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LOS ALAMOS, N.M., April 19, 2021--A new machine-learning program accurately identifies COVID-19-related conspiracy theories on social media and models how they evolved over time--a tool that could someday help public health officials combat misinformation online.

"A lot of machine-learning studies related to misinformation on social media focus on identifying different kinds of conspiracy theories," said Courtney Shelley, a postdoctoral researcher in the Information Systems and Modeling Group at Los Alamos National Laboratory and co-author of the study that was published last week in the Journal of Medical Internet Research. "Instead, we wanted to create a more cohesive understanding of how misinformation changes as it spreads. Because people tend to believe the first message they encounter, public health officials could someday monitor which conspiracy theories are gaining traction on social media and craft factual public information campaigns to preempt widespread acceptance of falsehoods."

The study, titled "Thought I'd Share First," used publicly available, anonymized Twitter data to characterize four COVID-19 conspiracy theory themes and provide context for each through the first five months of the pandemic. The four themes the study examined were that 5G cell towers spread the virus; that the Bill and Melinda Gates Foundation engineered or has otherwise malicious intent related to COVID-19; that the virus was bioengineered or was developed in a laboratory; and that the COVID-19 vaccines, which were then all still in development, would be dangerous.

"We began with a dataset of approximately 1.8 million tweets that contained COVID-19 keywords or were from health-related Twitter accounts," said Dax Gerts, a computer scientist also in Los Alamos' Information Systems and Modeling Group and the study's co-author. "From this body of data, we identified subsets that matched the four conspiracy theories using pattern filtering, and hand labeled several hundred tweets in each conspiracy theory category to construct training sets."

Using the data collected for each of the four theories, the team built random forest machine-learning, or artificial intelligence (AI), models that categorized tweets as COVID-19 misinformation or not.

"This allowed us to observe the way individuals talk about these conspiracy theories on social media, and observe changes over time," said Gerts.

The study showed that misinformation tweets contain more negative sentiment when compared to factual tweets and that conspiracy theories evolve over time, incorporating details from unrelated conspiracy theories as well as real-world events.

For example, Bill Gates participated in a Reddit "Ask Me Anything" in March 2020, which highlighted Gates-funded research to develop injectable invisible ink that could be used to record vaccinations. Immediately after, there was an increase in the prominence of words associated with vaccine-averse conspiracy theories suggesting the COVID-19 vaccine would secretly microchip individuals for population control.

Furthermore, the study found that a supervised learning technique could be used to automatically identify conspiracy theories, and that an unsupervised learning approach (dynamic topic modeling) could be used to explore changes in word importance among topics within each theory.

"It's important for public health officials to know how conspiracy theories are evolving and gaining traction over time," said Shelley. "If not, they run the risk of inadvertently publicizing conspiracy theories that might otherwise 'die on the vine.' So, knowing how conspiracy theories are changing and perhaps incorporating other theories or real-world events is important when strategizing how to counter them with factual public information campaigns."

A group of scientists have just made a key discovery that could prevent and eradicate immune responses that lead to treatment failure in about one-third of people with severe hemophilia A.

Hemophilia is the most common severe inherited bleeding disorder in men. The disease affects 1 in 10,000 males worldwide and results from deficiency of blood clotting factor VIII (FVIII). Both children and adults with hemophilia A (80 percent of all hemophilia) receive treatment that involves infusing FVIII protein into the bloodstream. However, about 30 percent of them develop an immune response in the form of antibodies to FVIII (inhibitors), rendering treatment ineffective and increasing risk of mortality.

For inhibitor-positive patients, immune tolerance induction (ITI) options are scarce, costly and invasive. Investigators at Indiana University School of Medicine, Children's Hospital of Philadelphia and University of Pennsylvania joined efforts to explore immune responses to FVIII under an NIH-funded U54 initiative.

The study, led by IU School of Medicine's Moanaro Biswas, PhD, and Valder R. Arruda, MD, PhD, from Children's Hospital of Philadelphia and the University of Pennsylvania, is titled "B cell activating factor modulates the factor VIII immune response in hemophilia," and was published in the Journal of Clinical Investigation earlier this month. Bhavya Doshi, MD, from Children's Hospital of Philadelphia, as is the first author.

In it, the group used plasma samples from pediatric and adult hemophilia A patients and animal models to determine whether BAFF plays a role in the generation and maintenance of FVIII inhibitors.

They also looked at combining antibody to BAFF in an ITI approach with a CD20 antibody (rituximab). Rituximab alone has shown mixed results in eradicating inhibitors when used alone in previous studies for hemophilia A.

Major findings from the study include:

BAFF levels in plasma are higher in both pediatric and adult hemophilia A patients with persistent FVIII inhibitors, and correlate with FVIII antibody titers, suggesting that BAFF could be a potential harbinger for an ongoing humoral immune response to FVIII

An increase in BAFF levels after rituximab-based therapy precludes tolerance to FVIII.

Blocking BAFF is effective in the prevention of FVIII inhibitors in an animal model of hemophilia A.

Combination CD20/BAFF monoclonal antibody therapy induces tolerance in a hemophilia A animal model with established FVIII inhibitors. This is due to a concerted effect of the combination therapy on memory B cells and plasma cells.

Next, the group will perform in-depth mechanistic studies to identify additional BAFF modifiers, which may provide additional insight into the pathways that lead to BAFF elevation and inhibitor formation.

These data also have important translational potential for inhibitor in hemophilia A, since there is an FDA-approved anti-BAFF antibody currently used as part of immunosuppressive regimens for autoimmune diseases.

ROCHESTER, Minn. -- A new Mayo Clinic study bolsters evidence that colorectal cancer is often imprinted in family genes and passed on from one generation to the next.

In the study, published in Clinical Gastroenterology and Hepatology, researchers within the Mayo Clinic Center for Individualized Medicine found 1 in 6 patients with colorectal cancer had an inherited cancer-related gene mutation, which likely predisposed them to the disease. In addition, the researchers discovered that 60% of these cases would not have been detected if relying on a standard guideline-based approach.

"We found that 15.5% of the 361 patients with colorectal cancer had an inherited mutation in a gene associated with the development of their cancer," says Niloy Jewel Samadder, M.D., a Mayo Clinic gastroenterologist and hepatologist, who is the study's senior author. "We also found that over 1 in 10 of these patients had modifications in their medical or surgical therapy based on the genetic findings."

The patients were tested with a sequencing panel that included more than 80 cancer-causing or predisposing genes. In comparison, standard panels for colorectal cancer only include 20 or fewer genes.

The patients with colorectal cancer were part of a larger cohort of 3,000 patients involved in the two-year Interrogating Cancer Etiology Using Proactive Genetic Testing (INTERCEPT) study, and were newly diagnosed with various cancers at Mayo Clinic Cancer Center locations in Arizona, Florida and Minnesota.

"Through the INTERCEPT study, the Center for Individualized Medicine has addressed a question of relevance to all cancer patients," says Aleksandar Sekulic, M.D., Ph.D., associate director of the Center. "The findings published by Dr. Samadder and colleagues shed a new light on the role our genes play in the development of colon cancer."

The colorectal cancer study emphasizes that uncovering hidden inherited genetic mutations using a universal testing approach and broader gene panels could lead to opportunities for cancer management in families and targeted cancer therapies that can save lives.

Colorectal cancer is the second leading cause of cancer death in the U.S., according to the American Cancer Society. Unlike many other cancers that are difficult to uncover in early stages, colon cancer begins as a polyp, which can be detected in a colonoscopy screening and removed to prevent cancer from developing and spreading. The American Cancer Society recommends people at average risk of colorectal cancer start regular screenings at age 45.

"Colorectal cancer screening is an important modality to prevent this deadly disease and many resultant unnecessary deaths," Dr. Samadder says. "Screening can be performed with a colonoscopy, stool tests or even specialized CT scans."

In the study, Dr. Samadder and his team examined gene variants (mutations) with which the patient was born and that predisposed them to developing cancer. Mutations are abnormal changes in the DNA of a gene. A gene mutation can affect the cell in many ways, including interfering with proteins or causing a gene to be activated.

Although many mutations that cause colorectal cancer happen by chance in a single cell -- including from environmental factors, diet, smoking and alcohol use -- the study confirms many are inherited mutations that set off a cycle of events that can lead to cancer.

"Though the most common mutations were found in genes typically associated with colorectal cancer, we found that a substantial number of mutations were present in genes typically associated with breast and ovarian cancer," Dr. Samadder explains. "This may lead to novel targeted therapies based on the cancer's unique genetic basis. For example, where a breast cancer drug can be used in a patient with colon cancer."

Equally important to the discovery of a patient's inherited cancer mutation is the potential for patients to share the heritable cause of their disease with their blood relatives, allowing family members to pursue care for earlier disease detection and cancer management.

"The power of genetics is that we can foresee the cancer that will develop in other family members," Dr. Samadder says. "This can allow us to target cancer screening to those high-risk individuals and hopefully prevent cancer altogether in the next generation of the family."

In the study, all blood-related family members of patients found to have a genetic mutation were offered free genetic testing. Overall, just 16% of these family members underwent testing, which may suggest there are nonfinancial barriers to genetic testing.

Dr. Samadder says the next steps will be to incorporate the study findings into the care of all patients with cancer at Mayo Clinic.

"Steps are being taken to ensure all patients are offered genomic sequencing to better understand the genes that led to the development of their cancer, and how to precisely target treatment and improve survival," Dr. Samadder says.

Genetic sequencing, deletion and duplication analysis, and variant interpretation were performed at Invitae Corp. in San Francisco. Dr. Nussbaum is the chief medical officer of Invitae. Support for this project was provided by the Mayo Transform the Practice Grant, Mayo Clinic Center for Individualized Medicine, Desert Mountain Members' CARE Foundation, and David and Twila Woods Foundation.

Varying severity of COVID-19 symptoms in patients is reflected by levels of a chemical biomarker in their body which scientists say could be used to better manage treatments and other interventions, including vaccinations.

In a new paper in International Journal of Infectious Diseases, medical experts in Italy and Australia examined levels of a chemical called serum amyloid A (SAA), a protein synthesised in the liver which can spike up to 1,000-fold within the first 24-48 hours of an infection.

In turn, an increase in SAA can further perpetuate inflammation and cause clot abnormalities and organ damage, researchers say, concluding SAA levels are associated with higher COVID-19 severity and mortality.

The University of Sassari and Flinders University researchers focused on the latest research including 19 studies of more than 5,600 COVID-19 patients for specific markers to predict disease severity and progression.

"Our analyses showed that COVID-19 patients with severe disease or who eventually died had significantly higher levels of SAA when compared to patients with mild COVID-19," says senior corresponding author Professor of Clinical Pharmacology Arduino Mangoni, from Flinders University in South Australia.

"Patients with severe forms of coronavirus disease 2019 have excessive inflammation, alterations in clot formation, and significant damage in several organs, particularly the lung, the kidney, the heart, and the liver,"

Given the key role of inflammation in COVID-19, markers that reflect a state of excessive inflammation might be particularly useful for risk stratification and effective management.

"This chemical may help, together with other patient characteristics, in predicting which COVID-19 patients are likely to deteriorate and require aggressive management," the researchers say.

While safe and effective vaccines are being rolled out worldwide there are currently few effective therapies to treat COVID-19 in the community and in hospital.

In this context, the use of specific markers to predict disease severity and would facilitate the early identification of patients requiring aggressive management and monitoring and assist with the judicious use of health care resources.

The link between SAA and COVID-19 severity and mortality focused on data collected from 5,617 patients hospitalised with COVID-10 with different degrees of severity and survival status, along with current literature.

UNIVERSITY PARK, Pa. -- As vaccines that help protect against COVID-19 become available for more people across the United States, questions have been raised about whether institutions like schools and universities should require their students and staff to become vaccinated.

A new study by Simon Haeder, assistant professor of public policy at Penn State, found that a majority of those surveyed supported mandates that required students and teachers to be vaccinated against COVID-19. However, more people supported broader vaccine mandates that don't specifically include those against COVID-19.

Haeder said political partisanship, along with race and gender, helped account for these differences.

"Even if children are less likely to get severely ill, vaccination of students has been shown to have benefits such as lower numbers of community deaths, particularly among the elderly," Haeder said. "Mandates may serve as a crucial policy tool to help reign in COVID-19 and reach herd immunity, which we otherwise might not reach any time soon."

Haeder added that the findings -- recently published in the journal Vaccine -- suggest that while the majority of Americans would be supportive of COVID-19 vaccine mandates in educational settings, about one in five would be indifferent and another one in five would be opposed.

Since the beginning of the pandemic, policy makers have debated about how to determine whether educational institutions are safe enough for students to return in person. The development of safe and effective vaccines, Haeder said, offers a potential way for society to eventually return to normal.

He added that while making vaccines mandatory -- also known as vaccine mandates -- has been a strategy to control epidemics in the past, they have not been without controversy.

"Massachusetts mandated smallpox vaccinations in the early 1800s, Alaska and California used mandates in the 1970s to control measles, and in more modern times, there are often certain vaccine mandates for living in the dorms on some college campuses," Haeder said. "But these policies have often been met with vocal opposition from certain groups of Americans, and with the pandemic being so politicized, we were curious about how Americans felt about potential COVID-19 vaccine mandates."

For the study, Haeder developed and sent a survey to 2,404 participants in the fall of 2020. The nationally representative survey included questions about how the participants felt about requiring vaccines for students and teachers in three different educational settings: daycares, K-12 schools, and universities and colleges.

The survey also asked participants questions designed to measure political partisanship, political knowledge, and beliefs about whether schools are an appropriate place to deliver health care, as well as demographic information such as race, ethnicity, education and gender.

The researchers found that Democrats were consistently more supportive of vaccine mandates than moderates or Republicans. White Americans and people who believed schools were appropriate settings for providing health services were also more likely to support any vaccine mandate.

Haeder said there are several possible reasons for some of these differences.

"Partisanship has permeated everything related to COVID-19 and lots of misinformation has been spread, including from individuals in leadership positions," Haedaer said. "Additionally, there's a general growing distrust of science and its elites, which when combined with the novelty of the illness and vaccines, could contribute to this lack of support for vaccine mandates in certain groups."

Additionally, the researchers found that in daycare settings, about 70% of participants "definitely" or "probably" supported general vaccine mandates for students, a little over 50% supported COVID-19 vaccine mandates for students, and about 60% supported COVID-19 vaccine mandates for teachers.

For K-12 schools, about 68% supported general mandates for students, just over 50% supported COVID-19 vaccine mandates for students, and just under 60% supported COVID-19 vaccine mandates for teachers. For colleges and universities, the results were about 65%, 55% and 58%, respectively.

Haeder said that in addition to helping to guide policy makers as efforts continue to be made to control the pandemic, the findings have other implications, as well.

"Efforts to provide Americans with more information about the safety and effectiveness of the vaccines should be undertaken to help alleviate fears around the COVID-19 vaccines," Haeder said. "Also, efforts could be made to reduce potential barriers for vaccinations, including providing the vaccine free of charge, making scheduling appointments easier, avoiding long travel times, and offering convenient opening hours."

OKLAHOMA CITY -- With an overall survival rate of 9% for those diagnosed, pancreatic cancer remains exceedingly difficult to treat. However, the patient's primary tumor typically isn't what leads to death - it is the cancer's ability to evade detection and metastasize to other organs.

A team of researchers at the OU College of Medicine has published a new study in the journal Gastroenterology, the world's leading publication on GI tract disease, that sheds new light on the ability of pancreatic cancer cells to spread throughout the body. Understanding why metastasis occurs is crucial for developing a therapeutic strategy to stop the spread.

The study, led by scientist Min Li, Ph.D., and physician-scientist Courtney Houchen, M.D., centers around ZIP4, a protein that transports zinc throughout the body. While zinc is important for good health, too much of the heavy metal causes problems. In the new study, researchers found that when ZIP4 is overexpressed in patients with pancreatic cancer, it essentially prompts the tumor cells to transform themselves in a manner that allows them to stealthily travel to the body's other organs. In scientific terms, the tumor cells transition from an epithelial to a mesenchymal phenotype.

"That transition means the tumor cells are doing everything they can to avoid the surveillance of the body's immune system, as well as chemotherapy and other therapies," Li said. "They become more evasive and are able to penetrate the blood vessels, which permits them to go anywhere in the body."

Several things occur during the epithelial-mesenchymal transition. The cells are shape-shifters, taking the form of a square in the primary cancer site, but switching to a spindle shape that helps them to sneak away and begin to metastasize. The cells' growth also slows, allowing them to "fly under the radar" of the immune system.

"This is important because when tumors are in the form of epithelial cells, they are easier to kill with chemotherapy," Li said. "But when they switch to mesenchymal cells, they become resistant to treatment. Tumor cells are very smart and are like creatures with multiple faces. That's why we are looking for the right moment to target them with different strategies."

More than 60% of patients with pancreatic cancer experience metastasis within the first 24 months after surgery. The epithelial-mesenchymal transition is increasingly recognized as a major component of that spread, Houchen said.

"Once a patient has metastatic disease, no therapy can extend life more than six to eight months," Houchen said. "It's clear that metastatic spread has to be stopped if we're going to improve survival rates. This study helped us to understand the role of ZIP4 in the epithelial-mesenchymal transition. Somewhere in that shape-shifting process is where we need to intervene to stop the metastasis."

This publication is the third in the past three years in the journal Gastroenterology for Li and Houchen's research team. Each study has focused on a different role for ZIP4, which serves as a "master switch" for several things to occur in pancreatic cancer. In their first publication, they demonstrated that ZIP4 plays a role in the onset of cachexia, a muscle-wasting condition that affects at least 80% of people with pancreatic cancer. The next publication focused on how the overexpression of ZIP4 causes pancreatic cancer cells to be more resistant to chemotherapy.

"People diagnosed with many other types of cancers have seen an increased survival rate in the past 30 years, but that's not the case with pancreatic cancer," Li said. "We are making progress because our research is truly a group effort; no single person could do this. We have many talented people in our lab. I think we're entering a different phase where we can soon start developing a drug to specifically target the process involving ZIP4."

What The Study Did: The fitted filtration efficiency of commonly available masks worn singly, doubled or in combinations was evaluated in this study.

Authors: Emily E. Sickbert-Bennett, Ph.D., M.S., of the UNC Medical Center in Chapel Hill, North Carolina, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jamainternmed.2021.2033)

Editor's Note: The article includes conflict of interest and funding/support disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, conflict of interest and financial disclosures, and funding and support.

Two new studies published in Blood suggest that the mRNA COVID-19 vaccine may have reduced efficacy in individuals with chronic lymphocytic leukemia (CLL) and multiple myeloma, two types of blood cancer. According to researchers, these studies could help inform the ideal time for vaccination of these populations.

Study suggests two-dose COVID-19 vaccine is less effective for people with CLL as compared to healthy controls

The first study reports that people with CLL had markedly lower immune response rates to the two-dose mRNA COVID-19 vaccine than healthy individuals of the same age. Because clinical trials of these vaccines did not include patients with blood cancers, who are at high risk of severe illness and complications from the virus, gauging the effectiveness of the vaccine in this population is critically important.

In this study of 167 patients with CLL, only four out of 10 (39.5%) had a positive antibody-mediated response to the vaccine; all healthy adults (controls), by comparison, marshalled an immune response.

Interestingly, the research revealed wide variations in immune response among patients with CLL depending on where they were in their cancer treatment process. For example, patients undergoing active cancer treatment had significantly lower response rates to the vaccine when compared with people who had completed treatment and were in remission, 16% vs 79% respectively. Treatment naïve patients (those whose disease is being watched but not yet treated) had a 55.5% response rate. As well, response to the vaccine was markedly higher in people who completed CLL treatment at least a year before vaccination compared with those who were still in treatment within the last year, 94% vs 50%, respectively.

"Overall, the response rate to the vaccine was significantly less than what we see in the general population, which is most likely attributed to the presence of cancer itself and certain CLL treatments," said lead author of the study Yair Herishanu, MD, associate professor in hematology and head of the CLL service at the Tel Aviv Sourasky Medical Center in Israel. "It would seem that if you are untreated, in what we call 'watch and wait' or do not have active disease, you can gain more benefit from the vaccine. Patients who responded the best were in remission, which makes sense because their immune system had a chance to recover."

Aside from not being on active CLL treatment, younger age, being female, and having normal immunoglobin levels at the time of vaccination independently predicted better response rates to the vaccine. In addition to poorer qualitative antibody responses to the vaccine, patients with CLL also had lower antibody titers, which tells us that, in addition to fewer patients responding to the vaccine, the intensity of the response was also lower, explained Dr. Herishanu.

For the study, researchers included 167 patients with CLL and 53 healthy controls from December 2020 through February 2021. All participants received two doses of BNT162b2 messenger RNA (Pfizer) COVID-19 vaccine 21 days apart; this was the only vaccine used in Israel at the time of the study. Patients were 71 years old on average, and 67% were men. Fifty-eight patients (34.7%) were treatment naïve; 75 (44.9%) were on active therapy; 24 (14.4%) were previously treated and in complete or partial remission; and 10 (6%) were in relapse. Antibody titers were also measured two weeks after the second dose. Patients were followed for a median of 75 days since receiving their first shot, and none had developed COVID-19 infection. There were no significant differences in reported side effects to the vaccine compared to the healthy population.

Researchers also looked at immune response to the vaccine based on which CLL treatment patients received. They found similarly low response rates among patients who were receiving common targeted therapies, including Bruton's tyrosine kinase (BTK) inhibitors (ibrutinib or acalabrutinib) or a combination of venetoclax with anti-CD20 antibodies such as rituximab. Notably, none of the patients who received anti-CD20 antibodies within 12 months of COVID-19 vaccination responded. Because only five patients were on venetoclax monotherapy, Dr. Herishanu said they could not draw any conclusions about the impact on response.

People with CLL and other blood cancers remain at high risk for severe illness and complications with COVID-19 infection, and while response rates are lower than ideal, vaccination against COVID-19 is strongly recommended. The authors suggest that an additional booster dose of the vaccine might be needed for patients with CLL who have completed therapy and previously failed to respond to COVID-19 vaccine, though this would need to be studied.

"Even though response rates were not optimal, patients with CLL should still get the vaccine and, if appropriate, it may be better to do so before CLL treatment starts although the disease itself may affect the response," said Dr. Herishanu. "Equally important is continuing to take precautions - wearing a mask, avoiding crowds, keeping a social distance, and being sure close contacts get vaccinated against COVID-19."

He and his team will continue to follow these patients for 12 months to see how many, if any, develop COVID-19 infection following vaccination. Since this study only assessed antibody response, they also plan to check the cellular immune response to gain a more complete picture of the extent to which patients are protected after vaccination.

The researchers note that the same trends would be expected with the other mRNA vaccine (Moderna).

Similar results in elderly patients with multiple myeloma

In a Blood Letter to the Editor also published online today, researchers report similar findings after the first dose of the same vaccine in elderly patients with multiple myeloma. Evangelos Terpos, MD, PhD, of the National and Kapodistrian University of Athens in Athens, Greece, and colleagues compared outcomes of 48 patients with multiple myeloma and 104 healthy controls at Alexandra Hospital in Athens. The median age of all participants was 83. On day 22 after the first dose of the vaccine but prior to the second dose, antibody titers were measured and the median response was 20.6% neutralizing antibodies for the multiple myeloma population as compared to 32.5% for the healthy controls.

At the time of the first dose, 35 (72.9%) patients were receiving anti-myeloma therapy, four were in remission after prior therapy and did not receive any therapy at the time of vaccination, and nine had smoldering (precancerous) myeloma. Based on their findings, researchers suggest that anti-myeloma therapy seems to negatively affect production of neutralizing antibodies after a single dose, although higher patient numbers are needed to further understand this effect. They also wrote that the administration of a second timely vaccine dose is essential for elderly patients with multiple myeloma to develop an adequate antibody-based response.

For more information about COVID-19 vaccines for people who are immunocompromised, see the American Society of Hematology's Frequently Asked Questions.

A new study has shown that underweight and overweight women are at a significantly higher risk of experiencing recurrent miscarriages compared to those of average weight.

A research team led by the University of Southampton assessed the link between women's lifestyle and risk of recurrent pregnancy loss, defined as women having two or more consecutive early miscarriages. The systematic review and meta-analysis study has been published in the journal Scientific Reports.

Miscarriage is the most common complication of early pregnancy, affecting 15 - 20% of all pregnancies. Recurrent pregnancy loss is a complex disease and although often attributed to numerous medical factors and lifestyle influences, the cause is deemed "unexplained" in around 50% of cases.

The results of this latest study found that there are higher occurrences of successive miscarriages in mothers who are underweight (having a Body Mass Index score of less than 18.5), overweight (having BMI between 25 and 30) and obese (having BMI above 30).

The study's first author, Dr Bonnie Ng, MRC Fellow in Clinical and Experimental Sciences at the University of Southampton said, "Our study included sixteen studies and showed that being underweight or overweight significantly increases the risk of two consecutive pregnancy losses. For those with BMI greater than 25 and 30, their risk of suffering a further miscarriage increases by 20% and 70% respectively.'

The research team also set out to assess the impact of factors such as smoking and consumption of alcohol and caffeine. However they were unable to establish conclusively whether these have any impact or not due to inconsistencies of the results from a small number of studies and heterogeneity in women taking part in them.

Co-author Dr George Cherian, Specialist trainee in Obstetrics and Gynaecology, at Princess Anne Hospital, Southampton said, 'while our study did not find any associations between recurrent pregnancy loss and lifestyle parameters such as smoking, alcohol and caffeine intake, further large-scale studies are required to clarify this.'

Whilst recognising that more observational and clinical research is needed to establish the full extent of lifestyle choices, the authors conclude that weight is a risk factor that can be modified to reduce the risk.

'Our findings suggest that having an abnormal BMI exacerbates a woman's risk of suffering from repeated miscarriages, and so clinicians really need to focus on helping women manage this risk factor' concluded Ying Cheong, Professor of Reproductive Medicine at the University of Southampton and senior author of the paper.

Academic medical centers continuously strive to enhance patient care. One of the major mechanisms to improve patient health outcomes is through translational research - bringing research breakthroughs from the lab to patients via clinical trials. Making clinical trials more efficient, and ultimately more successful, would significantly advance patient care. However, fragmentation of the relevant data necessary to implement improvements to translational science is a significant barrier.

While some bioinformatic tools have attempted to address this problem, they often lacked the ability to assess the efficiency of translational science. Researchers at the South Carolina Clinical & Translational Research (SCTR) Institute, a Clinical and Translational Science Awards (CTSA) hub with an academic home at the Medical University of South Carolina (MUSC), have developed a novel bioinformatic tool called RINS, the Research Integrated Network of Systems, that can be used to evaluate whether improvements to the clinical trial process are making a difference. Their results, published online on March 17 in the Journal of the American Medical Informatics Association, showed that RINS can integrate data about clinical studies across disparate systems and provide metrics about MUSC's clinical trial efficiency and effectiveness.

"You could call it meta-data - it's data about how we produce data in studies or how we get studies up and running and accelerate them," said Leslie A. Lenert, M.D., chief research information officer for MUSC and director of the Biomedical Informatics Center (BMIC). "Those were all in a different place, in a different format, using numbers that didn't have an agreed-upon definition. But we brought it all into one view to get a comprehensive look at the processes for doing science. And we've never had that before because the data lived in disparate systems."

Making informed decisions about how best to improve and streamline translational research practices requires detailed data, and to accumulate that data, institutions need strong evaluative tools. To that end, MUSC has developed and utilized a research transaction management system, SPARCRequest, that provides a powerful tool to help researchers determine budgets for grant applications, navigate the regulatory process, recruit diverse study participants and conduct clinical trials. As an open-source platform, SPARCRequest is utilized by 12 CTSA and Clinical and Translation Research (CTR) hubs comprising 27 institutions across the country.

While SPARCRequest was instrumental in streamlining clinical research, it wasn't originally set up for metric tracking across disparate systems. To address that problem, Lenert approached Royce R. Sampson, chief operating officer for SCTR and one of the inventors of SPARCRequest, with an idea to generate a research data mart. The data mart, envisioned by Lenert, took the research metric-tracking activities that Sampson was already leading with SPARCRequest to the next level and enabled cross-disciplinary group tracking and communication.

"A research data mart is a data warehouse that integrates data from multiple systems into a format that makes it easier to return metrics and analyses from different systems," said Katie G. Kirchoff, database administrator who runs the research data mart for BMIC.

"It's a simple concept, but hard to execute," added Lenert, who also serves as assistant provost for Data Sciences and Informatics. "No one's had the opportunity to bring together these diverse systems to tell us how long it takes an institutional review board protocol to get approved or whether this funding led to that outcome - those are difficult things to do."

In order to house and access the data within the warehouse, the RINS team needed a way to identify each study uniquely and link the disparate systems together. To solve the problem on identifying each study, the team created a research master identifier (RMID).

"RMID helped us be able to have a standardized protocol numbering system so we could link the systems that we have in-house," said Sampson. "RINS is the platform where we pull it all together."

Connecting the various systems together was achieved through the development of application programming interfaces (APIs). The APIs bridge the systems together and enable data to be updated across systems in near real-time.

Using RMIDs and APIs, RINS integrates SPARCRequest with other electronic databases, including MUSC's electronic health record; electronic institutional review board; and systems for grants award management, expenditure tracking and clinical trial management. RINS has been sufficiently flexible to accommodate new programs while also maintaining historical data.

As a new digital data warehouse, RINS provides two key improvements to monitoring translational science data. The first improvement is the integration of disparate systems onto one platform. This allows for a more complete picture of research processes and identifies the successes and challenges of the clinical trials.

The second improvement is the use of a decentralized system. Most platforms use a centralized system that would require each area of research administration to adopt whatever system had been integrated into the centralized solution, even if it was not the one best suited to its needs. In contrast, RINS is a decentralized system that enables each group to use its preferred system while maintaining comprehensive, integrated reporting. This allows clinical studies, for example, to be tracked across systems to give a much clearer idea of the life cycle of the project, provides metrics about the impact of translational efforts and identifies areas to improve clinical trial efficiency.

"We're not trying to build a system that fits all needs, but we're actually utilizing existing systems and linking them together for reporting needs," said Wenjun He, a systems engineer at SCTR who is the lead author for the report. "We can always expand it to any new system around campus - it's a seamless transition."

As more institutions look at how their programs perform, and as more funding agencies require performance data, institutions may look to RINS for help. While RINS is an open-source platform at MUSC, it could be difficult for other institutions to adopt the platform as is.

"It is customized, at this point, to systems that we utilize," said Andrew M. Cates, director of Research Web Solutions. "New integrations could be made, but another institution can't start using it without having to make some customizations or have systems similar to what we have at MUSC."

Although not currently available to all institutions, RINS has sparked interest from the SPARCRequest Open Source Consortium and may help to transition these institutions to better metric monitoring. Because many of these institutions already employ SPARC, it might be easier for them to integrate a broader range of systems through RINS.

Working together across a broad range of systems helps to ensure that clinical trials run smoothly and effectively. Through tools such as RINS and a wealth of services and resources, SCTR supports investigators in conducting effective research.

"The goal is to improve the performance of trials and study teams and remove barriers and challenges to clinical research," said Sampson. "SCTR provides over 900 consults, services and resources per year to support and educate study teams. RINS enables our ability to identify opportunities at an institutional level."

Overall, RINS is a powerful tool for extracting critical data on translational science. RINS integrates data from clinical studies across disparate systems and provides analyses that can be used to improve the clinical trial process. The Office of Clinical Research has been an integral, critical and leading stakeholder in RINS and with their continued support, the future of RINS could incorporate data from the basic sciences to provide new data on awarding research grants, core facilities and groundbreaking science.

A person who owns a car or who has a college education may be less vulnerable to COVID-19, according to an analysis of cases in Tehran, Iran, one of the early epicenters of the pandemic. While such variables do not inherently lower a person's risk, they do indicate an infrastructure of protection that persists despite how densely populated a person's district might be.

The international collaboration published their results on April 3 in Sustainable Cities and Society.

"In the past few decades, there have been various efforts aimed at increasing urban density to enhance efficiency and contribute to climate change mitigation -- but the COVID-19 pandemic has brought questions about the desirability of compact urban development to the forefront," said paper author Ayyoob Sharifi, associate professor in the Graduate School of Humanities and Social Sciences and in the Graduate School of Advanced Science and Engineering at Hiroshima University. Sharifi is also affiliated with the Network for Education and Research on Peace and Sustainability.

Through a comprehensive data analysis from the early months of the pandemic (to April 4 and June 27, 2020), the researchers found that a population's demographic structure -- age, social and economic class, access to resources -- is far more influential than simply how dense a population is. However, density is distinctly different than overcrowding for the resources available, the researchers said.

"We found that what drives the spread of infectious disease during a pandemic is overcrowding, which can occur in districts even with low density," said paper author Amir Reza Khavarian-Garmsir, assistant professor in the Department of Geography and Urban Planning in the Faculty of Geographical Sciences and Planning at the University of Isfahan.

While a person less likely to be aware of or follow public health guidelines or more likely to use public transportation may be more at risk for the disease, the researchers didn't find a statistically significant difference in urban districts with lower income and lower age compositions--indicating that age was one of the most significant risk factors for COVID-19 infection, despite density of living.

The data was obtained from Iran's AC-19 app, which tracks positive cases and deaths by geographic location, the researchers assessed whether certain variables affected infection rates across the 22 districts and roughly 8.6 million residents of Tehran. They used structural equation modeling, which can use multiple factors to indicate the influence of unobservable variables, such as likelihood to follow public health recommendations, in combination with measurable factors, such as ease of access to medical facilities.

There are some drawbacks to the study, the researchers said, the main one of which is data availability and accuracy. The pandemic evolved so rapidly in the early months that tracking may not capture the full picture; and testing shortages and cost, as well as a relative lack of severe symptoms in children and young adults, may skew the number of true positive cases.

"It is perhaps too early to draw definitive conclusions, so future research should continue to investigate the relationship between urban density and transmission patterns of infectious disease," Moradpour said.

The researchers said they hope their work will help policy makers develop guidelines to benefit all during urban and pandemic-preparedness planning.

"The next step is to further examine the impacts of urban density in other contexts," Shafiri said. "In addition, we are trying to examine the long-term impacts of the pandemic on compact urban development policies."

New research has shed light on how autism-spectrum disorder (ASD) manifests in the brains of girls, prompting the scientists to warn that conclusions drawn from studies conducted primarily in boys should not be assumed to hold true for girls.

The researchers discovered that there is a significant difference in the genes and "genetic burden" that underpin the condition in girls and boys. They also identified specific ways the brains of girls with ASD respond differently to social cues such as facial expressions and gestures than do those of girls without ASD.

"This new study provides us with a roadmap for understanding how to better match current and future evidenced-based interventions to underlying brain and genetic profiles, so that we can get the right treatment to the right individual," said lead investigator Kevin Pelphrey, PhD, a top autism expert at the University of Virginia School of Medicine and UVA's Brain Institute. "This advances our understanding of autism broadly by revealing that there may well be different causes for boys vs. girls; this helps us understanding the heterogeneity within and across genders."

Understanding Autism-Spectrum Disorder

The new insights come from a sweeping research project, led by Pelphrey at UVA, that brings together expertise from Yale; Harvard; University of California, Los Angeles; Children's National; University of Colorado, Denver; and Seattle Children's. At UVA, key players included both Pelphrey, of the School of Medicine's Department of Neurology and the Curry School of Education and Human Development, and John D. Van Horn, PhD, of the School of Data Science and UVA's Department of Psychology.

The research combined cutting-edge brain imaging with genetic research to better understand ASD's effects in girls. Those effects have remained poorly explored because the condition is four times more common in boys.

Pelphrey and colleagues used functional magnetic-resonance imaging (fMRI) to examine brain activity during social interactions. They found that autistic girls used different sections of their brains than girls who did not have ASD. And, most surprisingly, the difference between girls with and without autism was not the same as the difference in the brain seen when comparing boys with and without autism, revealing different brain mechanisms at play in autism depending on a person's gender.

Likewise, the underlying genetic contributors were quite different, the researchers found. Girls had much larger numbers of rare variants of genes active during the early development of a brain region known as the striatum. This suggests that the effects on the striatum may contribute to ASD risk in girls. (Scientists believe a section of the striatum called the putamen is involved in interpreting both social interaction and language.)

"The convergence of the brain imaging and genetic data provides us with an important new insight into the causes of autism in girls," Pelphrey said. "We hope that by working with our colleagues in UVA's Supporting Transformative Autism Research (STAR), we will be able to leverage our findings to generate new treatment strategies tailored to autistic girls."

Reston, VA--New research shows that a novel positron emission tomography (PET) tracer that targets inflammation is safe and can clearly identify early stages of rheumatoid arthritis. The promising PET tracer, 68Ga-DOTA-Siglec-9, rapidly clears from blood circulation, has a low radiation dose, and can be easily produced. This first-in-human study was published in the April issue of the Journal of Nuclear Medicine.

Inflammation is a significant part of several chronic diseases, including rheumatoid arthritis and its related issues. While PET imaging with 18F-FDG is a valuable tool for the diagnosis and monitoring of the effects of treatments, it is not specific enough to assess inflammation.

"It's important to detect inflammation early so that patients can receive the best treatment," said Anne Roivainen, PhD, professor of preclinical imaging and drug research at Turku PET Centre at the University of Turku and Turku University Hospital in Finland. "Our institution has worked for several years to develop an imaging agent that targets areas of inflammation, and in this study, tested its effectiveness in humans for the first time."

To evaluate the radiotracer's safety and biodistribution characteristics, six healthy study participants underwent whole body 68Ga-DOTA-Siglec-9 PET/computed tomography scans. 68Ga-DOTA-Siglec-9 was well-tolerated and cleared quickly from the blood, and its radiation dose was similar to other 68Ga tracers. In one additional study participant with rheumatoid arthritis, the tracer was able to clearly detect joints with arthritis.

"We have proven that the characteristics of 68Ga-DOTA-Siglec-9 are favorable for use in patient imaging studies," remarked Roivainen. "Future studies will clarify whether 68Ga-DOTA-Siglec-9 PET imaging has the potential to detect other inflammatory diseases early. It could also help to evaluate the effectiveness of treatments and promptly identify patients who are unlikely respond to therapy."

This study was made available online in August 2020 ahead of final publication in print in April 2021.

Immune checkpoint inhibitors have transformed cancer care to the point where the popular Cox proportional-hazards model provides misleading estimates of the treatment effect, according to a new study published April 15 in JAMA Oncology.

The study, "Development and Evaluation of a Method to Correct Misinterpretation of Clinical Trial Results With Long-term Survival," suggests that some of the published survival data for these immunotherapies should be re-analyzed for potential misinterpretation.

The study's senior author, Yu Shyr, PhD, the Harold L. Moses Chair in Cancer Research and chair of the Department of Biostatistics at Vanderbilt University Medical Center, and colleagues, Chih-Yuan Hsu, PhD, and Emily Lin, MD, PhD, have proposed an adjustment to convert the inappropriate Cox proportional-hazards model to the appropriate cure model. The adjustment utilizes the Cox-TEL (Cox PH-Taylor expansion for long-term survival data) method.

"The Cox proportional-hazards model has become ingrained as the preferred choice for survival analysis in clinical trials for many reasons, including its robustness; however, researchers should not blindly use this in immunotherapy trials," Shyr said.

"Because the model's proportional hazards assumption is clearly violated in some immunotherapy trials, the results and conclusions based on this model are inaccurate and misleading. We wanted to create an approach that would not only correct the hazard ratio of the Cox proportional-hazards model, but also be interpretable and practical for both clinicians and statisticians. We believe Cox-TEL will be used widely to avoid misinterpretation of clinical trials with long-term survival."

The team of researchers initiated their work because of the common observance of long tails and crossovers in survival curves with immune checkpoint inhibitors. These observances violate the proportional hazards assumption in the widely-used Cox proportional-hazards model. The researchers looked at simulated data and real-world data from published immune checkpoint inhibitor trials. In comparing the Cox proportional-hazards model to the Cox-TEL adjustment method, they determined that the Cox-TEL adjustment method was more accurate in assessing long-term survival. The Cox-TEL adjustment is user friendly and freely available as a package in the statistical software R.

Engaging in household chores may be beneficial for brain health in older adults. In a recent Baycrest study, older adults who spent more time on household chores showed greater brain size, which is a strong predictor of cognitive health.

"Scientists already know that exercise has a positive impact on the brain, but our study is the first to show that the same may be true for household chores," says Noah Koblinsky, lead author of the study, Exercise Physiologist and Project Coordinator at Baycrest's Rotman Research Institute (RRI). "Understanding how different forms of physical activity contribute to brain health is crucial for developing strategies to reduce the risk of cognitive decline and dementia in older adults."

In this study, published in the journal BMC Geriatrics, the researchers looked at the links between household chores, brain volume and cognition in a group of 66 cognitively healthy older adults living in the community. The participants attended three assessment visits at Baycrest Hospital, including a health evaluation, structural brain imaging and cognitive assessment.

Participants were asked about the time they spent on household chores, such as tidying, dusting, meal preparation and clean up, shopping, heavy housework, yard work, home repairs and caregiving.

The researchers found that older adults who spent more time engaging in such activities had greater brain volume, regardless of how much exercise they did. This was observed in the hippocampus, which plays a major role in memory and learning, and the frontal lobe, which is involved in many aspects of cognition.

Although it is possible that individuals with larger brains are more likely to take up household chores, there could be several explanations for the brain benefits of household physical activity.

First, we know that heart health is closely tied to brain health. It could be that household chores have a similar effect on the heart and blood vessels as low-intensity aerobic exercise.

Second, the planning and organization involved in household chores may promote the formation of new neural connections over time, even as we age.

Third, it could be that the older adults who engaged in more household chores spent less time being sedentary, which has been shown to be associated with negative health outcomes, including poor brain health.

"Besides helping to guide physical activity recommendations for older adults, these findings may also motivate them to be more active, since household chores are a natural and often necessary aspect of many people's daily lives, and therefore appear more attainable," says Dr. Nicole Anderson, Senior Scientist at the RRI, Director of the Ben and Hilda Katz Interprofessional Research Program in Geriatric and Dementia Care, and senior author of this study.

This study was funded in part by the Canadian Institutes of Health Research (CIHR).

As a next step, the researchers would like to assess household physical activity more objectively using wearable technology. With additional funding, they could also plan controlled trials with the aim of increasing individuals' household activity and studying brain changes over time.