A new study has found that a group of chemotherapy drugs can result in mutations that may trigger the relapse of blood cancer in children.Chemotherapy has helped make acute lymphoblastic leukemia (ALL) one of the most survivable childhood cancers. Now, researchers working in the US, Germany and China have shown how chemotherapy drugs called thiopurines can lead to mutations that set patients up for relapse. The findings of the study were published in the journal ‘Nature Cancer’.
The research provided the first direct genomic and experimental evidence in pediatric cancer that drug-resistant mutations can be induced by chemotherapy and are not always present at diagnosis. “The findings offer a paradigm shift in understanding how drug resistance develops,” said Jinghui Zhang, PhD, Department of Computational Biology chair at St. Jude Children’s Research Hospital.
“The results also suggest possible treatment strategies for ALL patients who relapse, including screening to identify those who should avoid additional thiopurine treatment,” added Zhang. Zhang is co-corresponding author of the study with Bin-Bing Zhou, Ph.D., of Shanghai Children’s Medical Center; and Renate Kirschner-Schwabe, M.D., of Charite-Universitaetsmedizin Berlin.
THE ROOTS OF RELAPSE
While 94 per cent of St. Jude patients with ALL become five-year survivors, relapse remains the leading cause of death worldwide for children and adolescents with ALL. This study involved ALL samples collected from relapsed pediatric ALL patients in the US, China and Germany. Researchers analysed more than 1,000 samples collected from the patients at different times in treatment, including samples from 181 patients collected at diagnosis, remission and relapse.Co-first author Samuel Brady, PhD, of St. Jude Computational Biology, identified a mutational signature that helped decipher the process. Mutational signatures reflect the history of genetic changes in cells.
Brady and his colleagues linked increased thiopurine-induced mutations to genes such as MSH2 that become mutated in leukemia. The mutations inactivated a DNA repair process called mismatch repair and rendered ALL resistant to thiopurines. The combination fueled a 10-fold increase in ALL mutations, including an alteration in the tumour suppressor gene TP53. The mutation, TP53 R248Q, promoted resistance to multiple chemotherapy drugs, including vincristine, daunorubicin and cytarabine.
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MORE THAN 5 HOURS’ EMERGENCY WAIT BEFORE ADMISSION LINKED TO INCREASED DEATH RISK: STUDY
A new study has found that waiting for more than five hours in emergency care before admission to the hospital is associated with a heightened risk of death from any cause within the next 30 days.
This can be measured and represented as a ‘number needed to harm metric’, of 1 extra death for every 82 patients delayed after 6-8 hours, concluded the researchers.
The 4-hour waiting time target before hospital discharge, admission, or transfer was introduced in 2004 in England, and shortly afterward in the other devolved nations of the UK, in a bid to tackle emergency department overcrowding.
Several other countries, including Canada and Australia, followed suit with similar measures. But in recent years, performance against this target has steadily declined amid rising patient demand.
Delays to timely admission from emergency departments have been linked to patient harm, and the researchers wanted to quantify the increased risk of death resulting from these delays.
They drew on Hospital Episode Statistics and Office of National Statistics data for England, covering every patient admitted to hospital from each major (type 1) emergency department in England between April 2016 and March 2018.
They compared recorded deaths from any cause within 30 days of admission with those that would be expected, allowing for a wide range of potentially influential factors.
These included sex, age, deprivation level, concurrent conditions, time of the day and month, previous attendances/emergency admissions, and crowding in the emergency department at the time.
Between April 2016 and March 2018, 26,738,514 people attended an emergency department in England: 5,249,891 of them were admitted to the hospital.
In all, 433,962 people died within 30 days during the study period. The overall unadjusted 30-day death rate was just under 9 per cent.
The average age of patients admitted was 55; the number of concurrent conditions rose in tandem with increasing age. Nearly twice as many patients came from areas of greatest deprivation as came from areas of least deprivation.
The most frequent time of arrival was between 12:00 and 17:59 hours, with the first 3 months of the year accounting for the biggest proportion of patients. The average wait in the emergency department was just under 5 hours; the breach rate of the 4-hour waiting time target averaged around 38 per cent
A statistically significant linear increase in the death rate emerged for waits longer than 5 hours in the emergency department.
After accounting for potentially influential risk factors, the death rate was 8 per cent higher than expected among those patients waiting between 6-8 hours before admission to hospital, and 10 per cent higher than expected for those waiting 8-12 hours, compared with patients moving on within 6 hours.
This can be measured and represented as a ‘number needed to harm metric’, of 1 extra death for every 82 patients delayed for 6-8 hours, said the researchers.
“The results from this study show that there is a ‘dose-dependent’ association between time in excess of 5 hours in the [emergency department] for admitted patients and their all-cause 30-day mortality,” they wrote.
“Moreover, 30-day mortality is a relatively crude metric that does not account for either increase in patient morbidity or for the inevitably worse patient experiences,” they added.
This is an observational study, and as such, can’t establish cause and effect.
But, said the researchers, “Despite limited supporting evidence, there are a number of clinically plausible reasons to accept that there is a temporal association between delayed admission to a hospital inpatient bed and poorer patient outcomes.”
Long stays in the emergency department are associated with exit block and crowding, which can delay access to vital treatments. And they are associated with an increase in subsequent hospital length of stay, especially for older patients, noted the researchers.
This, in turn, increases the risk of hospital-acquired infection and physiological and psychological deconditioning, they said.
Exit block is usually also related to bed occupancy levels, which are highest in the late afternoon and usually lower around midnight. A disproportionate number of delayed patients are therefore likely to be moved to a ward during the night when staffing levels are lowest, they added.
And they concluded, “This study confirms that healthcare policymakers should continue to mandate timely admission from the [emergency department] in order to protect patients from hospital-associated harm.”
In a linked editorial, Derek Prentice, lay member for the Royal College of Emergency Medicine, insisted, “Let nobody be in doubt any longer, the NHS 4-hour operational target is, as many of us have always known, of key importance to patient safety.”
With sufficient funding for NHS beds and staff and social care provision, and prioritisation from NHS leaders, hospitals should be able to meet this target, he said. But these have been in short supply in recent years, he suggested. “Could there be better measures? Possibly, but until there are, and crucially, ones that have the support and trust of patients, the 4-hour target or one very close to this, must remain the gold standard. Those in doubt need look no further than the evidence provided by this excellent paper,” he asserted.
The Study has been published in the Emergency Medicine Journal ‘.
STUDY FINDS COVID-19 VACCINES OFFER LASTING PROTECTION
A new research has found that COVID-19 vaccination offers long-lasting protection from the worst outcomes of COVID-19.
The emergence of the delta and omicron variants had raised questions about whether breakthrough infections are caused by waning immunity or by the more transmissible variants.
Results of the study suggested that declining immunity is responsible for breakthrough infections, but vaccines maintained protection from hospitalization and severe disease nine months after getting the first shot.
“The primary takeaway message from our study is that unvaccinated people should get vaccinated right away,” said lead study author Danyu Lin, PhD, Dennis Gillings Distinguished Professor of Biostatistics at the UNC Gillings School of Global Public Health.
“The results of our study also underscore the importance of booster shots, especially for older adults,” Lin added.
The study, which is a collaboration between the UNC-Chapel Hill and the North Carolina Department of Health and Human Services, examined data on COVID-19 vaccination history and health outcomes for 10.6 million North Carolina residents between December 2020 and September 2021.
The study results were used by the Centres for Disease Control and Prevention to support the use of booster shots.
“This is an excellent example of the wonderful research partnership between the Gillings School and NCDHHS, who are working together to generate the evidence base needed to keep our communities safe,” said Penny Gordon-Larsen, PhD, Carla Smith Chamblee Distinguished Professor of Global Nutrition and associate dean for research at UNC Gillings School of Global Public Health
This data included outcomes from COVID-19 cases caused by the delta variant. However, data from this study were collected before the discovery of the omicron variant.
“By applying a novel methodology to the rich surveillance data, we were able to provide a precise and comprehensive characterization of the effectiveness over a nine-month period for the three vaccines employed in the U.S.,” Lin said.
“Unlike previous studies, we estimated the vaccine effectiveness in reducing the current risks of COVID-19, hospitalization, and death as a function of time elapsed since the first dose,” Lin continued.
“This information is critically important in determining the need for and the optimal timing of booster vaccination,” Lin added.
The study found that the effectiveness of the Pfizer and Moderna mRNA vaccines in reducing the risk of COVID-19 reached a peak of about 95 per cent two months after the first dose and then gradually declined. At seven months, the Pfizer vaccine dropped to 67 per cent effectiveness, compared to the Moderna vaccine, which maintained 80 per cent effectiveness.
Among early recipients of the two mRNA vaccines, effectiveness dropped dramatically from mid-June to mid-July, when the delta variant was surging.
Effectiveness for the Johnson & Johnson adenovirus vaccine was 75 per cent at one month after injection and fell to 60 per cent after five months. All three vaccines were effective at keeping people out of the hospital due to severe COVID-19. Effectiveness of the Pfizer vaccine reached a peak of 96 per cent at two months and remained around 90 per cent at seven months; effectiveness of the Moderna vaccine reached a peak of 97 per cent at two months and remained at 94 per cent at seven months. The effectiveness of the Johnson & Johnson vaccine reached a peak of 86 per cent at two months and was higher than 80 per cent through six months.
For all three vaccines, effectiveness against death was higher than that of hospitalization.
“Because the majority of the vaccines in the U.S. were administered more than seven months ago and only a small percentage of the population has received boosters, waning immunity is likely contributing to the breakthrough infections with the omicron variant,” Lin said.
Everyone age 5 and older are eligible for a COVID-19 vaccine. Those ages 18 and up should get a booster shot.
The research was led by Lin with major contributions from Yu Gu, a doctoral student in biostatistics, and Donglin Zeng, PhD, professor of biostatistics. NCDHHS epidemiologists Bradford Wheeler, Hayley Young, Shadia Khan Sunny, and Zack Moore participated in the research. Shannon Holloway from the North Carolina State Department of Statistics also contributed.
The research has been published in the ‘New England Journal of Medicine ‘
NEW STUDY REVEALS BEING IN SPACE DESTROYS MORE RED BLOOD CELLS
A world-first study has revealed how space travel can cause lower red blood cell counts, known as space anemia.
Analysis of 14 astronauts showed their bodies destroyed 54 per cent more red blood cells in space than they normally would on Earth, according to a study published in ‘Nature Medicine’.
“Space anemia has consistently been reported when astronauts returned to Earth since the first space missions, but we didn’t know why,” said lead author Dr Guy Trudel, a rehabilitation physician and researcher at The Ottawa Hospital and professor at the University of Ottawa.
“Our study shows that upon arriving in space, more red blood cells are destroyed, and this continues for the entire duration of the astronaut’s mission,” added Dr Trudel.
Before this study, space anemia was thought to be a quick adaptation to fluids shifting into the astronaut’s upper body when they first arrived in space. Astronauts would lose 10 per cent of the liquid in their blood vessels this way. It was thought that astronauts rapidly destroyed 10 per cent of their red blood cells to restore the balance, and that red blood cell control came back to normal after 10 days in space.
Instead, Dr Trudel’s team found that the red blood cell destruction was a primary effect of being in space, not just caused by fluid shifts. They demonstrated this by directly measuring red blood cell destruction in 14 astronauts during their six-month space missions.
On Earth, our bodies create and destroy 2 million red blood cells every second. The researchers found that astronauts were destroying 54 per cent more red blood cells during the six months they were in space, or 3 million every second. These results were the same for both female and male astronauts.
Dr Trudel’s team made this discovery due to the techniques and methods they developed to accurately measure red blood cell destruction. These methods were then adapted to collect samples aboard the International Space Station.
At Dr Trudel’s lab at the University of Ottawa, they were able to precisely measure the tiny amounts of carbon monoxide in the breath samples from astronauts. One molecule of carbon monoxide was produced every time one molecule of heme, the deep-red pigment in red blood cells, was destroyed.
While the team didn’t measure red blood cell production directly, they assumed that the astronauts generated extra red blood cells to compensate for the cells they destroyed. Otherwise, the astronauts would end up with severe anemia, and would have had major health problems in space.
“Thankfully, having fewer red blood cells in space isn’t a problem when your body is weightless,” said Dr Trudel. “But when landing on Earth and potentially on other planets or moons, anemia affecting your energy, endurance, and strength can threaten mission objectives. The effects of anemia are only felt once you land, and must deal with gravity again,” he said.
In this study, five out of 13 astronauts were clinically anemic when they landed –one of the 14 astronauts did not have blood drawn on landing. The researchers saw that space-related anemia was reversible, with red blood cells levels progressively returning to normal three to four months after returning to Earth.
Interestingly, the team repeated the same measurements one year after astronauts returned to Earth, and found that red blood cell destruction was still 30 per cent above pre-flight levels. These results suggest that structural changes may have happened to the astronaut while they were in space that changed red blood cell control for up to a year after long-duration space missions.
The discovery that space travel increases red blood cell destruction had several implications. First, it supported the screening of astronauts or space tourists for existing blood or health conditions that are affected by anemia. Second, a recent study by Dr Trudel’s team found that the longer the space mission, the worse the anemia, which could impact long missions to the Moon and Mars. Third, increased red blood cell production would require an adapted diet for astronauts. And finally, it was unclear how long the body could maintain this higher rate of destruction and production of red blood cells.
These findings could also be applied to life on Earth. As a rehabilitation physician, most of Dr Trudel’s patients were anemic after being very ill for a long time with limited mobility, and anemia hindered their ability to exercise and recover. Bedrest had been shown to cause anemia, but how it did this was unknown.
“If we can find out exactly what’s causing this anemia, then there is a potential to treat it or prevent it, both for astronauts and for patients here on Earth,” said Dr Trudel.
He was further quoted saying, “This is the best description we have of red blood cell control in space and after return to Earth. These findings are spectacular, considering these measurements had never been made before and we had no idea if we were going to find anything. We were surprised and rewarded for our curiosity.”
SCIENTISTS FIND BIOMARKERS IN PLATELETS FOR DEPRESSION, ANTIDEPRESSANT RESPONSE
A new study has found biomarkers for depression in platelets that track the extent of the disorder.
Published in a new proof of concept study, researchers led by Mark Rasenick, University of Illinois Chicago distinguished professor of physiology and biophysics and psychiatry, have identified a biomarker in human platelets that tracks the extent of depression.
The research builds off of previous studies by several investigators that have shown in humans and animal models that depression is consistent with decreased adenylyl cyclase — a small molecule inside the cell that is made in response to neurotransmitters such as serotonin and epinephrine.
“When you are depressed, adenylyl cyclase is low. The reason adenylyl cyclase is attenuated is that the intermediary protein that allows the neurotransmitter to make the adenylyl cyclase, Gs alpha, is stuck in a cholesterol-rich matrix of the membrane — a lipid raft — where they don’t work very well,” Rasenick said.
The new study has identified the cellular biomarker for translocation of Gs alpha from lipid rafts. The biomarker can be identified through a blood test.
“What we have developed is a test that can not only indicate the presence of depression but it can also indicate therapeutic response with a single biomarker, and that is something that has not existed to date,” said Rasenick, who is also a research career scientist at Jesse Brown VA Medical Centre.
The researchers hypothesized that they will be able to use this blood test to determine if antidepressant therapies are working, perhaps as soon as one week after beginning treatment. Previous research has shown that when patients showed improvement in their depression symptoms, the Gs alpha was out of the lipid raft. However, in patients who took antidepressants but showed no improvement in their symptoms, the Gs alpha was still stuck in the raft — meaning simply having antidepressants in the bloodstream was not good enough to improve symptoms.
A blood test may be able to show whether or not the Gs alpha was out of the lipid raft
after one week.
“Because platelets turn over in one week, you would see a change in people who were going to get better. You’d be able to see the biomarker that should presage successful treatment,” Rasenick said.
Currently, patients and their physicians have to wait several weeks, sometimes months, to determine if antidepressants are working, and when it is determined they aren’t working, different therapies are tried.
“About 30 per cent of people don’t get better — their depression doesn’t resolve. Perhaps, failure begets failure and both doctors and patients make the assumption that nothing is going to work,” Rasenick said.
“Most depression is diagnosed in primary care doctor’s offices where they don’t have sophisticated screening. With this test, a doctor could say, ‘Gee, they look like they are depressed, but their blood doesn’t tell us they are. So, maybe we need to re-examine this,” he added.
Working with his company, Pax Neuroscience, Rasenick aims to develop the screening test after further research.
The Study has been published in the ‘Molecular Psychiatry Journal ‘.
A small molecule inside the cell that is made in response to neurotransmitters such as serotonin and epinephrine.
Study finds long-term exposure to air pollution may increase virus risk
Long term exposure to ambient air pollution may heighten the risk of COVID-19 infection, suggests recent research.
The association was strongest for particulate matter, with an average annual raise of 1 ug/m3 linked to a 5 per cent increase in the infection rate. This equates to an extra 294 cases/100,000 people a year, according to the findings, which focus on the inhabitants of one Northern Italian city.
While further research is needed to confirm cause and effect, the findings should reinforce efforts to cut air pollution, say the researchers.
Northern Italy has been hit hard by the coronavirus pandemic, with Lombardy the worst affected region in terms of both cases and deaths. Several reasons have been suggested for this, including different testing strategies and demographics. But estimates from the European Union Environmental Agency show that most of the 3.9 million Europeans residing in areas where air pollution exceeds European limits live in Northern Italy.
Recent research has implicated airborne pollution as a risk factor for COVID-19 infection, but study design flaws and data capture only up to mid-2020 have limited the findings, say the researchers.
To get around these issues, they looked at long term exposure to airborne pollutants and patterns of COVID-19 infection from the start of the pandemic to March 2021 among the residents of Varese, the eighth-largest city in Lombardy.
Among the 81,543 residents as of 31 December 2017, more than 97 per cent were
successfully linked to the 2018 annual average exposure levels for the main air pollutants, based on home address.
Regional COVID-19 infection data and information on hospital discharge and outpatient drug prescriptions were gathered for 62,848 adults yet to be infected with SARS-CoV-2, the virus responsible for COVID-19 at the end of 2019 until the end of March 2021.
Official figures show that only 3.5 per cent of the population in the entire region were fully vaccinated by the end of March 2021.
Estimates of annual and seasonal average levels of five airborne pollutants were
available for 2018 over an area more than 40 km wide: particulate matter (PM2.5, PM10); nitrogen dioxide (NO2); nitric oxide (NO); and ozone (O3).
The average PM2.5 and NO2 values were 12.5 and 20.1 ug/m3, respectively. The
corresponding population-weighted average annual exposures in Italy for the same year were 15.5 and 20.1 ug/m3, respectively.
Some 4408 new COVID-19 cases, which were registered between 25 February 2020 and March 13, 2021, were included in the study. This equates to a rate of 6005 cases/100,000 population/year. The population density wasn’t associated with a heightened risk of infection. But living in a residential care home was associated with a more than 10-fold heightened risk of the infection. Drug treatment for diabetes, high blood pressure, and obstructive airway diseases, as well as a history of stroke, were also associated with, respectively, a 17 per cent, 12 per cent, 17 per cent, and 29 per cent, heightened risk. After accounting for age, gender, and care home residency, plus concurrent long term conditions, averages, both PM2.5 and PM10 were significantly associated with an increased COVID-19 infection rate.
Every 1 ug/m3 increase in long term exposure to PM2.5 was associated with a 5 per cent increase in the number of new cases of COVID-19 infection, equivalent to 294 extra cases per 100,000 of the population/year.
Applying seasonal rather than annual averages yielded similar results, and these findings were confirmed in further analyses that excluded care home residents and further adjusted for local levels of deprivation and use of public transport. Similar findings were observed for PM10, NO2 and NO.
The observed associations were even more noticeable among older age groups,
indicating a stronger effect of pollutants on the COVID-19 infection rate among 55-64 and 65-74-year-olds, suggest the researchers.
This is an observational study, and as such, can’t establish cause. And although the researchers considered various potentially influential factors, they weren’t able to account for mobility, social interaction, humidity, temperature and certain underlying conditions, such as mental ill-health and kidney disease.
BOOSTER DOSE NEUTRALISES COVID-19 OMICRON VARIANT, SAYS EU RESEARCH
Aim of study was to characterise efficacy of therapeutic antibodies and scientists concluded that many mutations in spike protein of variant enabled it to largely evade immune response
An international team of researchers recently studied the sensitivity of Omicron to antibodies compared with the currently dominant Delta variant.
The new COVID-19 Omicron variant is more transmissible than the Delta variant. However, its biological characteristics are still relatively unknown.
In South Africa, the Omicron variant replaced the other viruses within a few weeks and led to a sharp increase in the number of cases diagnosed. Analyses in various countries indicate that the doubling time for cases is approximately 2 to 4 days. Omicron has been detected in dozens of countries, including France, and became dominant by the end of 2021.
In a new study supported by the European Union’s Health Emergency Preparedness and Response Authority (HERA), scientists from the Institut Pasteur and the Vaccine Research Institute, in collaboration with KU Leuven (Leuven, Belgium), Orleans Regional Hospital, Hospital Europeen Georges Pompidou (AP-HP) and Inserm, studied the sensitivity of Omicron to antibodies compared with the currently dominant Delta variant.
The aim of the study was to characterize the efficacy of therapeutic antibodies, as well as antibodies developed by individuals previously infected with SARS-CoV-2 or vaccinated, in neutralizing this new variant.
The scientists from KU Leuven isolated the Omicron variant of SARS-CoV-2 from a nasal sample of a 32-year-old woman who developed moderate COVID-19 a few days after returning from Egypt. The isolated virus was immediately sent to scientists at the Institut Pasteur, where therapeutic monoclonal antibodies and serum samples from people who had been vaccinated or previously exposed to SARS-CoV-2 were used to study the sensitivity of the Omicron variant.
The scientists used rapid neutralization assays, developed by the Institut Pasteur’s Virus and Immunity Unit, on the isolated sample of the Omicron virus. This collaborative multidisciplinary effort also involved the Institut Pasteur’s virologists and specialists in the analysis of viral evolution and protein structure, together with teams from Orleans Regional Hospital and Hospital Europeen Georges Pompidou in Paris.
The scientists began by testing nine monoclonal antibodies used in clinical practice or currently in preclinical development. Six antibodies lost all antiviral activity, and the other three were 3 to 80 times less effective against Omicron than against Delta.
The antibodies Bamlanivimab/Etesevimab (a combination developed by Lilly), Casirivimab/Imdevimab (a combination developed by Roche and known as Ronapreve), and Regdanvimab (developed by Celtrion) no longer had any antiviral effect against Omicron. The Tixagevimab/Cilgavimab combination (developed by AstraZeneca under the name Evusheld) was 80 times less effective against Omicron than against Delta.
“We demonstrated that this highly transmissible variant has acquired significant resistance to antibodies. Most of the therapeutic monoclonal antibodies currently available against SARS-CoV-2 are inactive,” commented Olivier Schwartz, co-last author of the study and Head of the Virus and Immunity Unit at the Institut Pasteur.
The scientists observed that the blood of patients previously infected with COVID-19, collected up to 12 months after symptoms, and that of individuals who had received two doses of the vaccine, taken five months after vaccination, barely neutralized the Omicron variant. But the sera of individuals who had received a booster dose of Pfizer, analyzed one month after vaccination, remained effective against Omicron.
Five to 31 times more antibodies were nevertheless required to neutralize Omicron, compared with Delta, in cell culture assays. These results help shed light on the continued efficacy of vaccines in protecting against severe forms of the disease.
“We now need to study the length of protection of the booster dose. The vaccines probably become less effective in offering protection against contracting the virus, but they should continue to protect against severe forms,” explained Olivier Schwartz.
“This study shows that the Omicron variant hampers the effectiveness of vaccines and monoclonal antibodies, but it also demonstrates the ability of European scientists to work together to identify challenges and potential solutions. While KU Leuven was able to describe the first case of Omicron infection in Europe using the Belgian genome surveillance system, our collaboration with the Institut Pasteur in Paris enabled us to carry out this study in record time,” commented Emmanuel Andre, co-last author of the study, a Professor of Medicine at KU Leuven (Katholieke Universiteit Leuven) and Head of the National Reference Laboratory and the genome surveillance network for COVID-19 in Belgium.
“There is still a great deal of work to do, but thanks to the support of the European Union’s Health Emergency Preparedness and Response Authority (HERA), we have clearly now reached a point where scientists from the best centres can work in synergy and move towards a better understanding and more effective management of the pandemic,” added Emmanuel.
The scientists concluded that the many mutations in the spike protein of the Omicron variant enabled it to largely evade the immune response. Ongoing research is being conducted to determine why this variant is more transmissible from one individual to the next and to analyze the long-term effectiveness of a booster dose.
The Study about this variant has been published in the ‘Nature Journal ‘
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