicles, while animals and humans traverse such terrain with ease and elegance. He believes that legs have the potential to extend the mobility of robots, enabling them to become useful in real-world situations, such as search and rescue.
Poulakakis is the principal investigator of a three-year, $265,532 grant from the National Science Foundation (NSF) to develop a family of systematic control strategies that work together with the robot's natural dynamics to generate fast, reliable and efficient running motions.
The project, funded under NSF's Division of Civil, Mechanical and Manufacturing Innovation (CMMI), will focus on the running motion of quadrupeds (four-legged robots) with elastic energy storage elements such as springs.
"Biomechanics research demonstrates that springs and running are intimately related. When you run," Poulakakis explains, "the knee of the leg that is on the ground initially bends and then extends to prepare the body for take-off. During knee bending, energy is stored in elastic elements such as tendons or muscle fibers. Then, this energy is released during knee extension, pushing the body upward and forward."
In other words, when animals run, they "tune" their musculoskeletal system so that their center of mass appears to be moving as if following the motion of a pogo-stick.
Using this hypothesis as inspiration, Poulakakis suggests the same theory can be applied to robots because the pogo-stick is an example of a simple mechanical system that can be studied using the basic laws of physics. In particular, the proposed research involves developing similar systematic "energy-saving" controls that can replicate this natural, intuitive running phenomenon in robots through feedback design, rather than through hardware redundancy.
If successful, the work would enable quadrupeds to move reliably at high speeds, self-correct to prevent falls and mimic their animal counterpart's running motion.
Under the grant, Poulakakis will develop:
models of locomotion behavior;
analytical methods to rigorously characterize cyclic motion generation and stability of quadrupedal running gaits;
constructive control techniques and systematic control law design tools that minimize laborious, trial-and-error experimentation;
verification procedures to test the controllers in a variety of running gaits; and
student education and engineering research experiences for K-12 teachers designed to inspire the next generation of engineers.
Robotic quadrupeds offer unique advantages due to their enhanced stability, high-load carrying capacity and low mechanical complexity. Their ability to travel to areas deemed unsafe for humans, Poulakakis believes, may also enable legged robots to provide critical assistance in search and rescue operations, and may have potential applications in industrial, agricultural and military industries.
The fundamental results of this work, however, are expected to apply to dynamically-stable legged robots with different leg numbers and postures.
"If successful, this research effort will impact the study of many other engineered and biological systems which, like legged robots, accomplish their purpose through forceful, cyclic interactions with the environment."
###
About the researcher
Ioannis Poulakakis joined UD in 2010 as an assistant professor in the Department of Mechanical Engineering. His expertise lies in formal control synthesis for hopping robot models and on intuitive control design for quarupedal running machines. He previously served as a postdoctoral associate in the Department of Mechanical and Aerospace Engineering at Princeton University.
Poulakakis earned his doctoral degree in electrical engineering systems and his master of science degree in applied mathematics from the University of Michigan, Ann Arbor. He also holds a master of engineering degree from McGill University in Montreal and a master of science in robotics and automation from the National Technical University of Athens, Greece, where he also earned his diploma in mechanical engineering.
He is the author of 23 journal publications, book chapters and refereed conference papers.
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AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert! system.
Contact: Andrea Boyle Tippett aboyle@udel.edu 302-831-1421 University of Delaware
A cheetah running in its natural environment is an elegant, fluid display of biomechanics. What if robots could run the same way, and be deployed for search and rescue operations in areas where conventional vehicles cannot go?
According to University of Delaware assistant professor Ioannis Poulakakis, a large fraction of the Earth's surface remains inaccessible to conventional wheeled or tracked vehicles, while animals and humans traverse such terrain with ease and elegance. He believes that legs have the potential to extend the mobility of robots, enabling them to become useful in real-world situations, such as search and rescue.
Poulakakis is the principal investigator of a three-year, $265,532 grant from the National Science Foundation (NSF) to develop a family of systematic control strategies that work together with the robot's natural dynamics to generate fast, reliable and efficient running motions.
The project, funded under NSF's Division of Civil, Mechanical and Manufacturing Innovation (CMMI), will focus on the running motion of quadrupeds (four-legged robots) with elastic energy storage elements such as springs.
"Biomechanics research demonstrates that springs and running are intimately related. When you run," Poulakakis explains, "the knee of the leg that is on the ground initially bends and then extends to prepare the body for take-off. During knee bending, energy is stored in elastic elements such as tendons or muscle fibers. Then, this energy is released during knee extension, pushing the body upward and forward."
In other words, when animals run, they "tune" their musculoskeletal system so that their center of mass appears to be moving as if following the motion of a pogo-stick.
Using this hypothesis as inspiration, Poulakakis suggests the same theory can be applied to robots because the pogo-stick is an example of a simple mechanical system that can be studied using the basic laws of physics. In particular, the proposed research involves developing similar systematic "energy-saving" controls that can replicate this natural, intuitive running phenomenon in robots through feedback design, rather than through hardware redundancy.
If successful, the work would enable quadrupeds to move reliably at high speeds, self-correct to prevent falls and mimic their animal counterpart's running motion.
Under the grant, Poulakakis will develop:
models of locomotion behavior;
analytical methods to rigorously characterize cyclic motion generation and stability of quadrupedal running gaits;
constructive control techniques and systematic control law design tools that minimize laborious, trial-and-error experimentation;
verification procedures to test the controllers in a variety of running gaits; and
student education and engineering research experiences for K-12 teachers designed to inspire the next generation of engineers.
Robotic quadrupeds offer unique advantages due to their enhanced stability, high-load carrying capacity and low mechanical complexity. Their ability to travel to areas deemed unsafe for humans, Poulakakis believes, may also enable legged robots to provide critical assistance in search and rescue operations, and may have potential applications in industrial, agricultural and military industries.
The fundamental results of this work, however, are expected to apply to dynamically-stable legged robots with different leg numbers and postures.
"If successful, this research effort will impact the study of many other engineered and biological systems which, like legged robots, accomplish their purpose through forceful, cyclic interactions with the environment."
###
About the researcher
Ioannis Poulakakis joined UD in 2010 as an assistant professor in the Department of Mechanical Engineering. His expertise lies in formal control synthesis for hopping robot models and on intuitive control design for quarupedal running machines. He previously served as a postdoctoral associate in the Department of Mechanical and Aerospace Engineering at Princeton University.
Poulakakis earned his doctoral degree in electrical engineering systems and his master of science degree in applied mathematics from the University of Michigan, Ann Arbor. He also holds a master of engineering degree from McGill University in Montreal and a master of science in robotics and automation from the National Technical University of Athens, Greece, where he also earned his diploma in mechanical engineering.
He is the author of 23 journal publications, book chapters and refereed conference papers.
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AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert! system.
FILE - In this March 16, 2011 file photo, Defense Undersecretary Michele Flournoy testifies on Capitol Hill in Washington. The Obama administration is preparing to begin talks with Iraq on defining a long-term defense relationship that may include expanded U.S. training help, according to Defense Secretary Leon Panetta?s chief policy aide. Flournoy, who is leaving her Pentagon post to return to private life, said in an interview with a small group of reporters that the administration is open to Iraqi suggestions about the scope and depth of defense ties. "One of the things we?re looking forward to doing is sitting down with the Iraqis in the coming month or two to start thinking about how they want to work with" the U.S. military to develop a program of exercises, training and other forms of security cooperation, Flournoy said. (AP Photo/Cliff Owen, File)
FILE - In this March 16, 2011 file photo, Defense Undersecretary Michele Flournoy testifies on Capitol Hill in Washington. The Obama administration is preparing to begin talks with Iraq on defining a long-term defense relationship that may include expanded U.S. training help, according to Defense Secretary Leon Panetta?s chief policy aide. Flournoy, who is leaving her Pentagon post to return to private life, said in an interview with a small group of reporters that the administration is open to Iraqi suggestions about the scope and depth of defense ties. "One of the things we?re looking forward to doing is sitting down with the Iraqis in the coming month or two to start thinking about how they want to work with" the U.S. military to develop a program of exercises, training and other forms of security cooperation, Flournoy said. (AP Photo/Cliff Owen, File)
WASHINGTON (AP) ? The Obama administration is preparing to begin talks with Iraq on defining a long-term defense relationship that may include expanded U.S. training help, according to Defense Secretary Leon Panetta's chief policy aide.
Michele Flournoy, who is leaving her Pentagon post on Friday to return to private life, said in an interview with a small group of reporters that the administration is open to Iraqi suggestions about the scope and depth of defense ties.
"One of the things we're looking forward to doing is sitting down with the Iraqis in the coming month or two to start thinking about how they want to work with" the U.S. military to develop a program of exercises, training and other forms of security cooperation, Flournoy said.
The U.S. military completed its withdrawal from Iraq in December after nearly nine years of war. Both sides had considered keeping at least several thousand U.S. troops there to provide comprehensive field training for Iraqi security forces, but they failed to strike a deal before the expiration of a 2008 agreement that required all American troops to leave.
As a result, training is limited to a group of American service members and contractors in Baghdad who will help Iraqis learn to operate newly acquired weapons systems. They are part of the Office of Security Cooperation, based in the U.S. Embassy in Baghdad and headed by Army Lt. Gen. Robert Caslen.
Additional and more comprehensive training is a major issue because Iraq's army and police are mainly equipped and trained to counter an internal insurgency, rather than deter and defend against external threats. Iraq, for example, currently cannot defend its own air sovereignty. It is buying ? but has not yet received ? U.S.-made F-16 fighter jets.
In a new report on conditions in Iraq, a U.S. government watchdog agency said the Iraqi army is giving so much attention to fighting the insurgents that it has had too little time to train for conventional combat.
"The Iraqi army, while capable of conducting counterterrorism and counterinsurgency operations, possesses limited ability to defend the nation against foreign threats," said the report submitted to Congress Monday by the Special Inspector General for Iraq Reconstruction, Stuart W. Bowen, Jr.
In an introductory note, Bowen wrote that while Iraq's young democracy is buoyed by increasing oil production, it "remains imperiled by roiling ethno-sectarian tensions and their consequent security threats."
Iraq has seen an upswing in violence since the last U.S. troop left, but senior U.S. officials have remained in touch in hopes of nudging the Iraqis toward a political accommodation that can avert a slide into civil war.
Vice President Joe Biden spoke by phone on Saturday with Osama Nujaifi, speaker of the Council of Representatives. And Biden spoke on Friday with a key opposition figure, Ayad Allawi, a former interim prime minister and a secular Shiite leader of the Iraqiya political bloc. Allawi has said Iraq needs to replace its prime minister, Nouri al-Maliki, or hold new elections to prevent the country from fracturing along sectarian lines.
In a positive sign, Iraq's Sunni leaders announced on Sunday that they will end their boycott of parliament. That may have paved the way for the political leadership to hold a national conference led by President Jalal Talabani to seek reconciliation and to end a sectarian political crisis.
George Little, the Pentagon press secretary, said Sunday that Panetta remains optimistic about the outlook in Iraq despite worsening violence.
"The secretary believes that the Iraqi people have a genuine opportunity to create a future of greater security for themselves, and that senseless acts of violence will not deter them from pursuing that goal," Little said. "The United States remains committed to a strong security relationship with Iraq."
U.S. officials have said they aim to establish broad defense ties to Iraq, similar to American relationships with other nations in the Gulf, including Saudi Arabia, Kuwait, the United Arab Emirates, Qatar, Oman and Bahrain.
Flournoy, 51, is stepping down from her position as undersecretary of defense for policy on Friday after three years in the job. She is the first woman to hold that post. Her chief deputy, Jim Miller, has been picked to succeed her.
In the interview last week, Flournoy reiterated that she is leaving government to focus more on her family. She and her husband, W. Scott Gould, have three children aged 14, 12 and nine.
She came to the Pentagon in February 2009 from the Center for a New American Security, where she was the think tank's first president. She had served in the Pentagon in the 1990s as a strategist.
Flournoy said in an Associated Press interview in December when she announced her decision to quit that she intends to play an informal role this year in supporting President Barack Obama's re-election effort. She was a member of his transition team after the November 2008 election.
___
Robert Burns can be reached on Twitter at http://www.twitter.com/robertburnsAP
LOS ANGELES ? Hundreds of Etta James' friends, fans and family gathered Saturday at a Los Angeles-area church to remember the legendary rhythm and blues singer, who died this month.
Mourners at James' funeral included entertainment luminaries, with both Stevie Wonder and Christina Aguilera performing. Aguilera sang the song that James made famous, "At Last," while Wonder performed with the church's choir.
The Rev. Al Sharpton was to deliver the eulogy.
James died Jan. 20 at age 73 after battling leukemia and other ailments. She was most famous for her rendition of "At Last," and in her decades-long career, she became revered for her passionate, soulful singing voice. Her version of the song has become an enduring anthem for weddings and commercials.
Perhaps most famously, President Barack Obama and the first lady danced to a version of the song at his inauguration ball.
"Etta James was a pioneer. Her ever-changing sound has influenced rock and roll, rhythm and blues, pop, soul and jazz artists, marking her place as one of the most important female artists of our time," Rock and Roll Hall of Fame President and CEO Terry Stewart said after her death.
James won four Grammy Awards, including a lifetime achievement honor and was inducted in the Rock and Roll Hall of Fame in 1993.
She scored her first hit when she was just a teenager with the suggestive "Roll With Me, Henry," which had to be changed to "The Wallflower" in order to get airplay. Her 1967 album, "Tell Mama," became one of the most highly regarded soul albums of all time, a mix of rock and gospel music.
Over her lifetime, James battled adversity, including a turbulent upbringing and drug addiction.
She rebounded from a heroin addiction to see her career surge after performing the national anthem at the 1984 Olympics in Los Angeles. She won her first Grammy Award a decade later, and two more in 2003 and 2004.
She is also an inductee into the Rock and Roll Hall of Fame.
DUBLIN ? An Irish Republican Army veteran long accused of laundering counterfeit U.S. $100 bills on behalf of North Korea could face trial in Ireland, a Dublin judge announced Friday.
High Court Justice John Edwards said he has forwarded an evidence file to state prosecutors against Sean Garland, 76, who denies smuggling more than $250,000 worth of fake American banknotes from the North Korean embassy in Moscow in 1998.
Edwards issued his follow-up statement one month after he rejected a 6-year-old U.S. extradition warrant for Garland. The judge explained that the alleged conspiracy was concocted in part on Irish soil, therefore Garland must stand trial in Ireland, not the United States.
The judge also ordered Garland's house deeds and euro75,000 ($98,000) in bail money returned to him pending any Irish decision to charge him.
In May 2005, a U.S. federal grand jury in Washington indicted Garland for allegedly dealing in North Korean "superdollars" ? so called because of their exceptional high quality ? and the U.S. Justice Department issued an international arrest warrant.
American officials said Garland received two loads of fake $100 bills during two 1998 trips to Moscow, when Russian interior ministry police said they tailed him traveling in North Korean diplomatic-plated cars to the North Korean embassy. Garland admitted traveling to Moscow but has denied everything else.
Officials in the Republic of Ireland took no immediate action following the American arrest demand. Instead, Garland was arrested during a rare 2005 foray into neighboring Northern Ireland, where British authorities traditionally are much more open to permitting a U.S. extradition.
However, Garland in October 2005 persuaded a Belfast judge to grant him bail to visit his home near Dublin. Weeks later, his lawyers told that court he wouldn't return.
In 2009, Garland was arrested in Dublin on the basis of the same U.S. warrant. His extradition trial was delayed to mid-2011.
Garland today remains national treasurer of the Workers Party, a fringe Marxist player in Irish politics linked to an Irish Republican Army faction called the Official IRA.
Garland was seriously wounded during a botched IRA attack on a Northern Ireland border police station in 1957. Two colleagues were killed, and he was interned without trial in the Irish Republic for two years.
When the outlawed IRA split into rival Official and Provisional factions in 1969 at the start of the modern Northern Ireland conflict, Garland served as an Official IRA commander.
He steered the Official IRA to a 1972 cease-fire. That faction then fought bloody feuds with both the Provisionals and a breakaway Official faction called the Irish National Liberation Army. The INLA shot and seriously wounded Garland in Dublin in 1975.
As Workers Party leader in 1986, Garland wrote a letter to the Communist Party of the then-Soviet Union seeking $1 million in hopes of inspiring Marxist revolution in Ireland.
The U.S. indictment and subsequent Justice Department affidavits accuse Garland of visiting the North Korean embassy in Moscow several times; of delivering superdollars to a British money-laundering contact at a Moscow hotel room in 1998; and of using other criminal contacts in Birmingham, England, and Dublin to sell the notes to Irish and English underworld contacts at less than half their face value.
LONDON ? The criminal investigation into British tabloid skullduggery turned full force on a second Rupert Murdoch publication Saturday, with the arrest of four current and former journalists from The Sun on suspicion of bribing police.
A serving police officer was also held, and authorities searched the newspaper's offices as part an investigation into illegal payments for information.
The arrests spread the scandal over tabloid wrongdoing ? which has already shut down one Murdoch paper, the News of the World ? to Britain's best-selling newspaper.
London police said two men aged 48 and one aged 56 were arrested on suspicion of corruption early in the morning at homes in and around London. A 42-year-old man was detained later at a London police station.
Murdoch's News Corp. confirmed that all four were current or former Sun employees. The BBC and other British media identified them as former managing editor Graham Dudman, former deputy editor Fergus Shanahan, current head of news Chris Pharo and crime editor Mike Sullivan.
A fifth man, a 29-year-old police officer, was arrested at the London station where he works.
Officers searched the men's homes and the east London headquarters of the media mogul's British newspapers for evidence.
The investigation into whether reporters illegally paid police for information is running parallel to a police inquiry into phone hacking by Murdoch's now-defunct News of the World.
Police said Saturday's arrests were made based on information provided by the Management and Standards Committee of Murdoch's News Corp., the internal body tasked with rooting out wrongdoing.
News Corp. said it was cooperating with police.
"News Corporation made a commitment last summer that unacceptable news gathering practices by individuals in the past would not be repeated," it said in a statement.
In an email to staff after the arrests, Tom Mockridge ? chief executive of Murdoch's British operation, News International ? said the internal investigation into wrongdoing at The Sun "is well advanced."
"News International is confronting past mistakes and is making fundamental changes about how we operate which are essential for our business," Mockridge said.
"Despite this very difficult news, we are determined that News International will emerge a stronger and more trusted organization," he added.
Thirteen people have now been arrested in the bribery probe, though none has yet been charged. They include Rebekah Brooks, former chief executive of Murdoch's News International; ex-News of the World editor Andy Coulson ? who is also Prime Minister David Cameron's former communications chief; and journalists from the News of the World and The Sun.
Two of the London police force's top officers resigned in the wake of the revelation last July that the News of the World had eavesdropped on the cell phone voicemail messages of celebrities, athletes, politicians and even an abducted teenager in its quest for stories.
Murdoch shut down the 168-year-old tabloid amid a wave of public revulsion, and the scandal has triggered a continuing public inquiry into media ethics and the relationship between the press, police and politicians.
An earlier police investigation failed to find evidence that hacking went beyond one reporter and a private investigator, who were both jailed in 2007 for eavesdropping on the phones of royal staff.
But News Corp. has now acknowledged it was much more widespread.
Last week the company agreed to pay damages to 37 hacking victims, including actor Jude Law, soccer star Ashley Cole and British politician John Prescott.
The furor that consumed the News of the World continues to rattle other parts of Murdoch's media empire.
As well as investigating phone hacking and allegations that journalists paid police for information, detectives are looking into claims of computer hacking by Murdoch papers.
News Corp. has admitted that the News of the World hacked the emails as well as the phone of Chris Shipman, the son of serial killer Harold Shipman. And The Times of London has acknowledged that a former reporter tried to intercept emails to unmask an anonymous blogger.
News Corp. is preparing to launch a new Sunday newspaper ? likely called the Sunday Sun ? to replace the News of the World.
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Jill Lawless can be reached at: http://twitter.com/JillLawless
New submitter klchoward writes "Working for NOAA, I have been really pleased to see the weather data from the new Suomi NPP satellite coming into our computer models already but have been blown away by its capability to take stunning high-definition images of our planet. See the article at Huffington Post or go straight to the image at NASA's website." Reader derekmead has some images from further afield, too: these beautiful images of Mars come from NASA's High Resolution Imaging Science Experiment camera, mounted on the Mars Reconnaissance Orbiter.
Aiding cancer therapy by mathematically modeling tumor-immune interactionsPublic release date: 25-Jan-2012 [ | E-mail | Share ]
Contact: Karthika Muthukumaraswamy karthika@siam.org 267-350-6383 Society for Industrial and Applied Mathematics
Math models can be used to assess the impact of therapies before clinical application
Cancer is one of the five leading causes of death. And yet, despite decades of research, there is no standardized first-line treatment for most cancers. In addition, disappointing results from predominant second-line treatments like chemotherapy have established the need for alternative methods.
Mathematical modeling of cancer usually involves describing the evolution of tumors in terms of differential equations and stochastic or agent-based models, and testing the effectiveness of various treatments within the chosen mathematical framework. Tumor progression (or regression) is evaluated by studying the dynamics of tumor cells under different treatments, such as immune therapy, chemotherapy and drug therapeutics while optimizing dosage, duration and frequencies.
In a paper published last month in the SIAM Journal on Applied Mathematics, 'Controlled Drug Delivery in Cancer Immunotherapy: Stability, Optimization, and Monte Carlo Analysis,' authors Andrea Minelli, Francesco Topputo, and Franco Bernelli-Zazzera propose a differential equation model to describe tumorimmune interactions. "We study the dynamics of the competition between the tumor and the immune system," Topputo explains.
The relationship between cancers and the immune system has been studied for many years, and immune therapy has been known to influence tumor regression. Clinically called immunotherapy, it involves using external factors to induce, enhance, or suppress a patient's immune response for treatment of disease. In this study, the therapy consists of injecting a type of immune cells called dendritic cells, which generate tumor-specific immunity by presenting tumor-associated antigens.
"In particular, cancer immunotherapy has the purpose of identifying and killing tumor cells," says Topputo. "Our research considers a model that describes the interaction between the neoplasia [or tumor], the immune system, and drug administration." Such modeling and simulation can be used to assess the impact of drugs and therapies before clinical application.
Using ordinary differential equations, the authors model the progress of different cell populations in the tumor environment as a continuous process. Within the dynamical system presented by the tumor environment, they apply the theory of optimal controla mathematical optimization methodto design ad-hoc therapies and find an optimal treatment.
The end goal of the control policy is to minimize tumor cells while maximizing effectors, such as immune cells or immune-response chemicals. "The aim is to minimize the tumor concentration while keeping the amount of administered drug below certain thresholds, to avoid toxicity," says Topputo. "In common practice, one searches for effective therapies; in our approach, we look for efficiency and effectiveness."
Elaborating on a prior study where indirect methods used to solve the optimal control problem are not effective, the authors use direct methods that apply algorithms from aerospace engineering to solve the associated optimal control problem in this paper. Optimal protocols are analyzed, and the duration of optimal therapy is determined.
The robustness of the optimal therapies is then assessed. In addition, their applicability toward personalized medicine is discussed, where treatment is customized to each individual based on various factors such as genetic information, family history, social circumstances, environment and lifestyle.
"We have shown that personalized therapy is robust even with uncertain patient conditions. This is relevant as the model coefficients are characterized by uncertainties," Topputo explains. "Further studies would include designing optimal protocols by considering personalized constraints based on individual patient conditions, such as maximum amount of drug, therapy duration, and so on."
Other future directions would be the use of more diverse models and studying the effectiveness of treatment combinations. "More detailed approaches like agent-based models that describe tumor-immune interactions and hybrid therapies that consist of combined chemotherapy-immunotherapy treatments should also be considered," says Topputo.
###
About the authors:
Andrea Minelli is a researcher in the Applied Aerodynamics Department at ONERA, The French Aerospace Lab in Meudon, France. Francesco Topputo is a post-doctoral research fellow and Franco Bernelli-Zazzera a full professor in the Aerospace Engineering Department at Politecnico di Milano in Milano, Italy.
Source article:
Controlled Drug Delivery in Cancer Immunotherapy: Stability, Optimization, and Monte Carlo Analysis
Andrea Minelli, Francesco Topputo, and Franco Bernelli-Zazzera, SIAM Journal on Applied Mathematics, 71, pp 2229-2245 (Online publish date: December 20, 2011)
This paper is part of a Special Section in the SIAM Journal on Applied Mathematics that examines various other mathematical models used in the design and development of controlled drug delivery systems, which are significant in helping us understand physical, chemical and biological processes that influence such systems.
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AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert! system.
Aiding cancer therapy by mathematically modeling tumor-immune interactionsPublic release date: 25-Jan-2012 [ | E-mail | Share ]
Contact: Karthika Muthukumaraswamy karthika@siam.org 267-350-6383 Society for Industrial and Applied Mathematics
Math models can be used to assess the impact of therapies before clinical application
Cancer is one of the five leading causes of death. And yet, despite decades of research, there is no standardized first-line treatment for most cancers. In addition, disappointing results from predominant second-line treatments like chemotherapy have established the need for alternative methods.
Mathematical modeling of cancer usually involves describing the evolution of tumors in terms of differential equations and stochastic or agent-based models, and testing the effectiveness of various treatments within the chosen mathematical framework. Tumor progression (or regression) is evaluated by studying the dynamics of tumor cells under different treatments, such as immune therapy, chemotherapy and drug therapeutics while optimizing dosage, duration and frequencies.
In a paper published last month in the SIAM Journal on Applied Mathematics, 'Controlled Drug Delivery in Cancer Immunotherapy: Stability, Optimization, and Monte Carlo Analysis,' authors Andrea Minelli, Francesco Topputo, and Franco Bernelli-Zazzera propose a differential equation model to describe tumorimmune interactions. "We study the dynamics of the competition between the tumor and the immune system," Topputo explains.
The relationship between cancers and the immune system has been studied for many years, and immune therapy has been known to influence tumor regression. Clinically called immunotherapy, it involves using external factors to induce, enhance, or suppress a patient's immune response for treatment of disease. In this study, the therapy consists of injecting a type of immune cells called dendritic cells, which generate tumor-specific immunity by presenting tumor-associated antigens.
"In particular, cancer immunotherapy has the purpose of identifying and killing tumor cells," says Topputo. "Our research considers a model that describes the interaction between the neoplasia [or tumor], the immune system, and drug administration." Such modeling and simulation can be used to assess the impact of drugs and therapies before clinical application.
Using ordinary differential equations, the authors model the progress of different cell populations in the tumor environment as a continuous process. Within the dynamical system presented by the tumor environment, they apply the theory of optimal controla mathematical optimization methodto design ad-hoc therapies and find an optimal treatment.
The end goal of the control policy is to minimize tumor cells while maximizing effectors, such as immune cells or immune-response chemicals. "The aim is to minimize the tumor concentration while keeping the amount of administered drug below certain thresholds, to avoid toxicity," says Topputo. "In common practice, one searches for effective therapies; in our approach, we look for efficiency and effectiveness."
Elaborating on a prior study where indirect methods used to solve the optimal control problem are not effective, the authors use direct methods that apply algorithms from aerospace engineering to solve the associated optimal control problem in this paper. Optimal protocols are analyzed, and the duration of optimal therapy is determined.
The robustness of the optimal therapies is then assessed. In addition, their applicability toward personalized medicine is discussed, where treatment is customized to each individual based on various factors such as genetic information, family history, social circumstances, environment and lifestyle.
"We have shown that personalized therapy is robust even with uncertain patient conditions. This is relevant as the model coefficients are characterized by uncertainties," Topputo explains. "Further studies would include designing optimal protocols by considering personalized constraints based on individual patient conditions, such as maximum amount of drug, therapy duration, and so on."
Other future directions would be the use of more diverse models and studying the effectiveness of treatment combinations. "More detailed approaches like agent-based models that describe tumor-immune interactions and hybrid therapies that consist of combined chemotherapy-immunotherapy treatments should also be considered," says Topputo.
###
About the authors:
Andrea Minelli is a researcher in the Applied Aerodynamics Department at ONERA, The French Aerospace Lab in Meudon, France. Francesco Topputo is a post-doctoral research fellow and Franco Bernelli-Zazzera a full professor in the Aerospace Engineering Department at Politecnico di Milano in Milano, Italy.
Source article:
Controlled Drug Delivery in Cancer Immunotherapy: Stability, Optimization, and Monte Carlo Analysis
Andrea Minelli, Francesco Topputo, and Franco Bernelli-Zazzera, SIAM Journal on Applied Mathematics, 71, pp 2229-2245 (Online publish date: December 20, 2011)
This paper is part of a Special Section in the SIAM Journal on Applied Mathematics that examines various other mathematical models used in the design and development of controlled drug delivery systems, which are significant in helping us understand physical, chemical and biological processes that influence such systems.
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MADRID ? The Spanish judge who became an international human rights hero went on trial Tuesday for daring to probe right-wing atrocities around the Spanish civil war that may be linked to the deaths or disappearances of more than 100,000 civilians.
It is the second trial in as many weeks for the 56-year-old Baltasar Garzon, although the charges at the Supreme Court are essentially the same: that he knowingly exceeded the bounds of his authority.
Last week he stood trial for ordering jailhouse wiretaps in a corruption investigation. In this case he has been indicted for investigating more than 100,000 civilians deaths and disappearances at the hands of supporters of the late dictator Gen. Francisco Franco.
The crimes took place during and after Spain's 1936-39 civil war, which brought Franco to power.
Such crimes were covered by an amnesty passed in 1977 as Spain moved to restore democracy after Franco's death in 1975, but Garzon investigated anyway. He argued that crimes involving missing persons cannot be covered by amnesty and that the killings and disappearances amounted to a crime against humanity by the Franco regime and such atrocities have no statute of limitations.
Spaniards are highly divided over Garzon ? he has rock star status among rights groups but conservatives deride him as being more interested in fame than in justice.
Human rights group say it is appalling that Garzon ? who has pioneered universal jurisdiction, or the idea that some crimes are so heinous they can be prosecuted anywhere ? is being put on trial at home for daring to probe what is arguably Spain's biggest unresolved human rights case. They say he is being targeted by Spanish right-wingers and it would be a tremendous embarrassment and setback for the Spanish justice system if he is convicted.
About 100 pro-Garzon demonstrators rallied outside the Supreme Court before the trial started, chanting "Garzon, our friend, the people are with you!"
Tuesday's session was taken up by procedural motions filed by Garzon's lawyer. The trial then recessed until Jan. 31 when Garzon is scheduled to testify.
The case has been brought because of a complaint filed by two right-wing groups, even though government prosecutors themselves say Garzon did nothing wrong and should be acquitted. This is a quirk of Spanish penal law ? private citizens can seek to bring criminal charges against someone even if prosecutors disagree.
One key motion filed Tuesday by Garzon's attorney Gonzalo Martinez-Fresneda sought to have the whole case thrown out on the grounds that the magistrate who indicted Garzon in 2010 was biased against him.
Magistrate Luciano Varela helped one of the right-wing groups with court papers it had to file as it sought the charges against Garzon, to the point where the group ended up cutting and pasting entire paragraphs from previous documents filed by Varela himself, the attorney said.
"They didn't even bother to correct the spelling mistakes," Martinez-Fresneda said.
The Supreme Court will take a few days to rule on the motions.
Asked how the day's proceedings went, Garzon told reporters "Just fine."
After Garzon testifies, the defense is expected to summon as witnesses people who lost relatives to pro-Franco militia. Human rights groups say this will be unprecedented in a Spanish court.
If he is found guilty, Garzon ? who was already suspended from his job at the National Court in 2010 ? can be removed from the bench for up to 20 years. That would effectively end his career.
The verdict in the first trial could come during this one. In that case, Garzon faces up to 17 years off the bench.
For many in Spain, the trials ? and a third case in which Garzon is being probed for his dealings with a big Spanish bank ? amount to a witch hunt aimed at punishing Garzon for his status as judicial celebrity who indicted former Chilean dictator Augusto Pinochet in 1998 and al-Qaida leader Osama bin Laden in 2003.
Emilio Silva, head of a group that spearheads efforts to help people find the remains of relatives who went missing during the Spanish civil war, is amazed at the Garzon trial.
"It is a paradox that someone who tried to help families who have the biggest problem you can have ? a forced disappearance ? has to go before a court to answer for it," Silva said. "It is sad and especially sad for the families."
BEIJING (Reuters) ? Chinese security forces fired tear gas to break up a protest by Tibetans in the southwest province of Sichuan, an advocacy group said, the latest sign of volatile ethnic unrest in the region.
Reports from advocacy groups earlier said that in a separate clash, coinciding with this week's Chinese New Year celebrations, troops fired on thousands of Tibetans protesting in the same province, killing at least one and wounding more.
Free Tibet, a London-based organization that campaigns for Tibetan self-determination, said in an email that on Monday troops fired tear gas at Tibetan protesters in Meruma township, Aba County, called Ngaba County by Tibetans.
"Tibetans had gathered to protest Chinese oppression on the occasion of Chinese New Year, having decided that they would not celebrate the lunar New Year because of the current repression in Tibet," Free Tibet said.
"Additional security forces have been deployed in the area and roads connecting Ngaba to the surrounding counties have been closed by the authorities."
This year the main Tibetan traditional new year celebrations begin on February 22; the Han Chinese Lunar New Year celebrations began on Sunday.
The confrontation in Aba came on the same day that, according to two advocacy groups, Chinese troops in another part of Sichuan's mountainous western edge fired on thousands of Tibetan protesters, killing at least one and wounding more.
Calls by Reuters to police in Aba on Tuesday were not answered, but an official in a court there said: "You should not believe in rumors."
"People say all kinds of things to get attention, but they're not all true. Wait for the government to explain the situation," said the official, who would not give his name.
The western part of Sichuan province where the recent unrest has been concentrated is dominated by ethnic Tibetans and lies next to the official Tibetan Autonomous Region.
It has long been a source of protest against Chinese rule, and is the site of a recent string of self-immolations, mostly by Tibetan Buddhist monks.
Free Tibet said the deadly shooting happened after protesting Tibetans gathered in Luhuo, about 590 km (370 miles) west of Sichuan's capital of Chengdu, and marched on government offices, where security forces opened fire.
The Tibetans were protesting about arrests earlier in the day in connection with the distribution of pamphlets carrying the slogan "Tibet Needs Freedom" and declaring that more Tibetans were ready to stage self-immolations to challenge Chinese rule, the group said in an emailed statement.
One resident -- a 49-year-old Tibetan man called Yonten -- was shot dead by government forces and another 30 or so residents were injured, said Free Tibet.
Another advocacy group, the International Campaign for Tibet, said three people were killed and about nine injured when police fired into the crowd in Luhuo, which is called Drango or Draggo by Tibetans.
A Tibetan resident of a village close to Luhuo told Reuters that he had not seen the clash, but had heard that 30 or more people were injured, and possibly three or four died.
"Today seems calm so far, but I don't know whether there'll be big problems later," said the resident, who asked that his name not be used out of fear of reprisals.
An official from the propaganda office of Luhuo, however, denied that anything abnormal had happened there and that there were any shooting deaths.
"There's nothing like that here," she told Reuters.
"Everything is normal. We're all just enjoying the holiday," said the official, who hung up without giving her name.
Chinese security forces have been on edge after 16 incidents of self-immolation by ethnic Tibetans over the last year in response to growing resentment of Beijing's controls on religion. Some have called for the return of the Dalai Lama, the exiled Buddhist leader revered by many Tibetans.
China's Foreign Ministry has branded the self-immolators "terrorists" and has said the Dalai Lama, whom it condemns as a supporter of violent separatism, should take the blame.
(Reporting by Chris Buckley, Editing by Jonathan Thatcher)
MELBOURNE, Australia ? After winning a grueling, tightly contested match that lasted nearly four hours, Tomas Berdych didn't expect to be met by a stadium full of booing and hisses.
Berdych, the seventh seed from Czech Republic, was jeered by the crowd for refusing to shake hands with his opponent, No. 10 seed Nicolas Almagro, because he believed the Spaniard had deliberately struck him with a ball during a point at the end of the fourth set.
Berdych was initially cheered by the spectators at Hisense Arena following his 4-6, 7-6 (5), 7-6 (3), 7-6 (2) win in the fourth round of the Australian Open on Sunday, but the crowd turned on him in an instant when he refused to shake Almagro's hand at the net.
The booing drowned out his post-match, on-court interview and continued until he walked off.
"I think when you have a point and someone wants to hit you straight to your face, I don't see this as a nice moment," Berdych said during the interview, struggling to be heard over the noise from the crowd.
Berdych was angered by what happened in the 11th game of the fourth set, with the score level at 5-all. The Czech player approached the net and hit a volley and Almagro chased it down and hit a forehand that struck Berdych in the arm.
As Berdych flopped to the ground, the ball bounced back over the net and Almagro put it away to win the point. He then approached the net to apologize to Berdych, but Berdych didn't look at him.
Berdych said during his post-match news conference he didn't believe Almagro acted in a sporting manner.
"Probably whoever played the tennis knows that the court is pretty big, and you always have some space to put the ball in," he said. "This is not the way how tennis is. Even if you have this point, you always have enough space to where to put the ball and not actually try to hit the other guy."
Almagro said he did what he needed to do to win the point.
"When I win the point, I say sorry to him three or four times," he said. He added through a translator, "I could leave the court with my head held high and I would like to thank the crowd for their support."
When Berdych was asked whether he thought Almagro's on-court apology was enough, he replied: "You think is this enough to apologize? He should play the ball differently. That's it."
The Australians in the crowd weren't the only ones on Almagro's side. Former player Brad Gilbert, who is working as a TV analyst at the tournament, tweeted: "Really poor of the Birdman not to shake hands with Nico ... I am stunned with Tomas."
Berdych tried his best to play down the incident in his news conference, saying it was already in the past.
"We don't have any problems at all together," he said of his relationship with Almagro. "That's how it is, you know. It was pretty tight match, and I think it's more about the game than just this story."
WASHINGTON ? Senate Republicans are returning to Washington in an angry mood over President Barack Obama's appointments to two key agencies during a year-end break.
More than 70 nominees to judgeships and senior federal agency positions are awaiting the next move from Republicans, who can use Senate rules to block votes on some or all of Obama's picks.
While Republicans return Monday to discuss their next step, recess appointee Richard Cordray is running a new Consumer Financial Protection Bureau, and the National Labor Relations Board ? with three temporary members ? is now at full strength with a Democratic majority.
Obama left more than 70 other nominees in limbo, well aware that Republicans could use Senate rules to block them.
The White House justified the appointments on grounds that Republicans were holding up the nominations to paralyze the two agencies. The consumer protection agency was established under the 2010 Wall Street reform law, which requires the bureau to have a director in order to begin policing financial products such as mortgages, checking accounts, credit cards and payday loans.
The Supreme Court has ruled that the five-member NLRB must have a three-member quorum to issue regulations or decide major cases in union-employer disputes.
Several agencies contacted by The Associated Press, including banking regulators, said they were conducting their normal business despite vacancies at the top. In some cases, nominees are serving in acting capacities.
At full strength, the Federal Deposit Insurance Corp. has five board members. The regulation of failed banks "is unaffected," said spokesman Andrew Gray. "The three-member board has been able to make decisions without a problem." Cordray's appointment gives it a fourth member.
The Comptroller of the Currency, run by an acting chief, has kept up its regular examinations of banks. The Federal Trade Commission, operating with four board members and one vacancy, usually makes decisions unanimously.
The State Department, however, said it's important to U.S. diplomacy to fill the post of assistant secretary for western hemisphere affairs and the ambassadorships to El Salvador and Ecuador.
""We value highly our relationship with our hemispheric partners and consider diplomatic representation at the level of ambassador a top priority. This is especially true of the top diplomat charged with hemispheric relations, the assistant secretary," said William Ostick, a State Department spokesman.
Republicans have pledged retaliation for Obama's recess appointments, but haven't indicated what it might be.
"The Senate will need to take action to check and balance President Obama's blatant attempt to circumvent the Senate and the Constitution, a claim of presidential power that the Bush administration refused to make," said Sen. Charles Grassley, an Iowa Republican who is his party's top member on the Senate Judiciary Committee.
Grassley wouldn't go further, and Senate Republican leader Mitch McConnell of Kentucky hasn't tipped his hand after charging that Obama had "arrogantly circumvented the American people." Before the Senate left for its break in December, McConnell blocked Senate approval of more than 60 pending nominees because Obama wouldn't commit to making no recess appointments.
Republicans have to consider whether their actions, especially any decision to block all nominees, might play into Obama's hands.
Obama has adopted an election-year theme of "we can't wait" for Republicans to act on nominations and major proposals like his latest jobs plan. Republicans have to consider how their argument that the president is violating Constitutional checks and balances plays against Obama's stump speeches characterizing them as obstructionists.
Senate historian Donald Ritchie said the minority party has retaliated in the past for recess appointments by holding up specific nominees. "I'm not aware of any situations where no nominations were accepted," he said. The normal practice is for the two party leaders to negotiate which nominations get votes.
During the break, Republicans forced the Senate to convene for usually less than a minute once every few days to argue that there was no recess and that Obama therefore couldn't bypass the Senate's authority to confirm top officials. The administration said this was a sham, and has released a Justice Department opinion backing up the legality of the appointments.
Obama considers the new Consumer Financial Protection Bureau a signature achievement of his first term. Republicans have been vehemently opposed to the bureau's setup. They argued the agency needed a bipartisan board instead of a director and should have to justify its budget to Congress instead of drawing its funding from the independent Federal Reserve.
Cordray is expected to get several sharp questions from Republicans when he testifies Tuesday before a House Oversight and Government Reform panel.
The NLRB has been a target of Republicans and business groups. Last year, the agency accused Boeing of illegally retaliating against union workers who had struck its plants in Washington state by opening a new production line at its non-union plant in South Carolina. Boeing denied the charge and the case has since been settled, but Republican anger over it and a string of union-friendly decisions from the board last year hasn't abated.
A neuropathic pain expert says, however, that in the past 30 years virtually no new drug targets have made it into the clinic as effective pain-relief drugs
By Katharine Sanderson and Nature magazine ?| January 22, 2012
Image: National Cancer Institute
An uncharted trawl through thousands of small molecules involved in the body's metabolism may have uncovered a potential route to treating pain caused by nerve damage.
Neuropathic pain is a widespread and distressing condition, and is notoriously difficult to treat. So Gary Siuzdak, a chemist and molecular biologist at the Scripps Research Institute in La Jolla, Calif., and his team decided to take an unusual route to finding a therapy. Their results are published today in?Nature Chemical Biology.
They took rats with surgically damaged paws, who were consequently suffering from neuropathic pain, and instead of analyzing changes in gene expression and proteins in the animals, focused on metabolites?the biochemical intermediates and end-products of bodily processes such as respiration and the synthesis and breakdown of molecules. The science that looks at the body's metabolite composition is known as metabolomics. Using mass spectrometry, which can detect many different chemicals simultaneously, the researchers were able to identify the metabolites present in these animals 21 days after surgery.
Surprise finding
The team analyzed samples of the injured rats? blood plasma, of tissue near the injured paw, and of tissue from different areas of the spinal column, and compared the metabolites present with that of the same site in healthy rats. One particular area differed markedly between the two cases: the dorsal horn in the spinal column.
"It took me by surprise,? says Siuzdak, who had expected to see most differences in metabolite composition near the site of injury.
The researchers then looked more closely at the metabolites and recognized that the ones that were changing the most were associated with the metabolic pathway that synthesizes and breaks down the phospholipid sphingomyelin, a component of cell membranes, and its ceramide precursors.
?It was a huge flare to us that this was something we should home in on,? says team member Gary Patti, a chemist at Washington University School of Medicine in St Louis, Missouri.
Using cultures of spinal cord cells the researchers then tried to work out which of the altered metabolites might be responsible for pain. One molecule,?the previously unidentified metabolite?N,N-dimethylsphingosine (DMS), stood out for the amount of pain signallng it triggered in the cells.
Untargeted screening
To test experimentally whether this molecule was involved in neuropathic pain, the team then injected small amounts of DMS into healthy rats, and sure enough, those rats showed signs of pain.
The team hopes that DMS might prove to be important in the biochemistry of pain, and perhaps offer a target for drug manufacturers. But neuropathic pain expert Andrew Rice at Imperial College London says that in the past 30 years he has seen many targets identified, but virtually none of them has made it into the clinic as an effective pain-relief drug.
Rice lauds the attention shown to neuropathic pain but is concerned that the current animal model for pain is limited: it only corresponds to pain resulting from trauma, and not to the many other sources of neuropathic pain, which include diabetes, HIV infection and stroke. ?I?d like to see if this is more than a peripheral nerve damage model,? he says.
Siuzdak says his untargeted screening technique could prove useful in identifying drug targets for many other conditions. The more conventional way of using metabolomics is with targeted searches, where the molecule of interest is identified first, before seeing where it might be present. ?[Our approach] is more challenging than targeted analyses,? he says. ?You have to be open to any possibility of what pathways are affected.?
ZAGREB (Reuters) ? Croatia voted on Sunday to join the European Union next year, shrugging off concerns over the economic turmoil in the bloc and fears that membership will compromise its hard-won sovereignty.
Provided all 27 member states ratify its accession, the Adriatic state will enter the EU on July 1, 2013, more than two decades after breaking away from socialist Yugoslavia and fighting a 1991-95 war to secure independence.
It will become the second former Yugoslav republic to join the EU, following Slovenia in 2004.
Sixty-six percent ticked "Yes" in the referendum, the state electoral commission said with almost all votes counted.
"This is a historic moment, and could be a turning point in our history," Prime Minister Zoran Milanovic told reporters.
Turnout, however, was low, at 44 percent of eligible voters, well below the resounding votes of many former communist countries that joined in 2004 and 2007.
That figure appeared to reflect widespread uncertainty among Croats over what membership will really mean.
But the result suggested the EU had not completely lost its appeal in the struggling western Balkans despite the debt crisis that is threatening the single currency.
Many Croats hope accession will mark a clear break with the region's recent past of war and nationalism, and help its weak economy through EU funds and full access to the bloc's common market.
The slow pace of reform in the rest of the western Balkans, and waning enthusiasm within the EU for further enlargement, mean other countries in Croatia's neighborhood - such as Serbia, Bosnia and Albania - will wait years before they too can join. Tiny Montenegro on the Adriatic coast is next in line.
"GREAT RELIEF"
"I feel great relief, for me, for my children," said bank worker Jasna Maric, 43. "Only fifteen years ago, we were still killing each other here, so this was a strategic decision."
Foreign Minister Vesna Pusic, though visibly delighted, sounded a note of caution:
"With this, we leave behind political instability, but the rest will depend on our ability and creativity," Pusic said. "Our chances will be better, but no one will do the job for us."
Croatia saw strong growth in the past decade on the back of foreign lending and waves of tourists to its Adriatic coast, but its economy has been hit hard by the global economic crisis.
It will have to work hard to make its public finances sustainable before it is allowed to join the euro zone, which analysts say is unlikely in the next five years.
Its gross domestic product per capita is 61 percent of the EU average.
Analysts and government officials had warned that rejection of EU accession on Sunday would have hit the country's credit rating, deterred investors and further dampened any prospect of a quick economic recovery.
The "No" camp expressed bitter disappointment, and argued the referendum did not truly reflect the will of the people because of the low turnout.
"This result is against the interests of the Croatian people," said Zeljko Sacic, a war veteran and leading Euro-skeptic.
"This is the end of Croatia's freedom. The EU is falling apart and the Croatian man will be worse off than today."
(Reporting by Zoran Radosavljevic and Igor Ilic; Editing by Matt Robinson)
Arguably, targeting things like lifestyle factors is also "personalized medicine", in the sense that treating patient X specially because a defect in their homozygous foo allele predisposes them to cardiac disease isn't all that different from treating patient X specially because getting no exercise predisposes them to cardiac disease.(and, in uncomfortably-many-but-not-all cases, the "personal" element is just the most visible factor in a stew that includes environmental and social influences, like diesel soot and cube farms...)
I'd be inclined to say that Emanuel is neither a dinosaur(he isn't rejecting the new-and-shiny out of hand, just pointing out that much of it offers questionable bang-for-buck compared to the low hanging fruit offered by seriously boring lifestyle stuff), nor a pragmatist(y'know why people like to ignore lifestyle factors and focus on genetic whiz-bangs and hypothetical personalized super-pills? Because lifestyle intervention lies dead at the center of the intersection of "really boring", "really hard", and "lousy patient compliance".
We already have plenty of good advice to go around(by no means perfect knowledge; but we know much better than we do), largely unheeded and often coexisting with social conditions that actively work against heeding it. We don't actually have personalized genetic-super-pills(with limited but important exceptions: oncology, for instance, has a number of genetic markers that have proved tractable to test for and highly useful to know. Some rare hereditary disorders have also been well worked up. Much of the rest of it remains in the "yeah, it sure does appear to run in families; and we made this mouse model by tweaking the genes like so; but that doesn't help you very much...); but we could probably get people to take them fairly regularly if we did...
WASHINGTON ? Mitt Romney perpetuated one unsubstantiated claim, about his record at Bain Capital, and more or less corrected himself on another, about President Barack Obama's health care law, in the latest Republican presidential debate.
His rivals flubbed history, Newt Gingrich blaming a Democratic president for a jobless rate he never had, and Ron Paul painting an idyllic picture of life before Medicare that did not reflect deprivations of that time.
A look at some of the claims in the debate Thursday night and how they compare with the facts:
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ROMNEY: "We started a number of businesses; four in particular created 120,000 jobs, as of today. We started them years ago. They've grown ? grown well beyond the time I was there to 120,000 people that have been employed by those enterprises. ... Those that have been documented to have lost jobs, lost about 10,000 jobs. So (120,000 less 10,000) means that we created something over 100,000 jobs."
THE FACTS: Romney now has acknowledged the negative side of the ledger from his years with Bain Capital, but hardly laid out the full story. His claim to have created more than 100,000 jobs in the private sector as a venture capitalist remains unsupported.
Romney mentioned four successful investments in companies that now employ some 120,000 people, having grown since he was involved in them a decade or ago or longer. From that, he subtracted the number of jobs that he said are known to have been lost at certain other companies.
What's missing is anything close to a complete list of winners and losers ? and the bottom line on jobs. Bain under Romney invested in scores of private companies that don't have the obligation of big publicly traded corporations to disclose finances. Romney acknowledged that he was using current employment figures for the four companies, not the number of jobs they had when he left Bain Capital, yet took credit for them in his analysis.
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GINGRICH: "Under Jimmy Carter, we had the wrong laws, the wrong regulations, the wrong leadership, and we killed jobs. We had inflation. We went to 10.8 percent unemployment. Under Ronald Reagan, we had the right job ? the right laws, the right regulators, the right leadership. We created 16 million new jobs."
FACT CHECK: Sure, inflation was bad and gas lines long, but under Carter's presidency unemployment never topped 7.8 percent. The unemployment rate did reach 10.8 percent, but not until November 1982, nearly two years into Reagan's first term.
Most economists attribute the jobless increase to a sharp rise in interest rates engineered by then-Federal Reserve Chairman Paul Volcker in an ultimately successful effort to choke off inflation. Unemployment began to fall in 1983 and dropped to 7.2 percent in November 1984, when Reagan easily won re-election.
The economy did add 16 million jobs during Reagan's 1981-1989 presidency. Gingrich's assertion that "we created" them may have left the impression that he was a key figure in that growth. Although Gingrich was first elected to the House in 1978, his first Republican leadership position, as minority whip, began when Reagan left office, in 1989.
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PAUL: "I had the privilege of practicing medicine in the early `60s, before we had any government (health care). It worked rather well, and there was nobody on the street suffering with no medical care. But Medicare and Medicaid came in and it just expanded."
THE FACTS: Before Medicare was created in the mid-1960s, only about half of the elderly had private insurance for hospital care, and they were facing rising costs for those policies on their fixed incomes. Medicare was hugely contentious at the time, seen by many doctors as a socialist takeover, but few argued that the status quo could be maintained.
A Health, Education and Welfare Department report to Congress in 1959, during the Republican administration of Dwight Eisenhower, took no position on what the federal government should do but stated "a larger proportion of the aged than of other persons must turn to public assistance for payment of their medical bills or rely on `free' care from hospitals and physicians."
Paul advocates a return to an era when doctors would treat the needy for free. But even in the old days, charity came with a cost. Research from the pre-Medicare era shows that the cost of free care was transferred to paying customers and the insurance industry.
___
ROMNEY: "I could have stayed in Detroit, like him, and gotten pulled up in the car company. I went off on my own. I didn't inherit money from my parents. What I have, I earned. I worked hard, the American way."
THE FACTS: It's true there's no evidence Romney's wealthy family gave him a trust fund, or helped him secure a job at Bain Capital, where he would ultimately make his fortune. But it's not entirely the case that his success is wholly the result of his own hard work.
Romney's father, George, was an automobile industry CEO and a Michigan governor. He paid for Mitt to attend the Cranbrook School, a private boarding school in the Detroit area. The education didn't hurt Romney's ability to get into Harvard, where he earned law and business degrees in 1975.
While Romney appears to have gotten a job at Bain out of college on his own, the Boston Globe book "The Real Romney" reports that Romney's parents helped him and his wife buy their first home when he was in his early 20s.
On Thursday night, the Romney campaign did not dispute the finding that Romney's parents helped pay for that house, in the Boston suburb of Belmont.
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ROMNEY: "The executive order is a beginning process. It's one thing, but it doesn't completely eliminate Obamacare. ... We have to go after a complete repeal. And that's going to have to have to happen with a House and a Senate, hopefully, that are Republican."
THE FACTS: With that statement, Romney essentially corrected his repeated suggestions in early debates and speeches that he would eliminate President Barack Obama's health care law with a stroke of the pen on his first day in office ? a power no president has.
In one variation of the claim, he had vowed in a Sept. 7 debate that on Day One, he would sign an executive order "granting a waiver from Obamacare to all 50 states." This, despite the fact that the law lays out an onerous process for letting individual states off the hook from its requirements, and that process cannot begin until 2017.
Now he acknowledges the political reality that a Republican president would need Republican control of Congress to have a strong shot at repealing the law.
___
Associated Press writers Steve Peoples, Jim Drinkard, and Christopher S. Rugaber contributed to this report.
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Public release date: 30-Jan-2012
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