Body

One of the key challenges in developing effective, targeted cancer treatments is the heterogeneity of the cancer cells themselves. This variation makes it difficult for the immune system to recognize, respond to and actively fight against tumors. Now, however, new advances in nanotechnology are making it possible to deliver targeted, personalized "vaccines" to treat cancer.

A new study, published on October 2, 2020 in Science Advances, demonstrates the use of charged nanoscale metal-organic frameworks for generating free radicals using X-rays within tumor tissue to kill cancer cells directly. Furthermore, the same frameworks can be used for delivering immune signaling molecules known as PAMPs to activate the immune response against tumor cells. By combining these two approaches into one easily administered "vaccine," this new technology may provide the key to better local and systemic treatment of difficult-to-treat cancers.

In a collaboration between the Lin Group in the University of Chicago Department of Chemistry and the Weichselbaum Lab at University of Chicago Medicine, the research team combined expertise from inorganic chemistry and cancer biology to tackle the challenging problem of properly targeting and activating an innate immune response against cancer. This work leveraged the unique properties of nanoscale metal-organic frameworks, or nMOFs -- nanoscale structures built of repeating units in a lattice formation that are capable of infiltrating tumors.

These nMOFs can be irradiated with X-rays to generate high concentrations of free oxygen radicals, killing the cancer cells directly and producing antigens and inflammatory molecules that help the immune system recognize and clear cancerous cells, much like a vaccine. Their lattice-like structure also makes nMOFs ideal transporters for delivering anti-cancer drugs directly to tumors. Thus far, however, it has been difficult to activate innate and adaptive immune responses necessary for eliminating cancerous tumors.

In this new study, the researchers fine-tuned their approach even further. This time, they generated a new type of nMOF structure that could be loaded with drugs known as pathogen-associated molecular patterns, or PAMPs. Now, when the nMOFs were applied to cancerous tumors, irradiating the tissue had a double effect: it triggered the nMOFs to kill local cancer cells to produce antigens against the tumor and released the PAMPs, which then triggered a much stronger activation of the immune response to the tumor antigens. This one-two punch was capable of killing both colon and pancreatic cancer cells with high efficacy, even in tumor models that are highly resistant to other kinds of immunotherapy.

In further experiments with mice, the investigators saw they could extend the effects of the nMOFs even to distant tumors with the application of checkpoint inhibitors, providing new hope for treating cancer both locally and systemically with this approach.

"By including PAMP delivery with the nMOFs, this is the first time we were able to really enhance the immune response to the antigens," said senior author Wenbin Lin, PhD, the James Franck Professor of Chemistry and a primary investigator of tumor immunology at the Ludwig Cancer Center at UChicago. "This is entirely different from all of our previous studies because we've shown that the nMOFs plus PAMPs can impact all of the aspects required for activating the immune system. We can use this nanoformulation to enable personalized cancer vaccinations that will work on any patient, because this strategy will not be subject to the heterogeneity we see among different patients."

The effects of the treatment were so pronounced that the researchers are eager to bring the technology to clinical trials, where other versions of the nMOF technology are already being tested, with promising results thus far.

"The brilliance of this system is twofold," said co-author Ralph Weichselbaum, MD, the Daniel K. Ludwig Distinguished Service Professor of Radiation and Cellular Oncology and Chair of the Department of Radiation and Cellular Oncology at UChicago. "First, it can improve local tumor control by increasing the killing power of X-rays. Second, while there has been interest in using radiation to stimulate the immune response to fight cancer, it has turned out to be harder than we thought. In this case, the nMOFs are able to activate the innate and adaptive immune systems, which makes this technology very promising for treating cancer in the clinic."

Already looking ahead to next steps, the investigators are working on refining the technology. "We're refining the design of the nMOF and its delivery of the PAMPs, in preparation for testing it in humans," said Lin. "We're really working on zooming in on the best formulation so we can get this into clinical trials, hopefully in the next two to three years, or even sooner."

The team credits the interdisciplinary and collaborative nature of UChicago and University of Chicago Medicine's Hyde Park campus for creating a space where chemistry and cancer biology have combined to produce such a promising potential therapy, as well as the support they've received from Ludwig Cancer Research along the way.

"From the conception of this project and getting it funded to starting with clinical trials where we're able to test the technology in clinical trials and get real patient data, this work has all been done right here at UChicago," said Weichselbaum. "We really are going from discovering something in the lab to testing it at the bedside."

Leesburg, VA, October 2, 2020--According to an open-access article in ARRS' American Journal of Roentgenology (AJR), dual-energy CT (DECT) added value to routine interpretation of emergency department (ED) imaging studies by increasing radiologists' diagnostic confidence, leading to a reduction in downstream imaging and associated costs.

William D. Wong of Vancouver General Hospital and colleagues queried his institution's radiologic information system for all DECT studies performed in the ED between January 1, 2016, and December 31, 2016. The team then sorted CT examinations into five body systems--head and neck, chest, abdomen and pelvis, spine, and musculoskeletal--and a board-certified radiologist, not initially involved in reading these cases, reviewed the corresponding reports for mentions of dual-energy or spectral examination as part of the study interpretation.

To determine the impact of DECT on downstream imaging, studies in which DECT was mentioned in the report were read again in a randomized double-blind manner with the mixed image datasets only, which simulate conventional CT images.

The difference between the numbers of follow-up studies recommended after conventional CT and DECT was converted into U.S. dollars via the U.S. Centers for Medicare & Medicaid Services Physician Fee Schedule and 2019 Current Procedural Terminology codes to estimate a projected cost benefit due to any reduction in follow-up imaging.

"Among the 3,159 cases, use of dual energy or spectral analysis potentially altered management in 298 (9.4%) cases, resulted in confirmation of suspected observations and increased diagnostic confidence in 455 (14.4%) cases, provided relevant additional information on an observation in 174 (5.5%) cases, resulted in characterization of an incidental finding in 44 (1.4%) cases, and was mentioned as being noncontributory in three (0.09%) cases." Wong et al. determined.

In terms of the five body systems they categorized, the musculoskeletal system accounted for the greatest number of studies wherein DECT potentially altered management (266/298 cases)--the most common use to confirm gout (185/266).

And although DECT was not noted in 2,272 reports (71.9%), compared with conventional CT alone, DECT findings avoided 162-191 recommended follow-up MRI examinations, 21-28 CT examinations, and 2-25 ultrasound examinations.

Meanwhile, DECT findings did prompt one additional recommended interventional angiography procedure, one ventilation-perfusion scan, and one imaging-guided biopsy.

Ultimately, for the Vancouver General ED in the year 2016, "DECT findings led to a decrease in recommended follow-up imaging examinations totaling an estimated $52,991.53-61,598.44," Wong and colleagues concluded.

Acknowledging a future need to evaluate how referring clinicians adapt to DECT, as well as how much they trust any added value, the authors of this AJR article added that Vancouver General has since completed the implementation of DECT acquisition for all CT examinations performed in the ED.

Despite increased use of telemedicine during the COVID-19 pandemic, Americans have had significantly fewer consultations with primary care doctors and markedly fewer assessments of common cardiac risk factors, according to a new study led by researchers at Johns Hopkins Bloomberg School of Public Health.

The study found that the number of primary care consultations fell by more than 21 percent during the second quarter of 2020, compared with the average second-quarter visit volume from the second quarters in 2018 and 2019. That drop in 2020 occurred despite a large, simultaneous surge in telemedicine--which increased from almost zero in prior years to about 35 percent of primary care visits from April through June 2020.

The study, based on an ongoing audit of outpatient care in the U.S., also found that the frequency of blood pressure and cholesterol assessments dropped by about 50 percent and 37 percent, respectively. These assessments, important tools for detecting elevated cardiovascular disease risks, typically require in-person care.

The results suggest a potential collateral effect of the COVID-19 pandemic--greater undiagnosed cardiovascular disease and less risk-factor monitoring than typically takes place through office-based primary care.

The study will be published October 2 in JAMA Network Open.

"These results indicate that there has been a significant decline in primary care use, at least in the early phases of the pandemic, and that telemedicine is an imperfect substitute for many office-based consultations," says study lead author G. Caleb Alexander, MD, a practicing internist and professor in the Department of Epidemiology at the Bloomberg School.

The COVID-19 pandemic has caused directly more than one million deaths worldwide, more than 200,000 have occurred in the U.S. Social distancing policies as well as health-system restructuring to prioritize COVID care and reduce the potential for health care-related transmission have led to sharp reductions in the activities of ordinary life including routine doctor's visits. During this period, there has also been increased reliance on telemedicine, in which doctors consult with their patients via telephone or the internet, but the precise impact of telemedicine on the level and content of primary care delivery has been unclear.

For their study, Alexander and colleagues examined the National Disease and Therapeutic Index (NDTI), a nationally representative audit of outpatient care conducted by IQVIA, a health care technology company.

One key finding was that the estimated number of primary care consultations fell from an estimated average of 126.3 million per quarter in the second quarters of 2018 and 2019 to 99.3 million during April through June 2020, the first full quarter following the start of the COVID-19 crisis in the U.S.

That represents a drop of 21.4 percent, and the findings indicate that this drop occurred despite an unprecedented surge in telemedicine use--from 1.1 percent of total visits in 2Q-2018 and 2Q-2019 to 35.3 percent in 2Q-2020.

The analysis also showed that the estimated number of office-based primary care visits declined by 50.2 percent from the second quarter 2Q-2018/2019 average to 2Q-2020.

The researchers examined several assessments or interventions that are commonly performed during primary care consultations, and again found large declines from the 2Q-2018/2019 averages to 2Q-2020. These included a 26.0 percent drop in visits where a medicine was initiated or renewed, as well as a 50.1 percent decline in blood pressure checks and a 36.9 percent decline in blood cholesterol tests.

The large declines in blood pressure and cholesterol checks during the pandemic reflect both a decrease in overall primary care visit volume as well as the less common assessment of these cardiac risk factors during telemedicine consultations.

"These are not trivial declines: They are large, clinically important declines involving two of the most fundamental elements of primary care--the prevention of heart attacks and strokes," Alexander says. "So these findings raise serious concerns regarding the collateral effects of the COVID-19 pandemic on cardiovascular disease prevention in the United States."

What The Study Did: This observational study quantified national changes in the volume, type and content of primary care delivered during the COVID-19 pandemic, especially with regard to office-based visits compared with telemedicine encounters.

Authors: G. Caleb Alexander, M.D., M.S., of the Johns Hopkins Bloomberg School of Public Health in Baltimore, 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/jamanetworkopen.2020.21476)

Editor's Note: The article includes conflict of interest 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.

Denver--October 2, 2020--Next-generation sequencing (NGS) of cell-free DNA (cfDNA) obtained from blood samples may improve diagnostic testing in patients with advanced NSCLC, and may also be faster and less expensive compared to standard tissue profiling, according to research presented today at the IASLC 2020 Lung Cancer Hot Topic: Liquid Biopsy Virtual Conference.

There have been numerous advances in liquid biopsy since its advent in 2018, and the concept of a "blood-first" approach--superseding or replacing tissue biopsy--is a current topic of much debate and discussion. The IASLC Liquid Biopsy Conference is a virtual forum to discuss research in this area and ultimately determine if the cost and effectiveness of the testing makes it applicable in public health and clinical settings.

Canadian researchers led by Dr. Natasha Leighl, Princess Margaret Cancer Centre, Toronto, Canada, examined the clinical utility and treatment outcomes with liquid biopsy in patients with advanced NSCLC from the perspective of the Canadian public healthcare system.

Dr. Leighl and her colleagues at six Canadian hospitals organized 210 patients into two cohorts:

Cohort 1 included 150 treatment naïve patients with measurable disease and smoking history of fewer than 10 packs of cigarettes per year.

Cohort 2 enrolled 60 patients with known oncogenic drivers whose disease progressed on tyrosine kinase inhibitors (TKIs).

After excluding variants of unknown significance and synonymous alterations, 118 patients in Cohort 1 (79%) had more than one alteration detected by G360 test (304 alterations detected in 35 genes). Of these, 284 alterations were considered actionable with FDA-approved drugs or available clinical trials. Actionable targets included EGFR (32.0%), ERBB2 (3.2%), MET (3.2%), ALK (1.4%), KRAS G12C (1.1%), and ROS1 (0.4%). Additional clinically relevant alterations included TP53 (27.8%), KRAS non-G12C (3.9%), PIK3CA (3.9%) and BRAF nonV600E (1.1%).

In Cohort 2, 53 patients (85%) had more than one characterized genomic alteration detected, with a total of 165 alterations in 28 genes including EGFR (45.8%, five were C797S), ALK (fusions 3.3%; mutations 2.0%), BRAF (V600E 0.7%; other 3.3%), MET (amplification 2.0%; exon 14 0.7%), FGFR3 (0.7%), and RET (0.7%) as well as non-driver mutations. Twenty-seven patients (14.0% in Cohort 1; 10% in Cohort 2) had no alterations detected by G360. In samples with alterations detected, the median number of alterations per patient was three (range 1-17). The median time to reporting of G360 was 7 days (range 5-27).

"Over 80% of patients with advanced NSCLC had characterized genomic alterations detected in cfDNA. At least 56% of treatment-naïve patients and 37% of TKI-resistant patients had clinically actionable alterations detected," Dr. Leighl said. Liquid biopsy is an important and timely method of molecular diagnosis in newly diagnosed patients with advanced NSCLC and in the setting of targeted therapy resistance.

Denver--October 2, 2020--A pilot study comparing the effects of a liquid biopsy with tissue-based test showed that liquid biopsy turn-around time for results was approximately 10 days faster than the tissue biopsy, according to research presented today at the IASLC 2020 Lung Cancer Hot Topic: Liquid Biopsy Virtual Conference.

Oncologists and pathologists prefer tissue-based analysis for patients with lung cancer, but liquid biopsy may provide a salvage approach in case of tissue exhaustion and may even be faster than tissue-based analysis according to Nir Peled, MD, a medical oncologist and Head of the Cancer Institute, Soroka Medical Center, Ben Gurion University of the Negev, Beer Sheva, Israel.

Dr. Or Sehayek, Dr. Peled and their colleagues developed a pilot study and evaluated 25 patients with treatment-naive advanced metastatic non-small cell lung cancer (NSCLC). Dr. Peled sought to compare time to report and time to treatment for next-generation sequencing (NGS)-based liquid biopsy vs. tissue-based analysis.

Tissue and blood biopsies were ordered for all patients. Tissue-based analysis was based on local standard of care, which was immunohistochemistry for ALK, ROS1, and PCR or amplicon-based NGS for EGFR mutation statuses. Each patient also was given a liquid NGS platform blood biopsy.

Turnaround-time analysis revealed that the median range (days) from the pathologic diagnosis to receipt of the tissue report on the last biomarker was 21.5 (7-45) days while the median ranges from blood draw to receiving the cfDNA findings was 10 (7-19) days.

Dr. Peled reported that actionable genes were identified in 11 tissue biopsies and in 14 by liquid biopsy. Liquid biopsy was able to identify mutations in PIK3CA and MET, as well as RET fusion, that were not tested by the local labs. One ALK fusion and one EGFR mutation were detected by tissue biopsy but not by liquid biopsy.

"This study suggests that NGS-based liquid biopsy improves time to report and more importantly, time to treatment, in patients with advanced NSCLC in comparison to tissue-based molecular analysis," Peled said. In addition, he said, "I am convinced that that the practice of 'liquid first' should be even implemented before tissue biopsy is performed; if so, we may see even more dramatic outcomes."

The results of a recent study moved University of Arizona Health Sciences researchers one step closer to developing effective vaccinations against flaviviruses, which infect more than 400 million people a year with diseases such as dengue, yellow fever, West Nile, Zika and Japanese encephalitis.

When a person is infected with a virus, antibodies are produced to fight the virus and provide immunity against reinfection. In the case of flaviviruses, however, if a person gets a second flavivirus infection - they were originally infected with Zika and then got dengue, for instance - the presence of antibodies can result in more severe symptoms through a process called antibody-dependent enhancement of infection.

"If, at some point in the past you've had Zika virus, later when you are exposed to dengue, you are at much greater risk of getting sick. Antibodies created by memory B cells as a result of the Zika infection can bind to certain parts of the dengue virus, but the dengue virus isn't affected," said Deepta Bhattacharya, PhD, an associate professor in the UArizona College of Medicine - Tucson's Department of Immunobiology. "In fact, the memory B cell-generated antibodies can work like a 'Trojan horse' and help the virus get into the cells, where it can make the disease worse."

The findings give Dr. Bhattacharya and his team a new way to think about creating flavivirus vaccines. Rather than targeting the whole virus, they propose targeting specific locations on the virus that are unique to each type and strain. Essentially, they would be removing memory B cells from the vaccination equation.

"We wanted to study how the immune system and antibody responses deal with sequential exposures to different flaviviruses," Dr. Bhattacharya said. "Antibody-dependent enhancement of infection is the main reason why it has been difficult to vaccinate against flaviviruses, dengue in particular."

Dr. Bhattacharya is the senior author on a paper, "Affinity-restricted memory B cells dominate recall responses to heterologous flavivirus challenges," published today in the journal Immunity. The study focused on two types of cells that produce antibodies: plasma cells and memory B cells.

Plasma cells are the primary drivers of long-lasting immunity, as they continue to produce antibodies once an infection has been cleared or after vaccination. Memory B cells only produce antibodies if a second infection occurs.

"One of the questions we've had for a long time is, what is the purpose of those memory B cells?" said Dr. Bhattacharya, also a member of the university's BIO5 Institute. "If you already have antibodies from plasma cells, why do you need the other cells?"

Using a combination of flavivirus infections, vaccinations and genetic mouse models, Dr. Bhattacharya and his team examined how memory B cells respond to subsequent flavivirus infections.

They found that when memory B cells are activated by a new infection, they produce antibodies that are diverse and capable of targeting viruses that have changed since the first infection, through mutation or infection with a slightly different strain, for example.

"There is a huge amount of hidden diversity in memory B cells. For most viral pathogens, like influenza or SARS-CoV-2, this is a good thing. It means that memory B cells are poised to make new antibodies and deal with mutations if and when they arise," Dr. Bhattacharya said. "For flaviviruses, this is not so great. We found that memory B cells produce a lot of suboptimal antibodies that could enhance the second infection."

Although memory B cells recognize the new virus as a flavivirus and produce antibodies, those antibodies are unable to stop the new virus from infecting cells. In fact, they may actually make the second infection worse.

The same holds true when it comes to vaccinations. Vaccines are designed to stimulate an immune response and prompt plasma cells and memory B cells to produce antibodies against a virus. If a person who never had dengue is vaccinated and develops antibodies, then later becomes infected with a different flavivirus, the antibodies produced by memory B cells in response to the vaccination may increase the severity of the disease.

"For people already immune to one flavivirus, this would avoid engaging these not-so-great memory B cells," Dr. Bhattacharya said. "For people who never were exposed, it avoids generating this problematic diversity in the first place."

Drugs to lower blood pressure of the type ACE inhibitors or angiotensin II receptor blockers reduce the mortality rate of influenza and pneumonia.

This is the main conclusion of a new reassuring study published in the Journal of the American Heart Association, which Christian Fynbo Christiansen and a number of Danish colleagues are behind. He is consultant, clinical associate professor and PhD at the Department of Clinical Epidemiology, which is part of the Department of Clinical Medicine at Aarhus University and Aarhus University Hospital in Denmark.

In the study, the researchers have compared mortality rates among 500,000 Danish patients who were admitted to hospitals in Denmark with influenza and pneumonia during the period 2005 to 2018. This has been done by correlating information from the National Patient Register (activity at Danish hospitals) with statistics from the Danish Register of Medicinal Products (the consumption of medicine in Denmark).

"A little over 100,000 of the admitted patients took ACE inhibitors or angiotensin II receptor blockers, and the study shows that fewer of them were put on a ventilator and that they had lower mortality rates than the hospitalised patients who took another type of drugs against elevated blood pressure, calcium blockers," says Christian Fynbo Christiansen.

The study arrives mid in a discussion of treatment which peaked while the corona pandemic was at its height. Some medical doctors and researchers pointed out that ACE inhibitors may actually have the completely opposite effect - that is increasing the risk of dying from COVID-19 as the virus SARS-CoV-2 which causes COVID-19 enters the lungs through the same ACE receptors as the ACE inhibitors.

The hypothesis was that when the ACE inhibitor reduces the level of ACE, the body compensates for this by activating a much greater number of ACE receptors on the surface of the cells, which the SARS-CoV-2 virus then utilises as some kind of access key. The greater the number of access keys available on the surface of the cells, the more easily the virus gains access to the cells.

The theory about increased mortality has been nurtured by the fact that a strikingly large proportion of the patients who were seriously ill due to COVID-19 had elevated blood pressure, which is extensively treated with ACE inhibitors - of the 600,000 Danes who have elevated blood pressure, approximately one-third ( 200,000) of them take ACE inhibitors.

"We haven't examined whether what applies to patients with influenza and pneumonia can be transferred directly to patients with COVID-19, but there is some evidence to suggest that ACE inhibitors have a protective effect against lung damage which we don't see in patients who take other types of medicine to lower blood pressure. The first studies find no correlation between ACE inhibitors/angiotensin II receptor blockers and COVID-19. However, further studies are needed using the good Danish registers," says Christian Fynbo Christiansen.

In Denmark, the discussion for and against the use of ACE inhibitors on corona patients has taken place (in Danish) in e.g. the Journal of the Danish Medical Association and another healthcare newspaper Dagens Medicin under headlines such as 'ACE inhibitors possibly increase the risk of dying of COVID-19'.

WASHINGTON -- The National Academies of Sciences, Engineering, and Medicine today released the final report of a consensus study recommending a four-phased equitable allocation framework that the U.S. Department of Health and Human Services (HHS) and state, tribal, local, and territorial (STLT) authorities should adopt in the development of national and local guidelines for COVID-19 vaccine allocation. Framework for Equitable Allocation of COVID-19 Vaccine recommends using existing systems across all levels of government to provide necessary resources to ensure equitable allocation, distribution, and administration of COVID-19 vaccine; launching a COVID-19 vaccine promotion campaign and risk communication and engagement program; and supporting equitable allocation globally.

In response to the COVID-19 pandemic, the U.S. and international communities have invested billions of dollars and immense amounts of human resources to develop a safe and effective vaccine in an unprecedented time frame, the report says. There are nearly 190 COVID-19 vaccines either in preclinical development or undergoing clinical trials in the U.S., Europe, and China. However, even if one or more safe and effective COVID-19 vaccine is authorized for use, it is very unlikely that sufficient quantities will be immediately available to vaccinate large portions of the U.S. population.

For the initial period when vaccine demand exceeds supply, the committee that conducted the study and wrote the report recommended a four-phased approach to allocation built on widely accepted foundational principles and guided by evidence to maximize societal benefit by reducing morbidity and mortality caused by the transmission of SARS-CoV-2.

Phase 1a covers approximately 5 percent of the population and includes front-line health workers (in hospitals, nursing homes, or providing home care); workers who provide health care facility services such as transportation and environmental services who also risk exposure to bodily fluids or aerosols; and first responders. This group has a critical role in maintaining health care system functionality, high risk of exposure to patients exhibiting symptoms of COVID-19, and higher risk of then transmitting the virus to others, including family members.

Phase 1b covers approximately 10 percent of the population and includes people of all ages with comorbid and underlying conditions (for example, cancer, serious heart conditions, and sickle cell disease) that put them at significantly higher risk of severe COVID-19 disease or death. Based on data from the COVID-19 Associated Hospitalization Surveillance Network, adults with two or more comorbid conditions make up the large majority of those hospitalized for COVID-19 in the U.S. Also included in this phase are older adults (age 65 and over) living in congregate or overcrowded settings including nursing homes, long-term care facilities, homeless shelters, group homes, prisons, or jails. This group faces the joint risk factors of severe disease and reduced resilience associated with advanced age and of acquisition and transmission due to their living settings, in which they have limited opportunity to follow public health measures such as maintaining physical distance.

Phase 2 covers approximately 30 percent to 35 percent of the population and includes K-12 teachers and school staff (including administrators, environmental services and maintenance workers, and bus drivers), and child care workers, who play a vital role in children's education and development. Also included are critical workers in high-risk settings who cannot avoid a high risk of exposure to COVID-19, such as workers in the food supply system and public transit. In addition, this phase includes people of all ages with comorbid and underlying conditions that put them at moderately higher risk, defined as having one of the conditions listed by the Centers for Disease Control and Prevention (CDC) as being associated with increased risk of severe COVID-19, and potentially some rare diseases as well. Phase 2 also includes people in homeless shelters or group homes for people with disabilities and those in recovery, as well as staff who work in those settings, as many of the individuals in this group have chronic health care needs and challenging living settings that increase potential exposure. In addition to people in prisons, jails, and detention centers and staff working in those settings, all older adults not included in Phase 1 should be included in Phase 2, as adults age 65 and older account for approximately 80 percent of reported deaths related to COVID-19.

Phase 3 covers approximately 40 percent to 45 percent of the population, and includes young adults, children, and workers in industries such as colleges and universities, hotels, banks, exercise facilities, and factories that are both important to the functioning of society and pose moderately high risk of exposure because there are likely to be some protective measures implemented in these work settings. Young adults between the ages of 18 and 30 typically have broader social networks than older adults, increasing their risks of infection and transmission, but they are less likely to become severely ill or die due to COVID-19, making them, along with children, targets for transmission prevention. The report notes that broad immunization of children will depend on whether COVID-19 vaccines have been adequately tested for safety and efficacy in these age groups.

Phase 4 covers everyone residing in the U.S. who did not have access to the vaccine in prior phases.

"Inequities in health have always existed, but at this moment there is an awakening to the power of racism, poverty, and bias in amplifying the health and economic pain and hardship imposed by this pandemic," said committee co-chair Helene Gayle, president and CEO of the Chicago Community Trust. "We saw our work as one way to address these wrongs and do our part to work toward a new commitment to promoting health equity."

For each group included in each phase, the committee recommended that STLTs ensure that special efforts are made to deliver vaccine to residents of high-vulnerability areas by using the CDC's Social Vulnerability Index or another more specific index such as the COVID-19 Community Vulnerability Index. This would incorporate the variables that the committee believes are most linked to the disproportionate impact of COVID-19 on people of color. Black, Hispanic or Latinx, American Indian and Alaska Native, and Native Hawaiian and Pacific Islanders have been disproportionately impacted by COVID-19 with higher rates of transmission, morbidity, and mortality. This reflects the impact of systemic racism leading to higher rates of comorbidities that increase the severity of COVID-19 infection and the socio-economic factors that increase likelihood of acquiring the infection, such as having front-line jobs, crowded living conditions, lack of access to personal protective equipment, and inability to work from home.

When individuals fit into multiple categorizations, the report notes, the higher phase should take precedence. The framework provides guidance to the STLT authorities for adapting its risk-based criteria to these realities while still maximizing benefit, mitigating health inequities, manifesting equal regard for all, being fair and transparent, and building on the best current evidence.

This framework can also inform the decisions of other groups, such as the Advisory Committee on Immunization Practices. In addition to the framework, the report includes recommendations that HHS should:

Leverage and expand the use of existing systems, structures, and partnerships across all levels of government and provide the necessary resources (including funding items such as needles, syringes, and personal protective equipment for vaccinators) to ensure equitable allocation, distribution, and administration of COVID-19 vaccine. Secure vaccine storage, transport, and safe, efficient, and equitable vaccine distribution are critical to a successful vaccination program, especially given potential vaccine ultra-cold-chain requirements and a multidose vaccine regimen.

Coordinate across agencies to provide and administer COVID-19 vaccine with no out-of-pocket costs for those being vaccinated, regardless of their social and economic resources or their employment, immigration, or insurance status. This will help assure equity and decrease vaccine hesitancy.

Create and appropriately fund a COVID-19 vaccination risk communication and community engagement program to support STLT authorities. Community-based organizations and other partner organizations -- including hospitals, pharmacies, faith-based organizations, community centers, and schools and universities -- can support community outreach and foster accountability. Employers and unions could support improved access by providing work-site clinics and by covering costs for employees. The communication workforce must reflect the diversity of the communities being vaccinated and should sustain proactive two-way communication, the report says.

To help improve vaccine acceptance, the CDC should rapidly develop and launch a national, branded, multidimensional COVID-19 vaccine promotion campaign, using rigorous, evidence-informed techniques from risk and health communication, social marketing, and behavioral science. CDC should partner with diverse stakeholders and prioritize promoting the vaccine to people of color and other communities in which vaccine hesitancy and skepticism have been documented. In addition, the U.S. government should commit to a leadership role in the equitable allocation of COVID-19 vaccine globally by opting into the COVAX facility at Gavi, the Vaccine Alliance, deploying a proportion of the U.S. vaccine supply for global allocation, and supporting the World Health Organization and its member states to optimize fair and equitable allocation of vaccine, regardless of income level.

There are many uncertainties affecting COVID-19 vaccine allocation, such as number and timing of available vaccine doses, number of available vaccine types, vaccine efficacy and safety, vaccine uptake, and vaccine distribution and administration. The report includes a summary of the application of the framework in various scenarios. Furthermore, while vaccine distribution is an essential part of pandemic response, other efforts such as social distancing, testing, diagnostic testing, contact tracing, and wearing masks will continue to be vital, especially during the early phases of vaccination.

"Despite the committee's intense effort, this framework should still be regarded as an evolving document -- meant to be adapted and refined in the face of continuing improvement in our understanding of the dynamics of the pandemic," said committee co-chair William H. Foege, emeritus distinguished professor of international health at Emory University and former CDC director. "We hope these guidelines serve as the impetus for one of the most consequential peacetime efforts this country has ever seen, as well as a springboard to resuming our place as a leader in global health."

"Ultimately, in these uncertain and challenging times, the integrity of the COVID-19 vaccine development, allocation, and distribution processes will be critical to ensuring widespread access to vaccines that are safe and effective, and convincingly so for the public," said National Academy of Medicine President Victor J. Dzau. "I hope the recommendations set forth in our report contribute to society's ability to respond to and recover from the COVID-19 pandemic here in the United States and globally."

What The Study Did: Researchers describe what to their knowledge is the first case of a cerebrospinal fluid leak after nasal testing for COVID-19.

Authors: Jarrett Walsh, M.D., Ph.D., of the University of Iowa Hospitals and Clinics in Iowa City, 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/jamaoto.2020.3579)

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

What The Study Did: Researchers examined variation among states in how common high blood pressure disorders of pregnancy (including pregnancy-induced hypertension or pre-eclampsia) and eclampsia were among 3.6 million women who had a live birth in 2017.

Authors: Alexander J. Butwick, M.B.B.S., M.S., of the Stanford University School of Medicine in Stanford, California, 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/jamanetworkopen.2020.18741)

Editor's Note: The article includes conflicts 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.

Automated analysis of breast cancer patients' routine scans can predict which women have a greater than one in four risk of going on to develop cardiovascular disease, according to research presented at the 12th European Breast Cancer Conference.

Women who have been treated for breast cancer may have a higher risk of developing cardiovascular disease and in some groups the risk of dying from cardiovascular disease is higher than the risk of dying from breast cancer.

The new study shows that it is possible to spot those at the greatest risk using computer analysis of the CT scans that are taken for planning cancer treatments. Researchers say that identifying patients most at risk of cardiovascular disease could allow steps to be taken to lower the risk.

The research was presented by Professor Helena Verkooijen, from the Division of Imaging and Oncology at the University Medical Center Utrecht in The Netherlands. She said: "We've seen great improvement in breast cancer survival, thanks in part to better treatment. However, treatments have side effects and some treatments - such as radiotherapy and certain types of cancer drug - can increase the risk of cardiovascular disease. In my opinion, treating breast cancer means finding the right balance between maximising chances of tackling the tumour, while minimising the risks of side effects, including the risk of cardiovascular disease."

The study included around 14,000 breast cancer patient who were treated with radiotherapy in three large hospitals in The Netherlands between 2005 and 2016.

Professor Verkooijen and her colleagues used a measure called coronary artery calcium (CAC) score. This is a calculation of the amount of calcium in the walls of the heart's arteries and it is known to be strong risk factor in cardiovascular disease because calcifications can lead to narrowing or blocking of the blood vessels.

The researchers developed a deep learning algorithm that could gauge the presence and extent of coronary artery calcifications from the CT scans that were already being carried out to help plan each woman's radiotherapy treatment. This allowed them to automate the measurement of CAC for all the women with only minimal extra workload.

Researchers followed the women for an average of 52 months to see whether any of them developed cardiovascular disease. In women with no calcifications (a score of zero), 5% went on to be hospitalised or to die from cardiovascular disease. In women with a score of between one and ten, 8.9% were hospitalised with or died from cardiovascular disease. In women with a score of 11-100, the figure was 13.5%, in women with a score of 101-400 it was 17.5% and in women with a score above 400, it was 28.3%.

When researchers took into account women's ages and the year they were diagnosed, they found a 3.7 times greater risk of cardiovascular disease in women with the highest score (above 400), compared with women with no calcifications. In women who were treated with a particular type of chemotherapy called an anthracycline, the association between high CAC score and cardiovascular risk was even stronger.

The researchers acknowledge that they were unable to take other cardiovascular disease risk factors, such as smoking, high blood pressure and diabetes, into account in this study, although these are factors they are looking at in another study.

Professor Verkooijen said: "We believe this is the first time anyone has conducted a large-scale study like this. We've shown that we can use routine CT scans to indicate which breast cancer patients are most likely to develop cardiovascular disease. Now we need to do more research to find out what can be done to help minimise this risk, for instance whether patients' cardiovascular health should be monitored or treated."

The researchers are now working to get their technique for predicting cardiovascular disease risk into use in several radiotherapy units in The Netherlands. Patients taking part in this study who are found have an increased risk will be offered further cardiovascular screening and lifestyle advice, and their CAC score will be used in planning their breast cancer treatment.

Professor Nadia Harbeck, from the University of Munich (LMU) in Germany, is chair of the 12th European Breast Cancer Conference and was not involved with the research. She said: "Our key aim is treating breast cancer effectively. However, it's just as important that we don't over-treat patients because cancer therapies can have serious and long-term side-effects.

"This is a clever study because it shows us how the CT scans we are already taking can also be used to discover which women have the highest risk of cardiovascular disease. We look forward to further results from these researchers and hope they might show us how best to help women who are at a higher risk of cardiovascular disease."

The study enrolled over 1000 participants, recruited from routine HIV services in and around the inner city area of Hillbrow, and analysed two of the current Department of Health antiretroviral regimens, recommended in the 2019 ART guidelines, and a third regimen favoured by higher-income countries. The newer regimens appeared to have side effect and resistance benefits over older regimens, and potential cost benefits, but little research had been done on African populations with them till now.

All three regimens were very potent and well tolerated by patients, however, the newer regimens containing dolutegravir (DTG) and tenofovir alafenamide (TAF) demonstrated a large increase in weight, especially in women.

After 96 weeks of treatment, the percentage of people with viral suppression was 79% in the TAF/emtricitabine (FTC)+DTG arm, 78% in the TDF (tenofovir disoproxil fumarate)/FTC+DTG arm and 74% in the TDF/FTC/EFV (efavirenz) arm.

There were no significant differences in overall efficacy between the three treatments tested.

In terms of weight gain, after 96 weeks of treatment, men gained 5.4 kg in the TAF/FTC+DTG arm, 3.6 kg in the TDF/FTC+DTG arm, and 1.1 kg in the TDF/FTC/EFV arm.

For women, at the same time point, the weight gain was 8.1 kg in the TAF/FTC+DTG arm, 4.8 kg in the TDF/FTC+DTG arm, and 3.2 kg in the TDF/FTC/EFV arm.

The treatment emergent obesity for women at week 96 was 28% for those on TAF/FTC+DTG (5% for men), 18% for those on TDF/FTC+DTG (4% for men), and 12% for those on TDF/FTC/EFV (3% for men).

Dr Simiso Sokhela, lead clinician on the study, presented additional results in a high-profile oral presentation at the 23rd International AIDS Conference in July. She commented, "We are concerned about the weight gain and body composition changes which are more severe in women, and we have predicted new risk of associated diabetes and other complications, especially when taking both TAF and DTG together. The 96 week results supports the WHO treatment guidelines which reserve TAF only for patients with osteoporosis or impaired renal function."

Professor Francois Venter, head of Ezintsha at Wits, added: "This was a huge and complex international collaboration, and I am proud of the team achieving such a high quality result. We thought we had found the magic bullet for our patients, but it is clear there is much more work to be done on antiretroviral safety. It is imperative we do these studies locally, as toxicity seems to vary significantly by population. One of the most worrying data points were that the women in the study were actually heavier than the men before starting treatment, a stark reminder that South Africa has a major obesity problem among women, made worse with these new drugs. It's a headache for public health programmes that have delivered HIV treatment so effectively in the last decade, and we need to be looking to the future for alternatives that are safer."

The study team is considering the best options for patients to reduce their risk of long-term co-morbidities, and will be consulting with patient groups, researchers and other expert groups to get guidance.

The results support the current recommendation from the World Health Organization to use dolutegravir as first-line treatment for HIV, with efavirenz as an alternative option. However the results suggest that dolutegravir should be combined with TDF/FTC, which is associated with suppression of weight gain, and not with the newer combination of TAF/FTC, which is associated with excess weight gain and clinical obesity, especially in women.

South Africa has the largest antiretroviral programme in the world, with over 6 million people on treatment. The programme has resulted in a large increase in South African life expectancy and it has contributed to a large decrease in new HIV transmissions over the last few years. Of concern, South Africa has an obesity epidemic, with related diabetes the second commonest cause of death in the country, and both are implicated in COVID-19 severity. The South African government has been briefed on the results, as has the South African Health Products Regulatory Authority, the Food and Drug Administration, and the World Health Organization. The results of ADVANCE have informed international and local HIV treatment guidelines.

A new analysis by North Carolina State University and Arizona State University outlines how a brand of frozen meat products took social media by storm - and what other brands can learn from the phenomenon.

"A lot of brands have struggled with how to use social media during the COVID-19 pandemic - they are unsure of how to talk with consumers," says Ekaterina Bogomoletc, corresponding author of a paper on the work and a Ph.D. student in NC State's Communication, Rhetoric, and Digital Media program. "How do you communicate with your audience without sounding tone deaf about our new reality?

"But Steak-umm's COVID-19 response brought the company thousands of new followers. Its approach actually worked. We thought: 'That's interesting. Why did this work?'"

Specifically, the researchers focused on Steak-umm's Twitter account (@steak_umm) - particularly a series of tweets in early April that addressed issues such as how to distinguish between true and false information. The Steak-umm Twitter account followed up with additional threads on everything from critical thinking to science communication.

In addition to looking at data from the Steak-umm Twitter account, the researchers also analyzed a random sample of 1,000 tweets that mentioned or replied to Steak-umm. All of the tweets were from a two-week period in April.

Four key themes emerged from that analysis - all of them supportive of the Steak-umm brand. First was praise - Twitter users were overwhelmingly positive about Steak-umm's foray into public-service tweets. Second was leadership. Third was surprise. And fourth was an intent to purchase Steak-umm products.

"It was pretty much everything a social media manager could hope for," Bogomoletc says. "Steak-umm grew its audience, built community around its social media presence, had overwhelmingly positive public reactions, and even raised money for a nonprofit organization aimed at addressing hunger in the United States."

But how did Steak-umm do it? And why did it work?

"Steak-umm was successful, in part, because it had adopted a 'human' approach to its social media presence before the pandemic, so it didn't have to shift gears too much," Bogomoletc says. "But its success also hinged on the fact that it communicated its values consistently and declared a commitment to public good. People responded to that.

"As for why it worked? There's something called expectancy violation theory that seems relevant here. The theory finds that violating someone's expectations can sometimes improve people's perceptions of us. Basically, if we're pleasantly surprised by something, it can make us like that thing more than we used to. In this case, the messages from this social media account were completely out of line with people's expectations of a frozen meat product's social media account. That sense of surprise was something we saw again and again in the social media messages we analyzed."

The study's findings may also give brands a path forward for communicating with audiences in the COVID and post-COVID eras.

"Steak-umm certainly demonstrated that a brand can connect effectively with its audiences online by communicating with them on a human-to-human level," Bogomoletc says. "And it highlights that brands can contribute to social change in a meaningful way. In this case, the brand shared media and science literacy tools that helped readers navigate a crowded and confusing media landscape. That's valuable.

"But that also means brands need to ensure they are behaving responsibly on social media platforms - because people are listening."

WASHINGTON (Oct. 1, 2020)--Anti-vaccination discourse on Facebook increased in volume over the last decade, coalescing around the argument that refusing to vaccinate is a civil right, according to a study published today in the American Journal of Public Health. This finding could have serious public health implications as vaccine opponents who unite around a single argument could quickly mobilize into a political movement able to lobby state lawmakers for vaccine exemptions, the researchers say.

Led by David Broniatowski, an associate professor of engineering management and systems engineering at the George Washington University, researchers from GW, the University of Maryland and Johns Hopkins University examined more than 250,000 posts on 204 Facebook pages expressing opposition to vaccines between October 2009 and October 2019. While opposition to vaccines historically takes many forms, from concerns about safety to conspiracy theories about government malfeasance, the researchers found vaccine opponents online gravitate toward a "civil liberty" argument that individuals have the civil right to refuse to take a vaccine.

"Framing vaccine refusal as a civil right allows vaccine opponents to sidestep the science, and instead debate about values, especially the value of freedom of choice," Broniatowski said. "However, this is a case where one person's exercise of that freedom can hurt everyone else."

The study also showed that anti-vaccine discourse online evolved following three distinct events: the measles outbreak at Disneyland in 2015, the release of the film "Vaxxed" in 2016 and a worldwide measles outbreak in 2019.

The first increase in anti-vaccination Facebook posts came in 2015 after a measles outbreak, which started at Disneyland in California and sickened 125 people. According to the researchers, the Disneyland measles outbreak drew widespread attention to vaccine opposition followed by promotional campaigns conducted in Facebook pages framing vaccine refusal as a civil right and discussions about political mobilization and totalitarianism.

There was a further increase in anti-vaccination posts in 2016, especially on Facebook pages framing vaccine refusal as a civil right, after the release of "Vaxxed," a film directed by a discredited former physician. The researchers found the proportion of civil liberties topics discussed actually decreased during this time while the proportion of topics about the film increased. They suggest that these pages may have been targeted to disseminate promotional material advertising the movie.

"We found Facebook pages that promoted vaccine choice narratives were also sharing 'Vaxxed'-related promotional content," Amelia Jamison, a faculty research assistant at the University of Maryland's Center for Health Equity, said. "This continued even after the film was released and linked civil liberties based arguments with broader anti-vaccine claims."

"It appears that the movie's producers may have hijacked these pages to lay the groundwork for a political movement," Broniatowski added.

The researchers saw another spike in anti-vaccination posts in 2019, this time in posts to Facebook pages with U.S. states in their titles, such as "Michigan for Vaccine Choice" and "Health Freedom Minnesota." Content posted during this time included civil liberties discourse, mostly encouraging people to vote for or against certain state bills, attend political rallies and oppose perceived vaccine mandates and perceived censorship. These groups also discussed vaccine safety concerns and alternative medicine.

"Starting in 2019, we saw a large increase in these state-level pages, and especially in places considering vaccine-related legislation," Mark Dredze, the John C. Malone Associate Professor of Computer Science at Johns Hopkins University, said. "These pages make it easy for vaccine opponents to know how to vote in their local elections to make it easier to opt out of vaccination. Without a clear counter-argument from public health agencies, the average voter may not realize how important these bills are, and may not consider them when voting."

The researchers say their results suggest vaccine opponents are becoming increasingly organized with considerable political clout. As the push for a COVID-19 vaccine continues, the researchers recommend public health agencies and advocates develop effective messages for communicating fact-based rationales for vaccination. They also urge public health agencies and advocates to build strong relationships with state policymakers, so they may take an active stance when proposed laws or exemptions would further threaten public health. The researchers caution, however, that public health agencies and advocates need to consider different approaches and messages to engage with civil liberties arguments beyond the fact- or science-based rationales to vaccinate.