Body

Researchers at the German Center for Neurodegenerative Diseases (DZNE) and Charité - Universitätsmedizin Berlin have identified highly effective antibodies against the coronavirus SARS-CoV-2 and are now pursuing the development of a passive vaccination. In this process, they have also discovered that some SARS-CoV-2 antibodies bind to tissue samples from various organs, which could potentially trigger undesired side effects. They report their findings in the scientific journal "Cell".

Initially, the scientists isolated almost 600 different antibodies from the blood of individuals who had overcome COVID-19, the disease triggered by SARS-CoV-2. By means of laboratory tests, they were able to narrow this number down to a few antibodies that were particularly effective at binding to the virus. Next, they produced these antibodies artificially using cell cultures. The identified so-called neutralizing antibodies bind to the virus, as crystallographic analysis reveals, and thus prevent the pathogen from entering cells and reproducing. In addition, virus recognition by antibodies helps immune cells to eliminate the pathogen. Studies in hamsters - which, like humans, are susceptible to infection by SARS-CoV-2 - confirmed the high efficacy of the selected antibodies: "If the antibodies were given after an infection, the hamsters developed mild disease symptoms at most. If the antibodies were applied preventively - before infection - the animals did not get sick," said Dr. Jakob Kreye, coordinator of the current research project. The DZNE scientist is one of the two first authors of the current publication.

Antibodies for passive vaccination

Treating infectious diseases with antibodies has a long history. For COVID-19, this approach is also being investigated through the administration of plasma derived from the blood of recovered patients. With the plasma, antibodies of donors are transferred. "Ideally, the most effective antibody is produced in a controlled manner on an industrial scale and in constant quality. This is the goal we are pursuing," said Dr. Momsen Reincke, also first author of the current publication.

"Three of our antibodies are particularly promising for clinical development," explained Prof. Dr. Harald Prüss, a research group leader at the DZNE and also a senior physician at the Clinic for Neurology with Experimental Neurology at Charité - Universitätsmedizin Berlin. "Using these antibodies, we have started to develop a passive vaccination against SARS-CoV-2." Such a project requires cooperation with industrial partners. That is why the scientists are collaborating with Miltenyi Biotec.

In addition to the treatment of patients, preventive protection of healthy individuals who have had contact with infected persons is also a potential application. How long the protection lasts will have to be investigated in clinical studies. "This is because, unlike in active vaccination, passive vaccination involves the administration of ready-made antibodies, which are degraded after some time," Prof. Prüss said. In general, the protection provided by a passive vaccination is less persistent than that provided by an active vaccination. However, the effect of a passive vaccination is almost immediate, whereas with an active vaccination it has to build up first. "It would be best if both options were available so that a flexible response could be made depending on the situation."

Modern technologies

Kreye, Reincke, Prüss and colleagues usually deal with autoimmune diseases of the brain, in which antibodies erroneously attack neurons. "In the face of the COVID-19 pandemic, however, it was obvious to use our resources also in other ways," said Prof. Prüss. For the current project, the researchers benefit from a project funded by the Helmholtz Association: the "BaoBab Innovation Lab". Within this framework, they are developing and refining technologies for the characterization and production of antibodies, which they are now applying. "Now, we are working with our industrial partner to establish the conditions that will allow for the most effective large-scale production of the antibodies we have identified," said Prüss. "The next step is clinical trials, that is testing in humans. However, this can not be expected before the end of this year at the earliest. The planning for this has already started."

Potential side effects

During their investigations, the researchers made a further discovery: some of the particularly effective antibodies against the coronavirus specifically attached to proteins of the brain, heart muscle and blood vessels. In tests with tissue samples from mice, several of the neutralizing antibodies exhibited such a cross-reactivity. Thus, they were excluded from the development of a passive vaccination. "These antibodies bind not only to the virus, but also to proteins in the body that have nothing to do with the virus. Future research is needed to analyse whether the associated tissues could potentially become targets of attacks by the own immune system," said Prof. Prüss. Whether these laboratory findings are relevant for humans cannot be predicted at present. "On the one hand, we need to be vigilant in order to detect any autoimmune reactions that may occur in the context of COVID-19 and vaccinations at an early stage. On the other hand, these findings can contribute to ensure the development of an even safer vaccine," the scientist said.

Small particles can have an angular momentum that points in a certain direction - the spin. This spin can be manipulated by a magnetic field. This principle, for example, is the basic idea behind magnetic resonance imaging as used in hospitals. An international research team has now discovered a surprising effect in a system that is particularly well suited for processing quantum information: the spins of phosphorus atoms in a piece of silicon, coupled to a microwave resonator. If these spins are cleverly excited with microwave pulses, a so-called spin echo signal can be detected after a certain time - the injected pulse signal is re-emitted as a quantum echo. Surprisingly, this spin echo does not occur only once, but a whole series of echoes can be detected. This opens up new possibilities of how information can be processed with quantum systems.

The experiments were carried out at the Walther-Meissner-Institute in Garching by researchers from the Bavarian Academy of Sciences and Humanities and the Technical University of Munich, the theoretical explanation was developed at TU Wien (Vienna). Now the joint work has been published in the journal "Physical Review Letters".

The echo of quantum spins

"Spin echoes have been known for a long time, this is nothing unusual", says Prof. Stefan Rotter from TU Wien (Vienna). First, a magnetic field is used to make sure that the spins of many atoms point in the same magnetic direction. Then the atoms are irradiated with an electromagnetic pulse, and suddenly their spins begin to change direction.

However, the atoms are embedded in slightly different environments. It is therefore possible that slightly different forces act on their spins. "As a result, the spin does not change at the same speed for all atoms," explains Dr. Hans Hübl from the Bavarian Academy of Sciences and Humanities. "Some particles change their spin direction faster than others, and soon you have a wild jumble of spins with completely different orientations".

But it is possible to rewind this apparent chaos - with the help of another electromagnetic pulse. A suitable pulse can reverse the previous spin rotation so that the spins all come together again. "You can imagine it's a bit like running a marathon," says Stefan Rotter. "At the start signal, all the runners are still together. As some runners are faster than others, the field of runners is pulled further and further apart over time. However, if all runners were now given the signal to return to the start, all runners would return to the start at about the same time, although faster runners have to cover a longer distance back than slower ones."

In the case of spins, this means that at a certain point in time all particles have exactly the same spin direction again - and this is called the "spin echo". "Based on our experience in this field, we had already expected to be able to measure a spin echo in our experiments," says Hans Hübl. "The remarkable thing is that we were not only able to measure a single echo, but a series of several echoes."

The spin that influences itself

At first, it was unclear how this novel effect comes about. But a detailed theoretical analysis now made it possible to understand the phenomenon: It is due to the strong coupling between the two components of the experiment - the spins and the photons in a microwave resonator, an electrical circuit in which microwaves can only exist at certain wavelengths. "This coupling is the essence of our experiment: You can store information in the spins, and with the help of the microwave photons in the resonator you can modify it or read it out," says Hans Hübl.

The strong coupling between the atomic spins and the microwave resonator is also responsible for the multiple echoes: If the spins of the atoms all point in the same direction in the first echo, this produces an electromagnetic signal. "Thanks to the coupling to the microwave resonator, this signal acts back on the spins, and this leads to another echo - and on and on," explains Stefan Rotter. "The spins themselves cause the electromagnetic pulse, which is responsible for the next echo."

The physics of the spin echo has great significance for technical applications - it is an important basic principle behind magnetic resonance imaging. The new possibilities offered by the multiple echo, such as the processing of quantum information, will now be examined in more detail. "For sure, multiple echos in spin ensembles coupled strongly to the photons of a resonator are an exciting new tool. It will not only find useful applications in quantum information technology, but also in spin-based spectroscopy methods", says Rudolf Gross, co-author and director of the Walther-Meissner-Institute.

Researchers at The University of Texas at Dallas have examined how manufacturers are -- or aren't -- pivoting successfully in response to major manufacturing disruptions as a consequence of the COVID-19 pandemic.

In a study published July 27 in IEEE Engineering Management Review, two faculty members from the Naveen Jindal School of Management found that manufacturing response to the disruption has been largely reactive and uncoordinated, and many firms' crisis communication plans do not include managing an infectious-disease outbreak.

The researchers identified the supporting enablers and competing barriers of manufacturing repurposing within the context of disruption caused by COVID-19. The article offers practitioners and policymakers best practices for pivoting successfully.

"The research was an eye-opener in terms of understanding the challenges for manufacturers in dealing with such an abrupt, massive disruption," said Dr. Ramesh Subramoniam, clinical associate professor of operations management and one of the paper's co-authors.

"The COVID-19 pandemic brought everything to a standstill. Even before that, supply chain disruption frequency had increased in recent years. Establishing a resilient framework to meet such supply chain disruptions is the immediate need for practitioners," he said.

Because of the extensive scope of disruption distributed across countries and industries, pandemics are different from typical disruptions, which are generally focused on specific industries or products, Subramoniam said.

According to the International Labour Organization, approximately 47 million employers, representing some 54% of all employers worldwide, operate businesses in the sectors hardest hit by COVID-19: manufacturing, accommodation and food services, wholesale and retail trade, and real estate, business and administrative activities.

Manufacturing is expected to be one of the most severely affected sectors in terms of the negative economic impact, said Dr. David Widdifield, a co-author of the paper, clinical associate professor of operations management and director of the Master of Science in Supply Chain Management program.

"A sudden disruption, such as the pandemic, opened up questions on the critical need for companies to reevaluate their existing supply chain risk mitigation strategies -- this includes the sectors of manufacturing responsible for the mass production of personal protection equipment (PPE) for health care workers," said Widdifield, who also serves as assistant dean of graduate programs in the Jindal School.

The researchers surveyed employees of manufacturing firms. Completed between June and July 2020, the study assessed online responses from 71 manufacturing practitioners across 39 facilities and six continents.

Some companies supplied critical equipment and devices needed by the public and health care workers, oftentimes exploring new technologies.

Others found "repurposing and pivoting" -- the process of manufacturers rapidly switching to a new product or process -- more challenging. Manufacturing repurposing includes adapting production plans, lines and capabilities to meet new demand goals.

"The research shows a lack of capability among some manufacturers to deal with the increased demand for new products, such as medical devices, while other manufacturers have the ability to pivot to a new normal," Widdifield said. "The study also brings forward the impact of digital technologies such as 3D printing, artificial intelligence and machine learning, and how they prime organizations to respond faster and be more resilient to such rapid disruptions in the future."

The study found:

-Almost all the organizations (94%) were operational during the peak of the pandemic. Of those, 56% were at full operations capacity, and 44% were at partial capacity.

-Multiple manufacturing firms repurposed during the pandemic. Target products included respirators and their components, medical PPE and hand sanitizers.

-Repurposing was less likely and did not occur for several product families, including mobile X-rays, surgical gloves, screening test kits and other diagnostic equipment.

-Despite the increasing number of disruptions caused by epidemics, natural disasters and other large-scale regional and global events, many firms' crisis communication plans do not specifically include managing an infectious-disease outbreak.

The research also has implications for consumers, Subramoniam said. Companies were tested on how well they took care of their employees during the pandemic.

"The average consumer should look at how companies responded to the pandemic in treating them, their friends and relatives," he said. "These are very strong indications of an organizational culture and capability. Future employees want to work for such companies with a strong culture of product and process innovation and growth, with the employees as the core asset."

September 24, 2020 - Nearly all women have breasts that are slightly different from each other. However, some women have more marked differences in the size, shape, or position of the breasts even after development is complete - leading to negative effects on emotional well-being and self-image.

For young women with such severe breast asymmetry, surgery to create a more even appearance of the breasts has significant benefits in terms of self-esteem, quality of life and mental health, according to a new study by Brian I. Labow, MD, FACS, FAAP, and colleagues of Boston Children's Hospital.

"Surgical treatment of breast asymmetry in young women yields significant and sustained improvements in psychosocial quality of life," the researchers write. Their study - one of the first to analyze the benefits of surgery for benign breast asymmetry - appears in the October issue of Plastic and Reconstructive Surgery®, the official medical journal of the American Society of Plastic Surgeons (ASPS).

Dr. Labow and colleagues report on their experience with surgery to correct breast asymmetry in 45 young women, average age 18 years, between 2008 and 2018. All of the women had severe asymmetry, averaging two cup sizes difference between breasts. In all cases, the breast asymmetry was "benign" - not due to cancer.

Almost 70 percent of the women had "hypoplastic" breast asymmetry, with underdevelopment of one or both breasts; the rest had macromastia (excessively large breasts) on one side. Some patients were diagnosed with conditions such as tuberous breast deformity (breasts with a narrow base), while others had no formal diagnosis for their breast asymmetry.

For 28 patients, surgery consisted of breast augmentation on one or both sides. Fourteen patients underwent breast reduction on one side, sometimes with other procedures on the opposite breast. The remaining three patients underwent a combination or these or other procedures.

Before surgery, the women had significant reductions in self-esteem and in various aspects of quality of life compared to their peers - particularly social functioning (limitations in social activities due to physical or emotional problems) and emotional roles (limitations in usual activities due to emotional problems).

At follow-up 3.5 years later after surgery, the women had significant improvements in self-esteem, social functioning, and emotional roles, as well as in overall mental health. "Postoperatively, patients returned to a level of functioning commensurate with their peers," Dr. Labow and coauthors write.

Minor differences between breasts are common, especially during the early stages of breast development. All too often, breast asymmetry in adolescents and young women is dismissed as "simply a cosmetic concern." The researchers note that surgery isn't the only answer: some patients are reassured by hearing that breast asymmetry is common. In others, breast prostheses can help to camouflage the asymmetry and improve social functioning.

Dr. Labow and colleagues hope their experience will help to make plastic surgeons more aware of the positive outcomes of surgical correction in women who are bothered by severe breast asymmetry. The authors conclude: "Providers should be aware of the potential positive impact that surgical treatment can provide developmentally and psychologically mature young women with symptomatic asymmetry and consider surgery when non-surgical options fail."

In mid-April 2020, the national unemployment rate reached 14.7 percent - the highest since the Great Depression. Forty-one million American workers filed for unemployment between February and May of 2020.

Unprecedented unemployment rates don't just have an impact on the unemployed, though. For people still employed during the COVID-19 pandemic, job insecurity and financial concern are associated with greater symptoms of depression and anxiety, according to findings from the UConn School of Nursing published recently in the Journal of Occupational and Environmental Medicine, or JOEM.

"The impact the virus and the pandemic is having on the economy and employment is not surprisingly taking a big toll," says Natalie J. Shook, a social psychologist, associate professor in the School of Nursing, and principal investigator for the study.

The findings are part of a year-long examination of how behavior and social attitudes change, and what factors influence those changes, when people in the United States are faced with the threat of widespread disease. Supported by a National Science Foundation grant, the study is tracking the well-being, feelings, and behavioral practices of about 1,000 individuals across the United States, and more than 18 surveys of the participants have already been conducted since March.

"We definitely are seeing, within our employed participants, higher rates of anxiety than in individuals who indicated they were not employed," says Shook, noting that most study participants who are not employed are retirees. "Controlling for demographics, controlling for income level, and also taking into account participant health and concerns about COVID - and the extent to which people were engaging in social distancing or quarantine - we are seeing that job security and financial concerns are the significant predictors associated with anxiety and depression."

The study asked participants to identify symptoms of anxiety by asking if they were feeling nervous, anxious, or on edge, or if they were not able to stop or control their worrying. They were also asked about the extent of their financial concerns - how worried they were about their employment and financial situation, if they expected their financial situation to get worse over the next 12 months, and if they had the means to secure food and housing for their family for the next 12 months.

Most study participants reported some level of worry about the effects of COVID-19 on their employment. While previous studies have linked large-scale disruptions like recessions and pandemics with poor mental health, the researchers note that their study importantly expands on these associations by demonstrating independent links between greater financial concern with greater anxiety symptoms, and greater job insecurity with greater depressive symptoms, after accounting for demographics, health, and other COVID-19 concerns and experiences.

Shook and her research team say employers can play a critical role in supporting the mental health of their employees by recognizing the increased anxiety that workers experience when their job security feels threatened during the pandemic.

"Our results demonstrate the potential adverse consequences that job insecurity and financial concern have on employee mental health," the researchers write. "Based on these findings, for those experiencing depressive symptoms during the pandemic, it may be particularly important for employers to be mindful and try to minimize feelings of uncertainty for the employees, as well as instilling hope or agency in employees. For those experiencing anxiety symptoms, employers could attempt to reduce financial concerns by allowing employees to continue to work (eg, telework), even with reduced hours and income, to ensure that employees do not lose their entire income."

September 24, 2020 - "Can you draw me a picture of your headache?" may sound like an unusual question - but drawings of headache pain provide plastic surgeons with valuable information on which patients are more or less likely to benefit from surgery to alleviate migraine headaches.

Patients with more "typical" patterns on pain sketches have larger reductions in headache scores after migraine "trigger site" surgery, suggests a new study by Lisa Gfrerer, MD PhD and William Gerald Austen, Jr., MD, and colleagues of Harvard Medical School. The study appears in the October issue of Plastic and Reconstructive Surgery®, the official medical journal of the American Society of Plastic Surgeons (ASPS).

Migraine surgery has become an established treatment alternative for some patients with intractable migraine headaches. Developed by plastic surgeons who noticed that some migraine patients had fewer headaches after cosmetic forehead-lift, migraine surgery targets specific trigger sites linked to certain headache patterns. More than 5,200 patients underwent migraine peripheral trigger site surgery in 2019, according to ASPS statistics.

However, it can be difficult to predict which patients will get good results from migraine surgery. Drs. Gfrerer, Austen and colleagues have noticed that there are "pathognomic" pain patterns for each trigger site. "In our experience, a valuable method to visualize pain/trigger sites is to ask patients to draw their pain," the researchers write. In the new study, they analyzed how well the patterns on these pain drawings predict the outcomes of migraine surgery.

The study included 106 patients who made pain sketches as part of their evaluation for migraine surgery. The sketches were reviewed by experienced researchers who were unaware of the patients' headache symptoms or other characteristics, and classified into three groups:

Typical - showing pain originating from and spreading along the expected path of a specific nerve (59 percent of sketches)

Intermediate - showing pain along the path of the nerve, but with an atypical spread (radiation) of pain (29 percent)

Atypical - pain originating and radiating outside of the expected nerve distribution (12 percent)

One year after surgery, outcomes were assessed using a standard score, the Migraine Headache Index (MHI). Patients with typical or intermediate patterns on their pain drawings had similarly good outcomes: MHI scores improved by 73 and 78 percent, respectively.

However, for patients with atypical pain sketches the results were not as good: only 30 percent improvement in MHI score. Just one-fifth of patients in the atypical group had more than 30 percent improvement after migraine surgery.

The researchers emphasize that pain drawings should be just one part of the standard patient assessment. Migraine patients with atypical pain drawings may still have "compelling reasons" for surgery but should understand that they have lower chances of a positive outcome.

As migraine surgery becomes more widely used, pain sketches could be one way to target those patients most likely to have good outcomes. Drs Gfrerer, Austen and coauthors conclude: "As we continue to develop algorithms to select patients for migraine surgery, patient drawings should be considered as an effective, cheap, and simple-to-interpret tool to select candidates for surgery."

In 1997, the very first Neandertal DNA sequence - just a small part of the mitochondrial genome - was determined from an individual discovered in the Neander Valley, Germany, in 1856. Since then, improvements in molecular techniques have enabled scientists at the Max Planck Institute for Evolutionary Anthropology to determine high quality sequences of the autosomal genomes of several Neandertals, and led to the discovery of an entirely new group of extinct humans, the Denisovans, who were relatives of the Neandertals in Asia.

However, because all specimens well-preserved enough to yield sufficient amounts of DNA have been from female individuals, comprehensive studies of the Y chromosomes of Neandertals and Denisovans have not yet been possible. Unlike the rest of the autosomal genome, which represents a rich tapestry of thousands of genealogies of any individual's ancestors, Y chromosomes have a peculiar mode of inheritance - they are passed exclusively from father to son. Y chromosomes, and also the maternally-inherited mitochondrial DNA, have been extremely valuable for studying human history.

New method to identify Y chromosome molecules

In this study, the researchers identified three male Neandertals and two Denisovans that were potentially suitable for DNA analysis, and developed an approach to fish out human Y chromosome molecules from the large amounts of microbial DNA that typically contaminate ancient bones and teeth. This allowed them to reconstruct the Y chromosome sequences of these individuals, which would not have been possible using conventional approaches.

By comparing the archaic human Y chromosomes to each other and to the Y chromosomes of people living today, the team found that Neandertal and modern human Y chromosomes are more similar to one another than they are to Denisovan Y chromosomes. "This was quite a surprise to us. We know from studying their autosomal DNA that Neandertals and Denisovans were closely related and that humans living today are their more distant evolutionary cousins. Before we first looked at the data, we expected that their Y chromosomes would show a similar picture," says Martin Petr, the lead author of the study. The researchers also calculated that the most recent common ancestor of Neandertal and modern human Y chromosomes lived around 370,000 years ago, much more recently than previously thought.

It is by now well established that all people with non-African ancestry carry a small amount of Neandertal DNA as a result of interbreeding between Neandertals and modern humans approximately 50,000-70,000 years ago, quite shortly after modern humans migrated out of Africa and started spreading around the world. However, whether Neandertals might also carry some modern human DNA has been a matter of some debate.

These Y chromosome sequences now provide new evidence that Neandertals and early modern humans met and exchanged genes before the major out of Africa migration - potentially as early as 370,000 years ago and certainly more than 100,000 years ago. This implies that some population closely related to early modern humans must already have been in Eurasia at that time. Surprisingly, this interbreeding resulted in the replacement of the original Neandertal Y chromosomes with those of early modern humans, a pattern similar to what has been seen for Neandertal mitochondrial DNA in an earlier study.

Selection for Y chromosomes from early modern humans

At first, the complete replacement of both Y chromosomes and mtDNA of early Neandertals was puzzling, as such replacement events are quite unlikely to occur by chance alone. However, the researchers used computer simulations to show that the known small size of Neandertal populations may have led to an accumulation of deleterious mutations in their Y chromosomes which would reduce their evolutionary fitness. This is quite similar to situations where extremely small population sizes and inbreeding can sometimes increase the incidence of some diseases. "We speculate that given the important role of the Y chromosome in reproduction and fertility, the lower evolutionary fitness of Neandertal Y chromosomes might have caused natural selection to favor the Y chromosomes from early modern humans, eventually leading to their replacement" says Martin Petr.

Janet Kelso, the senior author of the study, is optimistic that this replacement hypothesis could be tested in the near future: "If we can retrieve Y chromosome sequences from Neandertals that lived prior to this hypothesized early introgression event, such as the 430,000 year old Neandertals from Sima de los Huesos in Spain, we predict that they would still have the original Neandertal Y chromosome and will therefore be more similar to Denisovans than to modern humans."

A new study led by a cardiologist from Brigham and Women's Hospital has assessed the cardiovascular and renal outcomes for ertugliflozin, an SGLT2 inhibitor prescribed for patients with type 2 diabetes to help them control blood sugar levels. The Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes Trial (VERTIS CV) found that the drug had a safety profile similar to that of other SGLT2 inhibitors and did not increase risk of major adverse events compared to the placebo. The results did not show a statistically significant benefit, but, taken together with other recent studies of SGLT2 inhibitors, the study results add to a growing body of evidence that supports guidelines for using this class of drugs to help prevent adverse cardiovascular outcomes. The findings of their study were published in the New England Journal of Medicine.

"This class of medications has turned out to be a huge win for patients with benefits beyond blood glucose control," said Christopher Cannon, MD, a cardiologist at the Brigham. "Originally, the Food and Drug Administration had requested analyses of the safety of these medications, but studies have found that rather than causing harm, SGLT2 inhibitors show beneficial effects, lowering risk of adverse cardiovascular and renal outcomes."

Type 2 diabetes can lead to heart failure hospitalization and renal disease progression, with adult type 2 diabetic patients and their clinicians often navigating cardiovascular and renal concerns while working to control blood sugar levels. Recent studies of other SGLT2 inhibitors have found that they may provide a benefit to both renal and cardiovascular health.

VERTIS-CV relied on an event-driven, noninferiority structure, which was revised in the wake of a positive trial involving another drug in the class. In light of the positive outcomes of that EMPA-REG trial, the VERTIS-CV team doubled its sample size and reduced the time left in the trial from five years to an average of three years. Of the 8,238 patients enrolled in the trial, the average age was 64.4 and average length of type 2 diabetes diagnosis was 13 years.

Previous studies have established ertugliflozin as an effective medication for controlling blood sugar levels. VERTIS-CV assessed the drug's cardiovascular safety. Among patients with type 2 diabetes and atherosclerotic cardiovascular disease, ertugliflozin was non-inferior to placebo for the composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke -- an endpoint known as MACE. Overall, major adverse cardiovascular outcomes occurred in about 12 percent of patients in both the ertugliflozin and placebo groups. A combination of both cardiovascular death or hospitalization for heart failure occurred in about 8 percent and 9 percent in the ertugliflozin and placebo groups, respectively. A secondary endpoint of hospitalization for heart failure showed a 30 percent lower rate with ertugliflozin.

Ertugliflozin is the fourth drug in this class to be tested on such a large scale and demonstrate noninferiority against a placebo. The three other major SGLT2 drug trials -- testing dapagliflozin, canagliflozin, and empagliflozin -- produced significant benefits across different endpoints.

The American Diabetes Association guidelines established in 2019 recommend the use of SGLT2 inhibitors such as ertugliflozin in type 2 diabetes patients as an additional agent for lowering blood sugar and for lowering risk of cardiovascular and renal events in patients predisposed to these complications. Cannon describes his team's results as supportive of these guidelines.

"The guidelines, if anything, were a little bit ahead of their time and are spot on," said Cannon.

"These data reaffirm the guidelines, and now it's on us as clinicians to more completely follow the guidelines."

Researchers in the University of São Paulo’s School of Physical Education and Sports (EEFE-USP) in Brazil compared the effect of two widely used classes of anti-hypertensive drugs on post-exercise hypotension, an expected and beneficial fall in blood pressure after a session of aerobic exercise, especially in the late afternoon or early evening.

According to the researchers, the findings of their study can help health professionals choose the most beneficial time of day for patients to undergo physical therapy depending on the type of drug used to treat their high blood pressure.

The strategy could be particularly advantageous for patients who do not respond well to treatment with medication. “People with resistant hypertension, who take three or more types of drug, preferably including a diuretic, or four drugs or even more, without achieving the desired level of control may benefit by switching their exercise session to late in the day, subject to confirmation by further research,” said Leandro Campos de Brito, a postdoctoral researcher at EEFE-USP’s Exercise Hemodynamics Laboratory with a scholarship from FAPESP. Brito’s research supervisor is Professor Cláudia Lúcia de Moraes Forjaz. 

In this study, which was supported by FAPESP, the researchers compared the effect of angiotensin-2 receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs) on patients who performed morning and evening exercise sessions.

Post-exercise blood pressure fell 11 millimeters of mercury (mmHg) in the evening and 6 mmHg in the morning on average in the group that took ARBs, and 6 mmHg and 8 mmHg respectively in the group that took ACEIs. Thus there was a difference of almost 50% in the evening values, while the morning values showed a similar drop for both groups.

The findings are published in the journal Clinical and Experimental Hypertension.

“Our hypothesis was that ACEIs attenuate post-exercise hypotension, especially in the evening,” Brito said. “Our observation was that ACEIs did indeed attenuate the expected hypotensive effect of exercise in the evening, while ARBs did not.” 

The researchers reached this conclusion after submitting 29 men treated for high blood pressure with either ACEIs or ARBs for at least four months to two maximal cardiopulmonary exercise tests using a stationary ergometer exercise bicycle with increments of 15 watts per minute until they were unable to continue. The sessions took place from 7 am to 9 am and from 8 pm to 10 pm on two different days with an interval of three to seven days between sessions. The order of execution was randomly determined, and the evaluators did not know which type of drug each volunteer was taking. Blood pressure was measured in the pre-exercise period and in the post-exercise period after 30 minutes of recovery. 

Differences between ACEIs and ARBs 

ACEIs and ARBs act on the same hypertension pathway by regulating angiotensin-2, a hormone that causes vasoconstriction (contracts the blood vessels) and raises blood pressure. The mechanisms are different, however. “Think of two freeways running alongside each other,” Brito said. ARBs block angiotensin-2 receptors in blood vessels. ACEIs inhibit the enzyme responsible for converting angiotensin-1 into angiotensin-2. 

“The one permits angiotensin-2’s natural behavior in 24 hours but blocks its action. The other inhibits that behavior. In addition, by inhibiting this enzyme ACEIs chronically favor a different pathway that generates bradykinin and angiotensin-(1-7), both of which are vasodilators. Given that vasodilation has already been facilitated by the drug, this could reduce the vasodilatory effect of aerobic exercise, the main driver of the fall in blood pressure when the exercise training is performed in the evening,” Brito said.

For this very reason, this drug class was expected to attenuate post-exercise hypotension, especially in the evening. The study did not set out to investigate the mechanism that causes the difference. 

Influence of time of day

The study was part of Brito’s PhD research to estimate the effect of ten weeks of aerobic training at different times of day, concluding that the results were best in the evening. “In this study, we compared subjects treated with drugs for high blood pressure who performed exercise in the morning and others who trained in the evening,” Brito said.

Researchers have increasingly discovered significant variations depending on the time of day. “Our organism is guided by the circadian cycle, and blood pressure is no exception. The mechanisms that lower BP are more active in the evening to prepare us for rest, while those that raise it are more active in the morning when we wake up,” Brito explained. “In other words, our theory is that the evening is a window of opportunity to achieve significant reductions.” 

Effects can be long-lasting

Anyone who does aerobic exercise should experience some degree of hypotension afterwards, but in people with high blood pressure, the drop is more significant. “Systolic pressure falls by 5 to 10 mmHg on average, and diastolic pressure by 4 to 6 mmHg, without negative symptoms such as nausea, lightheadedness or blurred vision,” Brito said. 

One exercise session is sufficient to produce a degree of cardiovascular protection, as studies have shown that the reduction can last all day. “Moreover, some research groups believe each exercise session acts like one brick in a wall in the sense that training has a chronic beneficial effect,” he said. 

In 2018, Brito and colleagues published a review article favoring this hypothesis in the Journal of the American Society of Hypertension. 

Practical application

One of the strengths of this latest study is that the participants had been taking the medications for some time and the researchers were able to analyze the data in the patients’ usual clinical context. “Other studies along these lines follow the ‘washout’ model, in which the patient is required to stop taking the medication for a period,” Brito said.

Another positive point is that the scientists who measured the participants’ blood pressure after the exercise sessions did not know which drug they were taking. This enhances the study’s credibility and favors the practical application of its findings.

BOSTON -Many people are feeling anxious during these uncertain times as they navigate the risks associated with COVID-19 and experience the tension from physical distancing or isolation for what can seem like an eternity. But people of Asian ancestry face yet another set of challenges posed by racism and xenophobia which has soared during the COVID-19 pandemic amidst rumors and blame placed on China.

This pandemic-driven rise in anti-Asian racism is so pronounced, that in a commentary recently published in the American Journal of Public Health, psychiatrist Justin A. Chen, MD, MPH, and his coauthors have described it as a "secondary contagion" threatening this population.

Chen is an investigator in the Department of Psychiatry at Massachusetts General Hospital (MGH) and an assistant professor at Harvard Medical School. In addition, he serves as executive director and co-founder of the MGH Center for Cross Cultural Student Emotional Wellness. He is lead author on the commentary, and his co-authors are Emily Zhang Counseling Psychology PhD candidate at Boston College Lynch School of Education and Human Development and Cindy H. Liu, director of the Developmental Risk and Cultural Resilience Program within Pediatric Newborn Medicine and Psychiatry at Brigham and Women's Hospital.

The United States, the authors report, is no exception to this trend toward an uptick in anti-Asian racism during the pandemic. In the U.S., Asians share a long and well-documented history of discrimination and have been the frequent targets of both interpersonal and structural persecution. Asians of all ethnicities have been scapegoated, verbally attacked with racial slurs, coughed at, spat on, physically assaulted and more.

Observers may consider such acts as just small slights or brief episodes that can be shrugged off. But there is strong evidence that they can have much more serious effects than most people realize, especially on people who are already vulnerable.

In their commentary, Chen and his collaborators provide an overview of the history of anti-Asian discrimination in the United States, reviewing associations between discrimination and health, describing the associated public health implications of the COVID-19 pandemic and reviewing evidence from previous disasters in U.S. history that were "racialized."

The scope of the problem is large and growing. Asian Americans comprise just 5.6 percent of the US population. However, they are the fastest-growing racial/ethnic group in the country, with a 72 percent increase from 2001 to 2015, and are projected to become the largest immigrant group by 2055.

"Prior to the pandemic, Asians were often held up as the 'model minority' who were always successful and excelled at academics," explains Chen. This seemingly positive stereotype comes with its own set of problems, including overlooking differences between different Asian ethnicities and added pressure for Asian American youths to conform to a certain ideal of success and hide their challenges. But since COVID-19 swept across the world and news spread that the virus had originated in China, stereotyping of Asians has assumed a more negative tone, resulting in increasing racism, suspicion, xenophobia, bullying and even more aggressive behavior.

Stop AAPI Hate, a U.S.-based Web site created in March 2020 to track attacks against Asian Americans, received 1135 reports nationwide within the first two weeks of launching. Moreover, the FBI has warned of increased hate crimes against Asian Americans. The cumulative burden of these incidents, along with their coverage in the media, has the potential to exert significant negative health effects.

That trend is starting to be more widely appreciated, Chen says. For example, two recent reports released by the two groups Stop AAPI Hate and Stop Asian Americans and Pacific Islanders (AAPI) Hate Youth Campaign, both looked at the impact of racism and xenophobia against Asian-American youth during the COVID-19 pandemic.

The report They Blamed Me Because I Am Asian, was written and analyzed by the Stop AAPI youth campaign -- a group of 87 high school interns--and based on nearly 1,000 interviews they conducted with AAPI youth over the summer. The Stop AAPI Hate report, meanwhile, was written by experts who analyzed 341 incidents of anti-Asian discrimination involving youth reported to the Stop AAPI Hate reporting center from March 19 - July 22, 2020.

Findings from the 990 interviews in They Blamed Me Because I Am Asian show that eight out of 10 Asian American youth (77 percent) expressed anger over the current anti Asian hate in this nation, and six out of 10 (60 percent) are disappointed over the racism. Incidents of harassment focused on blaming China and Chinese people as the source of the virus and on mocking Chinese dietary habits, such as the consumption of bats.

Chen emphasizes that not all the news is bad. Positive developments include the emergence of mechanisms for reporting and tracking incidents of racial bias, increased awareness of racism's insidious harms and subsequent civic and political engagement by the Asian American community, and further research into resilience-promoting factors that can reduce the negative health effects of racism.

In an impressive proof-of-concept demonstration, an interdisciplinary team of scientists has developed a bioelectronic system driven by a machine learning algorithm that can shift the membrane voltage in living cells and maintain it at a set point for 10 hours.

Every living cell maintains a voltage across the cell membrane that results from differences in the concentrations of charged ions inside and outside the cell. Often called the membrane potential or resting potential, this voltage is regulated by ion channels in the cell membrane and plays important roles in cell physiology and functions such as proliferation and differentiation.

Controlling cells with bioelectronics is difficult due to the complex ways cells respond to changes in their environment and the natural self-regulating feedback process known as homeostasis. Cells regulate ion movements to maintain a steady membrane voltage, so the researchers had to develop a system that could counteract this natural response.

"Biological feedback systems are fundamental to life, and their malfunctioning is often involved in diseases. This work demonstrates that we can tweak this feedback using a combination of bioelectronic devices actuated by machine learning, and potentially restore its functioning," said Marco Rolandi, professor and chair of electrical and computer engineering at the UC Santa Cruz Baskin School of Engineering.

Rolandi is the senior corresponding author of the paper describing this work, published September 24 in the journal Advanced Intelligent Systems. The other corresponding authors who helped direct the project are Marcella Gomez, assistant professor of applied mathematics at UC Santa Cruz, and Michael Levin, director of the Center for Regenerative and Developmental Biology at Tufts University and associate faculty member of the Wyss Institute at Harvard University.

The researchers developed a system involving an array of bioelectronic proton pumps that add or remove hydrogen ions from solution in proximity to cultured human stem cells. The cells were genetically modified to express a fluorescent protein on the cell membrane that responds to changes in membrane voltage. The system is controlled by a machine learning algorithm that tracks how the membrane voltage responds to stimuli from the proton pumps.

"It is a closed-loop system, in that it records the behavior of the cells, determines what intervention to deliver using the proton pumps, sees how the cells react, then determines the next intervention needed to achieve and maintain the membrane voltage status we desire," Rolandi explained.

Gomez, who developed the machine learning algorithm, said the algorithm is not trained on any data in advance and does not rely on a model of the system. Instead, the "learning" happens in real time as the neural network responds to input regarding the current state of the membrane voltage.

"The adaptive nature of biology--that is, the ability of cells to change their response to external stimuli--calls for an adaptive approach in controls, where static models and past information can become obsolete," Gomez said.

Because the membrane voltage of stem cells is different from that of mature, differentiated cells, the researchers are interested in the possibility of using the system to induce and direct the differentiation of stem cells into specific cell types. They did not, however, explicitly look at cell differentiation in this proof-of-concept study.

More broadly, the combination of bioelectronics and machine learning in a closed-loop biohybrid system has many potential applications in regenerative medicine and synthetic biology, Rolandi said. He noted that the results of this study will inform the team's work on a major effort to develop a "smart bandage" providing bioelectronic intelligent control of wound regeneration.

"This study is an important proof of concept for the use of bioelectronics and machine learning to control cell functions," he said.

Adults conceived through sperm donation reported higher frequencies of allergies, type 1 diabetes and other autoimmune conditions in a world-first study that examined the long term health outcomes of donor-conceived people.

The study was conducted by Flinders University's Caring Futures Institute, led by researcher Damian Adams, and published in the Journal of Developmental Origins of Health and Disease. It looked at 272 donor-conceived adult participants from around the world together with 877 who were conceived naturally.

Results revealed that for most health outcomes, donor sperm conceived adults reported no significant difference to participants born through natural conception.

However, donor sperm conceived adults had seven times more type 1 diabetes diagnoses than naturally conceived adults, together with double the incidence of thyroid disease, acute bronchitis and sleep apnoea; and a 45% incidence of allergies compared to 35% in the naturally conceived population.

Mr Adams says most of the health conditions reported by donor conceived people had an immunological basis, suggesting an alteration to their immunological systems.

"What may potentially be driving this is the maternal complication of preeclampsia, which has increased incidences associated with the use of donated gametes (sex cells)," he says.

"Preeclampsia is an extremely serious condition that is mediated by the immune system. Research has shown that children born from a pregnancy complicated by preeclampsia have altered epigenetic profiles including links with an altered immune system."

Mr Adams is a PhD candidate at Flinders University, whose interest in the health outcomes of donor-conceived people was sparked by vast knowledge gaps in the area.

His supervisors include Flinders University Professor Sheryl de Lacey, who has a clinical background in infertility and assisted reproductive technology.

She says the use of donor gametes has been cloaked in secrecy and abetted by anonymity, with pregnancies assumed to be no different to natural conceptions.

"Being aware of an increased risk of pre-eclampsia in pregnancy and the implications for children in adulthood holds the potential to empower women beyond their pregnancy," Professor de Lacey says.

"For parents, this unique study provides important information that informs their decision of whether to disclose conception means to their child, and to choose the health care they receive.

For donor conceived people, having this information may improve vigilance in preventative health behaviours."

Mr Adams says donor-conceived people are a hard to reach population, with research consistently showing that the majority do not know they were conceived by sperm donation.

"We had to implement six different recruitment strategies to attract the sample size we achieved," he says.

The majority of participants were from Australia, the United States, the United Kingdom, Belgium and the Netherlands.

Those conceived by donor or through natural conception were matched for age, sex, height, smoking habits, alcohol consumption, exercise and fertility.

"This study was preceded by our systematic review of the literature, where we noted a dearth of studies investigating the perinatal and long-term health outcomes of donor sperm treatments, despite the technique being used for almost 140 years," Mr Adams says.

A new study presented at this year's annual meeting of the European Association for the Study of Diabetes (EASD) shows the disproportionate impact of early-onset adult type 2 diabetes (T2D) on individuals of South Asian and African-Caribbean ethnicity in the UK.

The research was conducted by Janthula Ranchagoda, Dr Shivani Misra and colleagues at the Department of Medicine, Imperial College London, and Imperial College Healthcare NHS Trust, London, UK. It analysed prevalence of early-onset adult T2D in diverse ethnic groups, as well as to investigate the link between a person's body mass index (BMI) and their age-at-onset of T2D.

The incidence of T2D in early adulthood has increased rapidly in the UK, and the individuals affected have a higher and accelerated risk of diabetes-related complications and mortality compared to those who develop the disease later in life. Previous studies into T2D in children have shown that non-white ethnicities are disproportionately affected. In older onset cases, south Asian people are relatively leaner at diagnosis of T2D than white individuals. The team sought to understand the ethnic distribution of cases of early-onset T2D in adults.

The team performed a cross-sectional study of individuals with T2D of white, South Asian (SA), or African-Caribbean (AC) ethnicity from an anonymised population dataset of 1,407,990, which had been compiled from general practice records in North West London. All cases of T2D were included in the analysis where the individuals last clinical encounter occurred between April 2015 and December 2019.

The researchers defined early-onset T2D if the affected individual was diagnosed between 18-44 years old, irrespective of their current age. Using these data, they calculated the proportion of cases of T2D by age of diagnosis and grouped by decade, as well as the mean BMI for each ethnicity. A further comparison was made between those individuals currently aged 18-44 years to those aged 55-79 years, all of whom had lived with T2D for less than 5 years.

The authors found that across the sample group as a whole, the overall prevalence of T2D across all ages was 6.5%, however there were significant differences in the proportion of each ethnicity living with the disease. T2D was present in 3.4% of white patients, compared to 10.1% and 8.3% of SA and AC individuals, respectively.

The proportion of cases by decade of onset also varied significantly by ethnicity. In white individuals 15.7% of cases were classed as early-onset, and there was a peak of 28.8% of diagnoses taking place within the 55-64 years age group. The proportion of early-onset cases was significantly higher in SA individuals at 30.7%, while their peak decade was among the 45-54 years age group during which 31.2% of diagnoses occurred. Those of AC background also had a higher proportion of early-onset diabetes with 25.8% of cases being found in individuals aged 18-44 years; and the most common age range for onset was also 45-54 years, making up 30.7% of diagnoses.

The researchers discovered that across all ethnicities the mean BMI of patients who had lived with T2D for less than 5 years was significantly higher in those currently aged 18-44 years than in individuals diagnosed aged 55-79 years. BMI for both age groups was highest in white individuals, significantly lower among AC people, and lowest in the SA group. In white individuals currently aged 18-45 (n=563), BMI was 34.8kg/m2 vs 31.8 for 55-79 yrs (n=3921). SA people had significantly lower BMI than white, but similar trends; BMI 30.3 kg/m2 (18-45, n=3806) vs 28.6 (55-79, n=8090). In AC individuals, BMI was 33.7 (18-45, n=475) and 31.0 age (55-79, n=1595).

The authors say: "Early adult-onset type 2 diabetes disproportionately affects South Asian and African-Caribbean ethnicities; compared to white individuals with early-onset T2D, the SA prevalence is double and AC prevalence 60% higher."

"In all ethnic groups, early-onset T2D is associated with significant obesity but the trend observed in previous studies of South Asian individuals developing T2D at a lower BMI than other ethnic groups is maintained for those patients presenting the disease early in adulthood, just as in late adulthood."

The team conclude: "Early-onset T2D in adults disproportionately affects people from minority ethnic groups in the UK and is associated with a higher level of obesity compared to those diagnosed at later age. We now need to investigate and understand why south Asian and African-Caribbean people appear to be at such higher risk of developing T2D at early age in order to address this growing health crisis."

New research presented at this year's annual meeting of the European Association for the Study of Diabetes (EASD) shows that high-intensity interval training (HIIT) combining cycling and rowing markedly improves insulin sensitivity, body composition and cardiorespiratory fitness in cases of obesity and type 2 diabetes (T2D). The study is by Dr Maria Petersen and colleagues at Steno Diabetes Centre Odense, Odense University Hospital, Odense, Denmark.

Physical activity is a cornerstone in the treatment and prevention of T2D, however typical aerobic endurance exercise training such as jogging has been found to provide only a modest (10-20%) improvement in insulin sensitivity. Recent studies suggest that HIIT consisting of short bursts of intense anaerobic exercise with less strenuous recovery periods in between may be a more effective strategy, and that the beneficial effects can be enhanced further through the involvement of more muscle groups.

Dr Petersen and her team recruited a total of 48 men for the study. They included 15 men with type 2 diabetes who were also obese (average BMI 31kg/m2), together with two age-matched groups of healthy glucose-tolerant men for comparison. The non-diabetic participants consisted of 15 with obesity (average BMI 31kg/m2) and 18 who were lean (average BMI 24kg/m2).

Participants undertook an 8-week supervised HIIT programme of 3 training sessions per week, which combined periods of cycling and rowing. The effects of the training on participants' bodies was evaluated through a combination of Dual-energy X-ray absorptiometry (DXA) scans to determine body composition, VO2 max tests to measure oxygen utilisation, and euglycemic-hyperinsulinemic clamps combined with indirect calorimetry to evaluate insulin sensitivity and metabolism, respectively. HIIT-sessions consisted of blocks of 5 x 1 min bursts of exercise interspersed with 1 min rest, shifting between blocks on cycle and rowing ergometers, and with an increasing volume from two to five blocks during the 8 weeks.

At the beginning of the study, men with T2D had 35-37% lower insulin sensitivity and around a 13% lower insulin-mediated suppression of lipid oxidation (lower suppression is an additional indicator of poor insulin sensitivity) compared with the non-diabetic subjects. After undergoing 8 weeks of HIIT, all participants showed big improvements in insulin sensitivity. Average increases of 32-37% were observed in lean men and men with obesity, while the increase among the diabetic group averaged 44%.

Blood sugar levels also improved in those participants with T2D, resulting in both lowered fasting plasma glucose and a fall in glycated haemoglobin (a measure of blood sugar control) (HbA1c).

The authors also found that body fat mass reduced by 1.6-2.3kg in all 3 groups, while fat-free mass (used as a proxy for muscle mass) increased by 0.9-1.5kg in men with obesity, both with and without T2D. In addition, it was observed that VO2max increased by 10% in lean and obese healthy men, and 15% in the T2D group.

The authors conclude: "A HIIT-protocol recruiting both lower and upper body muscles efficiently improves insulin sensitivity, VO2max and body composition to the same extent in obesity and type 2 diabetes as in lean healthy individuals." They add: "In patients with type 2 diabetes, the HIIT-protocol also improved glycaemic control."

New research from the UK, being presented at this week's ESCMID Conference on Coronavirus Disease (ECCVID, online from 23-25 September) shows that the diagnosis of several common conditions including cardiovascular and cerebrovascular (circulatory) disease, diabetes, and mental health conditions approximately halved during the country's COVID-19 lockdown. The study is to be published in The Lancet Public Health ahead of a special conference session featuring The Lancet journals.

The study, by Richard Williams of the University of Manchester and The National Institute for Health Research Greater Manchester Patient Safety Translational Research Centre, Manchester, UK, used data from Salford, a metropolitan area of Greater Manchester (UK) with a population of approximately 250000 people.

The authors used routinely collected primary care data that was recorded in the Salford Integrated Record system between Jan 1, 2010, and May 31, 2020. They extracted data on symptoms and observations, diagnoses, prescriptions, operations and procedures, laboratory tests, and other diagnostic procedures.

They then used computer modelling with data of monthly counts of first diagnoses of common conditions (common mental health problems, cardiovascular and cerebrovascular disease, type 2 diabetes, and cancer), and corresponding first prescriptions of medications indicative of these conditions. These models were used to predict the expected numbers of first diagnoses and first prescriptions between March 1 and May 31, 2020, which were then compared with the observed numbers for the same time period.

Between March 1 and May 31, 2020, 1073 first diagnoses of common mental health problems were reported compared with 2147 expected cases based on preceding years, representing a 50% reduction. There were 598 cases of circulatory disease observed, compared with 1054 expected, a 43% reduction, and for type 2 diabetes, 141 cases were diagnosed compared with an expected 276 cases - a 49% reduction. The number of first prescriptions of associated medications was also lower than expected for the same time period.

The gap between observed and expected cancer diagnoses (194 expected / 163 observed, difference 31 cases, a 16% reduction) during this time period was not statistically significant, but the authors suggest this could be due to a delay in cancer diagnosis data being recorded in primary care after diagnosis in hospital. The authors say: "The lower reduction in cancer diagnoses observed compared with the other diseases assessed could be partially explained by this time lag. This hypothesis is supported by the data for May, during which we observed a 44% reduction in cancer diagnoses - 38 observed versus 68 expected - which was statistically significant."

The authors say: "Most of the conditions included in our study develop over many years, so it is unlikely that people's behaviour during the COVID-19 pandemic has resulted in a lower incidence of these diseases...the reduced number of new diagnoses observed when compared with the expected numbers obtained from our models are most likely to represent a large number of true disease cases that have gone undetected, undiagnosed, and untreated."

They suggest that, when people begin to engage more with health services again, through less widespread fear of contracting COVID-19 in a health-care facility or because their symptoms have become intolerable, presentation rates for the four groups of conditions assessed in this study could increase sharply.

They say: "Should such a scenario occur, health-care services will need to manage this excess demand. The delay in diagnoses is also likely to have implications for the severity of these conditions when patients present. Prioritisation of people with these conditions over people with more minor illnesses will be important in primary care otherwise the backlog could plausibly overwhelm primary and secondary health-care services."

They also sound a warning about future health emergencies, including potential second waves of COVID-19. They conclude: "Should a public health emergency on the scale of the COVID-19 pandemic occur in the future, or if subsequent surges in COVID-19 cases arise, national communication strategies must be carefully considered to ensure that large numbers of patients with urgent health needs do not disengage with health services."

They note some limitations to their study, including that Salford is the 18th most deprived of 317 areas in England, and thus these results might not be generalisable to other parts of the country. Between March 1 and May 31, 2020, Salford had the fourth highest age-standardised all-cause mortality rate in England and Wales and the third highest age-standardised COVID-19 mortality rate outside of London.

Due to higher deprivation, a higher proportion of the population in Salford might be unable to consult with a GP via video link than the general population of the UK. But the authors add: "However, it seems reasonable to assume that the patterns observed in Salford would be similar to those in other parts of the UK, particularly in areas with similar populations. The high COVID-19 mortality rate in Salford should not affect the generalisability of our results, since we are reporting the consequences of the public health system response and the public response to the crisis rather than the consequences of COVID-19 itself."