#This sensor technology could make recharging a thing of the past If you own a smartphone,
The company lists medical monitoring, sportswear clothing and even connected cars as potential use cases for its technology-bend
This is the first time movement has been restored voluntarily without surgery.""These encouraging results provide continued evidence that spinal cord injury may no longer mean a lifelong sentence of paralysis and support the need for more research,"Roderic Pettigrew,
a bioengineer at the US National institutes of health who wasn't directly involved in the study, said in a press release."
"The potential to offer a life-changing therapy to patients without requiring surgery would be a major advance;
and has been shown to help mice with spinal cord injuries move again. At the start of the study the men's legs only moved
whether the procedure can help people with partial paralysis."We have focused on individuals with complete paralysis throughout this whole process
that those individuals with partial injuries have even more room for improvement.""""All patients are going to need something slightly different,
so that the physician and the patient can select a therapy that is best for them.""The results have been published open-access in the Journal of Neurotrauma u
#New Ebola vaccine is 100%successful in Guinea clinical trials A new single-dose vaccine has been shown to be 100 percent effective against Ebola after just one week.
000 people in Guinea offer the most promising evidence so far that we may be able to protect against the haemorrhagic fever.
Known as VSV-ZEBOV, the vaccine is now going through further trials in younger patients, and if all goes to plan could become the first licensed vaccine against Ebola.
As of right now around 28,000 people in Guinea, Sierra leone and Libera have been infected with Ebola,
A second study group of 3, 528 people were injected with the vaccine three weeks after they'd potentially been exposed to Ebola.
but the rest were protected fully against the haemorrhagic fever within six days.""Indeed, no vaccinee developed symptoms more than six days after vaccination, irrespective of whether vaccination was delayed immediate
or,"the researchers report in The Lancet. After it became clear that vaccinating people immediately was the best strategy,
the international team of researchers stopped waiting to vaccinate those at high-risk of infection.""The initial results of the study show that the vaccine can effectively contain the further spread of the Ebola virus,"the University of Bern in Switzerland,
which was involved in the research, wrote in a statement.""We believe that the world is on the verge of an efficacious Ebola vaccine,
"World Health Organisation (WHO) vaccine expert Marie Paule Kieny told reporters at a media briefing announcing the results on Friday.
The trial, which was supported by the drug firm Merck, THE WHO and the Canadian, Norwegian and Guinean governments, is now continuing in children between the ages of 13 and 17.
#Alzheimer's plaques reduced by targeting sugar attachment to the BACE1 enzyme A major factor contributing to Alzheimer's disease is the formation of pathogenic A?
and Naoyuki Taniguchi at RIKEN in collaboration with Tamao Endo and Shigeo Murayama at the Tokyo Metropolitan Institute of Gerontology showed that much of the BACE1 found in the brains of Alzheimer's disease patients is modified by the attachment of a particular sugar with the help of the enzyme
and can act to reduce Alzheimer's pathology with potentially few side effects. This research highlights the importance of glycosylation--the modification of proteins by sugars.
although a sugar change is considered often just a marker for disease or a specific cell type our team has demonstrated clearly the functional role of a glycan during AD development.
The sensor, reported in a proof-of-concept study in the ACS journal Analytical Chemistry, has the potential to eliminate finger-pricking for many people with diabetes.
Joseph Wang and colleagues in San diego note that diabetes affects hundreds of millions of people worldwide.
Many of these patients are instructed to monitor closely their blood glucose levels to manage the disease.
The researchers conclude that the device could potentially be used for diabetes management and for other conditions such as kidney disease e
This provides the conditions needed to study primary cells, such as neurons, opening doors for exploration of the pathogenic mechanisms of neural diseases and potentially leading to new gene therapies.
"Non-destructive manipulation of cells over time and in the correct environment is a key enabling technology highly needed within the biology and medical research communities,
#Novel method to predict postoperative liver cancer recurrence in transplant patients UCLA transplantation researchers have developed a novel method that more accurately calculates the risk of disease recurrence in liver cancer patients who have undergone a liver transplant,
Chair in Surgery and director of the Pfleger Liver Institute and Dumont-UCLA Transplant and Liver Cancer Centers presented the study during the annual meeting of the Southern Surgical Association.
The study appears in the early online edition of the peer-reviewed Journal of the American College of Surgeons.
The predictive calculator also known as a nomogram was developed after the research team analyzed data from UCLA's 30 years of experience with liver transplantation for liver cancer.
The retrospective study included 865 liver cancer patients who had transplants between 1984 and 2013 said study first author Dr. Vatche G. Agopian an assistant professor of surgery in the division
which liver cancer patients might be good candidates for transplant and patients with all sizes and numbers of tumors underwent transplantation often times with early recurrence of disease.
In 1996 radiologic criteria popularized as the Milan criteria were introduced and recommended transplantation be limited to patients with a single tumor of five centimeters or less or up to three tumors with not any single tumor larger than three centimeters.
However the criteria didn't take into account the aggressiveness of the tumor or other blood biomarkers that can help predict recurrence Agopian said.
UCLA's nomogram used three groups of factors to predict recurrence and was more accurate than the Milan criteria
and the existing American Joint Committee on Cancer pathologic TNM staging system giving transplant physicians and oncologists more information to work with in deciding how often to monitor for recurrence and whether or not adjuvant treatment
This novel nomogram includes three important groups of information that proved to be very accurate in predicting recurrence in liver cancer patients better than any other system out there Agopian said.
and have a meaningful discussion with transplant recipients regarding their post-transplant risk of cancer recurrence.
--or whether a patient with a high risk of recurrence might need treatment following the transplant.
The three groups of factors that comprise the UCLA nomogram include pre-transplant radiologic information
or the number and size of tumors on MRI and CT SCANS three pre-transplant blood biomarkers thought to be predictive for cancer recurrence
and pathological characteristics of the explanted liver. The diseased liver is studied to determine the grade
or aggressiveness of the tumor and whether the cancer has invaded the liver's blood vessels factors that can't be determined before transplant.
For example a patient with a 5 centimeter tumor who would have qualified for liver transplant under the Milan criteria might in fact have a very aggressive tumor that is likely to recur after transplant
while a patient with a larger tumor might have a very low grade cancer and be at lower risk for recurrence.
and get individualized predicted risks of cancer recurrence Agopian said. The Milan criteria presented a major step in improving the outcomes of liver cancer patients undergoing transplant Agopian said.
However there is now a growing consensus and body of evidence that these criteria are too conservative
and that incorporation of other factors may improve the ability to select for patients with favorable tumor biology regardless of size who stand to benefit from liver transplantation.
About 32000 Americans will be diagnosed with liver cancer this year. Of those 23000 will die of their disease.
Liver cancer is the sixth most common cause of cancer worldwide and the third most common cause of cancer-related death.
In the United states the incidence of liver cancer has doubled nearly over the last two decades.
For most patients who are diagnosed with liver cancer it generally is advanced too to treat with surgery.
For patients with underlying liver dysfunction who are unable to undergo surgery to remove the tumor liver transplantation is the best way to treat the patient.
In the largest single-institution experience with liver transplant for liver cancer excellent long-term survival was achieved.
Incorporation of routine pre-transplant biomarkers to existing radiographic size criteria significantly improves the ability to predict post-transplant recurrence
and should be considered in recipient selection the study states. A novel clinicopathologic prognostic nomogram accurately predicts liver cancer recurrence after liver transplant
and may guide frequency of post-transplant surveillance and adjuvant therapy y
#Rate of investment in medical research has declined in U s. increased globally From 2004 to 2012,
the rate of investment in medical research in the U s. declined, while there has been an increase in research investment globally, particularly in Asia, according to a study in the January 13 issue of JAMA.
For the last century medical research including public health advances has been the primary source of and an essential contributor to improvement in the health and longevity of individuals and populations in developed countries.
The United states has historically been where research has found the greatest support and has generated more than half the world's funding for many decades.
Few previous analyses have compared medical research in the United states with other developed countries according to background information in the article.
Hamilton Moses III M d. of the Alerion Institute and Alerion Advisors LLC North Garden Va. and Johns Hopkins School of medicine Baltimore and colleagues examined developments over the past two decades
and who supports medical research as well as resulting patents publications and new drug and device approvals.
and disease burden by source and industry type. Patents and publications (1981-2011) were evaluated using citation rates and impact factors.
Reduced science investment The largest increase in biomedical and health services research funding in the U s. occurred between 1994 and 2004
and (in real terms) decreased in 3 of the last 5 years reaching $117 billion (4. 5 percent) of total health care expenditures.
From 1994 to 2004 the medical device biotechnology and pharmaceutical industries had annual growth rates greater than 6 percent per year with biotechnology demonstrating the largest increases.
The share of U s. medical research funding from industry accounted for 46 percent in 1994
Industry reduced early-stage research favoring medical devices bioengineered drugs and late-stage clinical trials particularly for cancer and rare diseases.
National institutes of health (NIH allocations did not correlate proportionately with disease burden. Cancer and HIV/AIDS were funded well above the predicted levels based on U s. disability alone with cancer accounting for 16 percent of total NIH funding and 25 percent of all
medicines currently in clinical trials. Underfunding of service innovation Health services research (which examines access to care the quality
and cost of care and the health and well-being of individuals communities and populations) accounted for between 0. 2 percent and 0. 3 percent of national health expenditures between 2003 and 2011 an approximately 20-fold difference
in comparison with total medical research funding. Private insurers ranked last (0. 04 percent of revenue) and health systems 19th (0. 1 percent of revenue) among 22 industries in their investment in innovation.
An increment of $8 billion to $15 billion yearly would occur if service firms were to reach median research and development funding.
Globalization U s. government research funding declined from 57 percent (2004) to 50 percent (2012) of the global total as did that of U s. companies (50 percent to 41 percent) with the total U s
The analysis underscores the need for the United states to find new sources to support medical research
Restore the U s. Lead in Biomedical Researchto achieve a new strategic vision for research the United states will need a roadmap that sets priorities describes needed structural and organizational changes
and creates an environment that enables innovation write Victor J. Dzau M d. of the Institute of Medicine Washington D c. and Harvey V. Fineberg M d. Ph d. of the University of California San francisco in an accompanying editorial.
and efficiency the United states can retain its leadership position in biomedical research h
#Glass for battery electrodes In this regard researchers are diligently looking for new materials that exhibit a greater energy density
#Novel eye-tracking technology detects concussions head injury severity Neuroscientists and concussion experts from NYU Langone and elsewhere in a study publishing online January 29 in Journal of Neurotrauma present a unique simple and objective diagnostic tool for concussion that can be utilized in the emergency room or one day
or brain injury in patients presenting to emergency departments following head trauma. Concussion is a condition that has been plagued by the lack of an objective diagnostic tool
and fears among those affected and their families says lead investigator Uzma Samadani MD Phd assistant professor in the Departments of Neurosurgery Psychiatry Neuroscience and Physiology at NYU Langone.
and therapeutics and help assess recovery such as when a patient can safely return to work following a head injury.
The eyes have served as a window into the brain with disconjugate eye movements--eyes rotating in opposite directions--considered a principal marker for head trauma as early as 3500 years ago.
Current estimates by optometrists suggest that up to 90 percent of patients with concussions or blast injuries exhibit dysfunction in their eye movements.
along with a physician's finger according to Dr. Samadani who also serves as co-director of the Steven & Alexandra Cohen Veterans Center for the Study of Posttraumatic Stress and Traumatic Brain injury at NYU Langone.
and colleagues at the Cohen Veterans Center to assess eye movement in veterans of the long Middle east conflicts suspected of suffering from traumatic brain injury (TBI) concussion or other forms of brain injury.
In this new study researchers compared 64 healthy control subjects to 75 patients who had experienced trauma that brought them to the emergency department at Bellevue Hospital Center in New york city with
and had CT SCANS showing new brain damage as well as 39 trauma patients who had hit their heads
or extremity injuries but did not require head CT SCANS had similar abilities to coordinate eye movements as normal uninjured controls.
and had normal CT SCANS most were slightly worse at 1-2 weeks after the injury
and subsequently recovered about one month after the injury. Among all trauma patients the severity of concussive symptoms correlated with severity of disconjugacy.
and professor and chairman of the Department of Neurological Surgery at University of Washington Medicine and co-chair of the Head Neck and Spine Committee of the National Football league.
Traumatic brain injury is one of the most common causes of neurologic morbidity in the world today Dr. Ellenbogen says.
and occurs in all sports being able to make the diagnosis quickly and accurately is essential.
The challenge physicians have in identifying concussion is that the diagnosis is often based on self-reported symptoms.
and thus help the physician make a rapid and accurate diagnosis. By tracking eye movements they have been able to quantitatively assess the function of the brain.
which found that the use of this novel eye-tracking technology could reveal edema or swelling in the brain as a potential biomarker for assessing brain function and monitoring recovery in people with head injuries.
That study published Dec 16 in Journal of Neurosurgery looked exclusively at military veterans. Dr. Samadani's future work aims to replicate eye-tracking's diagnostic potential for head injuries on a larger scale in Iraq
and Afghanistan veterans with post-concussive syndrome and post-blast military brain injury. Estimates from the Centers for Disease Control and Prevention state about 2. 5 million U s. emergency department visits were associated with traumatic brain injury in 2010 with rates increasing by about 70 percent over the previous decade.
Currently there is no tool seen as a gold standard for diagnosing concussions and imaging tests like CT SCANS
and MRIS are ineffective in the absence of structural damage to the brain. Two patients who suffer a head injury
and present with virtually-identical CT SCANS might have completely different symptoms Dr. Samadani points out.
That's where eye-tracking can help objectively reveal when one patient may be affected much more by a concussion than another.
Also lending third-party support for Dr. Samadani's research is M. Sean Grady MD the Charles Harrison Frazier Professor and Chairman of the Department of Neurosurgery at the Perelman School of medicine at the University
#Genetic discovery about childhood blindness paves way for new treatments Finding genes for retinal degenerations has immediate benefits for people living with blindness and vision loss, their families,
Establishing a genetic cause confirms the clinical diagnosis at the molecular level, helps predict the future visual prognosis,
suggests therapies, and allows some patients to join clinical trials. While more than 200 genes for retinal degenerations have been identified,
When 11 year old Naomi Lalandec walked into Dr. Robert Koenekoop's clinic at the Montreal Children's Hospital of the Mcgill University Health Centre (MUHC) with blindness and dwarfism due to
Oliver Mcfarlane Syndrome (OMS her unknown mutation sparked an international gene hunt. Comparing her genome to others with OMS and Leber congenital amaurosis (LCA),
another form of childhood blindness, uncovered a new gene that is critical for vision. What makes this breakthrough exceptional is that it opens up new treatment avenues for OMS and LCA and potentially other retinal degenerative diseases."
"It was like finding a needle in a haystack, "said Dr. Koenekoop, who is also a researcher at the Research Institute of the MUHC and a Professor of Human genetics, Paediatric Surgery and Ophthalmology at Mcgill University."
"It was so obvious to all of us that this was big; a new gene, a possible new disease pathway, a new treatment avenue."
"With ongoing support from the Foundation Fighting Blindness (FFB), Canada's largest charity supporting vision research, Dr. Koenekoop has spent more than a decade searching for genes linked to blindness.
This search brought together an international team of scientists, including Dr. Michel Cayouette at the Institut de recherches cliniques de Montréal (IRCM), Dr. Doris Kretzschmar at the Oregon Health and Science University, Dr. Jacek Majewski
from the Mcgill University and Génome Québec Innovation Centre and more than 30 others from around the world.
and Dr. Cayouette,"said Dr. Mary Sunderland, Director of research & Education at the Foundation Fighting Blindness."
which will be essential to study how manipulating phospholipids could generate innovative strategies to treat blindness n
#More clues to how drug reverses obesity diabetes fatty liver disease In addition to illuminating how the drug amlexanox reverses obesity diabetes
and fatty liver disease the findings suggest a new pathway for future treatments. The research was published Jan 12 in Nature Communications.
Investigators in the lab of Alan Saltiel the Mary Sue Coleman Director of U-M's Life sciences Institute had discovered previously that this drug
which had been used in the treatment of asthma also has the ability to cause weight loss
and improve diabetes in obese mice. The current study revealed that amlexanox exerts its effects through a specialized type of fat cell by increasing the level of a second messenger molecule called camp.
In the livers of diabetic mice interleukin-6 reduces production of glucose so that overall blood sugar is lowered.
The finding is the latest piece of a complex obesity-inflammation-diabetes puzzle that Saltiel lab investigators have been working to solve
In 2013 the researchers discovered that amlexanox an off-patent drug currently prescribed for the treatment of asthma and other uses reversed obesity diabetes and fatty liver in mice.
The U-M study explains how increased camp in fat cells promotes the secretion of the hormone interleukin-6 which signals the liver to stop producing glucose--thus improving overall blood sugar levels in obese diabetic mice e
#Mechanism leading to drug resistance metastasis in melanoma patients discovered Moffitt Cancer Center researchers have discovered a mechanism that leads to resistance to targeted therapy in melanoma patients
Targeted biological therapy can reduce toxicity and improve outcomes for many cancer patients, when compared to the adverse effects of standard chemotherapeutic drugs.
However, patients often develop resistance to these targeted therapies, resulting in more aggressive cells that can spread to other sites or cause regrowth of primary tumors.
B-Raf is a protein that is frequently mutated in human cancers leading to increased tumor cell growth, survival and migration.
Drugs that target B-Raf or another protein in the same network called MEK have proved effective in clinical trials.
Several B-Raf and MEK inhibitors have been approved with the combination of A b-Raf and a MEK inhibitor being the current standard of care for patients with B-Raf mutant melanoma.
However over time many patients become resistant to B-Raf and B-Raf/MEK inhibitor therapy.
Moffitt researchers found that patients who are on B-Raf inhibitor drugs develop more new metastases than patients who are on standard chemotherapy.
The researchers wanted to determine how this acquired resistance develops in order to devise better treatment options for patients.
They found that melanoma cells that are resistant to B-Raf inhibitors tend to be more aggressive and invasive,
thereby allowing the tumor to spread to a new organ site. They used a large screening approach
and MEK inhibitors are given to patients intermittently may reduce the aggressiveness of the diseasemeaning patients could stay on therapy for more time,
"said Keiran S. Smalley, Ph d.,scientific director of the Donald A. Adam Comprehensive Melanoma Research center of Excellence at Moffitt.
The research also showed that targeting Epha2 reduced the aggressive behavior of the melanoma cells.
This suggests that drugs that target Epha2 may prevent the development of new disease in patients who receive B-Raf and B-Raf/MEK inhibitor therapy.
The study was published in the online edition of Cancer Discovery on Dec 26 2014 0
#Toward quantum chips: Packing single-photon detectors on an optical chip is crucial for quantum-computational circuits Single-photon detectors are notoriously temperamental:
Although there was a glimmer of hope for an end in sight to the Ebola epidemic these countries were reported to be on the brink of a major food crisis.
FAO and WFP stated that the Ebola epidemic has caused a significant shock to the food
Many farmers have abandoned their fields and harvests for fear of the disease. In Sierra leone for instance it is reported that up to 40%of farms were abandoned in the worst affected areas.
#WHO grants approval for safe effective meningitis A vaccine for infants The World health organization (WHO) has opened the door to routine immunization of infants in Sub-saharan africa by approving for use an innovative and affordable vaccine that has all but rid the meningitis belt of a major cause
of deadly epidemics. In the four years since its introduction in Africa, Menafrivac has had an immediate and dramatic impact in breaking the cycle of meningitis A epidemics,
leading the safe, effective technology to be approved by WHO through its prequalification process for use in infants,
and paving the way for protecting millions more children at risk of the deadly disease.
The announcement was made today by the Meningitis Vaccine Project (MVP)--a partnership between the global health nonprofit PATH and WHO--and Serum institute of india Ltd (SIIL),
which manufactures the Menafrivac vaccine.""Initial mass vaccination campaigns with Menafrivac have been highly effective in reducing the number of meningitis A cases,
"said Dr. Marie-Pierre Préziosi, director of MVP.""But epidemics will return when rising numbers of unprotected newborns become a larger proportion of the total population over time.
Now, with this decision, health officials will be able to ensure that population-wide protection is sustained by routinely immunizing infants."
5 g dose of the meningitis A vaccine meets international standards of quality, safety, and efficacy and can
Before the introduction of Menafrivac, people living in countries of the meningitis belt, which stretches from Senegal in the west to Ethiopia in the east,
were struck regularly by meningitis A epidemics in which sudden onset of symptoms could rapidly lead to death or permanent disability.
One of the most devastating outbreaks ever recorded was in 1996-1997 when an epidemic wave infected more than 250,000 people
and killed over 25,000 in just a few months. The only existing vaccine was insufficient to break the cycle.
Protection at an affordable price In 2004, MVP partnered with SIIL to develop an affordable, tailor-made vaccine for use against meningitis A in Sub-saharan africa.
Menafrivac was developed in record time at less than 1 tenth the cost of a typical new vaccine. Since campaigns started in 2010,
Menafrivac has been administered to over 215 million people in 15 countries of the African meningitis belt:
Benin, Burkina faso, Cameroon, Chad, Côte d'ivoire, Ethiopia, Ghana, Mali, Niger, Mauritania, Nigeria, Senegal, Sudan, Togo, and The gambia."
"Developing the Menafrivac vaccine fit exactly Serum's ingrained philosophy of bringing down prices of vaccines
"We at Serum Institute are extremely proud of being part of an international partnership that brought an end to a public health issue that has been plaguing Sub-saharan africa for more than a century."
"One year after large-scale vaccine introduction in late 2010, for example, experience from Burkina faso provided early evidence that mass vaccination was associated with a significantly reduced risk of meningitis in the targeted population,
Findings were confirmed in a major way in Chad in 2012 where researchers reported a dramatic reduction in transmission and incidence of meningitis A a drop of more than 90 percent following vaccination.
Support from Gavi, the Vaccine Alliance; the United nations children's fund (UNICEF; PATH; WHO; and national governments has been crucial for mass vaccination campaigns that are due to continue until 2016 to cover at-risk populations in all 26 countries where disease burden from meningitis A is greatest.
From mass campaigns to routine immunizations In parallel to the large-scale vaccination campaigns, clinical studies were designed
and conducted to determine the safety, immunogenicity, and optimal dosage and immunization schedule for administering Menafrivac to infants and toddlers alongside other routine childhood vaccines in African meningitis belt countries.
Results from two infant clinical studies in Ghana and Mali and vaccine introduction impact data were presented to THE WHO Strategic Advisory Group of Experts on Immunization (SAGE) in October 2014
and these SAGE experts concluded that a one-dose schedule at 9 months of age or older was recommended to achieve sustainable disease control following the initial mass campaigns in 1-29 year olds.
Specifically, THE WHO prequalification that was announced today allows United nations procurement agencies to purchase the vaccine for use in routine immunization programs in meningitis-belt countries
while serving as an endorsement of quality for countries interested in adopting it. WHO is already working with African countries to ensure a smooth transition from mass campaigns to routine immunization
and so ensure sustainable disease control in the region. Seven countries (Burkina faso Cameroon, Chad, Ghana, Mali, Niger,
while mass vaccination campaigns will continue in remaining countries. Created in June 2001 with the goal of eliminating epidemic meningitis as a public health problem in Sub-saharan africa,
MVP was one of the earliest product development partnerships funded by the Bill & Melinda Gates Foundation.
Menafrivac was the first vaccine developed outside"traditional pharma, "and the only vaccine developed specifically for people in Africa."
"With Menafrivac, we created a revolutionary new model for vaccine development and now we stand on the brink of protecting an entire generation,
and those to come, from a devastating disease, "said Dr. Kathy Neuzil, director of Vaccine Access and Delivery at PATH."
"Our efforts began with a request by African leaders to address a major health challenge affecting hundreds of millions of people,
and in less than a decade, we proved that a safe, effective vaccine could be developed and deployed across multiple countries at a price that was sustainable.""
""The benefits of childhood immunization last a lifetime and the Menafrivac vaccine is one of the greatest success stories that shows
what partners can accomplish when we commit together to a compelling cause, "said Chris Elias,
"Prequalification of the Menafrivac vaccine for infants clears the way for the routine immunization of every child before his
or her first birthday to ensure long-term meningitis control.""""We are more than halfway through with introducing the vaccine in meningitis-belt countries,
and the first introductions have been a stunning success, "said Dr. Jeanmarie Okwo-Bele, director of THE WHO Department of Immunization, Vaccines and Biologicals."
"But we cannot yet declare a win on meningitis epidemics in Sub-saharan africa. If we rest on our laurels
and don't finish the job, meningitis epidemics will return in a major way in the years to come.
Elimination of meningitis epidemics will require meningitis belt countries'political commitment to complete the mass campaigns
and introduce the vaccine in the Expanded Programme on Immunization. Then and only then will we win the battle against meningitis. a
Overtext Web Module V3.0 Alpha
Copyright Semantic-Knowledge, 1994-2011