Body

A team of engineers and clinicians has developed an ultra-thin, inflatable device that can be used to treat the most severe forms of pain without the need for invasive surgery.

The device, developed by researchers at the University of Cambridge, uses a combination of soft robotic fabrication techniques, ultra-thin electronics and microfluidics.

The device is so thin - about the width of a human hair - that it can be rolled up into a tiny cylinder, inserted into a needle, and implanted into the epidural space of the spinal column, the same area where injections are administered to control pain during childbirth.

Once correctly positioned, the device is inflated with water or air so that it unrolls like a tiny air mattress, covering a large section of the spinal cord. When connected to a pulse generator, the ultra-thin electrodes start sending small electrical currents to the spinal cord, which disrupt pain signals.

Early tests of the device suggest that it could be an effective treatment for many forms of severe pain - including leg and back pain - which are not remedied by painkillers. It could also be adapted into a potential treatment for paralysis or Parkinson's disease. However, extensive tests and clinical trials will be required before the device can be used on patients.

Although other types of spinal cord stimulation devices are currently used to treat severe pain, the most effective of these devices are bulky and require invasive surgery, while current keyhole devices are far less effective at treating pain. By combining the clinical effectiveness of the surgical devices and the ease of implantation of the keyhole devices, the Cambridge-developed device could be an effective, long-term solution to intractable pain, which affects millions worldwide. The results are reported in the journal Science Advances.

Pain is something that everyone experiences, and for the vast majority of people, it is temporary and treatable. However, for some, pain becomes debilitating. In the UK, back pain is the leading cause of disability, costing the economy around £12 billion per year. In the US, the Centers for Disease Control and Prevention estimates that as many as one in 12 Americans suffer from intractable back pain, which does not respond to conventional treatments such as non-steroidal anti-inflammatory drugs (NSAIDs) or opioids.

Spinal cord stimulation (SCS) is an option for those who suffer from intractable back pain or other types of neuropathic pain, but despite its effectiveness, its use is limited, with just 50,000 procedures carried out worldwide each year.

"Spinal cord stimulation is a treatment of last resort, for those whose pain has become so severe that it prevents them from carrying out everyday activities," said Dr Damiano Barone from Cambridge's Department of Clinical Neurosciences, one of the paper's senior authors. "However, the two main types of SCS devices both have flaws, which may be one reason their use is limited, even though millions struggle with chronic pain every day."

The most effective SCS device in clinical use is a paddle-type device, which covers a wide area of the spinal cord but is bulky and requires invasive surgery under general anaesthetic. The other type of device can be implanted with a needle and only requires local anaesthetic, but it covers a smaller area and is less clinically effective than a paddle-type device.

"Our goal was to make something that's the best of both worlds - a device that's clinically effective but that doesn't require complex and risky surgery," said Dr Christopher Proctor from Cambridge's Department of Engineering, the paper's other senior author. "This could help bring this life-changing treatment option to many more people."

"In order to end up with something that can be implanted with a needle, we needed to make the device as thin as possible," said co-first author Ben Woodington, also from the Department of Engineering.

The researchers used a combination of manufacturing techniques to build their device: flexible electronics used in the semiconductor industry; tiny microfluidic channels used in drug delivery; and shape-changing materials used in soft robotics.

Their finished device is just 60 microns thick - thin enough that it can be rolled up and placed in a needle for implantation. However, after implantation, the device expands out to cover a wide area of the spinal cord, thanks to the microfluidic channels.

"Thin-film electronics aren't new, but incorporating fluid chambers is what makes our device unique - this allows it to be inflated into a paddle-type shape once it is inside the patient," said Proctor.

"Our earlier versions were actually so thin that they were invisible to x-rays, which the surgeon would need to use to confirm they're in the right place before inflating the device," said Woodington. "We added some bismuth particles to make it visible without increasing the thickness too much. Designing a device is one thing, but putting it into surgical use is quite another."

The researchers validated their device in vitro and on a human cadaver model. They are currently working with a manufacturing partner to further develop and scale up their device and are hoping to begin tests in patients within two to three years.

"The way we make the device means that we can also incorporate additional components - we could add more electrodes or make it bigger in order to cover larger areas of the spine with increased accuracy," said Barone. "This adaptability could make our SCS device a potential treatment for paralysis following spinal cord injury or stroke or movement disorders such as Parkinson's disease. An effective device that doesn't require invasive surgery could bring relief to so many people."

A new vaccine to protect against deadly cholera has been made by grinding up genetically modified grains of rice. The first human trial has shown no obvious side effects and a good immune response. Researchers based at the University of Tokyo and Chiba University have published the peer-reviewed results of the Phase 1 clinical trial of the vaccine, named MucoRice-CTB, in The Lancet Microbe.

Vaccine manufacturing has made enormous strides in 2020, spurred on by COVID-19. However, the complexity of mRNA-based SARS-CoV-2 vaccines has highlighted the value of inoculations that can be made, transported and stored cheaply and without refrigeration.

The MucoRice-CTB vaccine is stable at room temperature from start to finish.

"I'm very optimistic for the future of our MucoRice-CTB vaccine, especially because of the dose escalation results. Participants responded to the vaccine at the low, medium and high doses, with the largest immune response at the highest dose," said Professor Hiroshi Kiyono, D.D.S., Ph.D., from the Institute of Medical Science at the University of Tokyo who leads the MucoRice project. Dr. Kiyono is also a faculty member at Chiba University in Japan and the University of California, San Diego, in the U.S.

Thirty volunteers received a placebo and groups of 10 volunteers received a total of four doses spaced every two weeks of either 3 milligrams (mg), 6 mg or 18 mg each of the vaccine. Tests two and four months after receiving the last dose revealed that volunteers who responded to the vaccine had IgA and IgG antibodies - two types of proteins the immune system produces to fight infections - specific to cholera toxin B (CTB). Participants who received a higher dose of vaccine were more likely to have CTB-specific antibodies.

An independent review board found no evidence of significant side effects.

Growing a new type of vaccine
Vibrio cholerae bacteria is spread most often by drinking water contaminated with sewage. Without medical attention, cholera can kill in mere hours due to diarrhea with severe dehydration. Cholera infects 1.3 million to 4 million people and causes 21,000 to 143,000 deaths each year, according to the World Health Organization.

There are four modern needle-free cholera vaccines, all of which are given as drops on the tongue, but require cold storage and are made from whole killed or live-attenuated (weakened) cholera cells; https://www.fda.gov/media/98688/download).

The new cholera vaccine grows in genetically modified Japanese short-grain rice plants that produce a nontoxic portion of CTB that can be recognized by the immune system. CTB is similar in structure to a toxin made by some types of disease-causing E. coli bacteria, so cholera vaccines often provide cross protection against travelers' diarrhea.

Researchers grow the rice plants in a purpose-built, indoor hydroponic farm that meets WHO good manufacturing practice standards for medicines, which ensures that the vaccine remains uncontaminated and that the plants are isolated from the natural environment.

The plants produce the CTB subunit in their seeds, the edible grains of rice, and store the antigens in droplets called protein bodies with membranes made of fat.

"The rice protein bodies behave like a natural capsule to deliver the antigen to the gut immune system," said Dr. Kiyono.

Other medicines have been grown in plants, most often in the leaves - including treatments for Ebola, lymphoma and flu - but the drugs have to be extracted and purified before being used. The grain-based aspect of the MucoRice system avoids those extra steps, the need for cold storage, and protects the antigens as they travel through the harsh acid of the stomach.

When the plants are mature, the rice is harvested and ground into a fine powder, then sealed in aluminum packets for storage. When people are ready to be vaccinated, the powder is mixed with about 90 milliliters (1/3 U.S. cup) of liquid and then drunk. Researchers have only tested the vaccine using saline (a salt solution equivalent to body fluids), but they expect it would work equally well with plain water.

Immunity through the gut is strong, but complicated by the microbiome

"The beautiful part of our vaccine is that it wisely uses the body's mucosal immune system through the gut for the induction of antigen-specific antibodies," said Dr. Kiyono.

MucoRice-CTB enters the body through intestinal mucosal membranes, mimicking a natural way of encountering and responding to germs. Stimulating the mucosal immune system produces two classes of antibodies that identify germs and target them for removal, IgG and IgA. Vaccines that are injected under the skin or into a muscle generally increase only IgG, not IgA, antibodies.

Volunteers who responded to MucoRice-CTB had their highest blood levels of antigen-specific IgG and IgA after eight to 16 weeks.

However, 11 of the 30 volunteers who received the vaccine showed low or no measurable immune response. All study volunteers reported never traveling outside of Japan, so it is unlikely that they had any previous exposure or natural immunity to V. cholerae or pathogenic E. coli.

"When we saw those data about the 11 low and nonresponders, we thought maybe gut microflora have an influence on the outcome of the immune response," Dr. Kiyono recalled.

The microflora or microbiome is the community of microorganisms that live in our bodies and either benefit us or are harmless. It is well accepted that the microflora of the digestive system influence health and immunity, but scientists are just beginning to understand the precise mechanisms of the relationship.

Extensive genetic analysis of all volunteers' fecal samples identified the thousands of bacterial species living in volunteers' intestines.

"In simplified terms, high responders had more diversified microflora, and in the low-responder group, diversity was much narrower," said Dr. Kiyono.

Researchers cautioned that the small size of the Phase 1 study - giving the vaccine to only 30 healthy Japanese male volunteers - means the relevance and prevalence of nonresponders is still unclear and that the total difference in microflora diversity was subtle. However, the results do hint at the larger role of microflora in vaccine effectiveness.

"It's all speculation right now, but maybe higher microflora diversity creates a better situation for strong immune response against oral vaccine," said Dr. Kiyono.

The link between the gut microbiome and vaccine effectiveness has been previously revealed by the unfortunate fact that most vaccines are developed in industrialized nations and some are then less effective when delivered in developing countries. Mucosal vaccines, including oral vaccines against polio and cholera, seem especially prone to this disparity. Most scientific theories to explain the phenomenon focus on chronic intestinal inflammation linked to poor sanitation. (https://doi.org/10.1186/1741-7007-8-129)

"Probably for every vaccination right now, even injected vaccines, we should think of the immune status of the individual based on the condition of their microflora," said Dr. Kiyono.

It remains to be seen how microflora diversity will impact the global effectiveness of the new MucoRice edible vaccine system compared to other oral vaccines' records.

For now, the researchers plan to work with partners in the pharmaceutical industry to bring MucoRice-CTB into the next phase of clinical trials in Japan and overseas.

TAMPA, Fla. -- E-cigarettes spark many concerns, especially when it comes to youth vaping. However, emerging evidence suggests that e-cigarettes can be a helpful tool in smoking cessation. Researchers in Moffitt Cancer Center's Tobacco Research and Intervention Program wanted to build upon this evidence by testing whether they could help dual users, people who use both combustible cigarettes and e-cigarettes, quit smoking. In a new article published in The Lancet Public Health, they report results from a first-of-its kind nationwide study evaluating a targeted intervention aimed at transforming dual users' e-cigarettes from a product that might maintain smoking into a tool that can be used to aid smoking cessation.

An estimated 8 million adults in the U.S. use e-cigarettes, often with the goal of quitting or reducing cigarette smoking. Nearly 41% are dual users, a practice that maintains, and in some cases might increase, both nicotine dependence and exposure to toxins.

"We were concerned that smokers who started vaping in order to quit smoking often ended up instead using both products," said Thomas Brandon, Ph.D., chair of the Health Outcomes & Behavior Department and director of the Tobacco Research and Intervention Program at Moffitt. "This prompted our team to develop an easy-to-distribute intervention that could enhance dual users' smoking cessation efforts and maintain smoking abstinence."

The research team, which included collaborators from Virginia Commonwealth University; Eastern Virginia Medical School; and the University of Auckland, New Zealand, interviewed vapers who were and were not able to quit smoking. Based on what they learned, they developed a series of "If You Vape" booklets that includes smoking cessation advice geared specifically for dual users.

To test their intervention, the Moffitt team launched a national trial with nearly 2,900 dual users. Participants were randomized into three groups: an assessment group receiving no intervention, a generic self-help group receiving standard smoking cessation materials, and the targeted intervention group receiving the new "If You Vape" booklets. Participants completed surveys every three months for two years to report their current smoking and vaping.

The results showed that the targeted intervention produced smoking abstinence rates about 5 to 10 percentage points higher than the assessment group over the 18 months of treatment. The generic intervention produced abstinence rates in between the two other arms. The researchers noted that while those who reported little to no dependence on combustible cigarettes had greater overall success in quitting, more dependent smokers benefited the most from the new intervention. For example, among dependent smokers who received the booklets, about 20% had quit smoking by six months, compared to 13% of those in the assessment arm.

"Our study indicates that dual users could benefit from specific interventions that leverage their ongoing e-cigarette use, which in turn could expand the public health potential of e-cigarettes," said Brandon. "I think it is important to note that while our materials did not endorse the initiation of vaping, it also didn't demonize use. We treated vapers with respect and passed along information to help them achieve their goal of quitting smoking."

Although the booklets suggest that participants might eventually consider giving up all nicotine, the researchers found no differences in vaping across groups.

The research team would like to expand their efforts to include testing alternative intervention modalities such as a mobile app, improving long-term smoking cessation, and testing the intervention in clinical settings.

Tuberculosis is one of the top ten causes of death worldwide, infecting about one-quarter of the world's population. Although it is treatable, the rise of multidrug-resistant tuberculosis poses a major threat to global health security, and has been declared by the World Health Organization as a global health emergency. Reduced access to diagnosis and treatment during the COVID-19 pandemic is expected to dramatically increase the number of tuberculosis infections. This will set global efforts to tackle the disease back several years.

Tuberculosis is caused by infection with Mycobacterium tuberculosis: a bacterium that infects human lungs and other organs by using complex molecular machineries. These include protein complexes known as type VII secretion systems, which enable M. tuberculosis to release molecules into its host, which disarm and ultimately kill the infected human cell. Five such secretion systems, labelled ESX-1 to ESX-5, are found among M. tuberculosis and other closely related mycobacteria, many of which are pathogenic. Without them, the bacteria are unable to infect human cells.

The Wilmanns group at EMBL Hamburg has been using high-resolution structural biology to study mycobacterial proteins for the last two decades. The molecular understanding of the bacterial machinery used to infect cells resulted in collaborations with industry to develop new drugs against tuberculosis. In their most recent study, they determined the molecular structure of the secretion system ESX-5 to a high level of detail. They saw that the core of ESX-5 is built of 30 protein units, which form a dynamic membrane pore to allow secretion of proteins that enable the bacterium to survive and multiply inside human cells. Knowledge of the ESX-5 structure at high-resolution is essential to target specific sites with small-molecule drugs.

"Our new structure of the ESX-5 secretion complex provides deep insight into a major sluice gate that separates the inner of these bacteria from the outer host environment. Opening this gate allow the pathogen to spit out its deadly weapons to infect humans to develop tuberculosis. We can use this structure as a toolbox with literally thousands of potential drug targets. This will open an entirely new field of studies on tuberculosis," says Matthias Wilmanns, who leads the study. Kate Beckham, who developed an innovative way to isolate ESX-5, adds: "The central pore we saw in ESX-5 could serve as a new drug target. Blocking it could prevent infection with pathogenic mycobacteria."

The study could also help scientists to develop new vaccines for tuberculosis. The widely used Bacillus Calmette-Guérin (BCG) vaccine, which has its 100th anniversary this year, is based on a strain of mycobacterium that has lost its ability to cause disease because of a defect in the ESX-1 system. However, as BCG vaccination offers insufficient protection and is most effective in young infants only, so alternative vaccines are urgently needed. Due to its close structural and functional relation with ESX-1, targeting the ESX-5 secretion system might spur the development of new vaccines that could complement or replace those currently used.

Determining the molecular structure of ESX-5 was particularly challenging because of its large size and complexity. No single structural biology method can provide the full picture. In this case, the key to success was using integrative structural biology, in which data obtained using different methods -cryo-electron microscopy, X-ray crystallography, mass spectrometry and computational methods - were used jointly to create a coherent model.

"Eighteen months ago, solving this structure looked like mission: impossible," says Matthias Wilmanns. "We managed to put the puzzle pieces together because each team member contributed unique expertise. To solve the complete structure, we collaborated with Jan Kosinski's group at EMBL Hamburg and the Centre for Structural Systems Biology, which provided necessary expertise in integrative structural biology. We also received great help from our colleagues at EMBL Heidelberg, who performed cryo-electron microscopy experiments."

This study illustrates some of EMBL's approaches to life science research in its forthcoming scientific programme, Molecules to Ecosystems 2022-2026. As part of this programme, EMBL will take an interdisciplinary approach to understanding the molecular basis of life in the context of environmental changes. This will provide translational potential to support advances in human and planetary health.

EMBL's approach, including this study, is aligned with the collaborative efforts of other research groups and institutions from Northern Germany working together at the Centre for Structural Systems Biology.

Liza Makowski, PhD, professor in the Department of Medicine and the UTHSC Center for Cancer Research, has long been interested in how the immune system is altered by obesity and how this impacts cancer risk and treatment.

"Obesity is complex, because it can cause both inflammation and activate counter-inflammation pathways leading to immunosuppression," Dr. Makowski said. "How obesity impacts cancer treatments is understudied."

Obese patients with breast cancer often have worse outcomes than non-obese patients. However, exciting developments are being made in other cancers that may also hold promise for treating breast cancer. In studies of a new type of immunotherapy drug, called a checkpoint inhibitor, obese patients appear to respond better, compared with their leaner counterparts in some cancers, such as melanoma, ovarian, certain lung, and kidney cancers. It is not clear if this finding is also true for breast cancer patients.

Dr. Makowski teamed up with Joe Pierre, PhD, assistant professor in Pediatrics and director of the UTHSC Center for Gnotobiotics, to investigate how obesity impacts immunotherapy and to identify potential biomarkers of success.

New findings they published in the June issue of Cell Reports have provided some clues to how breast cancer patients might respond.

Immunotherapies, such as immune checkpoint inhibitors, including atezolizumab (TECENTRIQTM, anti-PD-L1) or Pembrolizumab (KeytrudaTM, anti-PD-1), have been approved in 2019 and 2020, respectively, to treat some patients with triple negative breast cancer, a highly aggressive subtype. It is not currently known if obese breast cancer patients respond better to immunotherapies, similar to findings reported with melanoma. Clinical studies such as these are eagerly awaited by breast cancer patients and researchers.

Drs. Makowski and Pierre showed that obesity in mouse models led to accelerated tumor growth, compared to lean counterparts. Anti-PD-1 immune checkpoint blockade successfully blocked obesity-driven cancer progression. Anti-PD-1 increased immune cell numbers and effective anti-tumor markers. By comparing mice that didn't have tumors to mice with tumors, the team showed that the presence of the tumor exacerbated an environment allowing tumors to hide, resulting in high levels of immunosuppressive cells that were ineffective to reduce breast cancer.

Fortunately, these "sleepy cells" could be reprogrammed to reinvigorate anti-tumor immunity with anti-PD-1, despite persistent obesity. The group also worked to identify changes in the gut microbiome associated with obesity and a strong response to therapy.

The Makowski and Pierre labs are currently funded by the National Cancer Institute to further investigate why certain microbes may impact cancer therapies.

"Our gut is colonized by microbes including bacteria, fungi, and viruses, that may fundamentally impact our immune cells and our inherent ability to fight cancer in ways that we are only just beginning to understand," Dr. Pierre said.

New SARS-CoV-2 variants are spreading rapidly, and there are fears that current COVID-19 vaccines won't protect against them. The latest in a series of structural studies of the SARS-CoV-2 variants' "spike" protein, led by Bing Chen, PhD, at Boston Children's Hospital, reveals new properties of the Alpha (formerly U.K.) and Beta (formerly South Africa) variants. Of note, it suggests that current vaccines may be less effective against the Beta variant.

Spike proteins, on the surface of SARS CoV-2, are what enable the virus to attach to and enter our cells, and all current vaccines are directed against them. The new study, published in Science on June 24, used cryo-electron microscopy (cryo-EM) to compare the spike protein from the original virus with that the Alpha and Beta variants.

The structural findings indicate that mutations in the Beta variant (also known as B.1.351) change the shape of the spike surface at certain locations. As a result, neutralizing antibodies induced by current vaccines are less able to bind to the Beta virus, which may allow it to evade the immune system even when people are vaccinated.

"The mutations make antibodies stimulated by the current vaccine less effective," says Chen, in the division of Molecular Medicine at Boston Children's. "The Beta variant is somewhat resistant to the current vaccines, and we think a booster with the new genetic sequence can be beneficial for protecting against this variant."

However, the study also found that mutations in the Beta variant make the spike less effective in binding to ACE2 -- suggesting that this variant is less transmissible than the Alpha variant.

Reassurance on the Alpha variant; more variant studies underway

As for the Alpha variant (B.1.1.7), the study confirms that a genetic change in the spike (a single amino acid substitution) helps the virus bind better to ACE2 receptors, making it more infectious. However, testing indicates that antibodies elicited by existing vaccines can still neutralize this variant.

To be a heightened threat, the researchers say, a SARS-CoV-2 variant would need to do three things: spread more easily, evade the immune system in vaccinated people or those previously exposed to COVID-19, and cause more severe disease. Fortunately, the Alpha and Beta variants do not meet all these criteria.

"Our data suggest that the most problematic combination of such mutations is not yet present in the existing variants examined here," the researchers write.

Chen's team also plans to report the structures of other variants of concern, including the Delta variant (B.1.617.2), in the near future. Those investigations are still under way.

ROCHESTER, Minn. -- Researchers at Mayo Clinic Cancer Center are studying a potential new chimeric antigen receptor-T cell therapy (CAR-T cell therapy) treatment for multiple myeloma. Their findings were published on Friday, June 24, in The Lancet.

"CAR-T cell therapy is a type of immunotherapy that involves harnessing the power of a person's own immune system by engineering their T cells to recognize and destroy cancer cells," says Yi Lin, M.D., a Mayo Clinic hematologist and lead author of the study.

Dr. Lin says the Food and Drug Administration approved idecabtagene vicleucel, the first CAR-T cell treatment for multiple myeloma, in March. "Today, we are working toward another potential CAR-T cell treatment for multiple myeloma," says Dr. Lin.

Dr. Lin says the CARTITUDE-1 study is a registration-phase 1B/II clinical trial. The trial tested B cell maturation antigen targeting CAR-T cell therapy, ciltacabtagene autoleucel (cilta-cel), in patients with multiple myeloma who received at least three previous lines of therapy with standard drugs, including proteasome inhibitors, immunomodulatory drugs and CD38 antibodies.

"Cilta-cel is made from patient's own T cells that have been genetically engineered and administered as a single dose infusion," says Dr. Lin.

Dr. Lin says the overall response rate to the treatment was 97%, while the complete response rate and progression-free survival rates were 67% and 77%, respectively. The overall survival rate was 89%.

"Updates on this study were also recently presented at the American Society of Clinical Oncology annual meeting, which occurred after our paper was accepted for publication in The Lancet," says Dr. Lin. "Our ASCO presentation showed a continued deepening response for patients receiving this therapy, with a complete response rate of 80%," says Dr. Lin. "These are very impressive results for myeloma patients who have already gone through many lines of therapy for their disease."

Going forward, Dr. Lin says it will be important to better understand the clinical features of patients who have experienced durable remissions on this therapy and the mechanisms behind patients who relapse.

"While comparisons cannot be formally made across two separate single-arm studies of ide-cel and cilta-cel, the impressive high response rate and progression-free survival of patients treated with cilta-cel are very exciting," says Dr. Lin.

She cautions, however, that the potential translation of this research into a clinical individualized therapy will require solving many logistical details, including ensuring that the transition from manufacturing for research to a commercial product remains reliable.

PITTSBURGH, June 25, 2021 - It is widely assumed that Americans' sexual activity took a nosedive during the early chaotic months of the coronavirus pandemic. But a new study from the University of Pittsburgh School of Medicine challenges this popular narrative.

In a research letter published in the Journal of Internal Medicine, scientists from Pitt and UPMC found that some people were having more sex during the pandemic than ever before. That group? Older men with erectile dysfunction.

"People's sexual lives contribute to the psychosocial fabric of society," said senior author Benjamin Davies, M.D., director of the Urologic Oncology Program at UPMC Hillman Cancer Center and professor at Pitt's Department of Urology. "We saw a huge spike in sales of daily use erectile dysfunction drugs, which suggests that some people were having more spontaneous sex than ever--with their partners at home, they wanted to always be ready."

In a review of National Sales Perspective data, the researchers found that sales of prescription daily-use erectile dysfunction drugs, such as tadalafil, soared after March 2020, when the country went into the nationwide lockdown.

Scientists used the sales rates of the widely available erectile dysfunction drugs as a proxy for the amount of sexual activity--and compared the changes in sales trends pre-pandemic, before March 2020, and after the pandemic was declared, between March and December of 2020. To account for possible fluctuations of drug sales due to other factors, such as ease of access to pharmacies, the researchers tracked the sales of urological drugs--which didn't change in the months after the pandemic was declared.

Interestingly, scientists found, after a short decrease in sales in March and April, the sales of erectile dysfunction drugs have enjoyed a steady increase ever since. The sales of tadalafil, in particular--a longer-acting drug designed to be taken daily to help with spontaneous sexual activity--nearly doubled between February and December of 2020.

"Changes in sales of erectile dysfunction drugs can indicate important problems and point out issues in people's general well-being," said Davies.

Multisystem Inflammatory Syndrome in Children (MIS-C) significantly affected more Black and Latino children than white children, with Black children at the highest risk, according to a new observational study of 124 pediatric patients treated at Children's National Hospital in Washington, D.C. Researchers also found cardiac complications, including systolic myocardial dysfunction and valvular regurgitation, were more common in MIS-C patients who were critically ill. Of the 124 patients, 63 were ultimately diagnosed with MIS-C and were compared with 61 patients deemed controls who presented with similar symptoms but ultimately had an alternative diagnosis.

In the study, published in The Journal of Pediatrics, researchers provide insight into key features distinguishing MIS-C patients to provide a more realistic picture of the burden of disease in the pediatric population and aid with the early detection of disease and treatment for optimal outcomes. The COVID-linked syndrome has affected nearly 4,000 children in the United States in the past year. Early reports showed severe illness, substantial variation in treatment and mortality associated with MIS-C. However, this study demonstrated that with early recognition and standardized treatment, short-term mortality can be nearly eliminated.

"Data like this will be critical for the development of clinical trials around the long-term implications of MIS-C," says Dr. Roberta DeBiasi, M.D., lead author and chief of the Division of Pediatric Infectious Diseases at Children's National. "Our study sheds light on the demographic, clinical and biomarker features of this disease, as well as viral load and viral sequencing."

Of the 63 children with MIS-C, 52% were critically ill, and additional subtypes of MIS-C were identified including those with and without still detectable virus, those with and without features meeting criteria for Kawasaki Disease, and those with and without detectable cardiac abnormalities. While median age (7.25 years) and sex were similar between the MIS-C cohort and control group, Black (46%) and Latino (35%) children were overrepresented in the MIS-C group, especially those who required critical care. Heart complications were also more frequent in children who became critically ill with MIS-C (55% vs. 28%). Findings also showed MIS-C patients demonstrated a distinct cytokine signature, with significantly higher levels of certain cytokines than those of controls. This may help in the understanding of what drives the disease and which potential treatments may be most effective.

In reviewing viral load and antibody biomarkers, researchers found MIS-C cases with detectable virus had a lower viral load than in primary SARS-CoV-2 infection cases, but similar to MIS-C controls who had alternative diagnoses, but who also had detectable virus. A larger proportion of patients with MIS-C had detectable SARS-CoV-2 antibodies than controls. This is consistent with current thinking that MIS-C occurs a few weeks after a primary COVID-19 infection as part of an overzealous immune response.

Viral sequencing was also performed in the MIS-C cohort and compared to cases of primary COVID-19 infection in the Children's National geographic population. 88% of the samples analyzed fell into the GH clade consistent with the high frequency of the GH clade circulating earlier in the pandemic in the U.S. and Canada, and first observed in France.

"The fact that there were no notable sequencing differences between our MIS-C and primary COVID cohorts suggests that variations in host genetics and/or immune response are more likely primary determinants of how MIS-C presents itself, rather than virus-specific factors," says Dr. DeBiasi. "As we've seen new variants continue to emerge, it will be important to study their effect on the frequency and severity of MIS-C."

Researchers are still looking for consensus on the most efficacious treatments for MIS-C. In a recent editorial in the New England Journal of Medicine, Dr. DeBiasi calls for well-characterized large prospective cohort studies at single centers, and systematic and long-term follow-up for cardiac and non-cardiac outcomes in children with MIS-C. Data from these studies will be a crucial determinant of the best set of treatment guidelines for immunotherapies to treat MIS-C.

"Red flag" gun laws--which allow law enforcement to temporarily remove firearms from a person at risk of harming themselves or others--are gaining attention at the state and federal levels, but are under scrutiny by legislators who deem them unconstitutional. A new analysis by legal scholars at NYU School of Global Public Health describes the state-by-state landscape for red flag legislation and how it may be an effective tool to reduce gun violence, while simultaneously protecting individuals' constitutional rights.

Gun violence is a significant public health problem in the U.S., with more than 38,000 people killed by firearms each year. Following several mass shootings this spring, President Biden urged Congress to pass legislation to reduce gun violence, including a red flag law--also known as a "extreme risk protection order" law--at the federal level and legislation to incentivize states to pass their own. In June, the Department of Justice published model legislation to help states craft their own red flag laws.

"Research shows that prior to an attempted suicide or homicide, there are warning signs that a shooter intends to act," said Jennifer Pomeranz, assistant professor of public health policy and management at NYU School of Global Public Health and the lead author of the study, which was published in the American Journal of Preventive Medicine. "Removing firearms during crisis situations allows for mental health intervention or law enforcement investigation, and can prevent tragedies from occurring."

In May 2020, Oklahoma passed the nation's first law preempting or blocking local governments from enacting their own red flag laws. The state's "anti-red flag" bill was one of several proposed across the country based on arguments that red flag laws are unconstitutional. Legal scholars have evaluated constitutional arguments supporting and opposing red flag laws, and while lower courts have upheld the laws, to date there is limited case law on their constitutionality.

To better understand the current landscape of red flag laws, the researchers gathered and analyzed all state red flag laws and related preemption bills and laws proposed or enacted as of July 1, 2020. They found that 19 states and the District of Columbia enacted a total of 43 red flag laws for both temporary and final orders; the majority were enacted between 2018 and 2020. They also identified five preemption bills in four states (Alaska, Georgia, Minnesota, and Kansas with two bills) and one that was signed into law (Oklahoma).

State legislators had a variety of rationales for wanting to stop local governments from passing red flag laws. The four most common concerns were based on constitutional law:

The First Amendment: State legislators argued that red flag laws violated the First Amendment, which protects against unwarranted government interference with expression; however, threats of violence, intimidation, harm, or death are not protected.

The Second Amendment: State legislators also argued that red flag laws violate the right to bear arms for self-defense. If a firearm is removed under a protection order, the respondent would temporarily not be able to exercise this right, but the Supreme Court has confirmed that some people may be "disqualified" from possessing firearms.

The Fourth Amendment: Two states introducing preemptive bills pointed to the Fourth Amendment, which protects against unreasonable searches and seizures and requires probable cause to issue a warrant. All laws required probable cause (or higher) for a warrant; one law allowed for warrantless firearm removal, which the Supreme Court considers reasonable when a person is armed and presently dangerous.

The Fifth Amendment: State legislators argued that red flag laws violate the right to due process, which requires procedures that provide notice, an opportunity to be heard, and appeal. However, all existing red flag laws provide these due process protections, including requiring strict or heightened burden of proof standards for final orders removing firearms.

The researchers found that red flag laws are similar to other civil laws that protect people from harming themselves or others, including laws for involuntary commitment and removing children from unfit parents. Red flag laws provide the same or even more procedural due process than do some of these laws that confine or remove individuals--as opposed to their property--against their will.

"Without judicial determination that red flag gun laws are unconstitutional, it is premature for states to block the ability of local governments to temporarily remove firearms from people in crisis situations," said Gilberto Ochoa, a research intern at NYU School of Global Public Health and the study's coauthor.

"States have drafted red flag laws in an effort to allow authorities to restrict or remove firearms from people at risk to themselves or others, while simultaneously protecting their constitutional right. As such, there are strong arguments in favor of enacting these laws, rather than preempting them," Pomeranz concluded.

TAMPA, Fla. (June 24, 2021) -- A newly published study by the University of South Florida Health (USF Health) and Tampa General Hospital (TGH) shows that monoclonal antibodies (MABs) work well in reducing COVID-19 related emergency department visits and hospitalizations when given early to high-risk patients. If used under FDA guidelines, the researchers suggest, this treatment can ease the pandemic's continuing burden on patients and on limited health care resources.

The collaborative study was published June 4 in Open Forum Infectious Diseases.

Investigational monoclonal antibody therapies, administered intravenously, are specifically designed to block infection by SARS-CoV-2, the virus that causes COVID-19. The FDA has granted emergency use authorization (EUA) of MABs in outpatients with mild-to-moderate COVID-19 at increased risk of developing severe disease. Such high-risk patients are prone to hospitalizations, mechanical ventilation and other complications, including death from coronavirus.

"While the emphasis now is rightfully on getting more vaccines in arms, thousands of people in the U.S. are still infected with COVID-19 every day and a significant number suffer serious complications," said the study's senior author Asa Oxner, MD, associate professor and vice chair of the Department of Internal Medicine, USF Health Morsani College of Medicine.

"Unfortunately, only a fraction of those outpatients eligible for monoclonal antibodies receive them," Dr. Oxner said. "We hope results like ours reinforce to the public and health care providers the importance of targeting timely monoclonal antibody treatment to this high-risk patient population to help minimize stress on health care systems during the COVID-19 pandemic."

Limited clinical trials previously indicated that MABs work best when given soon after diagnosis. But this USF Health-TGH collaborative study was one of the first to evaluate the practical effectiveness of MABs when administered exclusively to patients deemed at high risk for progression to severe COVID-19. The FDA defines medical conditions and factors that place adults and children age 12 or older at higher risk for COVID-19, including older age (65 plus), obesity, diabetes, immunosuppressive disorders or treatment, chronic lung disease and cardiovascular disease, to name a few.

The academic medical center's retrospective study, conducted Nov 18, 2020, to Jan. 5, 2021, included high-risk outpatients with a confirmed COVID-19 diagnosis, all experiencing mild-to-moderate symptoms for 10 days or less. A group of 200 patients received one of two MAB therapies (a single infusion) - either casirivimab/imdevimab, a combination drug made by Regeneron, or the medication bamlanivimab made by Eli Lilly. This treatment group was compared against a control group of 200 randomly selected outpatients who declined or were not referred for MABs during the same period.

Among the findings:

- Overall, patients treated with the MABs were significantly less likely to be hospitalized or visit the emergency department (13.5%) than the control patients (40.5%). These results remained significant when comparing the individual monoclonal antibody therapies against the control group.

- No deaths were reported in the MABs-treated group, compared to 3.5% in the control group.

- Patients treated with MABs within six days of symptom onset were significantly less likely to be hospitalized or visit the emergency department (7.7%) than those treated after six days (28.1%). The study data indicated MABs are best given within seven days of initial symptoms to reduce the odds of hospitalization within 29 days of infusion.

"Reflecting on our findings, it would be prudent to consider decreasing the FDA eligibility window for MABs to within seven days of symptom onset," the study authors write. "These medications are a relatively scarce resource, and it would be practical to administer them to patients who are likely to see the most benefit."

COVID-19 has strained financial and personnel resources across all health systems, with the Florida Hospital Association estimating total losses of $7.4 billion from the beginning of the pandemic through August 2020. The study authors conclude that maximizing the use of monoclonal antibody therapies under EUA guidance has the potential to "keep high-risk COVID-19 patients out of the hospital and reduce the negative impact on the health care system."

An updated analysis of American COVID-19 deaths throughout 2020 reveals an even bigger drop in average life expectancy as well as still-substantial disparities by race and ethnicity.

Lead author Theresa Andrasfay, a postdoctoral scholar at the USC Leonard Davis School of Gerontology, and coauthor Noreen Goldman of Princeton University first examined the pandemic's effect on American life expectancy in October 2020. Their initial study, published in Proceedings of the National Academy of Sciences in January 2021, showed the largest single-year decline in life expectancy in at least 40 years and the lowest life expectancy estimated since 2003.

The updated analysis, which included the more than 380,000 US COVID-19 deaths in 2020 and used 2018 life expectancies as a comparison, indicates that COVID-19 reduced overall life expectancy by 1.31 years (up from the initial estimate of 1.13 years lost) to 77.43 years. The reductions in average lifespan are more than three times as large for Latinos (3.03 years) and twice as large for the Black population (1.90 years) compared to whites (0.94 years).

"Impacts on life expectancy are likely to be even larger once excess mortality from other causes is taken into account." Andrasfay cautioned.

The changing geography of the pandemic's impact since last fall has made a significant difference in total average life expectancy loss as well as for whites, who were previously projected to lose 0.68 years on average.

"Since our October 2020 projections, disproportionately white Midwestern and Mountain states experienced surges in COVID-19 cases and deaths," Andrasfay explained. "As a result, the disparities are not quite as large as we initially projected, but are still striking."

As noted in the previous study, Black and Latino Americans have experienced a disproportionate burden of coronavirus infections and deaths, reflecting persistent structural inequalities that heighten risk of exposure to and death from COVID-19. The particularly large decrease in average life expectancy among Latinos likely stems from social and economic inequities that result in both higher exposure to infection and higher fatality among those infected. Compared to Black and white populations, Latinos have lower rates of health insurance, are more likely to live in multi-generational or crowded households and are more likely to hold frontline jobs with COVID-19 exposure risks, Andrasfay noted.

"Life expectancy is a metric of population-level mortality in a given year, and it is sensitive to deaths at younger ages," Andrasfay explained. "Though COVID-19 disproportionately killed older Americans, substantial numbers of younger Black and Latino Americans had their lives taken by COVID-19, which contributed to greater life expectancy reductions for these populations."

Andrasfay and Goldman also examined data from the first few months of 2021, which showed that average life expectancy is still affected by the pandemic.

"Though it is too early to estimate 2021 life expectancy, the deaths that occurred in just the first three months of 2021 already indicate that 2021 will have reduced life expectancy compared to pre-pandemic levels, and substantial racial and ethnic disparities in these reductions will persist," Andrasfay said. "The ultimate impact of COVID-19 on 2021 US life expectancy will depend on whether there is sufficient and equitable vaccination across the US. Looking to the future beyond COVID-19, reducing racial disparities in life expectancy requires investments beyond healthcare, including a commitment to make the economy more equitable."

Although IAT is commonly performed, there is variation in how, why, and where it is done. EULAR aimed to help standardise the way IAT is delivered, and explain to people what they can expect from the treatment. A EULAR taskforce was set up to develop a set of new recommendations to give guidance and advice on best practice for IAT.

The taskforce included doctors, nurses, surgeons, and other health professionals, as well as patients. The taskforce looked at the evidence on IAT. Because there is little published evidence, the taskforce also conducted two surveys to collect information. The first was sent out to patients to get their perspectives on what it is like to have IAT, and the second went to healthcare providers to collect information about how IAT is done in different clinics and settings. After looking at the evidence, they developed five overarching principles, and eleven individual recommendations.

The principles say that IAT is recommended and widely used in the management of joint diseases, and that the technique aims to improve patient-centred outcomes. They also emphasise that contextual factors are important and contribute to the effect of IAT. As such, IAT should be offered as part of a full set of individualised information and a shared decision-making process. Finally, they acknowledge that a variety of health professionals are able to perform these procedures routinely. The individual recommendations cover information about the kind of support and advice people undergoing IAT should expect to get from their healthcare team. They also set out the minimum for clinic operating procedures, such as making sure IAT is done in a clean, quiet room, and maintaining good aseptic technique to prevent infections.

EULAR hopes these new recommendations will be included in different educational programmes, used by patient associations, and put into practice via scientific societies to help improve uniformity and quality of care when performing IAT.

The study was conducted by an international collaboration involving the research team led by Luca Tiberi of the Armenise-Harvard Laboratory of Brain Cancer at the Department of Cellular, computational and integrative biology - Cibio of UniTrento, the Paris Brain Institute-Institut du Cerveau at Sorbonne Université in Paris, the Hopp Children´s Cancer Center (KiTZ) in Heidelberg, Germany, and Sapienza University in Rome. It was supported by Fondazione Armenise-Harvard, Fondazione Airc (Italian Association for Cancer Research) and Fondazione Caritro from Trento. The findings of the study, published in Science Advances, could lead to better and more effective treatments.

The team of researchers is proud of the results achieved. Luca Tiberi, coordinator of the study and corresponding author of the paper, comments: "For the first time, we have used an organoid model that we created and developed in past months. Thanks to these in vitro cancer tissues in 3D, we were able to identify the type of cell that can develop into medulloblastoma. These cells in fact express Notch1/S100b, and play a key role in the onset, progression and prognosis of this type of childhood brain cancer".

Organoids, grown by the hundreds in the laboratories of the University of Trento, are generated from skin or blood cells and look like irregular spheres the size of a peanut. Scientists use them to understand the genetic mechanisms responsible for the most common brain cancer affecting children and to explore new treatments for incurable conditions. Organoids were used to provide a model of the tumors in the laboratory. The findings may lead to advancements in brain cancer research and, in the future, could be used to study other tumors in a laboratory setting at a reduced cost, compared with previous technologies, and to conduct larger screenings to test new drugs and tailored treatments.

About organoids

Organoids are generated from skin or blood cells and look like irregular balls the size of a peanut. They are not cell aggregates, but specialized and organized cells that replicate as much as possible the organ under study.

These three-dimensional models allow scientists to do research in a laboratory setting. Working with patients in the case of the present study would be impossible, given that it focuses on brain cancer in children. That is why the team of researchers of the Armenise-Harvard Laboratory of the Department of Cellular, Computational and Integrated Biology - Cibio of the University of Trento used organoids to understand the genetic mechanisms of brain cancer in childhood and to find new treatments for these almost untreatable conditions.

Brain tumors are the first cause of death due to cancer in children. They are very aggressive and require a multidisciplinary and integrated approach. While significant progress has been made in treating these tumors, surviving patients may suffer long-term side effects that significantly compromise their quality of life. When the tumor reappears after some time, therapies are usually ineffective. Medulloblastoma, the focus of this study, is the most common malignant brain tumor in children affecting the central nervous system. The survival rate at five years from the diagnosis of medulloblastoma is around 70% (source: AIRC Italian Association for Cancer Research).

Understanding work participation is important, but the way in which this is defined and measured in clinical trials is not always the same, which has made it hard to compare data. EULAR set up a taskforce to draft points to consider when designing studies that use work participation as a measure. The taskforce included doctors, experts and patients from 11 countries. They used the published evidence to draw up a set of points to consider.

Two overarching principles and nine points to consider were developed. The principles say that work participation is important for people with inflammatory arthritis, their families and society as a whole. They also point out that there are unique methodological aspects around designing,
analysing and reporting studies with work participation as an outcome that require attention.

The points focus on identifying contextual factors upfront and account for them in analyses, as well as accounting for links between different work outcome domains and changes in work status over time. They also advise presenting results as means as well as proportions of patients reaching predefined meaningful categories. This helps people using the data to make comparisons between studies. Finally, they suggest that volume of productivity loss should be explicitly stated when costs are an outcome.

EULAR's current strategy states that 'by 2023, EULAR's activities and related advocacy will have increased participation in work by people with rheumatic and musculoskeletal diseases. EULAR hope that using these points to consider when designing new studies will improve the quality of data available about work in people with inflammatory arthritis, enabling comparisons across studies and the production of good-quality meta-analyses that can inform clinical practice and management for people with these diseases.