SARS-CoV-2, the virus that causes COVID-19, has mutated throughout the pandemic. New variants of the virus have arisen throughout the world, including variants that might possess increased ability to spread or evade the immune system. Such variants have been identified in California, Denmark, the U.K., South Africa and Brazil/Japan. Understanding how well the COVID-19 vaccines work against these variants is vital in the efforts to stop the global pandemic, and is the subject of new research from the Ragon Institute of MGH, MIT and Harvard and Massachusetts General Hospital.
In a study recently published in Cell, Ragon Core Member Alejandro Balazs, PhD, found that the neutralizing antibodies induced by the Pfizer and Moderna COVID-19 vaccines were significantly less effective against the variants first described in Brazil/Japan and South Africa. Balazs’s team used their experience measuring HIV neutralizing antibodies to create similar assays for COVID-19, comparing how well the antibodies worked against the original strain versus the new variants.
“We were able to leverage the unique high-throughput capacity that was already in place and apply it to SARS-CoV-2,” says Balazs, who is also an assistant professor of Medicine at Harvard Medical School and assistant investigator in the Department of Medicine at MGH. “When we tested these new strains against vaccine-induced neutralizing antibodies, we found that the three new strains first described in South Africa were 20-40 times more resistant to neutralization, and the two strains first described in Brazil and Japan were five to seven times more resistant, compared to the original SARS-CoV-2 virus.”
Neutralizing antibodies, explains Balazs, work by binding tightly to the virus and blocking it from entering cells, thus preventing infection. Like a key in a lock, this binding only happens when the antibody’s shape and the virus’s shape are perfectly matched to each other. If the shape of the virus changes where the antibody attaches to it — in this case, in SARS-CoV-2’s spike protein — then the antibody may no longer be able to recognize and neutralize the virus as well. The virus would then be described as resistant to neutralization.
“In particular,” says Wilfredo Garcia-Beltran, MD, PhD, a resident physician in the Department of Pathology at MGH and first author of the study, “we found that mutations in a specific part of the spike protein called the receptor binding domain were more likely to help the virus resist the neutralizing antibodies.” The three South African variants, which were the most resistant, all shared three mutations in the receptor binding domain. This may contribute to their high resistance to neutralizing antibodies.
Currently, all approved COVID-19 vaccines work by teaching the body to produce an immune response, including antibodies, against the SARS-CoV-2 spike protein. While the ability of these variants to resist neutralizing antibodies is concerning, it doesn’t mean the vaccines won’t be effective.
“The body has other methods of immune protection besides antibodies,” says Balazs. “Our findings don’t necessarily mean that vaccines won’t prevent COVID, only that the antibody portion of the immune response may have trouble recognizing some of these new variants.”
Like all viruses, SARS-CoV-2 is expected to continue to mutate as it spreads. Understanding which mutations are most likely to allow the virus to evade vaccine-derived immunity can help researchers develop next-generation vaccines that can provide protection against new variants. It can also help researchers develop more effective preventative methods, such as broadly protective vaccines that work against a wide variety of variants, regardless of which mutations develop.

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There is a great need to generate various types of cells for use in new therapies to replace tissues that are lost due to disease or injuries, or for studies outside the human body to improve our understanding of how organs and tissues function in health and disease. Many of these efforts start with human induced pluripotent stem cells (iPSCs) that, in theory, have the capacity to differentiate into virtually any cell type in the right culture conditions. The 2012 Nobel Prize awarded to Shinya Yamanaka recognized his discovery of a strategy that can reprogram adult cells to become iPSCs by providing them with a defined set of gene-regulatory transcription factors (TFs). However, progressing from there to efficiently generating a wide range of cell types with tissue-specific differentiated functions for biomedical applications has remained a challenge.
While the expression of cell type-specific TFs in iPSCs is the most often used cellular conversion technology, the efficiencies of guiding iPSC through different “lineage stages” to the fully functional differentiated state of, for example, a specific heart, brain, or immune cell currently are low, mainly because the most effective TF combinations cannot be easily pinpointed. TFs that instruct cells to pass through a specific cell differentiation process bind to regulatory regions of genes to control their expression in the genome. However, multiple TFs must function in the context of larger gene regulatory networks (GRNs) to drive the progression of cells through their lineages until the final differentiated state is reached.
Now, a collaborative effort led by George Church, Ph.D. at Harvard’s Wyss Institute for Biologically Inspired Engineering and Harvard Medical School (HMS), and Antonio del Sol, Ph.D., who leads Computational Biology groups at CIC bioGUNE, a member of the Basque Research and Technology Alliance, in Spain, and at the Luxembourg Centre for Systems Biomedicine (LCSB, University of Luxembourg), has developed a computer-guided design tool called IRENE, which significantly helps increase the efficiency of cell conversions by predicting highly effective combinations of cell type-specific TFs. By combining IRENE with a genomic integration system that allows robust expression of selected TFs in iPSCs, the team demonstrated their approach to generate higher numbers of natural killer cells used in immune therapies, and melanocytes used in skin grafts, than other methods. In a scientific first, generated breast mammary epithelial cells, whose availability would be highly desirable for the repopulation of surgically removed mammary tissue. The study is published in Nature Communications.
“In our group, the study naturally built on the ‘TFome’ project, which assembled a comprehensive library containing 1,564 human TFs as a powerful resource for the identification of TF combinations with enhanced abilities to reprogram human iPSCs to different target cell types,” said Wyss Core Faculty member Church. “The efficacy of this computational algorithm will boost a number of our tissue engineering efforts at the Wyss Institute and HMS, and as an open resource can do the same for many researchers in this burgeoning field.” Church is the lead of the Wyss Institute’s Synthetic Biology platform, and Professor of Genetics at HMS and of Health Sciences and Technology at Harvard and MIT.
Tooling up
Several computational tools have been developed to predict combinations of TFs for specific cell conversions, but almost exclusively these are based on the analysis of gene expression patterns in many cell types. Missing in these approaches was a view of the epigenetic landscape, the organization of the genome itself around genes and on the scale of entire chromosome sections which goes far beyond the sequence of the naked genomic DNA.

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“The changing epigenetic landscape in differentiating cells predicts areas in the genome undergoing physical changes that are critical for key TFs to gain access to their target genes. Analyzing these changes can inform more accurately about GRNs and their participating TFs that drive specific cell conversions,” said co-first author Evan Appleton, Ph.D. Appleton is a Postdoctoral Fellow in Church’s group who joined forces with Sascha Jung, Ph.D., from del Sol’s group in the new study. “Our collaborators in Spain had developed a computational approach that integrated those epigenetic changes with changes in gene expression to produce critical TF combinations as an output, which we were in an ideal position to test.”
The team used their computational “Integrative gene Regulatory Network model” (IRENE) approach to reconstruct the GRN controlling iPSCs, and then focused on three target cell types with clinical relevance to experimentally validate TF combinations prioritized by IRENE. To deliver TF combinations into iPSCs, they deployed a transposon-based genomic integration system that can integrate multiple copies of a gene encoding a TF into the genome, which allows all factors of a combination to be stably expressed. Transposons are DNA elements that can jump from one position of the genome to another, or in this case from an exogenously provided piece of DNA into the genome.
“Our research team composed of scientists from the LCSB and CIC bioGUNE has a long-standing expertise in developing computational methods to facilitate cell conversion. IRENE is an additional resource in our toolbox and one for which experimental validation has demonstrated it substantially increased efficiency in most tested cases,” corresponding author Del Sol, who is Professor at LCSB and CIC bioGUNE. “Our fundamental research should ultimately benefit patients, and we are thrilled that IRENE could enhance the production of cell sources readily usable in therapeutic applications, such as cell transplantation and gene therapies.”
Validating the computer-guided design tool in cells
The researchers chose human mammary epithelial cells (HMECs) as a first cell type. Thus far HMECs are obtained from one tissue environment, dissociated, and transplanted to one where breast tissue has been resected. HMECs generated from patients’ cells, via an intermediate iPSC stage, could provide a means for less invasive and more effective breast tissue regeneration. One of the combinations that was generated by IRENE enabled the team to convert 14% of iPSCs into differentiated HMECs in iPSC-specific culture media, showing that the provided TFs were sufficient to drive the conversion without help from additional factors.
The team then turned their attention to melanocytes, which can provide a source of cells in cellular grafts to replace damaged skin. This time they performed the cell conversion in melanocyte destination medium to show that the selected TFs work under culture conditions optimized for the desired cell type. Two out of four combinations were able to increase the efficiency of melanocyte conversion by 900% compared to iPSCs grown in destination medium without the TFs. Finally, the researchers compared combinations of TFs prioritized by IRENE to generate natural killer (NK) cells with a state-of-the-art differentiation method based on cell culture conditions alone. Immune NK cells have been found to improve the treatment of leukemia. The researchers’ approach outperformed the standard with five out of eight combinations increasing the differentiation of NK cells with critical markers by up to 250%.
“This novel computational approach could greatly facilitate a range of cell and tissue engineering efforts at the Wyss Institute and many other sites around the world. This advance should greatly expand our toolbox as we strive to develop new approaches in regenerative medicine to improve patients’ lives,” said Wyss Founding Director Donald Ingber, M.D., Ph.D., who is also the Judah Folkman Professor of Vascular Biology at HMS and Boston Children’s Hospital, and Professor of Bioengineering at the Harvard John A. Paulson School of Engineering and Applied Sciences.

Since the pandemic hit, researchers have been uncovering ways COVID-19 impacts other parts of the body, besides the lungs.
Now, for the first time, a visual correlation has been found between the severity of the disease in the lungs using CT scans and the severity of effects on patient’s brains, using MRI scans. This research is published in the American Journal of Neuroradiology. It will be presented at the 59th annual meeting of the American Society of Neuroradiology (ASNR) and has also been selected as a semifinalist for that organization’s Cornelius Dyke Award.
The results show that by looking at lung CT scans of patients diagnosed with COVID-19, physicians may be able to predict just how badly they’ll experience other neurological problems that could show up on brain MRIs, helping improve patient outcomes and identify symptoms for earlier treatment.
CT imaging can detect illness in the lungs better than an MRI, another medical imaging technique. However, MRI can detect many problems in the brain, particularly in COVID-19 patients, that cannot be detected on CT images.
The study was led by Achala Vagal, MD, professor in the department of radiology, and Abdelkader Mahammedi, MD, assistant professor of radiology. Both are UC Health radiologists and members of the UC Gardner Neuroscience Institute.
“We’ve seen patients with COVID-19 experience stroke, brain bleeds and other disorders affecting the brain,” says Mahammedi. “So, we’re finding, through patient experiences, that neurological symptoms are correlating to those with more severe respiratory disease; however, little information has been available on identifying potential associations between imaging abnormalities in the brain and lungs in COVID-19 patients.
“Imaging serves as proof for physicians, confirming how an illness is forming and with what severity and helps in making final decisions about a patient’s care.”
In this study, which was conducted not only at UC, but also at large institutions in Spain, Italy and Brazil, researchers reviewed electronic medical records and images of hospitalized COVID-19 patients from March 3 to June 25, 2020. Patients who were diagnosed with COVID-19, experienced neurological issues and who had both lung and brain images available were included.
Of 135 COVID-19 patients with abnormal CT lung scans and neurological symptoms, 49, or 36%, were also found to develop abnormal brain scans and were more likely to experience stroke symptoms.
Mahammedi says this study will help physicians classify patients, based on the severity of disease found on their CT scans, into groups more likely to develop brain imaging abnormalities. He adds that this correlation could be important for implementing therapies, particularly in stroke prevention, to improve outcomes in patients with COVID-19.
“These results are important because they further show that severe lung disease from COVID-19 could mean serious brain complications, and we have the imaging to help prove it,” says Mahammedi. “Future larger studies are needed to help us understand the tie better, but for now, we hope these results can be used to help predict care and ensure that patients have the best outcomes.”
This research was supported by the National Institutes of Health (the National Institute of Neurological Disorders and Stroke and National Institute on Aging) (NS103824, NS117643, NS100417, 1U01NS100699, U01NS110772). Researchers cite no conflict of interest.

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Materials provided by University of Cincinnati. Original written by Katie Pence. Note: Content may be edited for style and length.

As the world continues to grapple with the COVID-19 pandemic, an international team of researchers have published a review of the best techniques to collect airborne aerosols containing viruses.
In the review, which was published by the Science of the Total Environment journal, a team led by the University of Surrey concluded that the most effective way to collect and detect airborne pathogens, particularly viruses, was to use cyclone sampling techniques.
For example, the sampler draws the air through the cyclone separator. It then uses centrifugal forces to collect the particles on a sterile cone containing the liquid collection vessel, such as DMEM (Dulbecco’s minimal essential medium). The collected sample can then be readily used for any analysis for virus detection.
The research team hope that this wide-ranging review can serve as an information hub packed with the best methods and samplers involved in airborne virus collection.
The study is part of the INHALE project — an EPSRC funded project that aims to assess air pollution’s impact on personal health in urban environments. The project involves Imperial College London, the University of Surrey and the University of Edinburgh.
The INHALE team also reviewed effective techniques for capturing fine (PM2.5) and ultrafine (PM0.1) particles to understand their toxicity and their role on reactive oxygen species in cells, their elemental composition and carbon content. The team also set out to find the best solution to prevent samples from being destroyed, a common problem found in toxicological experiments that makes large sample collection challenging. The study concluded that Harvard impactor samplers could be used for both indoor and outdoor environments to effectively collect these fine and ultrafine samples.
Professor Prashant Kumar, lead author of the study and Founding Director of the Global Centre for Clean Air Research at the University of Surrey, said: “The scientific community will have to become more efficient and resourceful if we are to overcome foes such as airborne viruses and air pollution. Knowing the right tools to use — as well as how and where to use them — is crucial in our ongoing fight to make the air we breathe cleaner and safer for all.”
Professor Fan Chung, co-lead of INHALE from Imperial College London, said: “I am pleased that this timely review found support for the techniques that have been adopted in the INHALE research program. The collection of ultrafine particles is of particular importance because of the commonly found difficulties of collecting enough for toxicity studies. Ultimately, the success of INHALE will depend on the ability to capture enough of these fine and ultrafine particles as far as possible in their natural state.”
Professor Chris Pain, co-lead of INHALE from Imperial College London, said: “Understanding the application of these sampling techniques is hugely important for environmental and health research in general and for the INHALE project itself, particularly concerning collecting ultra-fine particles.”
This work was supported by the EPSRC INHALE (Health assessment across biological length scales for personal pollution exposure and its mitigation) project (EP/T003189/1).

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In asthma, the airways become hyperresponsive. Researchers from Uppsala University have found a new mechanism that contributes to, and explains, airway hyperresponsiveness. The results are published in the scientific journal Allergy.
Some 10 per cent of Sweden’s population suffer from asthma. In asthmatics, the airways are hyperresponsive (overreactive) to various types of stimuli, such as cold air, physical exertion and chemicals. The airways become constricted, making breathing difficult.
To diagnose asthma, a “methacholine test” is commonly used to determine whether a person is showing signs of airway hyperresponsiveness. Methacholine binds to what are known as muscarinic receptors in the smooth muscle cells lining the inside of the trachea. These muscle cells then begin to contract, causing constriction of the trachea.
In the new study, the scientists show that the airway hyperresponsiveness induced by methacholine is due partly to the body’s mast cells. The research was conducted using a mouse model of asthma, where the mice were made allergic to house dust mites.
Mast cells, which are immune cells of a specific type belonging to the innate immune system, are found mainly in tissues that are in contact with the external environment, such as the airways and the skin. Because of their location and the fact that they have numerous different receptors capable of recognising parts of foreign or pathogenic substances, they react quickly and become activated. In their cytoplasm, mast cells have storage capsules, known as granules, in which some substances are stored in their active form. When the mast cell is activated, these substances can be rapidly released and provoke a physiological reaction. This plays a major part in the body’s defence against pathogens, but in asthma and other diseases where the body starts reacting against harmless substances in the environment, it becomes a problem.
In their study, the researchers were able to demonstrate that the mast cells contribute to airway hyperresponsiveness by having a receptor that recognises methacholine: muscarinic receptor-3 (M3). When methacholine binds M3, the mast cells release serotonin. This then acts on nerve cells, which in turn control the airways. Thereafter, the airways produce acetylcholine, which also acts on M3 in smooth muscle cells and makes the trachea contract even more. A vicious cycle is under way.
The scientists’ discovery also means that drugs like tiotropium, which were previously thought to work solely by blocking M3 in smooth muscle, are probably also efficacious because they prevent activation through M3 in mast cells. Accordingly, the ability of mast cells to rapidly release serotonin in response to various stimuli, thereby contributing to airway hyperresponsiveness, has been underestimated.

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Materials provided by Uppsala University. Original written by Linda Koffmar. Note: Content may be edited for style and length.

A comprehensive modeling study sheds new light on socioeconomic-based mechanisms that drive disparities in influenza burden across the U.S. Casey Zipfel of Georgetown University in Washington D.C. and colleagues present this analysis in the open-access journal PLOS Computational Biology.
People of lower socioeconomic status experience increased burden of influenza. Past studies have identified various factors that underlie this health inequity, including decreased flu vaccination, lack of access to paid sick leave, lack of healthcare access, increased susceptibility to infection, and different exposure patterns. However, no previous study has considered all of these factors at once.
For the new study, Zipfel and colleagues considered how multiple underlying factors independently and synergistically drive health disparities in influenza burden. They combined large-scale disease datasets and observations from past studies to develop data-driven computational models, enabling them to explore how various factors impact influenza transmission and burden for people of varying socioeconomic status across the U.S.
The analysis showed that people of lower socioeconomic status bear a disproportionate burden of influenza infection in the U.S., and this disparity arises from the synergistic combination of multiple social-economic and healthcare factors. The researchers also identified geographic regions where disparities are most severe and where existing systems to track influenza tend to overlook flu cases among people of low socioeconomic status.
“As the divide in health disparities grows wider across the world, it is imperative that we continue to understand how social determinants impact health, and how this is reflected geographically,” Zipfel says. “Our work spotlights inequities in respiratory disease transmission, currently on display due to the COVID-19 pandemic.”
The new findings could help inform efforts to eliminate public health disparities due to socioeconomic status and systemic racism. Meanwhile, the researchers note the need to collect better data on healthcare access and usage among people of low socioeconomic status in order to validate their model findings and inform future research and public health efforts.

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University of Otago researchers have discovered one of the reasons why more than 50 per cent of people with type 2 diabetes die from heart disease.
And perhaps more significantly, they have found how to treat it.
Associate Professor Rajesh Katare, of the Department of Physiology, says it has been known that stem cells in the heart of diabetic patients are impaired. While stem cell therapy has proved effective in treating heart disease, it is not the case in diabetic hearts.
It has not been known why; until now.
It comes down to tiny molecules called microRNA which control gene expression.
“Based on the results of laboratory testing, we identified the number of microRNAs that are impaired in stem cells of the diabetic heart,” Associate Professor Katare says.

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“Among several microRNAs we identified that one particular microRNA called miR-30c — which is crucial for the stem cells’ survival, growth and new blood vessel formation — is reduced in the diabetic stem cells. All these functions are required for stem cell therapy to be successful in the heart.
“Importantly, we also confirmed that this microRNA is decreased in the stem cells collected from the heart tissue of the patients undergoing heart surgery at Dunedin Hospital.”
Researchers were able to then increase the level of the lacking miR-30c in the heart by a “simple injection.”
“This resulted in significantly improving the survival and growth of stem cells in the diabetic heart,” Associate Professor Katare says.
“This fascinating discovery has newly identified that impairment in the microRNAs is the underlying reason for the stem cells being not functional in the diabetic heart. More importantly, the results have identified a novel therapy for activation of stem cells in the heart using microRNA, without the need to inject stem cells, which is a time and cost consuming process.”
Associate Professor Katare calls the finding “significant” and says it could help diabetes- sufferers — who are ten per cent of New Zealanders — lead a longer, quality life.
“Apart from identifying the reasons for poor stem cells function in a patient with diabetes, the novel therapy of using microRNA could change the treatment method for heart disease in diabetic individuals.”
Researchers will now undertake more laboratory testing before moving on to humans.
“Our initial analysis revealed that there might be another four potential candidate microRNAs. Therefore, it is essential to test the function of those microRNAs as well. It may be possible that combination therapy with more than one microRNA could further increase the beneficial effects.”

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#masthead-section-label, #masthead-bar-one { display: none }The Coronavirus OutbreakliveLatest UpdatesMaps and CasesRisk Near YouVaccine RolloutGuidelines After VaccinationAdvertisementContinue reading the main storySupported byContinue reading the main storyFaulty Software Snarls Vaccine Sign-UpsHealth departments continue to grapple with delays caused by technical problems with numerous websites used for making appointments.Awaiting shots in Richmond, Va. Health departments around the country continue to face delays giving vaccines, in part because of flawed appointment software like that used in Richmond.Credit…Carlos Bernate for The New York TimesMarch 12, 2021Updated 9:26 a.m. ETWhen coronavirus vaccines first became available, state health officials in Virginia turned to software recommended by the Centers for Disease Control and Prevention to schedule appointments. But people complained that the software, called VAMS, was too confusing for older adults to use.So the state switched to another system, PrepMod — but that had problems, too. Links sent to seniors for their appointments were reusable and found their way to Facebook, leading to one vaccination event in Richmond with dozens of overbookings. Some of those people threatened health care workers when they were turned away.“It was a nightmare scenario,” said Ruth Morrison, the policy director for the Richmond and Henrico County health district. “People showing up confused, irate, thinking they had an appointment.”State and local health departments around the country continue to face delays dispensing shots, in part because flaws remain in the appointment software tools like those used in Richmond. The problems threaten to slow the vaccine rollout even as supplies and distribution are picking up quickly across the country.Large software systems have often been problematic for companies and governments. HealthCare.gov, a site released after the Affordable Care Act, crashed early on. But the issues with the vaccine sites have an added sense of urgency because health officials are trying to vaccinate as many people as possible, as fast as possible.On Thursday, President Biden said that his administration would send out technical teams to help states improve their websites. He also said the federal government would open a website by May 1 that would allow Americans to find out where the vaccine is available.Many state officials have switched software providers, only to see little or no improvement. In California, tech mishaps have allowed ineligible people to snatch up appointments. Massachusetts residents have been stymied by crashing websites. Some North Carolina residents are eschewing online sign-ups entirely, instead engaging in a vaccine free-for-all.PrepMod is being used by 28 states and localities, after many states shunned the $44 million VAMS tool built by Deloitte. Salesforce and Microsoft have developed vaccine software, too, with their customers being similarly frustrated. Smaller tech companies have pitched their own scheduling tools as well.“Some of these systems have strengths, but they all have weaknesses, too,” said Ruth Morrison, the policy director for the Richmond and Henrico County health district.Credit…Carlos Bernate for The New York Times“It’s like a patchwork quilt,” said Ms. Morrison, who decided after the failed PrepMod trial that her county would try something else. “Some of these systems have strengths, but they all have weaknesses, too.”Other health officials have defended the appointment systems, and the developers behind the software said the complaints about their products were overblown.Tiffany Tate, PrepMod’s creator and the executive director of the Maryland Partnership for Prevention, said criticisms of her system largely stemmed from health providers’ lack of knowledge about how to use it, or from the constantly shifting needs of states.“The pandemic’s evolving, and we’ve got to be able to keep up with it,” she said. “We just have to be a very flexible platform.”Deloitte, whose software is used by nine states, said VAMS was originally intended for smaller groups at early stages of states’ vaccine rollouts, so the company was “responding quickly to meet their changing needs” and was updating the system to handle a greater load.Health experts say multiple factors complicated the software rollout. In some cases, developers condensed work that would normally take years into weeks, leading to glitches. In addition, the varied approaches to determining eligibility in the dozens of localities using the software have made it difficult to develop a one-size-fits-all approach.Some states use more than half a dozen appointment scheduling systems, from tools used by federal, state and local agencies to the software employed by private hospitals and pharmacies to rudimentary solutions like SignUpGenius. Some sites do not support appointment scheduling at all, but allow people to browse databases to find available vaccines or get on wait lists. Often, the systems cannot communicate with one another.At one vaccination event in Richmond intended for older adults, dozens of people who had re-used appointment links showed up, overbooking the event.Credit…Carlos Bernate for The New York Times“You’re basically building and testing data systems on the fly as millions of people are trying to find vaccines,” said Claire Hannan, the executive director of the Association of Immunization Managers, which advocates for state health departments.The Coronavirus Outbreak

#masthead-section-label, #masthead-bar-one { display: none }The Coronavirus OutbreakliveLatest UpdatesMaps and CasesRisk Near YouVaccine RolloutGuidelines After VaccinationAdvertisementContinue reading the main storySupported byContinue reading the main storyFaulty Software Snarls Vaccine Sign-UpsHealth departments continue to grapple with delays caused by technical problems with numerous websites used for making appointments.Awaiting shots in Richmond, Va. Health departments around the country continue to face delays giving vaccines, in part because of flawed appointment software like that used in Richmond.Credit…Carlos Bernate for The New York TimesMarch 12, 2021Updated 9:26 a.m. ETWhen coronavirus vaccines first became available, state health officials in Virginia turned to software recommended by the Centers for Disease Control and Prevention to schedule appointments. But people complained that the software, called VAMS, was too confusing for older adults to use.So the state switched to another system, PrepMod — but that had problems, too. Links sent to seniors for their appointments were reusable and found their way to Facebook, leading to one vaccination event in Richmond with dozens of overbookings. Some of those people threatened health care workers when they were turned away.“It was a nightmare scenario,” said Ruth Morrison, the policy director for the Richmond and Henrico County health district. “People showing up confused, irate, thinking they had an appointment.”State and local health departments around the country continue to face delays dispensing shots, in part because flaws remain in the appointment software tools like those used in Richmond. The problems threaten to slow the vaccine rollout even as supplies and distribution are picking up quickly across the country.Large software systems have often been problematic for companies and governments. HealthCare.gov, a site released after the Affordable Care Act, crashed early on. But the issues with the vaccine sites have an added sense of urgency because health officials are trying to vaccinate as many people as possible, as fast as possible.On Thursday, President Biden said that his administration would send out technical teams to help states improve their websites. He also said the federal government would open a website by May 1 that would allow Americans to find out where the vaccine is available.Many state officials have switched software providers, only to see little or no improvement. In California, tech mishaps have allowed ineligible people to snatch up appointments. Massachusetts residents have been stymied by crashing websites. Some North Carolina residents are eschewing online sign-ups entirely, instead engaging in a vaccine free-for-all.PrepMod is being used by 28 states and localities, after many states shunned the $44 million VAMS tool built by Deloitte. Salesforce and Microsoft have developed vaccine software, too, with their customers being similarly frustrated. Smaller tech companies have pitched their own scheduling tools as well.“Some of these systems have strengths, but they all have weaknesses, too,” said Ruth Morrison, the policy director for the Richmond and Henrico County health district.Credit…Carlos Bernate for The New York Times“It’s like a patchwork quilt,” said Ms. Morrison, who decided after the failed PrepMod trial that her county would try something else. “Some of these systems have strengths, but they all have weaknesses, too.”Other health officials have defended the appointment systems, and the developers behind the software said the complaints about their products were overblown.Tiffany Tate, PrepMod’s creator and the executive director of the Maryland Partnership for Prevention, said criticisms of her system largely stemmed from health providers’ lack of knowledge about how to use it, or from the constantly shifting needs of states.“The pandemic’s evolving, and we’ve got to be able to keep up with it,” she said. “We just have to be a very flexible platform.”Deloitte, whose software is used by nine states, said VAMS was originally intended for smaller groups at early stages of states’ vaccine rollouts, so the company was “responding quickly to meet their changing needs” and was updating the system to handle a greater load.Health experts say multiple factors complicated the software rollout. In some cases, developers condensed work that would normally take years into weeks, leading to glitches. In addition, the varied approaches to determining eligibility in the dozens of localities using the software have made it difficult to develop a one-size-fits-all approach.Some states use more than half a dozen appointment scheduling systems, from tools used by federal, state and local agencies to the software employed by private hospitals and pharmacies to rudimentary solutions like SignUpGenius. Some sites do not support appointment scheduling at all, but allow people to browse databases to find available vaccines or get on wait lists. Often, the systems cannot communicate with one another.At one vaccination event in Richmond intended for older adults, dozens of people who had re-used appointment links showed up, overbooking the event.Credit…Carlos Bernate for The New York Times“You’re basically building and testing data systems on the fly as millions of people are trying to find vaccines,” said Claire Hannan, the executive director of the Association of Immunization Managers, which advocates for state health departments.The Coronavirus Outbreak

Scientists at the Case Western Reserve University School of Medicine have determined the structure of protein “fibrils” linked to Lou Gehrig’s disease and other neurodegenerative disorders — findings that provide clues to how toxic proteins clump and spread between nerve cells in the brain.
Their results may also lead to developing drugs to treat diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
“These devastating brain disorders that affect tens of thousands of Americans?are on the rise worldwide, and there are no effective treatments to stop their progression,” said Witold Surewicz, a professor in the Department of Physiology and Biophysics at the School of Medicine and the study’s senior author.
The study was published March 12 in the online journal Nature Communications. Qiuye Li, a graduate student in the department, was lead author; Case Western Reserve medical student Michael Babinchak contributed.
The study was supported by the National Institutes of Health.
TDP-43 is normally a soluble protein that interacts with nucleic acids. However, in several neurodegenerative disorders, this protein forms large, harmful rope-like clumps that accumulate in brains of afflicted patients.

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These abnormal structures, known as amyloid fibrils, are a signature of brain pathology in amyotrophic lateral sclerosis (ALS; also called Lou Gehrig’s disease) and FTD, the most common cause of dementia in people at younger ages — in their 50s and 60s.
Similar fibrilar structures of TDP-43 are also linked to other brain disorders, including Alzheimer’s disease and chronic traumatic encephalopathy, a condition caused by repeated brain injuries and often found in athletes who played football and other contact sports.
By using a technique of electron microscopy at very low temperature (cryo-electron microscopy), the authors analyzed thousands of images of fibrils formed in the test tube by the key fragment of TDP-43. They determined the complex architecture of these elongated structure at a resolution close to individual atoms. This structural insight revealed, among other findings, the nature of the template on which more copies of TDP-43 can lock.
Based on this structural model, the researchers also discussed how the fibril structure could be controlled by amino acid mutations in TDP-43 linked to hereditary forms of ALS and FTD, as well as by aging-dependent modifications of the protein.
“This is really an exciting development because it reveals a mechanism for the growth of these toxic aggregates,” Li said.
“This, in turn, provides important clues as to how these aggregates may spread between the cells in affected brains.”
“Detailed knowledge about fibrillar structures formed by TDP-43 may also lead to the development of drugs to treat these devastating brain disorders,” Surewicz said.

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Materials provided by Case Western Reserve University. Note: Content may be edited for style and length.