Body

In a SWOG Cancer Research Network trial that put three targeted drugs to the test, the small molecule inhibitor cabozantinib was found most effective in treating patients with metastatic papillary kidney cancer - findings expected to change medical practice.

These findings will be presented at ASCO's virtual 2021 Genitourinary Cancers Symposium on Feb. 13, 2021 at 1 p.m. ET. The findings will be simultaneously published in The Lancet.

There are currently no effective treatments for metastatic papillary kidney cancer, or metastatic pRCC, a rare subtype of kidney cancer. One study of 38 patients found that the average survival rate was eight months after diagnosis.

Sumanta Pal, MD, clinical professor of medical oncology at City of Hope, a comprehensive cancer center, and an investigator at SWOG, a cancer clinical trials group funded by the National Cancer Institute (NCI), part of the National Institutes of Health (NIH), said there is hope for metastatic papillary kidney cancer patients. Mutations in the MET gene are a hallmark of this type of cancer, and there are new drugs that target the MET gene among other important signaling pathways. Pal decided to put three of them to the test against the current standard treatment, sunitinib, a receptor tyrosine inhibitor.

In his study, S1500, Pal studied 147 eligible patients with papillary kidney cancer, most of whom had not received any prior treatment. Patients were randomly assigned to one of four treatment groups - those who took sunitinib and those who took one of the three MET target drugs - cabozantinib, crizotinib, and savolitinib.

Pal and his team wanted to see how long it would take patients' cancer to spread or return, a measure known as progression-free survival. What they found: Patients receiving sunitinib went a median of 5.6 months before their cancer progressed; patients receiving savolitinib and crizotinib fared much worse overall. But cabozantinib, which inhibits VEGF receptors and AXL in addition to MET, gave patients a median of 9.2 months before their cancer progressed. In addition, 23% of patients had a significant reduction in the size of their tumor with cabozantinib. In contrast, only 4% of patients saw this kind of tumor response with sunitinib.

"The magnitude of the response was surprising," Pal said. "We still have a long way to go to help make patients' lives longer and better, but we do have a new standard treatment for these rare cancer patients. This result is a testament to SWOG and to City of Hope, who have the motivation and expertise needed to successfully conduct rare cancer clinical trials."

Building on the momentum of S1500, SWOG will lead the next pivotal trial in papillary kidney cancer, one with a focus on the potential synergy between targeted treatments like cabozantinib and immune therapy. Pal will lead that study with SWOG investigator Dr. Benjamin Maughan at Huntsman Cancer Institute at the University of Utah.

SWOG 1500, also called PAPMET, was sponsored by NCI, designed and led by the SWOG Cancer Research Network under the leadership of Dr. Pal, and conducted through the NCI's National Clinical Trials Network.

S1500 was also funded by the NIH through NCI grants CA180888, CA180819, CA180820, CA180821, CA180863, and CA180868; and in part by AstraZeneca plc/AB, Exelixis, Inc., and Pfizer, Inc. The companies provided savolitinib, cabozantinib, crizotinib, and sunitinib, respectively, for the trial under each company's Cooperative Research and Development Agreement with the NCI.

"NCI's drug development program in the Cancer Therapy Evaluation Program facilitated the collaborations between pharmaceutical companies as well as collaborations between companies and SWOG investigators to make this trial possible. We are proud to have played a part in defining which of these therapies is most effective for patients with papillary renal cell carcinoma," said John Wright, MD, PhD, the associate branch chief of CTEP's Investigational Drug Branch, and the NCI's medical monitor for the study.

Lenvatinib plus pembrolizumab yields better overall survival than single-agent sunitinib when given as first-line therapy in untreated patients with metastatic kidney cancer

The combination also improved progression-free survival and overall response rate

BOSTON - Patients with advanced kidney cancer, who received a targeted drug combined with a checkpoint-blocker immunotherapy agent had longer survival than patients treated with the standard targeted drug, said an investigator from Dana-Farber Cancer Institute, reporting results from a phase 3 clinical trial.

The survival benefit demonstrates that an immune checkpoint inhibitor together with a targeted kinase inhibitor drug "is important in the first-line treatment of patients with advanced renal cell carcinoma," said the authors of a study published in The New England Journal of Medicine today and simultaneously presented during American Society of Clinical Oncology (ASCO) 2021 Genitourinary Cancers Symposium. The senior author is Toni Choueiri, MD, director of the Lank Center for Genitourinary Oncology at Dana-Farber.

The phase 3 CLEAR study results showed significant benefits from the combination comprised of lenvatinib, an oral kinase inhibitor that targets proteins involved in the formation of blood vessels supplying a tumor, and pembrolizumab, a checkpoint inhibitor given by infusion that helps the immune system attack the cancer. Another group of patients received a combination of lenvatinib and everolimus, a drug that targets a protein, mTOR.

The comparison drug was sunitinib, an inhibitor that targets multiple kinases and has been the standard treatment in these patients with advanced kidney cancer, which carries a poor prognosis. However, standard-of-care options now include treatment with immune checkpoint inhibitors, either as a combination of two checkpoint inhibitors or a checkpoint inhibitor plus a kinase inhibitor. These combinations have achieved improved outcomes for advanced kidney cancer patients compared with sunitinib.

The results of the CLEAR study showed that those receiving the combination of lenvatinib and pembrolizumab not only had longer overall survival but also longer progression-free survival - the period before their disease worsened - and a higher response rate. In addition to lenvatinib plus pembrolizumab, the clinical trial also tested the combination of lenvatinib and everolimus, which is approved for patients with advanced kidney cancer whose disease progresses following sunitinib treatment.

The primary endpoint of the trial was progression-free survival (PFS). Both combinations proved superior to sunitinib alone: lenvatinib/pembrolizumab achieved a median PFS of 23.9 months vs 9.2 for sunitinib; PFS for lenvatinib/everolimus was 14.7 months.

The 24-month overall survival rate was 79.2% with lenvatinib/pembrolizumab, 66.1% with lenvatinib/everolimus, and 70.4% with sunitinib.

The confirmed objective response rate (percentage of patients whose disease shrank) was 71% with lenvatinib/pembrolizumab, 53.5% with lenvatinib/everolimus, and 35.1% with sunitinib. The rate of complete responses - total tumor shrinkage - was 16.1% in patients receiving lenvatinib/pembrolizumab, 9.8% in the lenvatinib plus everolimus group, and 4.2% in the sunitinib group.

"The rate of responses and complete responses, and the progression-free survival were the longest we have seen to date in a phase 3 combination of a targeted VEGF inhibitor and an immune checkpoint inhibitor," said Choueiri. The CLEAR trial is the last of the clinical trials that were launched to compare immunotherapy and targeted drug combinations to sunitinib, and sunitinib will not be the comparison drug in future trials because the combinations have proven superior in these advanced kidney cancer patients, said Choueiri.

Almost all patients in the CLEAR trial experienced some adverse events from treatment. The most frequent adverse events were diarrhea and hypertension. These side effects led to stopping the treatment in 37.2% of patients in the lenvatinib/pembrolizumab group, and dose reduction of lenvatinib in 68.5% of patients. "Although the combination of lenvatinib and pembrolizumab was associated with some notable side effects, these adverse events are often adequately managed" the researchers said.

What The Study Did: Pediatric admissions to U.S. hospitals decreased last year across an array of pediatric conditions and some may represent unmet needs in pediatric care during the COVID-19 pandemic.

Authors: Christopher M. Horvat, M.D., M.H.A., of UPMC Children's Hospital of Pittsburgh, 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.2020.37227)

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.

Every year around 20 Australian children die from the incurable brain tumour, Diffuse Intrinsic Pontine Glioma (DIPG). The average age of diagnosis for DIPG is just seven years. There are no effective treatments, and almost all children die from the disease, usually within one year of diagnosis.

A paper published today 12 Feb 2021 in the prestigious journal, Nature Communications, reveals a potential revolutionary drug combination that - in animal studies and in world first 3D models of the tumour - is "spectacularly effective in eradicating the cancer cells," according to lead researcher and paediatric oncologist Associate Professor David Ziegler, from the Children's Cancer Institute and Sydney Children's Hospital.

In pre-clinical testing in mouse models, the researchers found that the promising drug combination led to survival in two thirds of the mice and that the drug combination completely halted growth of these highly aggressive tumours in these mice.

Importantly, the drug therapy, which is currently in early trials in adult cancer, is the most effective treatment ever tested in laboratory models of this incurable childhood cancer. The treatment is a combination of two drugs: difluoromethylornithine (DFMO), an established drug, and AMXT 1501, an investigational agent being developed by Aminex Therapeutics.

The DFMO is increasingly getting attention as a treatment for difficult-to-control cancers like neuroblastoma, another aggressive childhood cancer, and colorectal cancer in adults. DFMO works by targeting the polyamine pathway - an important mechanism that allows tumour cells to grow.

Associate Professor Ziegler has shown for the first time that the polyamine pathway is critical to the growth of DIPG cells. Ziegler and his team developed Australia's first research program into DIPG by using tumour cells donated by the parents of children who have passed away from the disease. From these, they created the first laboratory models of the tumour in order to test new drugs. These models have been used to show that DIPG can bypass the activity of DFMO by pumping polyamines into the cancer, essentially allowing the tumour to continue growing despite treatment with DFMO. They have now made the breakthrough discovery that treatment with a new developmental drug, AMXT 1501, potently blocks the transport of polyamines into the DIPG cancer cell.

Treatment with AMXT 1501 was found to re-sensitize the DIPG cells to DFMO leading to what Associate Professor Ziegler said, "was a spectacular response in animal models, with a significantly increased survival and minimal toxicity (side effects)".

Associate Professor Ziegler said that clinical trials of the drug combination in DIPG are planned to begin this year in children in a global study led by the Children's Cancer Institute and the Kid's Cancer Centre at Sydney Children's Hospital.

The Australian DIPG Tumour Database was started by the Children's Cancer Institute in 2011.. Australia's first DIPG tumour data base has allowed Associate Professor Ziegler and colleagues to make great inroads into solving this disease. "Since establishing the tumour bank we have been able to grow this very aggressive cancer in our laboratories to allow us to screen hundreds of drugs to find those that are effective at killing the cancer cells. Its due to this capacity that we have been able to discover what we hope will be the first effective treatment for DIPG," he said.

Rachael Gjorgjijoska was the first parent to agree to donate DIPG tumour tissue following the death of her daughter Liliana at just 4 years old, 15 months after her diagnosis. Rachael comments "We made the difficult decision to donate Liliana's tumour because we wanted to make a difference, there were no treatments to save Liliana from this devastating disease, but if her cancer cells help advance research so there be new treatments for children in the future, this will be a lasting memory of our little girl."

Dr. Mark R. Burns, the Founder, President and Chief Scientific Officer at Aminex Therapeutics, and inventor of AMXT 1501 said "the dramatic results against this devastating disease demonstrated by Dr. Ziegler and his team adds greater fire to our motivation to see these findings duplicated against human cancers. We share hope that this treatment will make a difference in the lives of those with DIPG and other aggressive cancers."

(BOSTON) -- Many life-threatening medical conditions, such as sepsis, which is triggered by blood-borne pathogens, cannot be detected accurately and quickly enough to initiate the right course of treatment. In patients that have been infected by an unknown pathogen and progress to overt sepsis, every additional hour that an effective antibiotic cannot be administered significantly increases the mortality rate, so time is of utmost essence.

The challenge with rapidly diagnosing sepsis stems from the fact that measuring only one biomarker often does not allow a clear-cut diagnosis. Engineers have struggled for decades to simultaneously quantify multiple biomarkers in whole blood with high specificity and sensitivity for point-of-care (POC) diagnostic applications as this would avoid time-consuming and costly blood processing steps in which informative biomarker molecules could potentially be lost.

Now, a multi-disciplinary team at Harvard's Wyss Institute for Biologically Inspired Engineering and the University of Bath, UK, led by Wyss Founding Director Donald Ingber, M.D., Ph.D., and Wyss Senior Staff Scientist Pawan Jolly, Ph.D., has further developed the Institute's eRapid technology as an affinity-based, low-cost electrochemical diagnostic sensor platform for the multiplexed detection of clinically relevant biomarkers in whole blood. The device uses a novel graphene nanocomposite-based surface coating and was demonstrated to accurately detect three different sepsis biomarkers simultaneously. The findings are reported in Advanced Functional Materials.

"In this study, we have taken an important step towards deploying our electrochemical sensor platform in clinical settings for fast and sensitive detection of multiple analytes in human whole blood. As the nanocomposite coating we developed here is inexpensive, it has the potential to revolutionize point-of-care diagnostics not only to test for sepsis biomarkers, but a much broader range of biomarkers that can be multiplexed in sets to report on the states of many diseases and conditions," said Ingber, who also is a lead of the Wyss Institute's Bioinspired Therapeutics and Diagnostics platform, and the Judah Folkman Professor of Vascular Biology at Harvard Medical School and Boston Children's Hospital, and Professor of Bioengineering at SEAS.

Ingber, Jolly and their Wyss team are currently also developing eRapid electrochemical sensors with the newly engineered graphene-based nanocomposite coating as a critical component of a point-of-care diagnostic for COVID, traumatic brain injury, myocardial infarction, and many other disorders.

By developing their electrochemical sepsis-sensing technology, Ingber's team built on earlier work published in Nature Nanotechnology, in which they had solved the problem of "biofouling" with electro-chemical sensing elements with their eRapid technology. In theory, electrochemical biosensors would be preferred for many clinical applications because of their ability to quantify the content of biological samples by directly converting the binding event of a biomarker to an electronic signal, their low power consumption and cost, and easy integration with diagnostic readers. However, especially when using whole blood, many blood components nonspecifically bind to the surface coatings of the sensors' electrodes and lead to their degradation, as well as electric noise in the form of false signals.

The team's eRapid technology uses a novel antifouling nanocomposite coating for electrodes to which binding reagents are attached that capture biomarker molecules from small quantities of blood and other complex biological fluids. Upon chemically detecting any one of these biomarker molecules with high sensitivity and selectivity, the eRapid platform generates an electrical signal at the electrodes that correlates in strength with the levels of target molecules that are detected. The initial nanocomposite coating allowed excellent conversion of chemical to electrical signals, and relied on tiny electrically conductive gold nanowires that were embedded in a matrix of a crosslinked protein known as bovine serum albumin. However, the high costs of the gold materials had been the major barrier to commercializing eRapid for clinical applications.

"In our advanced eRapid version, we replaced the coating's gold nanowires with graphene oxide nanoflakes that also have anti-fouling and electrochemical properties, but they are much less expensive and allow even more sensitive measurements. In fact, the costs of fabricating the nanocomposite were reduced to a fraction of its original cost, which together with the sensing technology's speed, efficiency, and versatility should enable the eRapid platform to have immediate commercial impact," said Jolly.

After optimizing and characterizing their nanocomposite coating in binding assays for the inflammatory cytokine interleukin 6, the team applied it to the diagnosis of sepsis. Essentially, by attaching an antibody molecule to the coating that binds procalcitonin (PCT), and adding a second PCT-specific antibody to the complex that is linked to an enzyme, a precipitate is formed from a chemical substrate and deposited on the coating. This changes the current of electrons reaching the electrode, and helps register the PCT binding event as an electronic signal.

"We demonstrated that this electrochemical sensor element can detect PCT with high accuracy in whole blood, and validated it by quantifying PCT levels in 21 clinical samples, directly comparing it with a conventional ELISA assay - with excellent correlation," said first-author Uroš Zupančič, who was a visiting scholar in Ingber's group from the University of Bath. Zupančič is a Ph.D. candidate mentored by the study's co-authors Despina Moschou, Ph.D., a Lecturer at the University of Bath, and Pedro Estrela, Ph.D., Associate professor and the head of the Centre for Biosensors, Bioelectronics and Biodevices at the University.

The team then extended their approach to simultaneously detecting multiple sepsis biomarkers by also designing sensor elements for C-reactive protein, another sepsis biomarker, and pathogen-associated molecular patterns (PAMPs). The PAMP sensor element in particular leverages the Wyss Institute's broad-spectrum pathogen capture technology that uses a genetically engineered protein called FcMBL, which binds more than 100 different pathogens of all classes, as well as molecules on their surfaces that are released into blood when pathogens are killed (PAMPs) and act to trigger the sepsis cascade.

"Assembling three dedicated electrochemical sensor elements for biomarkers that can be present in blood at vastly different concentrations on a single chip posed a significant challenge. However, the three elements in the final sensor exhibited specific responses within the clinically significant range without interfering with each other, and they did so with a turnaround time of 51 minutes, which meets the clinical need of sepsis diagnosis within the first hour," said Zumpančič.

To make the current eRapid technology even more effective and useful for clinical sample analysis, the team integrated it with a microfluidic system that takes out the human element involved in handling the sensor in the laboratory, and enhances the number of biomarker binding events at its surface. This allows biomarker analysis with the system to be automated, and enabled the researchers to decrease the turnaround time for measuring PCT to 7 minutes.

(Friday, February 12, 2021 - Toronto) -- Inhibiting a key enzyme that controls a large network of proteins important in cell division and growth paves the way for a new class of drugs that could stop glioblastoma, a deadly brain cancer, from growing.

Researchers at Princess Margaret Cancer Centre, the Hospital for Sick Children (SickKids) and University of Toronto, showed that chemically inhibiting the enzyme PRMT5 can suppress the growth of glioblastoma cells.

The inhibition of PRMT5 led to cell senescence, similar to what happens to cells during aging when cells lose the ability to divide and grow. Cellular senescence can also be a powerful tumour suppression mechanism, stopping the unrelenting division of cancer cells.

The results of the study are published in Nature Communications on February 12, 2021, by lead author former Postdoctoral Fellow Dr. Patty Sachamitr, SickKids and University of Toronto, and senior authors Drs. Panagiotis Prinos, Senior Research Associate, Structural Genomics Consortium, University of Toronto, Senior Scientist Cheryl Arrowsmith, Princess Margaret, and Senior Scientist and Neurosurgeon Peter Dirks, SickKids.

The researchers are part of the Stand Up To Cancer Canada Dream Team that focuses on brain tumours that have the worst outcomes, such as glioblastomas. By combining wide and deep expertise in research, clinical strengths, and unique partnerships, the researchers hope to accelerate new cures for some of the hardest-to-treat cancers.

Currently, the prognosis for glioblastoma remains very poor, with fewer than 10% of patients surviving beyond five years. Current therapies are severely limited.

While PRMT5 inhibition has been suggested previously as a way to target brain and other cancers, no one has tested this strategy in a large cohort of patient tumour-derived cells that have stem cell characteristics, cells that are at the roots of glioblastoma growth.

"We used a different strategy to stop cancer cells from proliferating and seeding new tumours," says Dr. Arrowsmith, who also leads the University of Toronto site of the International Structural Genomics Consortium, a public-private partnership with labs around the world, accelerating the discovery of new medicines through open science.

"By inhibiting one protein, PRMT5, we were able to affect a cascade of proteins involved in cell division and growth. The traditional way of stopping cell division has been to block one protein. This gives us a new premise for future development of novel, more precise therapies."

"This strategy also has the opportunity to overcome the genetic variability seen in these tumours" says Dr. Dirks, who led the pan-Canadian team. "By targeting processes involved in every patient tumour, which are also essential for the tumour stem cell survival, we side-step the challenges of individual patient tumour variability to finding potentially more broadly applicable therapies."

The poor outcome of glioblastoma could be attributed, at least in part, to the presence of tumour-initiating cancer stem cells, which have been shown by the Dirks laboratory to drive tumour growth and resistance to therapy. Novel therapeutic strategies are urgently needed to target these cancer stem cells, in addition to bulk tumour cells.

In this study, researchers tested a group of new experimental small molecules designed to specifically inhibit key cellular enzymes being developed and studied by the Structural Genomics Consortium to see if any would stop the growth of glioblastoma brain tumour cells in the laboratory. The brain tumour cells were isolated from patients' tumours and grown in the laboratory in a way that preserved the unique properties of cancer stem cells.

They found that specific molecules - precursors to actual therapeutic drugs -inhibited the same enzyme, PRMT5, stopping the growth of a large portion of these patient-derived cancer stem cells. Many current drugs do not eliminate cancer stem cells, which may be why many cancers regrow after treatment.

But they also caution that actual treatments for patients are many years away, and require development and testing of clinically appropriate and safe versions of PRMT5 inhibitors that can access the brain.

The researchers also examined the molecular features of the patient-derived glioblastoma cells by comparing those that responded well to those that did not respond as well. They found a different molecular signature for the tumour cells that responded. In the future, this could lead to specific tumour biomarkers, which could help in identifying those patients who will respond best to this new class of drugs.

"Right now, we have too few medicines to choose from to make precision medicine a reality for many patients," says Dr. Arrowsmith. "We need basic research to better understand the mechanism of action of drugs, particularly in the context of patient samples. This is what will help us develop the right drugs to give to the right patients to treat their specific tumours."

Peer-reviewed / Review, Survey and Opinion piece

To ensure an effective global immunisation strategy against COVID-19, vaccines need to be produced at scale, priced affordably, and allocated globally so that they are available where needed, and successfully rolled out.

Review of evidence includes a comparison of 26 leading vaccines on their potential contribution to achieving global vaccine immunity, and a new survey of COVID-19 vaccine confidence in 32 countries.

Having new COVID-19 vaccines will mean little if people around the world are unable to get vaccinated in a timely manner. Vaccines have to be affordable and available to all countries, and governments must have the administrative and political capacities to deliver them locally to ensure an effective global immunisation strategy against COVID-19, say the authors of a Health Policy piece published in The Lancet.

Global distribution of safe vaccines is imperative for spurring economic recovery, protecting lives, achieving herd immunity, and minimising the risk of new variants emerging against which existing vaccines are less effective.

The seven authors, who are leading experts in vaccines, health policy, and infectious disease, discuss potential challenges to production, affordability, allocation, and roll-out of an effective global vaccination strategy against COVID-19, and score the 26 leading vaccines using a traffic light system to indicate their potential contribution to achieving global vaccine immunity (figure 2).

Dr Olivier Wouters, lead author from the London School of Economics and Political Science, UK, says: "Several manufacturers have successfully developed COVID-19 vaccines in under 12 months, an extraordinary achievement. But the stark reality is that the world now needs more doses of COVID-19 vaccines than any other vaccine in history in order to immunise enough people to achieve global vaccine immunity. Unless vaccines are distributed more equitably, it could be years before the coronavirus is brought under control at a global level. The questions now are when these vaccines will become available, and at what price." [1]

Overcoming production challenges

Scaling up vaccine production to meet global demand is a monumental challenge. Most countries still lack the domestic capacity to rapidly produce COVID-19 vaccines on their own, and the sheer number of vaccines that are needed places huge pressure on global supply chains for materials like glass vials and syringes.

With vaccine manufacturing capabilities limited to a handful of global regions and by the relationships agreed between specific vaccine developers and manufacturers, the authors say that developers should share knowledge, technology, and data with a wider group of manufacturers to produce more COVID-19 vaccines. They note that some vaccine developers are collaborating with manufacturers in other regions [2], but the terms of these agreements are not clear about who decides where the vaccine manufactured in that region will be supplied to (ie, it may be shipped to another location, rather than being used in the country where it was manufactured).

The authors also point out that there have been several initiatives to facilitate the scale-up of global production. For instance, the WHO has called on member states and manufacturers to commit to sharing knowledge, intellectual property, and data on COVID-19 vaccines, but responses to this initiative have been limited.

With large amounts of public funding being invested into COVID-19 vaccines, the authors argue that funders should encourage vaccine developers to share their expertise to help expand global production. Governments and non-profit groups have committed unprecedented sums of money to the development of COVID-19 vaccines and the infrastructure to produce them at scale--with the top five vaccine manufacturers receiving between $957 million and $2.1 billion.

Achieving timely, universal access

Scarce supply, coupled with advanced orders by the world's richest nations for billions of vaccine doses--enough to protect some populations several times over--creates challenges to achieving timely, universal access. COVAX (the global initiative to ensure access to COVID-19 vaccines for all countries) was set up to avoid this, but vaccine nationalism could leave COVAX with limited supplies.

"Securing large quantities of vaccines in this way amounts to countries placing widespread vaccination of their own populations ahead of the vaccination of health-care workers and high-risk populations in poorer countries", says co-author Professor Mark Jit from the London School of Hygiene & Tropical Medicine, UK. "Based on known deals, governments in high-income countries representing 16% of the global population have secured at least 70% of doses available in 2021 from five leading vaccine candidates." [1]

COVAX says it will need a further US$6.8 billion in funding to fulfil its aim to secure 2 billion doses by the end of 2021, including 1 billion vaccine doses for 92 LMICs. "With additional funding, COVAX could compete better in the global scramble for vaccines", explains Dr Wouters. "Vaccines developed by Chinese, Indian, and Russian manufacturers may also offer a lifeline for the lowest-income nations if they show good results in phase 3 trials, allowing them to procure abundant doses of vaccines that have not yet been authorised in most high-income countries. Once authorised by WHO, these vaccines could also potentially contribute to the COVAX portfolio." [1]

A COVID-19 vaccine should be affordable to everyone

Affordability also remains a major concern, with some vaccine manufacturers setting prices for COVID-19 vaccines that are among the highest ever charged for a vaccine (figure 3). Without price controls, low-income countries are unlikely to be able to afford or access enough vaccines to protect their populations--with the lowest prices developers have offered to any country or purchasing bloc ranging from US$5 to US$62 per course (see the table in the Article).

"The extensive involvement of public funders in COVID-19 vaccine development provides an opportunity to make these vaccines globally available and affordable. Governments can insist that, as a condition of getting public funding, companies engage in sufficient licensing to enable widespread global production, and they must set affordable prices", says co-author Professor Kenneth Shadlen from the London School of Economics and Political Science, UK. [1]

The need for varied vaccine options

Many LMICs also face substantial logistical and administrative barriers to delivering vaccination programmes, including infrastructure, vaccination registries, and cold storage. The review highlights important trade-offs between the leading 26 COVID-19 vaccines that can help governments decide which vaccines best suit their needs (figure 2). For instance, while many multi-dose, ultra-cold storage vaccines are highly efficacious, resource-constrained countries might be better to use single-dose vaccines which only have to be kept refrigerated, and are in late stages of clinical development.

The distinct characteristics of leading COVID-19 vaccines generate trade-offs, which mean that a range of vaccines will be needed to bring the global pandemic under control.

Inspiring public confidence and trust to optimise uptake

Successful roll-out can also be hampered by vaccination hesitancy. New findings from a 32-country survey of potential acceptance of COVID-19 vaccines (involving almost 27,000 adults), conducted by the authors between October 2020 and December 2020, suggest that Vietnam (98%), India, China (both 91%), Denmark and South Korea (both 87%) had the highest proportion of respondents who said they would "definitely" or "probably" get vaccinated when a COVID-19 vaccine becomes available; while Serbia (38%), Croatia (41%), France, Lebanon (both 44%), and Paraguay (51%) reported the highest proportion of people saying they would "probably not" or "definitely not" be vaccinated (figure 4) [3].

"To overcome challenges in vaccine hesitancy and ensure that vaccines are administered to as many people as possible, governments need to do much better at building public trust in the safety of vaccines and to combat misinformation and rumours around COVID-19", says Professor Heidi Larson, co-author from the London School of Hygiene & Tropical Medicine, UK. "This will require increasing vaccination knowledge and awareness, promoting community engagement, and making vaccines available in convenient and accessible locations. Vaccine manufacturers should aim for maximum transparency and scrutiny of their clinical trial data, and post-marketing safety surveillance with compensation schemes for severe adverse events in resource poor countries with poor consumer protection. These factors are vital to build confidence during vaccine roll-out." [1]

Osteoporosis is a leading global health challenge. Besides its own adverse effects, it also impairs the function of bone implants - normally made of a metal called titanium (Ti). Because there is less bone than normal in the implantation site, the implants could easily loosen, and persistent inflammation often accompanies.

Recently, Chinese scientists from the University of Macau and Nanjing University, in collaboration with National Dental Centre Singapore, invent a bioactive coating that can be chemically linked onto normal Ti surface. This coating, made from a chemically-modified glycan (a string of sugars), can sequentially turn on and off inflammation on bone implants. When applied under osteoporotic conditions, it first turns on "good inflammation" by instructing host macrophages to release the molecules that can activate bone cells and promote healing; when the bone cells grow and function to an extent, they naturally secrete an enzyme, called alkaline phosphatase, to cut the chemically-modified glycan from the Ti surface. This "sugar-coated bullets" can specifically kill macrophages to turn off "bad inflammation" for better healing and higher safety.

The lead contact and corresponding author of this paper, Prof Chunming Wang at the University of Macau, said: "Interestingly, these macrophages to be killed in the latter part of this healing process, are exactly the guys who have made the major contribution to release pro-bone forming cytokines in the earlier stage. So, we described this design as a 'bridge-burning' strategy." He indicates that this coating's main advantage is to maximize the power of the limited number of bone cells around the implants under osteoporosis.

The co-corresponding author, Prof Lei Dong at Nanjing University, added that under these pathological conditions it is unrealistic to sharply increase the number or stimulate the function of bone cells around the implants to achieve better bone-implant integration. "Our method harnesses the inherent power of immune responses to enhance implanting efficacy, without using complicated methods that might bring about safety issues. "

Based on this coating's favourable performance in a rat osteoporosis model, both investigators anticipate next-stage research to be carried out in larger animals. This study was published on 10 Feb 2021 in Advanced Functional Materials, a premier journal in materials science, and selected to feature on the Front Cover of the issue.

WHAT:

The rise of several significant variants of SARS-CoV-2, the virus that causes COVID-19, has attracted the attention of health and science experts worldwide. In an editorial published in JAMA: The Journal of the American Medical Association, experts from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, outline how these variants have arisen, concerns about whether vaccines currently authorized for use will continue to protect against new variants, and the need for a global approach to fighting SARS-CoV-2 as it spreads and acquires additional mutations.

The article was written by NIAID Director Anthony S. Fauci, M.D.; John R. Mascola, M.D., director of NIAID's Vaccine Research Center (VRC); and Barney S. Graham, M.D., Ph.D., deputy director of NIAID's VRC.

The authors note that the overlapping discovery of several SARS-CoV-2 variants has led to confusing terms used to name them. The appearance of SARS-CoV-2 variants is so recent that the World Health Organization and other groups are still developing appropriate nomenclature for the different variants.

Numerous SARS-CoV-2 variants have emerged over the last several months. The authors note that the variants known as B.1.1.7 (first identified in the United Kingdom) and B.1.351 (first identified in South Africa) concern scientists because of emerging data suggesting their increased transmissibility.

Variants can carry several different mutations, but changes in the spike protein of the virus, used to enter cells and infect them, are especially concerning. Changes to this protein may cause a vaccine to be less effective against a particular variant. The authors note that the B.1.351 variant may be partially or fully resistant to certain SARS-CoV-2 monoclonal antibodies currently authorized for use as therapeutics in the United States.

The recognition of all new variants, including a novel emergent strain (20C/S:452R) in California, requires systematic evaluation, according to the authors. The rise of these variants is a reminder that as long as SARS-CoV-2 continues to spread, it has the potential to evolve into new variants, the authors stress. Therefore, the fight against SARS-CoV-2 and COVID-19 will require robust surveillance, tracking, and vaccine deployment worldwide.

The authors also note the need for a pan-coronavirus vaccine. Once researchers know more about how the virus changes as it spreads, it may be possible to develop a vaccine that protects against most or all variants. While similar research programs are already in place for other diseases, such as influenza, the changing nature of SARS-CoV-2 indicates that they will be necessary for this virus.

ARTICLE:

JR Mascola et al. SARS-COV-2 Viral variants--Tackling a moving target. JAMA DOI: 10.1001/jama.2021.2088 (2021).

WHO:

NIAID Director Anthony S. Fauci, M.D., John R. Mascola, M.D., director of NIAID's Vaccine Research Center (VRC); and Barney S. Graham, MD, PhD, Deputy Director of NIAID's VRC, are available for comment.

CONTACT:
To schedule interviews, please contact Elizabeth Deatrick, (301) 402-1663, NIAIDNews@niaid.nih.gov.

The drug thalidomide was sold as a sedative under the trade name Contergan in the 1950s and 1960s. At the time, its side-effects triggered one of the largest pharmaceutical scandals in history: The medication was taken from the market after it became known that the use of Contergan during pregnancy had resulted in over 10,000 cases of severe birth defects.

Currently, the successor preparations lenalidomide and pomalidomide are prescribed under strict supervision by experienced oncologists - the active ingredients are a cornerstone of modern cancer therapies. The use of lenalidomide and pomalidomide has considerably improved the success rate of therapies and patient survival, particularly for hematological malignancies such as multiple myeloma. Since these substances can influence the immune system, they are referred to as immunomodulatory drugs (IMiDs).

Many membrane proteins affected

Previous studies have shown that IMiDs bind to a protein called cereblon, which results in the malfunction of a protein complex on the surface of tumor cells, thus inhibiting tumor growth. A research team led by Prof. Florian Bassermann and Vanesa Fernández of the university hospital Klinikum rechts der Isar of TUM has now deciphered the exact mechanism and the scope of this dysregulation in a new study.

They discovered that cereblon supports the protein HSP90 as what is known as a co-chaperone; HSP90 is responsible for the correct folding of thousands of proteins in human cells. The scientists were able to show that the support function of the co-chaperone cereblon is specific for membrane proteins. These proteins, which are anchored on the surface of a cell, are essential for tumor cells to grow: They enable cells to communicate with neighboring cells, they pass on growth signals and take in important nutrients.

Upon IMiD-treatment, cereblon can no longer bind to the HSP90 machinery, and as a result loses its supportive function in the quality control of membrane proteins. "Using proteome-wide analyses, we were able to show that a large number of essential proteins on the surface of cancer cells are destabilized by IMiD-treatment," says oncologist Florian Bassermann. "This ultimately explains the unusually broad effects of these substances."

Starving tumor cells

In multiple myeloma the proteins CD98hc and LAT1 are particularly affected. Together these proteins usually ensure that cancer cells are supplied with amino acids. Since cancer cells in the case of multiple myeloma have an especially high need for nutrients like amino acids, CD98hc and LAT1 are very abundant proteins in these cells. The research team has now shown that IMiD-treatment significantly reduces the uptake of essential amino acids and thus inhibits the growth of the tumor cells. "This literally starves out the cancer cells," explains Michael Heider, first author of the study.

New targeted therapeutic options

The discovery that multiple myeloma cells can be attacked by targeting the proteins CD98hc and LAT1 opens up new possibilities for innovative therapies in this currently incurable cancer. Together with Wolfgang Weber, TUM Professor for Nuclear Medicine, the researchers tested a molecule which is aimed at CD98hc, known as an anticalin. The molecule was recently developed by Arne Skerra, Professor for Biological Chemistry at TUM. The results show that the molecule binds specifically to the cell surface protein CD98hc in both cell culture and mouse models. This anticalin could therefore be used for targeted therapy and diagnosis in the future. "Early clinical studies to further evaluate the anticalin are already being planned," says Bassermann.

A new study from Washington University School of Medicine in St. Louis demonstrates that a liquid biopsy examining blood or urine can help gauge the effectiveness of therapy for colorectal cancer that has just begun to spread beyond the original tumor. Such a biopsy can detect lingering disease and could serve as a guide for deciding whether a patient should undergo further treatments due to some tumor cells evading an initial attempt to eradicate the cancer.

The study appears online Feb. 12 in the Journal of Clinical Oncology Precision Oncology, a journal of the American Society of Clinical Oncology.

While a few liquid biopsies have been approved by the Food and Drug Administration, mostly for lung, breast, ovarian and prostate cancers, none has been approved for colorectal cancer.

Patients in this study had what is known as oligometastatic colorectal cancer, meaning each patient's cancers had spread beyond his or her original tumor but only to a small number of sites. Such patients undergo chemotherapy to shrink the tumors before having surgery to remove whatever remains of the primary tumor. There is debate in the field about whether, after initial therapy, oligometastatic cancer should be treated like metastatic cancer, with more chemotherapy -- or like localized cancer, with more surgery plus radiation at those limited sites.

Contributing to the problem is that doctors have a limited ability to predict how patients will respond to early chemotherapy, especially since most patients don't have access to cancer genome sequencing to identify the DNA mutations in their original tumors.

"Being able to measure response to early chemotherapy without prior knowledge of the tumor's mutations is a novel idea and important for being able to determine whether the patient responded well to the therapy," said senior author Aadel A. Chaudhuri, MD, PhD, an assistant professor of radiation oncology. "This can provide guidance on how to treat oligometastatic disease. For example, if the liquid biopsy indicates that a patient responded well to the early chemotherapy, perhaps they should be offered the possibility of more surgery, which could potentially cure their disease. But if they didn't respond well, it's likely the cancer is too widespread and can't be eradicated with surgery, so those patients should receive more chemotherapy to control their disease."

Liquid biopsies for colorectal cancer detect tumor DNA that has broken free of the cancer and is circulating in the blood and, to a lesser extent, has collected in the urine. The biopsies described in this study are unique compared with other liquid biopsies being developed for colorectal cancer in three major ways. First, most such biopsies have been developed to track metastatic cancers or to verify that local cancers have not started to spread. Second, most liquid biopsies for cancer rely on knowledge of the original tumor's mutations, to see if those mutations are still present in the blood after therapy. But many patients don't get the opportunity to have their original tumors sequenced. Instead, the new biopsies rely on detecting DNA mutations in the blood or urine and comparing them with DNA mutations measured in the treated primary tumor, after it's surgically removed. And finally, the urine biopsy is unique for colorectal cancer as most urine biopsies have been limited to use in cancers of the genitourinary system, especially bladder cancer.

"The levels of circulating tumor DNA that we were able to measure in urine were lower than what we measured in blood, but this is still a proof of concept that it is possible to measure residual disease in a nonurinary cancer in this totally noninvasive way," said Chaudhuri, who also treats patients at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine. "We will need to develop more sensitive techniques to detect colorectal tumor DNA in urine to make this a useful clinical test. But this is a promising start."

The study showed that lower circulating tumor DNA levels correlated with better responses to early chemotherapy. Indeed, most patients who had undetectable levels of tumor DNA in blood samples also had no measurable cancer in their surgical specimens.

There was also evidence that the residual disease detected in liquid biopsies was more predictive of outcomes than residual disease found in the surgical specimens. For example, the researchers described the experience of one man who, after early chemotherapy to shrink or eliminate the tumor, still had detectable cancer removed during surgery. But his blood sample taken that same day showed no circulating tumor DNA. He experienced long-term survival with no cancer recurrence. On the other hand, a woman with no detectable cancer cells in her surgical specimen, removed after early chemotherapy, was found to have circulating tumor DNA in her same-day blood sample. Eight months later, the cancer returned in her liver.

The study suggests that such liquid biopsies could help personalize treatment for oligometastatic colorectal cancer. Beyond identifying patients at high risk of recurrence and helping guide decisions about which traditional therapies should be given, the new study also identified patients who might benefit from immune therapies and other targeted treatments.

"Based on mutations in the blood biopsy, we could identify patients who might benefit from a type of immune therapy called immune checkpoint inhibitors after their initial therapy is complete," Chaudhuri said. "We also found mutations that could be targeted with drugs approved for other cancers. Our current study is observational, but it paves the way for designing future clinical trials that could test some of these potential therapies."

Masks help protect the people wearing them from getting or spreading SARS-CoV-2, the virus that causes COVID-19, but now researchers from the National Institutes of Health have added evidence for yet another potential benefit for wearers: The humidity created inside the mask may help combat respiratory diseases such as COVID-19.

The study, led by researchers in the NIH's National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), found that face masks substantially increase the humidity in the air that the mask-wearer breathes in. This higher level of humidity in inhaled air, the researchers suggest, could help explain why wearing masks has been linked to lower disease severity in people infected with SARS-CoV-2, because hydration of the respiratory tract is known to benefit the immune system. The study published in the Biophysical Journal.

"We found that face masks strongly increase the humidity in inhaled air and propose that the resulting hydration of the respiratory tract could be responsible for the documented finding that links lower COVID-19 disease severity to wearing a mask," said the study's lead author, Adriaan Bax, Ph.D., NIH Distinguished Investigator. "High levels of humidity have been shown to mitigate severity of the flu, and it may be applicable to severity of COVID-19 through a similar mechanism."

High levels of humidity can limit the spread of a virus to the lungs by promoting mucociliary clearance (MCC), a defense mechanism that removes mucus ? and potentially harmful particles within the mucus ? from the lungs. High levels of humidity can also bolster the immune system by producing special proteins, called interferons, that fight against viruses ? a process known as the interferon response. Low levels of humidity have been shown to impair both MCC and the interferon response, which may be one reason why people are likelier to get respiratory infections in cold weather.

The study tested four common types of masks: an N95 mask, a three-ply disposable surgical mask, a two-ply cotton-polyester mask, and a heavy cotton mask. The researchers measured the level of humidity by having a volunteer breathe into a sealed steel box. When the person wore no mask, the water vapor of the exhaled breath filled the box, leading to a rapid increase in humidity inside the box.

When the person wore a mask, the buildup of humidity inside the box greatly decreased, due to most of the water vapor remaining in the mask, becoming condensed, and being re-inhaled. To ensure no leakage, the masks were tightly fitted against the volunteer's face using high-density foam rubber. Measurements were taken at three different air temperatures, ranging from about 46 to 98 degrees Fahrenheit.

The results showed that all four masks increased the level of humidity of inhaled air, but to varying degrees. At lower temperatures, the humidifying effects of all masks greatly increased. At all temperatures, the thick cotton mask led to the most increased level of humidity.

"The increased level of humidity is something most mask-wearers probably felt without being able to recognize, and without realizing that this humidity might actually be good for them," Bax said.

The researchers did not look at which masks are most effective against inhalation or transmission of the virus and defer to the CDC for guidance on choosing a mask. Earlier studies from Bax and his colleagues showed that any cloth mask can help block the thousands of saliva droplets that people release through simple speech ? droplets that, if released, can remain in the air for many minutes. While the current study did not examine respiratory droplets, it does offer more evidence as to why masks are essential to battling COVID-19.

"Even as more people nationwide begin to get vaccinated, we must remain vigilant about doing our part to prevent the spread of the coronavirus that causes COVID-19," said NIDDK Director Dr. Griffin P. Rodgers. "This research supports the importance of mask-wearing as a simple, yet effective, way to protect the people around us and to protect ourselves from respiratory infection, especially during these winter months when susceptibility to these viruses increases."

Peer reviewed / Review and opinion

First comprehensive assessment of damage to health inflicted by former President Trump cites decades of policy failures made worse by the Trump administration, resulting in 461,000 unnecessary US deaths annually before the COVID-19 pandemic, and tens of thousands of unnecessary COVID-19 and pollution-related deaths attributable to his actions.

Lancet Commission calls for immediate rollback of Trump's health-harming policies and additional sweeping reforms to reverse the deteriorating health of the US population: "The path away from Trump's politics of anger and despair cannot lead through past policies."

The first comprehensive assessment of the health effects of Donald Trump's presidency is published today in The Lancet revealing devastating impacts on every aspect of health in the USA. The Lancet Commission on Public Policy and Health in the Trump Era [1] also traces the policy failures that preceded and fueled Trump's ascent and left the USA lagging behind other high-income nations on life expectancy.

In new analyses, the Commission finds that 461,000 fewer Americans would have died in 2018, and 40% of US deaths during 2020 from COVID-19 would have been averted if the USA had death rates equivalent to those of the other G7 nations (Canada, France, Germany, Italy, Japan, and the United Kingdom). The report also estimates that Trump's rollbacks of environmental protections led to 22,000 excess deaths in 2019 alone.

The Commission finds that US life expectancy began trailing other high-income nations' in about 1980 as President Ronald Reagan initiated anti-government, wealth-concentrating policies that reversed many of the advances of the New Deal and Civil Rights eras. Reagan's political philosophy, known as neo-liberalism, has continued to influence US health and economic policy under both Republican and Democratic administrations. Many Trump policies, including tax cuts and deregulation that benefit the wealthy and corporations, austerity for the poor, and privatization of Medicare, emulate Reagan's.

The report warns that a return to pre-Trump era policies is not enough to protect health. Instead, sweeping reforms are needed to redress long-standing racism, and the four-decades of policy failures that weakened social and health safety nets and led to widened inequality.

The Commission emphasizes that these failures left the USA particularly vulnerable to the COVID-19 pandemic. Cuts in funding for public health agencies led to the loss of 50,000 front line staff vital to fighting epidemics between 2008 and 2016. The fragmented and profit-oriented health-care system was ill-prepared to prioritize and coordinate pandemic response. Nearly 11% of Americans suffered food insecurity, increasing their risk of obesity and diabetes, and hence death from COVID-19. And housing crowding due to poverty helped spread infection in communities of color with poor access to medical care.

The report notes that prior to the pandemic, midlife mortality for Native and Black Americans was 59% and 42% higher, respectively, than for non-Hispanic white people. The pandemic has widened the Black:white mortality gap by 50%, and has cut Latinx life expectancy by more than 3.5 years. Mortality rates from COVID-19 for people of color are 1.2-3.6 times higher than for non-Hispanic white people. Opioid deaths, a leading cause of death prior to the pandemic that was increasing fastest among middle-aged Black men, have increased in 40 out of 50 states since the emergence of COVID-19.

The report also condemns Trump's withdrawal from the World Health Organization (WHO) and defunding of the Pan American Health Organization (PAHO) - bodies critical for pandemic response globally - and his undermining of global health efforts prior to the pandemic.

"While the USA ranks highly in its global health security index, the COVID-19 pandemic has shown how woefully inadequate the country's health care and public health system has been in protecting the nation's health. The COVID-19 pandemic has exploited existing health and social inequalities and nowhere is this more apparent than in the USA. At moments of instability, the world needs a strong USA, bolstered by a healthy population, to lead a global response," says Dr Richard Horton, Editor-in-Chief, The Lancet. [2]

"Americans' health was deteriorating even as our economy was booming," says Dr Steffie Woolhandler, who co-chairs the Commission with Dr David U. Himmelstein, and who both serve as Distinguished Professors at the City University of New York at Hunter College and Lecturers in Medicine at Harvard. "This unprecedented decoupling of health from national wealth signals that our society is sick. While the wealthy have thrived, most Americans have lost ground, both economically and medically. The Biden administration must reboot democracy and implement the progressive social and health policies needed to put the country on the road to better health." [2]

President Trump exploited chronic ill health and deeply entrenched inequalities

The Lancet Commission on Public Policy and Health in the Trump Era [1], formed in April 2017, brings together 33 leading experts from the United States, United Kingdom and Canada, with backgrounds in clinical medicine, public health, epidemiology, medical care policy, community medicine, economics, nutrition, law, and politics.

While the Commission initially intended to focus narrowly on the health effects of the Trump administration, its analyses revealed that deep-seated problems that preceded Trump had undermined health and set the stage for his political ascent. Trump gained his largest 2016 electoral margins in counties with the worst economic and mortality trends; in counties where Trump got more than 60% of the vote, life expectancy had been better in 1980 than in those where he was soundly defeated. By the time of his presidential run, life expectancy in the pro-Trump counties was 2 years shorter than in counties where he was defeated (fig. 4 [3])

The Commission concludes that Trump exploited low- and middle-income white people's anger over their deteriorating life prospects to mobilize racial animus and xenophobia; he then enlisted their support for policies that benefit wealthy individuals and corporations and threaten the health of most Americans, including Trump's supporters.

Trump's policies, while injurious to many non-wealthy people, brought particular harm to people of color. The Commission outlines how he undermined civil rights enforcement, encouraged repressive policing and voter suppression, implemented harsh and racist immigration policies, and pursued housing and medical care policies that encouraged segregation and cut health coverage.

"The Commission highlights how racial disparities in health have grown in the last four years, especially as COVID-19 has taken its grim and unequal toll in Black, Latinx and Indigenous people," says Dr Mary T. Bassett, Commission member and Director of the FXB Center for Health and Human Rights at Harvard University, "The disastrous, bungled response to the pandemic made clear how existing, longstanding racial inequities simply have not been addressed. It's time to stop saying these preventable gaps cannot be eliminated. The report calls for structural solutions, including reparations, to ensure everyone has the right to health." [2]

The Commission found that Trump's actions added 2.3 million to the 28 million US residents who were uninsured when he took office, with coverage losses concentrated in minority communities and among children. An additional 726,000 children became uninsured during his time in office. Meanwhile, he augmented the flow of public funds through private insurers, who now derive most of their revenues from government programs, raise Medicare's costs by an estimated $24 billion annually, and have garnered record profits during the COVID-19 pandemic.

"Our ICU is the last stop for many patients harmed by Trump's disdain for facts, science, and compassion," says Commission member Dr Adam Gaffney, a pulmonary and critical care specialist at Cambridge Health Alliance and Harvard Medical School "But decades of health care inequality, privatization and profiteering set the stage for these tragedies. Our Commission has concluded that single payer, Medicare for All reform is the only way forward." [2]

In addition to reviewing the widespread failings of the US health care system, the Commission highlights the egregious underfunding of the US Indian Health Service (IHS), which is obligated by treaties to provide care to 2.2 million tribal citizens. The IHS budget is approximately one quarter of the average per head health spending in the USA; an additional $2.7 billion would be needed to meet IHS' minimal operating needs and $37.6 billion would be required in 2021 to meet the high health needs of tribal populations.

The Commission cites Trump's acceleration of global warming through encouragement of fossil fuel combustion and withdrawal from the Paris Climate Agreement as perhaps his longest lasting harm. It details his roll back of at least 84 separate environmental and workplace protections. Ironically, US states that Trump won in 2016 and 2020 have suffered the greatest increases in pollution and in deaths from environmental and occupational causes. In 2019 alone, the Commission estimates that 22,000 more Americans died from environmental and occupationally related causes than in 2016, the first time such deaths have increased after 15 years of steady progress (fig 9).

Sweeping reforms needed to chart a healthy future for all Americans

As the new administration takes office, the Commission advocates widespread reform, holding that "The path away from Trump's politics of anger and despair cannot lead through past policies". The Commission recommends immediate executive actions, including some that President Biden has already taken, such as the revocation of Trump's Muslim ban and rejoining the WHO and Paris Climate Agreement.

Additional recommendations (panel 6), many of which will require Congressional approval, include calls for:

Implementation of a nationwide, science-led response to the COVID-19 pandemic.

Repeal the 2017 tax cuts on corporations and the wealthy, implement new taxes on assets, and increase taxes on capital gains and high earnings.

Implementation of the Green New Deal, ending subsidies and tax breaks for fossil fuels, and banning coal mining and single use plastics.

Increase public expenditures for social programs, currently 18.7% of gross domestic product, to 24.2% (the average of G7 nations), and repeal time limits and immigration restrictions on welfare and nutrition programs.

Vigorous enforcement of voting and civil rights.

Reforming the policing and criminal justice systems that oppress communities of color and have filled prisons.

New investments in education and minority-serving health institutions, and compensation to communities of color for wealth denied to and confiscated from them in the past.

Enactment of a single-payer system (Medicare for All) reform covering all US residents that would redirect the $626 billion currently wasted annually on billing and administration to patient care, and a direct role for government in drug development, rather than merely paying for research that subsequently brings profits to private firms.

A reduction in military spending from the current level of 3.4% of GDP to the 1.4% average of other G-7 nations. About ¼ of this should be redirected to foreign aid in order to reach the level recommended by the United Nations. The rest should be used to address urgent social needs.

Repeal the Hyde Amendment and regulations that treat sexual-health services differently from other health services.

A massive mobilization of resources to avert climate catastrophe.

"Trump's disastrous actions compounded longstanding failures in health policy in the USA. We know what it will take to create a healthy society. We just need the political will to do it," says Commission member Dr Kevin Grumbach, Hellman Endowed Professor and Chair of the Department of Family and Community Medicine, University of California, San Francisco [2].

Writing in a linked Comment, David Blumenthal, President of the Commonwealth Fund and Margaret Hamburg, Vice President of the Nuclear Threat Initiative and former Commissioner of the U.S. Food and Drug Administration (FDA) (who were not involved in the report), write: "The Commission's critique of US health care is broad, deep, and innovative. It provides a thorough review of the presidency and administration of Donald Trump and the many destructive executive orders he signed, which have led to, among other things, loss of health coverage for millions of US residents. The report could serve as a starting point for the corrective actions and policies of the new administration of President Joseph Biden and Vice President Kamala Harris." They add: "The hard fact is that the way to health-care reform in the USA requires political activism of the most basic kind, something that is far beyond the comfort zone of many health professionals. Should that work--by health professionals and others--prove successful, buttressed by the copious and compelling evidence in this Commission's report, the USA could be repositioned to address the fundamental roots of our health-care crisis, which often arise from inequalities in income, education, nutrition, housing, justice, and employment opportunities available to Americans."

Researchers from North Carolina State University used a three-model approach to trace the between-farm spread of porcine epidemic diarrhea virus (PEDV), as well as to analyze the efficacy of different control strategies in these scenarios. The approach may enable farmers to be more proactive in preventing the spread of PEDV and to optimize their efforts to control the disease.

PEDV is a virus that causes high mortality rates in preweaned piglets. The virus emerged in the U.S. in 2013 and by 2014 had infected approximately 50 percent of breeding herds. PEDV is transmitted by contact with contaminated fecal matter.

"We wanted to compare three different models by using actual outbreak data in order to test their efficacy," says Gustavo Machado, assistant professor of population health and pathobiology at NC State and corresponding author of a paper describing the work. "Then we could use the data to determine the best intervention strategy in each case."

The team compared three models. One was PigSpread, a novel epidemiological modelling framework developed by coauthor Jason Galvis specifically to model disease spread in swine populations. The other two models were SimInf (a commercial disease spread simulator) and PoPS, which was developed by NC State's Center for Geospatial Analytics to model the spread of pests or pathogens within fields and forests.

"There are mainly two ways PEDV can spread - either between the pigs on the same farm, or when pigs are moved from one farm to another," Machado says. "Each of the models we picked had a different strength: PigSpread looks at the number of pigs per farm and differences in numbers to make predictions, SimInf looks at disease in the environment, and PoPS uses both differences in numbers and environmental factors like temperature and precipitation."

Using data from recorded PEDV outbreaks from three separate companies, the team calibrated the models weekly and looked at which one performed best in each given week.

"While PoPS was the most accurate overall, each model had its own advantages or disadvantages," Machado says. "What we're doing here is similar to the way meteorologists model weather data, using different models with different strengths to give us more flexibility. We calibrate the models each week and predictively, we would use the model that performed best on the most recent data."

The team analyzed the predictive capability of the models in conjunction with disease control strategies such as herd closure, vaccination and biosecurity measures. They estimate that by combining modeling and control protocols farms could see a 76% to 89% reduction in outbreaks in sow farms and a 33% to 61% outbreak reduction among gilt farms.

"This is a flexible way to keep farmers up to date during an outbreak and enable them to make decisions," Galvis says. "We hope to be able to provide farmers with potential hot spot maps prior to an outbreak so that they can increase surveillance and preempt the spread of disease. Our next steps will be to look more closely at how the infection responds to specific interventions."

A new study published in CMAJ (Canadian Medical Association Journal) found that the risk of death from COVID-19 was 3.5 times higher than from influenza.

"We can now say definitively that COVID-19 is much more severe than seasonal influenza," says Dr. Amol Verma, St. Michael's Hospital, Unity Health Toronto, and the University of Toronto. "Patients admitted to hospital in Ontario with COVID-19 had a 3.5 times greater risk of death, 1.5 times greater use of the ICU, and 1.5 times longer hospital stays than patients admitted with influenza."

These findings are similar to study results recently reported in France and the United States.

The study compared hospitalizations for influenza between November 1, 2019, and June 30, 2020, in 7 large hospitals in Toronto and Mississauga -- areas with large populations and high levels of COVID-19. It included all patients admitted to medical services or the intensive care unit (ICU) for influenza or COVID-19. There were 783 hospitalizations for influenza in 763 unique patients compared with 1027 hospitalizations for COVID-19 in 972 unique patients (representing 23.5% of all hospitalizations for COVID-19 in Ontario during the study period).

Most patients hospitalized with COVID-19 had few other illnesses, and 21% were younger than 50 years of age. People younger than 50 also accounted for almost 1 in 4 (24%) admissions to the ICU.

"Many people believe that COVID-19 mainly affects older people," says Dr. Verma. "It is true that COVID-19 affects older adults most severely. We found that among adults over 75 years who were hospitalized with COVID-19, nearly 40% died in hospital. But it can also cause very serious illness in younger adults. Adults under 50 accounted for 20% of all COVID-19 hospitalizations in the first wave of the pandemic. Nearly 1 in 3 adults younger than 50 hospitalized with COVID-19 required intensive care, and nearly 1 in 10 required an unplanned readmission to hospital after discharge."

People hospitalized for COVID-19 had greater use of the ICU, were more likely to be put on a ventilator and had longer hospital stays than people with influenza.

"These differences may be magnified by low levels of immunity to the novel coronavirus compared with seasonal influenza, which results from past infections and vaccination," says Dr. Verma. "Hopefully, the severity of COVID-19 will decrease over time as people are vaccinated against the virus and more effective treatments are identified. There is, unfortunately, also the possibility that variants of the virus could be even more severe."