Body

BOSTON - New research led by a team at Massachusetts General Hospital (MGH) points to a promising strategy to boost tumors' intake of cancer drugs, thereby increasing the effectiveness of chemotherapy treatments. The group's findings are published in Nature Nanotechnology.

Getting enough anticancer drugs into a tumor is often difficult, and a potential strategy to overcome this challenge involves binding the medications to albumin, the most abundant protein in blood. The strategy relies on tumors' large appetite for protein nutrients that fuel malignant growth. When consuming available albumin, the tumors will inadvertently take in the attached drugs.

A popular albumin-bound drug approved by the U.S. Food and Drug Administration is nanoparticle albumin-bound paclitaxel (nab-PTX), and it has been successfully used to treat late-stage lung and pancreatic cancers. "Not all patients respond to nab-PTX, though, and the effectiveness of its delivery to tumors has been mixed, owing to an incomplete understanding of how albumin impacts drug delivery and actions," says senior author Miles Miller, PhD, a principal investigator in the MGH Center for Systems Biology and assistant professor of Radiology at Harvard Medical School.

To provide insights, Miller and his colleagues assessed the delivery of nab-PTX to tumors at a single-cell resolution in mouse models of cancer. Using 3D microscopy and what's called tissue clearing technology, the team found that cancer cells can take up a significant amount of nab-PTX, and that the consumption of these drugs is controlled by signaling pathways that are involved in the cells' uptake of nutrients such as albumin.

"This discovery suggested that if we could manipulate these pathways, we might be able to trick cancer cells into a nutrient-starved state, thereby enhancing their consumption of nab-PTX," explains Ran Li, PhD, first author on the study and an instructor in the MGH Department of Radiology and the Center for Systems Biology. Indeed, treating tumors with an inhibitor of insulin-like growth factor 1 receptor, an important component of one of the signaling pathways, improved the accumulation of nab-PTX in tumors and boosted its effectiveness.

"These results offer new possibilities to improve delivery of albumin-bound drugs in patients with diverse types of cancer," says Miller.

Students struggling academically benefited most when schools around the world transitioned from classroom teaching to online learning in response to the COVID-19 pandemic, and the switch also didn't negatively impact higher achievers.

A new study has analysed the impact of online learning during the pandemic by crunching data at three middle schools in China, which administered different educational practices for about 7 weeks during the country's Covid-19 lockdown.

Online learning was shown to have a positive impact on overall student performance when compared to not receiving any support from school during lockdown, and the best results were achieved by higher quality teachers preparing content for both rural and city students, regardless of their location.

Senior Lecturer in Economic at Flinders University, Dr Rong Zhu, says the study results show online delivery of education materials can help narrow the achievement gap between struggling students and their higher-achieving peers to improve academic performance despite the COVID-19 lockdowns.

"Our findings have important policy implications for educational practices when lockdown measures are imposed during a severe pandemic like what we have witnessed around the world due to COVID-19,"

"First, when physically shut down, schools should create distance learning resources for students given the beneficial influence of online education with low-ability students shown to be the biggest beneficiaries."

"Our study also highlights that the quality of teachers who design and deliver recorded online lessons has a positive impact on academic performance. Local government can organise top quality teachers to prepare online lessons in advance, complying with local curriculum standards and then make them available when necessary."

Students who used a computer as a remote learning device instead of a smartphone also achieved more improved academic results.

Dr Zhu says online programs are a cost-effective method with great potential to generate substantial economies of scale, since each school does not have to prepare its own version of online classes if a system in setup in advance to facilitate online learning.

"Governments should ensure all students have the resources necessary to access online education, potentially through joint efforts with the telecommunications sector."

"If resources available are constrained, priority should be given to low-achieving children as they benefit the most from distance learning. Since students with access to a computer as the online learning device can benefit more than those using a smartphone, government can play a more active role in providing or subsidizing investment in computers for students having no access to one at home."

Israel is the first country to report national data on the Pfizer-BioNTech vaccine, with observational analysis showing that two doses provide more than 95% protection against COVID-19 infection, hospitalisation, and death, including among the elderly, at a time when the B.1.1.7 variant was the dominant strain.

A single dose of the vaccine was associated with 58% protection against infection, 76% against hospitalisation, and 77% against death, emphasising the importance of fully vaccinating adults.

Challenges to controlling the pandemic remain, including uncertainty about the duration of immunity, the possible emergence of vaccine-resistant variants, and the need to increase vaccine coverage.

Two doses of the Pfizer-BioNTech COVID-19 vaccine provide more than 95% protection against infection, hospitalisation, severe illness, and death, including among the elderly, according to the first national-level observational assessment of its effectiveness in Israel, published in The Lancet.

The analysis, based on de-identified national data, also reveals for the first time the public health benefits of a national vaccination programme, which was found to be the key driver of a decline in COVID-19 infections in Israel.

While the findings are encouraging, the authors stress that a number of challenges to controlling the pandemic remain. The duration of immunity to COVID-19 - both from infection and immunisation - remains unknown, and it is possible that new, vaccine-resistant variants could emerge in the future. In addition, achieving herd immunity will require a continued increase of vaccination coverage worldwide.

By April 2021, COVID-19 had resulted in over 131 million cases and more than 2.8 million deaths worldwide. Preliminary vaccine effectiveness (VE) estimates of one dose of the Pfizer-BioNTech vaccine - which was approved for emergency use in Israel in December 2020 - have been reported in the UK, Denmark, Israel, and the USA. VE estimates for two doses have also been carried out in a subset of the population in Israel. However, until now, national-level VE estimates of two doses of the Pfizer-BioNTech vaccine - the only COVID-19 vaccine available in Israel during the study period of 24th January to 3rd April 2021 - were not available for a range of key outcomes, including VE among the elderly.

Lead author, Dr Sharon Alroy-Preis, of the Israel Ministry of Health, says: "As the country with the highest proportion of its population vaccinated against COVID-19, Israel provides a unique real-world opportunity to determine the effectiveness of the vaccine and to observe wider effects of the vaccination programme on public health.

"Until this point, no country in the world had described the national public health impact of a nationwide COVID-19 vaccination campaign. These insights are hugely important because, while there are still some considerable challenges to overcome, they offer real hope that COVID-19 vaccination will eventually enable us to control the pandemic." [1]

The authors used national pandemic surveillance data recorded by the Israel Ministry of Health to produce VE estimates of two doses of the vaccine against outcomes including COVID-19 infection, severe and critical hospitalisations, and deaths. Data was analysed in groups based on participants' age. The average follow-up time for people who had received two doses was 48 days. An evaluation of the nationwide impact of Israel's vaccination programme on public health, in terms of COVID-19 cases, was also conducted.

Vaccinations with the Pfizer-BioNTech vaccine began amid a surge of infections that led to a national lockdown on 27th December 2020. Daily infections peaked at 10,213 cases on 20th January 2021, and lockdown was lifted on 7th March 2021. By 3rd April, 2021, 72% (4,714,932/6,538,911) of people over 16 years, and 90% (1,015,620/1,127,965) of those over 65 years, had received two doses of the Pfizer-BioNTech vaccine.

During the analysis period, there were 232,268 confirmed COVID-19 infections in the country. The most prevalent strain was B.1.1.7 - also known as the UK variant - which accounted for 94.5% (8,006/8,472) of specimens tested through Israel's free and widely available PCR testing service. Two-thirds of cases were in people over 16 years (66.6%, 154,648/232,268), and there were 7,694 hospitalisations - of which 4,481 were severe and 188 were critical - and 1,113 deaths.

The analysis revealed that the Pfizer-BioNTech vaccine is highly effective against COVID-19 for all people over the age of 16 years, providing 95.3% protection against infection and 96?7% protection against death seven days after the second dose. Protection against symptomatic and asymptomatic infection was 97.0% and 91.5%, respectively. The vaccine is also highly effective for preventing hospitalisations and severe illness, providing 97.2% protection against hospitalisation overall and 97?5% protection against severe and critical hospitalisation. By 14 days after vaccination, protections conferred by a second dose increased to 96.5% protection against infection, 98.0% against hospitalisation, and 98.1% against death. More data on the duration of VE will become available over time.

Protections among the elderly were as strong as those for younger people, with analysis indicating that people over 85 years had 94.1% protection against infection, 96.9% against hospitalisation, and 97% against death 7 days after receiving their second dose. People aged 16-44 years had 96.1% protection against infection, 98.1% against hospitalisation, and 100% against death.

By assessing VE after one dose of the Pfizer-BioNTech vaccine, the authors demonstrated the importance of fully vaccinating adults. Protections were considerably lower between seven and 14 days after receiving the first dose compared to two doses, with 57.7% protection against infection, 75.7% against hospitalisation, and 77.0% against death. The authors also highlight that little is known about the duration of protection of one dose and how this compares to two doses, and caution that one dose may provide a shorter window of protection, particularly in an environment where new variants continue to emerge.

Observed correlations between declines in national COVID-19 infections and the timing of high vaccine uptake for each age group, rather than the start of lockdown on 27th December, suggest that the vaccination programme also had public health benefits.

Infections among those over 65 years continued to rise until mid-January, peaking at around 55 cases per 100,000. However, infections started to decline as people began receiving their second vaccine doses, with daily cases of around 30 per 100,000 by the first phase of reopening on 7th February. Daily infections continued to decline markedly as more people received the vaccine. Steeper and swifter declines were observed for people over 65 years of age - reflecting higher and earlier vaccination rates among older people - however, similar patterns were identified in all age groups.

"As vaccination programmes continue to ramp up around the world, more data is needed urgently about the effectiveness of the Pfizer-BioNTech vaccine against severe disease and death, and about the levels of protection it provides to elderly people. Research examining long-term vaccine effectiveness will ultimately play a vital role in tackling the pandemic," says Dr Luis Jodar, Senior Vice President and Chief Medical Officer, Vaccines at Pfizer, Inc., USA. [1]

The authors acknowledge some limitations. Given the differences between countries in how vaccines are rolled out and how the pandemic continues to evolve, caution should be used in generalising these findings to other nations. Further real-world studies of the Pfizer-BioNTech vaccine, and other vaccines, in other countries and settings are needed.

The dominant COVID-19 strain during the study period was the B.1.1.7 variant. However, another prominent variant, B.1.351 - known as the South Africa variant - has recently been identified in Israel. It was not possible to produce VE estimates for B.1.351 in this report due to the limited number of identified B.1.351 infections in Israel during the analysis period, so this should be investigated in future studies. While VE estimates accounted for factors including age and sex, there was no analysis of the possible effects of other covariates, race/ethnicity, socioeconomic status, or likelihood of seeking a COVID-19 test, and these should be evaluated in future research. With nearly seven weeks of follow-up after the second vaccine dose, the study has the longest reported follow-up to date. However, longer-term data on effectiveness are needed. Variations in the time from symptom onset to hospitalisation and death may have prevented identification of all hospitalisations and deaths during the analysis period.

Writing in a linked Comment, Prof Eyal Leshem of the Chaim Sheba Medical Centre, Israel, and Prof Annelies Wilder-Smith of the London School of Hygiene & Tropical Medicine, who were not involved in the study, note, "Haas and colleagues' findings from Israel suggest that high vaccine coverage rates could offer a way out of the pandemic. Regrettably, rapid population-level coverage cannot be easily replicated in many other countries. The global use of BNT162b2 vaccine is limited by supply issues, high costs, and ultra-cold chain storage requirements."

They continue, "Israel's experience provides impetus for countries to proactively pursue high vaccine coverage to protect the population; however, rollout would need to follow the WHO prioritisation roadmap to maximise the public health impact, in light of vaccine supply constraints. More post-introduction vaccine effectiveness studies will be required. Timely reporting of vaccine effectiveness against variants of concern, the duration of protection across age groups and geographical settings, and the effectiveness of alternative dosing regimens is crucial to provide data-driven immunisation policies."

One of the dangerous health conditions that can occur among premature newborns, children born with heart defects, and some others is pulmonary arterial hypertension (PAH).

Commonly mistaken for asthma, this condition occurs when blood vessels in the lungs develop excessive resistance to blood flow. This forces the heart's right ventricle to work harder, causing it to enlarge, thicken and further elevate blood pressure. While early treatment usually succeeds, the condition can become persistent and progressive, which can lead to heart failure and death.

The exact incidence and prevalence of PAH remains unclear, but reviews of patient registries in Europe have estimated that the condition occurs in nearly 64 of every 1 million children, including transient cases. So far, there is no cure.

Now a team of scientists at Stanford University and Cincinnati Children's report finding a potentially effective needle in a haystack.

"In this study, we screened a library of 4500 compounds at different stages of clinical development in eight different doses. Of the six compounds that improved cell survival, we identified the tyrosine kinase inhibitor AG1296 as the lead compound for further investigation," says Mingxia Gu, MD, PhD, lead author of a study published May 5, 2021, in Science Translational Medicine.

This compound has been available for research for several years but has not been approved for medical use. Its potential value as a PAH treatment emerged only after testing an entire library of compounds using several lines of induced pluripotent stem cells (iPSCs) grown to reflect the genetic signatures of actual patients with the condition.

The researchers found that AG1296 outperformed several other TKI inhibitors on a series of gene expression, cell signaling and mechanistic measures. Most importantly, the compound reversed key biomarkers of the disease in human cells and improved vascular function in animal models.

Center of Excellence

The Pulmonary Hypertension Clinic at Cincinnati Children's is one of eight pediatric centers in the nation to earn accreditation from the Pulmonary Hypertension Association (PHA) as a Pulmonary Hypertension Accredited Comprehensive Care Center.

Cincinnati Children's also hosts the PAH Biobank, an NIH/NHLBI funded resource of biological samples, genetic data, and clinical data for the PAH research community.

Next Steps

The use of human, PAH-specific stem cells as a drug screening platform reflects a crucial step forward, Gu says. In previous studies, about 90% of potential treatments that showed promise in animal studies failed to show benefits in human clinical trials.

"This is the first time for using iPSCs to screen for compounds for PAH, but people have been using similar strategies to screen for new therapy for other conditions," Gu says. "Overall, using patient-specific iPSCs for developing precision medicine is a new and promising field."

Launching a clinical trial for AG1296 likely will require a year or more of preparation and safety evaluations, Gu says. If a trial is launched, it could take a few more years to complete. Then an application process to seek approval from the US Food and Drug Administration would begin.

Inspired by the powerful eyes of the mantis shrimp, scientists have designed an imaging system that can distinguish between cancerous and healthy tissues during cancer surgery. The system accurately labeled tumors in mice and visualized lymph nodes near tumors in 18 patients undergoing surgery for breast cancer. With further development, the camera could help surgeons remove the marginal tumor tissues that can remain after unguided surgery, potentially lowering the risk of cancer relapse. It is critical for surgeons to remove as much tumor tissue as possible during surgery, but anywhere from 25% to 40% of patients still undergo incomplete tumor surgery for malignancies such as head and neck cancer. Digital cameras can help highlight cancerous tissue when combined with fluorescent molecules, but previous fluorescent imaging systems have not been widely adopted. Steven Blair and colleagues blended technology and nature in a fluorescent platform inspired by the mantis shrimp, a marine crustacean with highly complex eyes that provide information at a density unmatched by any human-made spectral camera. To mimic the mantis shrimp eye, Blair et al. vertically stacked layers of silicon photodetectors and spectral filters into a single-chip system platform, which can detect multiple colors and near-infrared light through 6 channels. The sensor successfully detected two fluorescent molecules in human prostate tumors in mice and distinguished cancerous tissue from healthy tissue in 92% of cases. The team also used their camera in the operating room to visualize 18 patients with breast cancer, where it allowed surgeons to accurately map out lymph nodes close to tumors. The researchers note their system's compact nature and low weight allow it to be integrated seamlessly into the operating room without slowing down a surgeon's workflow.

The idea of deriving health benefits from live microorganisms is well known, but some non-living microorganisms, too, can have beneficial health effects. Yet even with an increasing number of scientific papers published on non-viable microbes for health, the category is not well defined and different terms are used in different contexts.

Now, a group of international experts has clarified this concept in a recently published scientific consensus definition in Nature Reviews Gastroenterology & Hepatology. The authors use an established term --postbiotics-- and precisely define it as "a preparation of inanimate microorganisms and/or their components that confers a health benefit on the host".

According to the definition, postbiotics may include either whole microbial cells or components of the cells, as long as they have somehow been deliberately inactivated.

Professor Seppo Salminen, lead author on the publication, says the group of experts -- from across the disciplines of probiotics and postbiotics, adult and pediatric gastroenterology, pediatrics, metabolomics, regulatory affairs, microbiology, functional genomics, cellular physiology and immunology -- wanted to clarify that postbiotics are more complex than the common idea of 'heat-killed probiotics'.

"With this definition of postbiotics, we wanted to acknowledge that different live microorganisms respond to different methods of inactivation," says Prof. Salminen. "Furthermore, we used the word 'inanimate' in favor of words such as 'killed' or 'inert' because the latter could suggest the products had no biological activity."

The authors emphasize that a postbiotic does not need to be derived from a probiotic. That is, scientists do not have to show that the live precursor microorganism itself has a health benefit before using it to create a postbiotic.

The definition was discussed at a panel convened by the International Scientific Association for Probiotics and Prebiotics (ISAPP) in late 2019. This published definition is the latest in a series of international consensus definitions by ISAPP: probiotics, prebiotics, synbiotics, fermented foods and postbiotics.

Mary Ellen Sanders, ISAPP's Executive Science Officer, says, "This was a challenging definition to settle. There are some who think that any purified component from microbial growth should be considered to be a postbiotic, but the panel clearly felt that purified, microbe-derived substances, for example, butyrate or any antibiotic, should just be called by their chemical names. We are confident we captured the essential elements of the postbiotic concept, allowing for many innovative products in this category in the years ahead."

Postbiotics have long been on the market in Japan, and fermented infant formulas with postbiotics are commercially available in South America, the Middle East, and some European countries. Given the scientific groundswell, postbiotic applications are likely to expand quickly.

Sanders says, "The definition will be a touchstone for scientists, both in academia and industry, as they work to develop products that benefit host health in new ways. We hope this clarified definition will be embraced by all stakeholders, so that when the term 'postbiotics' is used on a product, consumers will know what to expect."

R21/Matrix-M becomes the second malaria vaccine candidate ever to start a phase III licensure trial

This builds on the recent finding of high level efficacy of this vaccine in a phase IIb trial in children in Burkina Faso, published today in The Lancet

The first phase III trial doses were administered by the team at the Malaria Research and Training Centre, Bamako, Mali, one of five trial sites across West and East Africa

The malaria vaccine was designed at the Jenner Institute, University of Oxford, who have partnered with the Serum Institute of India for commercial development

The annual death toll from malaria is over 400,000, with most of these deaths amongst children in sub-Saharan Africa. There has been little improvement noted in the last 5 years despite the large amounts of funding allocated to bed nets, insecticide spraying and antimalarial drugs. An efficacious vaccine is needed to try and reach the WHO goal of reducing malaria deaths by at least 90% by 2030.

R21/Matrix-M, a malaria vaccine developed at the Jenner Institute, University of Oxford, showed efficacy of 77% over 12 months in a recently reported phase IIb trial. First vaccinations have now begun in Mali in a larger phase III trial which is hoped to lead to licensure of this malaria vaccine by 2023. This phase III trial will assess efficacy and safety in 4800 children across five sites in Burkina Faso, Kenya, Mali and Tanzania. This is a double-blind, randomised, controlled trial where participants, aged 5-36 months, will receive three vaccinations 4 weeks apart and a booster vaccination 1 year later. The vaccine is being assessed in areas of differing malaria transmission and seasonality.

The University of Oxford has partnered with Serum Institute of India Pvt Ltd. (SIIPL) for the manufacturing of R21/Matrix-M to ensure provision of low high volumes of low-cost vaccine, and access in countries where it is required the most. SIIPL has confirmed its commitment to the provision of >200 million doses per year after licensure, which will be adequate supply for children most at risk of malaria in sub-Saharan Africa.

Quotes

Professor Adrian Hill, Director of the Jenner Institute, University of Oxford said: "The start of a phase III licensure trial is always an import milestone in the development of a vaccine. This large malaria trial is the culmination of many years of laboratory research and assessment of numerous candidate vaccines in early-stage clinical trials with large numbers of collaborators."

Professor Alassane Dicko, Head of the Bougouni Clinical Research Unit, MRTC-P, USTTB and Malian Principal Investigator said: "We are very pleased to see the enthusiasm with which the communities of Bougouni received the first doses of this new candidate malaria vaccine. We are hopeful that the encouraging Phase 2 results will be confirmed in this larger Phase 3 trial".

Professor Abdoulaye Djimdé, Director of the Malaria Research and Training Centre - Parasito (MRTC-P), University of Science, Techniques and Technologies of Bamako (USTTB), said: "We are thrilled to be the first site to enroll volunteers in the Phase 3 trial of this very promising R21 vaccine. We will utilize our more than two decades of experience in malaria vaccine testing towards successful completion of this trial"

Professor Halidou Tinto, Principal Investigator of the Nanoro, Burkina Faso trial site, said: "This is a very important moment in the development of the R21 malaria vaccine candidate. We hope that the public-private partnership behind this pivotal Phase III trial will confirm the high efficacy and good safety profile seen in our phase II trial in Nanoro. The five African institutions involved in this partnership have here a historic role to play. We are all committed to work hard in order to generate data that will provide regulators and policy makers with the evidence needed to support the registration of this vaccine. If successful, this vaccine should be made available as quickly as possible to complement existing malaria prevention tools''

Professor Jean Bosco Ouedraogo, Principal Investigator at The Institute of Sciences and Techniques in Bobo-Dioulasso, Burkina Faso said: "The R21 vaccine is a promising malaria prevention tool to help accelerate malaria elimination, particularly in high burden countries in Africa. The Phase II trial demonstrated high vaccine efficacy in children and I'm proud that it was done in Burkina Faso. I am really happy to be part of this key new trial to evaluate the vaccine's safety and efficacy in an area of perennial transmission near Bobo-Dioulasso."

Dr Umesh Shaligram, Chief Scientist at the Serum Institute of India said: "Malaria has been one of the most difficult diseases to make an effective vaccine against. We are committed to ensuring that the supply of this very promising vaccine, manufactured here in Pune, India, meets public health needs by supplying over 200 million doses annually."

Sophia Antipolis, 6 May 2021: One in four heart attack patients have atypical symptoms such as breathing difficulties, extreme exhaustion, and abdominal pain, according to a study published today in European Heart Journal - Acute Cardiovascular Care, a journal of the European Society of Cardiology (ESC).1 Patients with atypical symptoms were less likely to receive emergency help and more likely to die within 30 days compared to those with chest pain.

"We found that atypical symptoms were most common among older people, especially women, who called a non-emergency helpline for assistance," said study author Ms. Amalie Lykkemark Møller, PhD student, Nordsjællands Hospital, Hillerød, Denmark. "This suggests that patients were unaware that their symptoms required urgent attention."

Heart attacks require fast treatment to restore blood flow and reduce mortality. Symptom recognition by patients and health staff is crucial to reduce delays. Ms. Møller said: "Little is known about how symptoms influence the actions of patients and medical services and impact survival."

The study examined the associations between initial heart attack symptoms, the medical service response and 30-day mortality. The researchers collected data on all calls to a 24-hour medical helpline and an emergency number in the Capital Region of Denmark from 2014 to 2018. At the two services the primary symptom is registered along with the response. The researchers identified adults aged 30 and over who received a heart attack diagnosis within 72 hours of the call. Patients were divided into groups according to their primary symptom.

During the five-year period, a specific primary symptom was recorded for 7,222 of 8,336 heart attacks - chest pain was the most common (72%) while 24% of patients had atypical symptoms, the most frequent being breathing problems. The prevalence of chest pain was highest among men aged 30-59 calling the emergency number and lowest among women older than 79 calling the medical helpline. Atypical symptoms were mainly found among older patients, especially women, who called the helpline.

Among heart attack patients with chest pain, 95% and 76% received an emergency dispatch from the emergency number and medical helpline, respectively. In comparison, just 62% and 17% of heart attack patients with atypical symptoms received an emergency dispatch from the emergency number and medical helpline, respectively.

The 30-day mortality rate for heart attack patients with chest pain was 5% among those who called the emergency number and 3% among those who called the helpline. Rates were higher among heart attack patients with atypical symptoms: 23% and 15% died within 30 days after calling the emergency number and helpline, respectively.

To make a more like-for-like comparison of mortality between patients with chest pain versus atypical symptoms, the researchers standardised for age, sex, education level, diabetes, previous heart attack, heart failure, and chronic obstructive pulmonary disease. The standardised 30-day mortality was 4.3% for patients with chest pain and 15.6% for those with atypical symptoms.

Ms. Møller said: "Taken together, our results show that heart attack patients with chest pain were three times more likely to receive an emergency ambulance than those with other symptoms. People with atypical symptoms more often called the helpline, which could indicate that their symptoms were milder, or they were not aware of the severity. Vague symptoms may contribute to health staff misinterpreting them as benign."

While breathing difficulties, extreme exhaustion, impaired consciousness, and abdominal pain were the most common heart attack symptoms after chest pain, Ms. Møller noted that in most cases these problems are not caused by a heart attack. "Unfortunately, people in this situation will not know the cause, but we hope our study improves awareness - particularly among older patients and health professionals - that it could be a heart attack," she said.

"Death within 30 days was more than three-fold higher in those with atypical symptoms compared to chest pain," she added. "This could be due to treatment delays caused by not receiving the appropriate emergency dispatch. However, it is unknown whether an increase in emergency dispatches alone would improve survival among heart attack patients with atypical symptoms - we aim to investigate this in future research projects."

After reviewing a database of gene mutations in children with autism spectrum disorder (ASD), a team of Medical University of South Carolina (MUSC) researchers decided to study a specific gene mutation that likely caused ASD in a girl. They demonstrated that the mutation was damaging to the gene, and that female, but not male, mice lacking a working copy of the gene also showed ASD-associated symptoms. Better understanding the interplay between genetics and sex in ASD could set the stage for developing sex-specific treatments for autism.

The MUSC team was led by Christopher Cowan, Ph.D., the William E. Murray SmartState Endowed Chair in Neuroscience and chair of the Department of Neuroscience, and Ahlem Assali, Ph.D., research assistant professor in the same department. Their findings are published in Nature Neuropsychopharmacology.

One in 54 children is diagnosed with an ASD. Of the children with ASD, four boys are diagnosed for every girl. Individuals with ASD typically have deficits in communication and social interaction and exhibit restricted, repetitive patterns of behavior, activities, or interests. Many people with ASD also present with associated symptoms, such as hyperactivity, attention deficits, epilepsy and intellectual abilities that can range from severely disabled to gifted.

Cowan and Assali investigated the effect of a mutation in the gene, EPHB2, detected in a female patient with autism. EPHB2 is important for forming connections, or synapses, in the brain. The patient had a version of EPHB2 that caused the protein to be cut short. "It's as if a sentence had a period in the middle instead of the end," said Cowan. The shortened protein can no longer serve its function, leaving this ASD individual with less functional protein than neurotypical people.

To confirm that this gene can cause autism, Cowan and Assali created mice that had only one of two working copies of EPHB2. They found that these animals showed repetitive behaviors, hyperactivity and learning and memory problems as well as changes in brain cell function.

Cowan and Assali went a step further and divided the animals based on sex. They did this because the child with ASD and the EPHB2 mutation was a female. They found that the female mice showed much stronger behavior symptoms and brain cell dysfunction than the male mice. Understanding the interplay between genetics and biological sex could be important for understanding autism risk and eventually for developing therapeutics.

"We know that 80% to 90% of autism risk is genetic, but this is a very clear-cut case where the gene and the sex of the animal are interacting to alter neurotypical development," said Cowan.

Historically, ASD has been diagnosed mostly in boys, so research on ASD has often been biased toward male subjects. The work of Cowan and Assali highlights the importance of sex-specific differences in ASD and the need to examine those differences in research studies that include both sexes. This could set the stage for developing sex-specific treatments for ASD.

"That's the only way we're going to start to change research inequalities that have happened in the past," said Assali.

In future studies, Cowan and Assali hope to explore more deeply the mechanisms of EPHB2 actions in the developing brain. They want to understand why this gene causes symptoms predominantly in female subjects and how hormones might affect autism risk. Their aim is to improve the understanding of the interplay between genetics and biological sex in autism, with a view to informing future personalized, sex-specific treatments for ASD.

A recent study from the University of Helsinki monitors the breakthrough progresses in the development of microneedles for immunotherapy and discusses the challenges regarding their production. Researchers suggest using microneedles for immunotherapy due to the high abundance of immune cells under the skin. The aim is to vaccinate or treat different diseases, such as cancer and autoimmune disorders, with minimal invasiveness and side effects.

"Our study addresses the recent achievements in the development of microneedles for immunotherapy of hard-to-treat and chronic diseases to achieve the highest efficiency with minimal side effects," says Professor Hélder A. Santos, from the University of Helsinki, Faculty of Pharmacy.

As a result of the dynamic nature of the human immune system, the current immunotherapy approaches have mostly been challenged by the lack of adequate long-term responses in patients. On the other hand, the development of microneedles has resulted in the improvement and expansion of immuno-reprogramming strategies since the dermis layer of the skin house a high accumulation of dendritic cells, macrophages, lymphocytes, and mast cells. These cells can transfer generated immunotherapeutic signals to the damaged organs.

According to the paper, microneedles maintain many outstanding properties, such as direct delivery of antibodies, allergens, and therapeutic antigens into the skin, minimal invasiveness, facile fabrication, excellent biocompatibility, convenient administration, and bypassing the first-pass metabolism that allows direct translocation of therapeutics into the systematic circulation. Moreover, transdermal microneedle can improve the biological effect of drugs through adjustable drug release.

Recent advancements of microneedles for immunotherapy of cancer

One of the primary objectives of cancer immunotherapy is the establishment of a broad tumor-targeting T cell repertoire that is able to recognize and destroy heterogeneous tumor cell populations. The paper indicates the suitability of the microneedles for this purpose and their future clinical use, owing to the short treatment time with improvement of patient convenience, and prolonging the overall survival compared to traditional vaccination.

In the case of intramuscular or subcutaneous vaccination, patients might experience stress, fear, pain, and undesirable specific immune responses. In this regard, using microneedles could be a good choice to achieve maximum delivery while limiting side effects. In conclusion, microneedle patches may represent an excellent alternative to conventional cancer vaccine designs by allowing a painless administration in the skin area, which is rich in antigen-presenting cells.

Finally, microneedles can also play a role in improving the efficacy of immune checkpoint inhibitors, allowing for local delivery in the tumor area with a decrease in the immune side effect associated with systemic delivery.

Unanswered challenges and future trends of microneedles for immunotherapeutic applications

According to the researchers, concerns regarding the future success of microneedles for clinical immunotherapy are also dependent on FDA approval for novel biomaterials used in this delivery system for microneedles fabrication.

"In addition, future developments should take into account some of the current challenges, including the difficulty of precise coating of biomolecules on the microneedles and insufficient delivery of therapeutic antigens, allergens, or immunotherapeutic drugs to the desired site," says Professor Santos.

The improvement of the mechanical properties of microneedles is another decisive factor for successful clinical translation and future commercialization. The mechanical characteristics of microneedles must meet two properties to ensure successful immunotherapy. First, the insertion force should be enough to neglect the skin friction force for the insertion of the microneedles before puncturing the skin. Second, the insertion force must be higher than the skin force to perforate the skin and create holes in the epidermis/dermis layer.

Researchers have recently focused on polymer science to fabricate biocompatible or dissolvable polymeric microneedles with minimum side effects. Therefore, it is expected to see a tremendous interest in designing biocompatible and dissolvable microneedle systems in the near future with current advances in polymer science.

"The selection of a suitable material that contributes to the localization of antigen within the microneedles is a substantial issue that needs much attention to optimize immunotherapy of various diseases by microneedles. We estimate that in the near future, we will observe a high interest in the design and fabrication of biocompatible and dissolvable polymeric microneedles systems for immunotherapeutic applications, among others," concludes Professor Santos.

In 2019, Professor Santos' research team, together with the Helsinki Innovation Services, received over 1.3 M€ from Business Finland to further study microneedles for drug delivery applications and their potential to become a commercial product.

There is currently no consensus on what quality end-of-life care for children with cancer looks like, or how to measure and deliver it; however, investigators recently assembled an expert panel to help fill this void. In a study published early online in CANCER, a peer-reviewed journal of the American Cancer Society, the panel endorsed 16 measures that cover different aspects of care that are important for children with cancer and their families.

"Measuring the quality of the care delivered is an essential part of ensuring high quality end-of-life care for all patients. Although there are numerous quality measures for end-of-life care for adults with cancer, there are zero for children with cancer," said lead author Emily Johnston, MD, MS, of the University of Alabama at Birmingham.

To address this, Dr. Johnston and her colleagues selected a panel of individuals with expertise in pediatric and adult oncology, pediatric palliative care, social work, nursing, and hospice care. The investigators provided the panel with information on 20 proposed measures derived from adult measures and from interviews with bereaved parents whose child died of cancer.

After the panel members scored each measure and participated in discussions, they endorsed a set of 16 measures that covered four distinct aspects of care: avoiding medically intensive care at end-of-life; helping families achieve the location of death preferred for their child; advancing hospital policies and procedures for end-of-life care; and expanding supportive services for the child, as well as for parents and siblings.

"This is the first study to identify quality measures for end-of-life care for children with cancer. Some of the measures are similar to those used in adults, like avoiding intubation at the end-of-life, but others are novel, such as assessing sibling needs at end-of-life," said Dr. Johnston. "Therefore, it is essential that we have quality measures specific for children with cancer."

The team noted that the measures need to be refined and validated with bereaved families before they can be applied as a tool to help standardize care. Once validated, these measures may be useful for determining the quality of end-of-life care that different programs provide and for identifying disparities. "For example, they will allow us to determine if Hispanic and Black children with cancer are receiving as high quality end-of-life care as non-Hispanic white children," Dr. Johnston explained. "Once we have identified groups that are at risk of receiving poor quality end-of-life care, we can develop targeted interventions to improve it."

An accompanying editorial notes that the study's results may have implications for improving end-of-life care for adults as well. "This is an exciting time when more research will emerge to move end-of-life care forward in a way that can serve all patients and families better," the authors of the editorial wrote.

A large study from Denmark and Norway published by The BMJ today sheds more light on the risk of rare blood clots in adults receiving their first dose of the Oxford-AstraZeneca covid-19 vaccine.

The findings show slightly increased rates of vein blood clots including clots in the veins of the brain, compared with expected rates in the general population. However, the researchers stress that the risk of such adverse events is considered low.

Cases of rare blood clots in people who have recently received their first dose of the Oxford-AstraZeneca covid-19 vaccine have been reported. Whether these cases represent excess events above expected rates in the general population has, however, been debated.

Both the UK and European medicine regulators say the benefits of the Oxford-AstraZeneca vaccine still outweigh the risks. Denmark and Norway have suspended use of the vaccine and several other countries have opted to suspend its use in certain age groups.

To explore this further, researchers based in Denmark and Norway set out to compare nationwide rates of blood clots and related conditions after vaccination with the Oxford-AstraZeneca vaccine with those in the general populations of the two countries.

Their findings are based on 280,000 people aged 18-65 who received a first dose of the Oxford-AstraZeneca covid-19 vaccine in Denmark and Norway from February 2021 through to 11 March 2021.

Using national health records, they identified rates of events, such as heart attacks, strokes, deep vein blood clots and bleeding events within 28 days of receiving a first vaccine dose and compared these with expected rates in the general populations of Denmark and Norway.

In the main analysis, the researchers found 59 blood clots in the veins compared with 30 expected, corresponding to 11 excess events per 100,000 vaccinations. This included a higher than expected rate of blood clots in the veins of the brain, known as cerebral venous thrombosis (2.5 events per 100,000 vaccinations).

However, they found no increase in the rate of arterial clots, such as heart attacks or strokes.

For most remaining outcomes, results were largely reassuring, with slightly higher rates of less severe events such as thrombocytopenia (a condition related to low blood platelet levels), clotting disorders and bleeding, which they say could be influenced by increased surveillance of vaccine recipients.

This is an observational study, so can't establish cause, only correlation. And the researchers point to some limitations, such as a lack of data on underlying risk factors for clotting and the possibility that their results may not apply to other ethnicities.

However, strengths include the large population based approach, using reliable national registry data and near complete follow-up of participants.

They conclude that "the absolute risks of venous thromboembolic events described in this study are small, and the findings should be interpreted in the context of the benefits of covid-19 vaccination at both the societal and the individual level."

In a linked editorial, BMJ editors Rafael Perera and John Fletcher point out that covid-19 is itself associated with cerebral venous thrombosis and say vaccination remains overwhelmingly the safest option.

"The choice we nearly all face is between eventual SARS CoV2 infection or vaccination. The Astra-Zeneca vaccine is clearly a good choice, despite the likely risks reported in this study," they write.

"Quantifying the comparative risk associated with other vaccines is now a research (and public health) priority," they conclude.

In a linked opinion, Professor Paul Hunter at the University of East Anglia, says this study improves our understanding of the population risk of thrombotic events after the Oxford-AstraZeneca vaccine, but it does not change the conclusions of the UK and European medicine regulators that the benefits of the Oxford-AstraZeneca vaccine far outweigh its risks for most age groups.

"Those countries that delayed their own vaccination programmes at a time of high transmission rates by declining to use available Oxford-AstraZeneca vaccines should know that their decision will have contributed to an increase in the number of avoidable deaths from covid-19," he argues.

Many people with diabetes endure multiple, painful finger pricks each day to measure their blood glucose. Now, researchers reporting in ACS Sensors have developed a device that can measure glucose in sweat with the touch of a fingertip, and then a personalized algorithm provides an accurate estimate of blood glucose levels.

According to the American Diabetes Association, more than 34 million children and adults in the U.S. have diabetes. Although self-monitoring of blood glucose is a critical part of diabetes management, the pain and inconvenience caused by finger-stick blood sampling can keep people from testing as often as they should. Scientists have developed ways to measure glucose in sweat, but because levels of the sugar are much lower than in blood, they can vary with a person's sweat rate and skin properties. As a result, the glucose level in sweat usually doesn't accurately reflect the value in blood. To obtain a more reliable estimate of blood sugar from sweat, Joseph Wang and colleagues wanted to devise a system that could collect sweat from a fingertip, measure glucose and then correct for individual variability.

The researchers made a touch-based sweat glucose sensor with a polyvinyl alcohol hydrogel on top of an electrochemical sensor, which was screen-printed onto a flexible plastic strip. When a volunteer placed their fingertip on the sensor surface for 1 minute, the hydrogel absorbed tiny amounts of sweat. Inside the sensor, glucose in the sweat underwent an enzymatic reaction that resulted in a small electrical current that was detected by a hand-held device. The researchers also measured the volunteers' blood sugar with a standard finger-prick test, and they developed a personalized algorithm that could translate each person's sweat glucose to their blood glucose levels. In tests, the algorithm was more than 95% accurate in predicting blood glucose levels before and after meals. To calibrate the device, a person with diabetes would need a finger prick only once or twice per month. But before the sweat diagnostic can be used to manage diabetes, a large-scale study must be conducted, the researchers say.

A new service piloted at Penn Medicine allowed a proportion of patients to avoid hospitalization by providing them with greater support after visiting the emergency department. The vast majority of the patients enrolled in the service - nearly 9 out of 10 - did not need to return to the hospital for care in the month that followed their initial visit. The study was published in Healthcare.

"The culture is shifting where we realize that hospitalization is not always the best option for patients - particularly patients with chronic illness," said one of the study's lead authors, Austin Kilaru, MD, an emergency physician at Penn Medicine. "We need to find better ways of helping patients not just get healthy in a hospital, but stay healthy at home - whenever they are ready to be there."

Increasingly, emergency departments care for greater shares of patients with acute symptoms and illnesses. Increased visits can lead to strain on hospitals, so Kilaru, co-author David Resnick, a senior innovation manager at Penn Medicine's Center for Health Care Innovation, and their team devised a method to open capacity in emergency departments and hospitals - by sending patients home with the right resources and support to help them recover safely.

The project, which began in 2018 within the Center for Health Care Innovation's annual Innovation Accelerator, was named Practical Alternative to Hospitalization (PATH). It contained two important elements.

First, the PATH team deployed an advanced practice provider (APP) to screen hospital bed requests to determine which patients met criteria for discharge to home. They considered the reasons for the patient's visit, their vital signs, medical history, and social support systems. If the patient's emergency physician agreed with enrolling in PATH, the APP developed a comprehensive plan in partnership with that physician and the patient's care team.

Patients enrolled in the program received personalized support at home. This included phone calls or text messages to assess their status, coordination of outpatient appointments, and additional diagnostic testing. This tailored plan might also include home nursing visits, physical or occupational therapy, or transportation assistance.

"We were concerned that emergency physicians would be reluctant to discharge patients who they would have normally hospitalized, but it turns out that they liked having the option of choosing our services," Kilaru said. "It's a new alternative to staying in the hospital or going home completely on their own. We were seen as an added support, acting in the best interests of patients and medical providers alike."

In this study's 14-day trial period set in a single hospital during December 2019, 52 patients met PATH's eligibility requirements (of 199 possible patients). More than half of them, 30, enrolled in the program, with most of the remainder still requiring hospitalization at the discretion of the treating emergency physician.

Many of the patients enrolled in the program for common conditions, such as chest pain, high blood sugar, and congestive heart failure. The study authors estimate that patients would have spent more than two days, on average, in the hospital and eight additional hours waiting in the emergency department. Only four patients needed to return to the hospital within 30 days of their initial visit, when the PATH team recognized that patients again required hospital-level care.

"Another concern in this pilot was that patients might have worsening illness at home and need to return to the emergency department," Kilaru said. "Fortunately, our patients did well and had good outcomes - even 30 days later. We created careful safeguards to select the right patients, so while a few patients did need to return, it was not unexpected, and we could help communicate key medical and social issues to the emergency department and hospital teams."

The study took place just a few months before the COVID-19 pandemic swept the East Coast. While the service was paused as a result, the pandemic created a surge of interest in shifting care from hospitals to home, like Penn Medicine's Cancer Care at Home. In addition, lessons from this study have been applied to efforts to manage COVID at Penn Medicine, including an "accelerated care pathway," where patients who only needed short hospital stays were identified in the emergency department, efficiently treated in the hospital, and followed closely at home.

"This could be promising for payers, health systems, and patients alike," Resnick said. "Payers benefit by having their members avoid costly inpatient stays. Patients benefit by having more safe days at home. And hospitals with busy emergency departments and full beds benefit by freeing up resources that can be utilized by the most sick and complex patients."

The new Danish-Norwegian study is the first study to document possible adverse events in relation to the COVID-19 vaccine Vaxzevria? from AstraZeneca, in which all vaccine recipients have been followed systematically, as opposed to previous studies, which have relied primarily on reported adverse reactions.

The new study was a cooperation between Danish and Norwegian research institutions.

- In this study, we were able to identify all hospital contacts among vaccinated persons by utilising the unique Danish and Norwegian health registers. This ensures that we get a comprehensive of the rate of adverse reactions. Previous studies have been dependent on spontaneous reporting of adverse events in individual patients, which carries a risk of under-reporting, says Anton Pottegård, who is a professor at the University of Southern Denmark and co-author of the study.

Study results have been continuously disseminated to Danish, Norwegian and international authorities and have already been accounted for in the assessments that have been made. Therefore, it is not expected that the publication of the study results will prompt new assessments by regulators.

The researchers behind the study stress that their findings do not conflict with the European Medicines Agency's (EMA) assessment that the vaccine is generally safe. The effects of the vaccine should be seen in the light of the benefits of using the vaccine, which protects against a potentially fatal infection. Depending on how severely affected the individual countries are by the epidemic, the benefits will therefore in many situations outweigh the risks of using the vaccine.

- The balancing of effects and risks of the vaccine depends on many factors. In many countries, for example those where there are no other vaccines available, where the elderly are not fully vaccinated or where there is a large spread of infection, the benefits of the vaccine will outweigh the risk, both at a societal level and for the individual vaccine recipient, says Anton Pottegård.

Systematic study of 280,000 vaccinated people aged 18-65

The study is based on data from the reputable Danish and Norwegian health registries, which allowed for systematic follow-up of all 280,000 vaccinated people aged 18-65 who have received Vaxzevria? in Norway and Denmark. The recipients of the vaccine were followed for 28 days after vaccination regarding hospital contacts in relation to a number of conditions and disorders that could represent adverse events. The incidence of these conditions and disorders was compared with the incidence in the background population.

The study is generally reassuring as researchers have not found an increased incidence for most of the studied adverse events. However, they identified an increased incidence of blood clots in the veins (venous blood clots), including a slightly increased incidence of blood clots in the veins of the brain, corresponding to one additional such clot per 40,000 vaccine recipients.

These rare blood clots in combination with low platelet counts are referred to as the VITT syndrome. The occurrence of VITT after receiving the AstraZeneca vaccine has led to the removal of the vaccine from the Danish and Norwegian vaccination programmes against COVID-19.

The absolute risk to the individual vaccine recipient is still considered to be low.