Vitamin D Flops in Moderate-Severe COVID


A close up of a blister pack of vitamin D capsules

Among patients with moderate to severe COVID-19, there was no difference in length of hospital stay in those given a single 200,000-IU dose of vitamin D3 versus those given placebo in a randomized trial in Brazil.

Median length of hospital stay was about 7 days for both groups, with no significant differences in secondary outcomes including in-hospital mortality, admission to ICU, or need for mechanical ventilation, reported Rosa Pereira, MD, PhD, of Universidade de Sao Paulo, and colleagues in an online edition of JAMA.

An accompanying editorial by David Leaf, MD, of Brigham and Women’s Hospital in Boston, and Adit Ginde, MD, MPH, of University of Colorado School of Medicine in Aurora, noted that prior research showed that lower levels of vitamin D were independently associated with worse outcomes in patients with acute illness, but also that vitamin D supplementation as a treatment had no impact on clinical outcomes.

Leaf and Ginde said that COVID-19 has generated renewed interest in vitamin D, adding that this study was “the largest published randomized, double-blind, placebo-controlled trial of vitamin D3 administration among hospitalized patients with COVID-19 to date.”

While the findings taken in isolation “may appear ambiguous” and show no evidence of benefit for moderately to severely ill patients, they said, perhaps the door should not be closed altogether.

“It is important to remain open-minded to emerging results from rigorously conducted studies of vitamin D (despite smaller sample sizes and important limitations of some studies),” they wrote, adding that the study did not address outpatients with mild COVID-19 or the use of vitamin D as prophylaxis against the disease.

Pereira and colleagues examined data from hospitalized patients with moderate to severe COVID-19 at two sites in Sao Paulo from June to August 2020, with the final follow-up in October. Participants were eligible if they were adults who tested positive for SARS-CoV-2 via PCR or had a CT scan finding “compatible with the disease,” as well as “diagnosis of flu syndrome with criteria for hospitalization.” Primary outcome was length of hospital stay, defined as date of randomization to hospital discharge.

Overall, 240 patients were randomized: 120 to a single oral dose of 200,000 IU of vitamin D and 120 to placebo. Of these, 237 were included in the primary analysis. Participants’ mean age was 56, about 44% were women, and mean baseline 25-hydroxyvitamin D level was 20.9. They were given the intervention after a mean of 10.3 days from symptom onset.

The adjusted hazard ratio for hospital discharge was 0.99 (95% CI 0.71-1.37, P=0.94). There were also non-significant differences between the intervention and placebo groups in secondary outcomes, including in-hospital mortality (7.6% vs 5.1%, respectively, P=0.43), admission to the ICU (16.0% vs 21.2%, P=0.30), and need for mechanical ventilation (7.6% vs 14.4%, P=0.09).

In the intervention group, 86.7% achieved 25-hydroxyvitamin D sufficiency versus 10.9% of the placebo group, meaning “the present null findings cannot be attributed to the failure of increasing serum 25-hydroxyvitamin D levels.”

Researchers noted no adverse events, except a single episode of vomiting linked to the intervention. They also noted no significant differences between groups in any health-related laboratory markers following the intervention.

Limitations to the data included that a minimal clinically important difference in hospital length of stay among COVID-19 patients has yet to be determined, as well as the small and heterogeneous sample size, with different patients with co-existing diseases on different medication regimens.

Leaf and Ginde noted that 30 studies on vitamin D interventions in COVID-19 are currently listed on, globally and across the disease spectrum. However, they suggested that many of these studies may be “underpowered or will not achieve target enrollment,” based on experience during the pandemic.

Omicron in the U.S.: What to Know

What to know about the omicron variant

The Omicron coronavirus variant has been found in dozens of states across the country since it was first identified in South Africa in November, and many may be wondering: Will it upstage Delta and cause a winter surge? Is it still safe to gather with others for the holidays? How is this variant affecting children?

Experts addressed those and other questions in a webinar hosted by New York University last week, acknowledging that it will take some time to find out all the crucial facts about Omicron.

But in the meantime, here’s what’s known — and not — about Omicron in the fast-changing COVID landscape.

How widespread is Omicron now?

As of Dec. 15, Omicron transmission had been reported in 80 nations, according to Michael H. Merson, MD, a visiting professor of global health at the New York University School of Global Public Health. In the 35 states with Omicron cases, the numbers vary. Right now, New York and New Jersey are detecting the Omicron variant at about four times the overall rate in the country, he said. But whether or not the variant will remain in ”pockets” is currently unknown, he said.

How can people enjoy the holidays safely?

When it comes to deciding about gatherings and travel, “trust your instincts,” Elodie Ghedin, PhD, chief of the systems genomics section at the National Institute of Allergy and Infectious Diseases and affiliate faculty member at NYU, said.

As an example of safe holiday gatherings, the experts cited President Joe Biden’s appearance last Tuesday at a party of 400, which was held on a hotel rooftop due to COVID concerns.

“It’s very important to spend the holidays with family and friends,” Merson said. “But do so wisely. That’s my advice about travel.”

That means getting vaccinated and boosted when eligible, making use of rapid testing when called for, masking, handwashing, avoiding crowded indoor spaces, and keeping your distance from others.

Knowing your risk level and that of family and friends when making plans for the holidays is also important, Merson said.

Is Omicron greatly affecting children?

Experts are waiting on data to find out.

“The jury is still out on how virulent Omicron will be for kids,” said Celine R. Gounder, MD, a member of President Biden’s COVID-19 task force and a clinical assistant professor of medicine and infectious diseases at NYU Grossman School of Medicine. “We don’t know.”

The best thing parents can do right now is to vaccinate their children ages 5 years and up who are eligible, she said.

Do monoclonal antibody drugs work well against Omicron?

No, Ghedin said.

“Most of the monoclonal antibodies do not seem to work very well against Omicron,” she said.

What’s known about how infectious Omicron is?

“It appears to be the most infectious variant to date,” said Gounder.

“Relative to Delta, Omicron appears to be 2-3 times more infectious.”

Put another way, she said, you are likely to infect 2 to 3 times more people than if infected with other variants.

People should not count on their natural immunity from a prior COVID infection to protect them from the Omicron variant, Gounder said.

It also does seem that the Omicron variant might be less virulent than other variants, she said. (Virulence refers to how severe a disease an infected person can get.)

If Omicron is less virulent, isn’t that good news?

Yes and no, Gounder said.

“Even if it’s a mild disease, you can still have lots of deaths. Let’s say COVID has a case fatality rate of 1% and you have 100 people who get infected — and one death,” she said.

Then say Omicron’s rate is .25%, but if you have 400 cases, since it is more infectious, that’s still one death.

“We really have to be very careful when we say less deadly and less severe [when talking about Omicron]. On a population level, Omicron could be just as deadly as Delta even if it causes mild disease, if more are infected,” she said.

If a COVID test is positive, will the results specify whether it’s the Delta or the Omicron variant?

“Unfortunately, you will not be able to get that information from a PCR test done in the community,” Ghedin said. “If you are doing it through a research entity, they might provide that information, but I highly doubt it.”

With more people vaccinated now than in the past, can we consider COVID endemic, not a pandemic, now?

No, Gounder said.

“We are nowhere near endemic [status],” she said. “We are still very much pandemic. Saying it is endemic now is like saying, ‘Let’s do nothing.'”

Currently the U.S. is at a level of about 60% of the population vaccinated, she said.

“We really need to be getting to 85, 90 percent” before transitioning into endemic status.

In tropical countries, the flu is endemic, Ghedin said, ”and it’s there year-round. We are not there with SARS-CoV-2.”

Gut bacteria influence brain development

Extremely premature infants are at a high risk for brain damage. Researchers have now found possible targets for the early treatment of such damage outside the brain: Bacteria in the gut of premature infants may play a key role. The research team found that the overgrowth of the gastrointestinal tract with the bacterium Klebsiella is associated with an increased presence of certain immune cells and the development of neurological damage in premature babies.

Complex interplay: the gut-immune-brain axis

The early development of the gut, the brain and the immune system are closely interrelated. Researchers refer to this as the gut-immune-brain axis. Bacteria in the gut cooperate with the immune system, which in turn monitors gut microbes and develops appropriate responses to them. In addition, the gut is in contact with the brain via the vagus nerve as well as via the immune system. “We investigated the role this axis plays in the brain development of extreme preterm infants,” says the first author of the study, David Seki. “The microorganisms of the gut microbiome — which is a vital collection of hundreds of species of bacteria, fungi, viruses and other microbes — are in equilibrium in healthy people. However, especially in premature babies, whose immune system and microbiome have not been able to develop fully, shifts are quite likely to occur. These shifts may result in negative effects on the brain,” explains the microbiologist and immunologist.

Patterns in the microbiome provide clues to brain damage

“In fact, we have been able to identify certain patterns in the microbiome and immune response that are clearly linked to the progression and severity of brain injury,” adds David Berry, microbiologist and head of the research group at the Centre for Microbiology and Environmental Systems Science (CMESS) at the University of Vienna as well as Operational Director of the Joint Microbiome Facility of the Medical University of Vienna and University of Vienna. “Crucially, such patterns often show up prior to changes in the brain. This suggests a critical time window during which brain damage of extremely premature infants may be prevented from worsening or even avoided.”

Comprehensive study of the development of extremely premature infants

Starting points for the development of appropriate therapies are provided by the biomarkers that the interdisciplinary team was able to identify. “Our data show that excessive growth of the bacterium Klebsiella and the associated elevated ??-T-cell levels can apparently exacerbate brain damage,” explains Lukas Wisgrill, Neonatologist from the Division of Neonatology, Pediatric Intensive Care Medicine and Neuropediatrics at the Department of Pediatric and Adolescent Medicine at the Medical University of Vienna. “We were able to track down these patterns because, for a very specific group of newborns, for the first time we explored in detail how the gut microbiome, the immune system and the brain develop and how they interact in this process,” he adds. The study monitored a total of 60 premature infants, born before 28 weeks gestation and weighing less than 1 kilogram, for several weeks or even months. Using state-of-the-art methods — the team examined the microbiome using 16S rRNA gene sequencing, among other methods — the researchers analysed blood and stool samples, brain wave recordings (e.g. aEEG) and MRI images of the infants’ brains.

Research continues with two studies

The study, which is an inter-university clusterproject under the joint leadership by Angelika Berger (Medical University of Vienna) and David Berry (University of Vienna), is the starting point for a research project that will investigate the microbiome and its significance for the neurological development of prematurely born children even more thoroughly. In addition, the researchers will continue to follow the children of the initial study. “How the children’s motoric and cognitive skills develop only becomes apparent over several years,” explains Angelika Berger. “We aim to understand how this very early development of the gut-immune-brain axis plays out in the long term. ” The most important cooperation partners for the project are already on board: “The children’s parents have supported us in the study with great interest and openness,” says David Seki. “Ultimately, this is the only reason we were able to gain these important insights. We are very grateful for that.”

Vegetarians Have Better Cholesterol Than Meat Eaters

Vegetarians have better cholesterol and other measurements of heart health than meat eaters, according to the largest study of its kind to date.

Researchers compared 19 health measures related to diabetes, blood pressure, heart disease, cancer, liver and kidney function in 178,000 study participants who said they had followed a vegetarian or meat-eating diet for at least the last 5 years. They presented their results at this year’s online European Congress on Obesity.

The health benefits the researchers found for vegetarians were consistent despite different levels of obesity, sociodemographic factors and related lifestyle factors, said senior author Carlos Celis-Morales, PhD, of the University of Glasgow in Scotland.

Total cholesterol and LDL cholesterol concentrations for vegetarians in the study were 21% and 16.4% lower than in meat eaters. But some biomarkers considered beneficial, including vitamin D, were lower in vegetarians, while some considered unhealthy — including triglycerides and the kidney function indicator cystatin-C — were higher.

The study’s findings clearly confirm the importance of not looking at any health measurement in isolation, said John C. Mathers, PhD, of the Human Nutrition Research Centre at Newcastle University in the U.K.. “Health is complex and individual markers tell you just part of the story.”

Mathers says a vegetarian diet can be nourishing but cautioned that “just because someone excludes meat from their diet does not mean necessarily that they will be eating a healthy diet.”

The results support previous evidence from large studies, said Jose Lara Gallegos, PhD, senior lecturer in human nutrition at Northumbria University in the U.K., which showed that a vegetarian diet is associated with a lower risk of heart disease.

Strictly restricted diets could also lead to certain nutritional deficiencies, Gallegos said. “Other, less restrictive dietary patterns, such as a Mediterranean diet, are also associated with…health benefits.”

Many people, whether vegetarians or meat eaters, follow short-term diets, for example, the Atkins or the 5:2 diet, and often switch from one to another, or stop dieting altogether.

Metabolic markers tend to show clear improvement at around 3 months of adopting a particular diet, Celis-Morales said, but improvements in disease outcomes take a lot longer to become evident. In a separate study published last December, he and colleagues found that vegetarians have a lower risk than meat eaters for heart attacks and other heart disease over nearly a decade of follow-up.

Celis-Morales and his team are also looking at the data to understand if the vegetarian diet also brings a lower risk of cancer, depression, and dementia compared with meat-eaters.

Eye color genetics not so simple, study finds

The genetics of human eye colour is much more complex than previously thought, according to a new study published today.

An international team of researchers led by King’s College London and Erasmus University Medical Center Rotterdam have identified 50 new genes for eye colour in the largest genetic study of its kind to date. The study, published today in Science Advances, involved the genetic analysis of almost 195,000 people across Europe and Asia.

These findings will help to improve the understanding of eye diseases such as pigmentary glaucoma and ocular albinism, where eye pigment levels play a role.

In addition, the team found that eye colour in Asians with different shades of brown is genetically similar to eye colour in Europeans ranging from dark brown to light blue.

This study builds on previous research in which scientists had identified a dozen genes linked to eye colour, believing there to be many more. Previously, scientists thought that variation in eye colour was controlled by one or two genes only, with brown eyes dominant over blue eyes.

Co-senior author Dr Pirro Hysi, King’s College London, said: “The findings are exciting because they bring us to a step closer to understanding the genes that cause one of the most striking features of the human faces, which has mystified generations throughout our history. This will improve our understanding of many diseases that we know are associated with specific pigmentation levels.”

Co-senior author Dr Manfred Kayser, Erasmus University Medical Center Rotterdam, said:

“This study delivers the genetic knowledge needed to improve eye colour prediction from DNA as already applied in anthropological and forensic studies, but with limited accuracy for the non-brown and non-blue eye colours.”

Managing diabetes after incarceration: A difficult journey

For the average adult, a diabetes diagnosis is life-changing. Managing diabetes involves a daily routine that shifts toward remembering to take medication, check blood sugar, and monitor carbohydrate intake.

Frequent trips to multiple doctors’ offices become the norm, as regular foot checks, dental appointments, eye exams, and primary care visits are crucial for avoiding the complications of poorly managed disease.

These complications can include gum disease, cardiovascular problems, nerve damage, kidney failure, blindness, and even amputation. Individuals who receive an early diagnosis and manage the disease well can expect to live as long as those without diabetes, but research has linked poor disease management to reduced life expectancy of up to 8 years.

For someone reentering society after being in prison, managing diabetes can be quite difficult. In the United States, more than 2 million people are incarcerated in jails and prisons on a given day, and nearly 5% of them have diabetes.

These individuals typically do not serve life sentences; rather, 95% eventually return to community settings that may not readily embrace them or their medical needs.

For example, taking medication every day requires having a safe place to live and store medications. This is not a given for formerly incarcerated people, many of whom often struggle simply to find a place to live.

In the U.S., individuals who have been inmates in jails or prisons just once are seven times more likely to experience homelessness than the general population. Meanwhile, those who have been incarcerated two or more times are 13 times more likely than other people to lack housing.

Individuals with a criminal history face numerous collateral consequences of conviction — legal restrictions that disqualify them from accessing a range of resources and opportunities upon release.

Unemployment is a major concern for people with a criminal history. According to the Prison Policy Initiative, individuals with a criminal history are nearly five times more likely to be unemployed than the general population.

Many employment sectors bar those with a criminal history, limiting their ability to earn the money necessary to afford adequate housing. Those who turn to low-income housing programs often face being denied access, as many public housing programs have strict eligibility criteria that exclude individuals with a criminal history.

This is true even for older adults. Many low-income senior housing assistance programs deny access to individuals with recent criminal convictions and permanently ban those with a history of criminal sexual conduct, even if the crime occurred decades earlier.

Additionally, food insecurity complicates diabetes management for formerly incarcerated adults. Access to adequate quantities of nutritious food is crucial for effective diabetes management.

A diabetes-friendly diet restricts carbohydrate intake, as carbohydrate-rich foods often raise blood glucose levels higher and faster than foods rich in protein and fiber.

Formerly incarcerated individuals, however, often report great difficulty in accessing healthful foods. Estimates of food insecurity among formerly incarcerated individuals returning to community settings are as high as 91%.

Among the many collateral consequences of criminal conviction in the U.S. are limitations on the receipt of federal supplemental nutrition assistance program benefits (i.e., SNAP or food stamps) for individuals convicted of certain criminal offenses.

While most states have eliminated lifetime bans on food assistance, more than 30 states still place some restrictions on food assistance for individuals with felony drug convictions.

Faced with an inability to afford nutritious foods, food-insecure individuals often turn to cheap, high calorie foods, which can lead to weight gain, poor blood glucose control, and an increased risk of diabetes-related health complications.

Likewise, poor healthcare access and utilization negatively affect diabetes management among formerly incarcerated adults. Access to affordable health insurance is crucial for disease management, as the self-management of diabetes requires visits to primary care doctors and specialists; the ongoing use of medication, such as insulin and oral medications; and daily use of testing supplies, including glucose test strips and glucose meters.

Uninsured adults with diabetes engage in fewer preventive healthcare activities than their insured counterparts, including less daily blood glucose monitoring, reduced participation in diabetes education classes, and fewer foot and eye exams.

Historically, a lack of health insurance has been a significant barrier to healthcare access for formerly incarcerated individuals. Given the difficulties of finding employment after incarceration, employer-based health insurance is typically not an option.

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Traditionally, Medicaid coverage has been limited to pregnant women, parents with a low income, and those under the age of 65 with disabilities. Notably, this does not include men (who make up about 93% of the U.S. state and federal prison population), unless they care for minor children or have disabilities.

At the end of their sentence, individuals with diabetes may have trouble obtaining health insurance, depending on where they live. Since the Affordable Care Act of 2010, 39 U.S. states (including the District of Columbia) have expanded Medicaid to include all adults with a low income, regardless of gender, disability, or parenting status.

Given the barriers that formerly incarcerated individuals face, ensuring adequate diabetes management in this population will require a host of system-level changes. Providing widespread access to health insurance for individuals with diabetes and a low income is crucial.

Without it, formerly incarcerated adults with diabetes will forego necessary medical care simply because they cannot afford it. This lack of treatment will only increase their risk of adverse disease-related complications.

The benefits of Medicaid expansion have been well-documented — if all remaining states fully implemented Medicaid expansion, nearly 4 million people would gain health insurance, decreasing the number of uninsured adults by 28%. The remaining states must be encouraged to expand their Medicaid programs to provide greater access to healthcare coverage in this population.

Additionally, there must be increased policy advocacy surrounding the health-related collateral consequences of criminal conviction. As they reenter community settings, individuals with a criminal history face countless barriers that adversely affect their ability to manage diabetes or any other chronic health condition effectively.

Most criminal justice advocacy work examines the impact of collateral consequences on economic security. However, policies that restrict employment, housing, and access to healthful food for those with criminal records also ultimately endanger population health.

Chronic disease management and population health must be a part of the conversation when advocating for criminal justice reform.

As the U.S. population ages, and chronic health conditions become more prominent, failure to integrate these issues into larger criminal justice policy discussions will just add to the difficulties that formerly incarcerated adults must deal with as they attempt to reintegrate into society.

What Does Asymptomatic COVID-19 Look Like Under the Surface?

Asymptomatic individuals carrying SARS-CoV-2 shed the virus longer than those with COVID-19 symptoms, with other lab findings suggesting the symptomatic patients mounted more robust immune responses, a small study in China found.

Median duration of viral shedding among 37 asymptomatic patients was 19 days (interquartile range 15-26; range 6-45) versus 14 days among 37 matched symptomatic patients (IQR 9-22; log-rank P=0.028), reported Jing-Fu Qiu, PhD, of Chongqing Medical University, and colleagues, though viral shedding does not necessarily mean the patients were infectious.
Virus-specific IgG antibody titers and cytokine levels were also significantly lower among asymptomatic patients in the acute phase of infection, when viral RNA can be found in respiratory specimens, the authors wrote in Nature Medicine — both of which indicated that immune responses weren’t as strong in the asymptomatic group.

Asymptomatic transmission of COVID-19 is one of its biggest mysteries, with the World Health Organization recently reminding the public of the distinction between asymptomatic patients, who never develop symptoms, and presymptomatic patients, who go on to develop symptoms later in the course of disease.

Qiu and colleagues characterized asymptomatic carriers as the “silent spreaders” of COVID-19.

“However, our understanding of the clinical features and immune responses of asymptomatic individuals with SARS-CoV-2 infection is limited,” the researchers added.

For the study, they examined data from 178 patients with PCR-confirmed SARS-CoV-2 infection in the Wanzhou District in China, including 37 without symptoms. Median age in the latter was 41, and 22 were women. These individuals were matched by age, sex, and comorbidity with 37 symptomatic patients for antibody detection and cytokine measurement. Qiu and colleagues also included a group of 37 individuals who tested negative via RT-PCR for cytokine comparisons.

Lab values and imaging were not entirely normal for the asymptomatic group. Eleven had increased C-reactive protein levels and six had elevated levels of alanine aminotransferase. Chest CT found “focal ground-glass opacities” in 11 and “stripe shadows and/or diffuse consolidation” in another 10 of the group; in two-thirds of these 21 patients, the abnormalities were in only one lung. The remaining 16 showed entirely normal imaging.

Around 80% of both symptomatic and asymptomatic patients tested positive for IgG antibodies about 3-4 weeks after exposure. The difference was greater when examining IgM antibodies, with positive findings in 78.4% of symptomatic patients and 62.2% of asymptomatic patients.

In the early convalescent phase, defined as 8 weeks after hospital discharge, symptomatic patients had higher IgG levels, though both groups experienced over 90% decreases in IgG levels. A larger proportion of asymptomatic patients had decreases in neutralizing serum antibody levels versus symptomatic patients (81.1% vs 62.2%, respectively).

These findings should serve as a caution against assuming prior infection confers immunity to future infection, Qiu and colleagues said.

“These data might indicate the risks of using COVID-19 ‘immunity passports’ and support the prolongation of public health interventions, including social distancing, hygiene, isolation of high-risk groups, and widespread testing,” the team wrote.

Plasma levels of cytokines were also similar between asymptomatic patients and healthy controls, though significantly higher levels of stem cell factor and leukemia inhibitory factor were found in the asymptomatic group, the researchers noted, calling this a “reduced inflammatory response characterized by low circulating concentrations of cytokines and chemokines.”

Qiu and co-authors cited the varying sensitivity and specificity of antibody tests (obtained from a company called Bioscience) as a limitation to their study, adding that the results may be confounded by existing antibodies to other coronaviruses, such as SARS or MERS, as well as common cold viruses.

Vaccine makers face biggest medical manufacturing challenge in history

Developing a COVID-19 vaccine in record time will be tough. Producing enough to end the pandemic will be the biggest medical manufacturing feat in history.
That work is underway.

From deploying experts amid global travel restrictions to managing extreme storage conditions, and even inventing new kinds of vials and syringes for billions of doses, the path is strewn with formidable hurdles, according to Reuters interviews with more than a dozen vaccine developers and their backers.

Any hitch in an untested supply chain – which could stretch from Pune in India to England’s Oxford and Baltimore in the United States – could torpedo or delay the complex process.

Col. Nelson Michael, director of the U.S. Army’s Center for Infectious Disease Research who is working on the government’s “Warp Speed” project to deliver a vaccine at scale by January, said companies usually have years to figure this stuff out.

“Now, they have weeks.”

Much of the world’s attention is focused on the scientific race to develop a vaccine. But behind the scenes, experts are facing a stark reality: we may simply not have enough capacity to make, package and distribute billions of doses all at once.

Companies and governments are racing to scale-up machinery to address a critical shortage in automated filling and finishing capacity – the final step in the manufacturing process of putting the vaccine into vials or syringes, sealing them and packaging them up for shipping.

“This is the biggest logistical challenge the world has ever faced,” said Toby Peters, an engineering and technology expert at Britain’s Birmingham university. “We could be looking at vaccinating 60% of the population.”

Several developers, including frontrunner Moderna, are experimenting with new ways to mitigate the extreme cold storage demands of their vaccines, which at present need to be kept at minus 80 degrees Celsius (-112 Fahrenheit).

SiO2 Materials Science is working on producing vials that won’t shatter at super-cold temperatures.

Travel restrictions, meanwhile, are posing more prosaic problems; Johnson & Johnson, which plans to start clinical trials this summer, has struggled to send its vaccine experts to oversee the launch of production sites, for example.

By setting up massive clinical trials involving 10,000 to 30,000 volunteers per vaccine, scientists hope to get an answer on whether a vaccine works as early as this October. But even if they succeed, manufacturing in bulk, getting regulators to sign off and packaging billions of doses is a monumental challenge.

Seth Berkley, chief executive of the GAVI vaccines alliance, said in reality, the world is unlikely to go straight from having zero vaccines to having enough doses for everyone.

“It’s likely to be a tailored approach to start with,” he said in an interview. “We’re looking to have something like one to two billion doses of vaccine in the first year, spread out over the world population.”

J&J has partnered with the U.S. government on a $1 billion investment to speed development and production of its vaccine, even before it’s proven to work. It has contracted Emergent Biosolutions and Catalent to manufacture in bulk in the United States. Catalent will also do some fill-and-finish work.

“Never in history has so much vaccine been developed at the same time – so that capacity doesn’t exist,” said Paul Stoffels, J&J’s chief scientific officer, who sees filling capacity as the main limiting factor.

Emergent’s manufacturing plant in Bayview, Maryland, can accommodate four vaccines in parallel using different manufacturing platforms and equipment.

Funded by the government in 2012, the plant includes single-use disposable bioreactor equipment featuring plastic bags rather than stainless steel fermentation equipment, which makes it easier to switch from one vaccine to another.

This month, the company received an additional $628 million to make those four suites available to support any candidate the government selects, CEO Bob Kramer told Reuters.


As well as working with J&J, New Jersey-based Catalent signed a deal with British drugmaker AstraZeneca last week to provide vial-filling and packaging services at its plant in Anagni, Italy. It aims to handle hundreds of millions of doses, starting as early as August 2020 and possibly running through until March 2022.

It has ordered high-speed vial-filling equipment to boost output at its Indiana plant, where it is also hiring an additional 300 workers.

Michael Riley, Catalent’s North American president for biologics, told Reuters his biggest challenge was trying to compress work that normally takes years into months.

Adding to the challenge is that glass vials are in short supply.

To save glass, companies plan to use larger vials of five to 20 doses – but this raises new problems, such as potential waste, if not all the doses are used before the vaccine spoils.

“The downside is that after a healthcare practitioner opens a vial, they need to then vaccinate 20 people in a short, 24-hour time,” said Prashant Yadav, a global healthcare supply-chain expert at the Center for Global Development in Washington.

As part of the same drive, the U.S. Department of Health and Human Services and the Department of Defense have awarded ApiJect Systems up to $138 million to upgrade its facilities to be able to make up to 100 million plastic pre-filled syringes by the end of this year, and as many as 600 million in 2021.

The company plans to use a technology called Blow-Fill-Seal, where syringes are blown out of plastic, filled with vaccine and sealed in seconds. This will need Food and Drug Administration approval, CEO Jay Walker told Reuters.

SiO2 Materials Science is, meanwhile, ramping up capacity of plastic vials with a glass lining, which are more stable at ultra-low temperatures.

“You can bring us down to minus 196 Celsius, which none of the vaccines need,” Chief Business Officer Lawrence Ganti said. “You can throw it against the wall and it doesn’t break. Our founder has done that. He’s thrown frozen vials at me.”

The company expects to boost production from the current 5-10 million vials a year to 120 million within three-and-a-half months, he told Reuters.

Once packaged, many vaccines need to be kept cold – and some leading contenders made from genetic material such as messenger RNA need to be kept very cold – presenting another challenge that may limit access.

“People who work with mRNA store it at minus 80 degrees centigrade, which is not something you’re gonna find in most pharmacies or doctor’s offices,” said Dr. Paul Offit, director of the Vaccine Education Center at Children’s Hospital of Philadelphia and co-inventor of the rotavirus vaccine.

Peters of Birmingham university has been gathering data from poorer regions of Africa and Asia, and said breaks in the temperature-controlled supply chain – “cold chain” – are already frequent.

In some places, it is common to lose 25% or more of vaccines because of broken cold chains, he told Reuters.

“So if you’re looking to manufacture four billion, and you reckon you’re going to lose 25%, then you have to manufacture five billion,” he said. “It’s all the elements to move it from the point of manufacture to the point of aggregation, right down to the health centres and then out to the community.”

Companies developing mRNA vaccines, including Moderna and Translate Bio, which is partnering with Sanofi, are working to make candidates stable at higher temperatures.

Ron Renaud, CEO of Translate Bio, said he was confident this would happen “within a short amount of time”.

Colleen Hussey, a Moderna spokeswoman, said: “We are getting more confident that we could run our supply chain at -20C, which is an easier storage condition than deep freezing,” she said.

Moderna plans to add a small period of time in which the vaccine can be stored at normal fridge temperatures of 2 to 8 degrees Celsius in doctors’ offices or clinics.

“We will know more in the next 2-3 months,” she said.

The pandemic is also presenting obstacles of a less technical nature.

Catalent, which has some 30 plants globally, has had to write special permission slips in eight languages explaining that their workers are considered essential.

J&J is having trouble getting experienced personnel to far-flung labs to oversee the transfer of technology to contract manufacturers because they’re subject to 14-day quarantines.

“It is absolutely a factor,” said Stoffels. “If you have to send your people to the middle of India to get to filling capacity, that’s not easy at the moment.”

Alzheimer’s gene risk triggers blood-brain barrier damage

Scientists have known for some time that the APOE4 gene is a risk factor for Alzheimer’s disease. A new study helps to explain why, by showing that the variant has an association with damage to the blood-brain barrier.

APOE4 is the leading genetic risk factor for Alzheimer’s disease. Almost one-quarter of people have one copy of the gene, which increases the risk of developing Alzheimer’s disease by up to four times.

In rarer cases, approximately 2–3% of the population, people carry two copies of the gene, which increases the risk of developing the disease by up to 15 times.

People who carry the variant, whether they have one copy or both, also develop the disease earlier than those who do not.

Although APOE4 is clearly important in the onset of many cases of Alzheimer’s disease, precisely how the genetic variant increases risk has been unclear.

Scientists from the University of Southern California (USC) have now shown a link between APOE4 and damage to the blood-brain barrier, the key structure that protects the brain from toxic substances.

The findings, which could aid the development of personalized treatment strategies for Alzheimer’s disease, appear in Nature.

APOE4 and the blood-brain barrier
This latest study focused on the blood-brain barrier, the protective border of cells separating the blood from the brain. Previous research from the group had shown that people who develop problems with their memory early on also had damage to this structure.

Their research has also shown that people with the APOE4 variant who go on to develop Alzheimer’s disease have a leaky blood-brain barrier, even before doctors can see any changes to cognition.

To investigate the connection between APOE4 and the blood-brain barrier in more detail, the team behind this study used a specialized form of MRI. They looked at the blood-brain barrier of people with mild cognitive impairment — which can be a precursor to Alzheimer’s disease — and those with normal cognitive function, both with and without APOE4.

They found that people who carried the APOE4 variant had a leaky blood-brain barrier in parts of the brain that are critical for memory function, including the hippocampus, even if they were cognitively healthy at the time of the scan.

Those who were experiencing cognitive decline had even worse damage to their blood-brain barrier.

Changes link with cognitive decline
To understand what was causing the leakage in the blood-brain barrier, the researchers looked for damage to a particular cell type — the pericytes — which wrap around blood vessels in the brain to form the critical barrier.

Using a biomarker of pericyte injury, they found higher levels of damage in APOE4 carriers. What is more, the researchers associated levels of the biomarker with both blood-brain barrier damage and cognitive decline.

“Severe damage to vascular cells called pericytes was linked to more severe cognitive problems in APOE4 carriers,” explains senior author Prof. Berislav Zlokovic, director of the Zilkha Neurogenetic Institute at USC.

Further experiments showed that the damage also correlated with levels of a protein that causes inflammation called cyclophilin A, which is known to be an early sign of Alzheimer’s disease.

Thus, the team was able to put together a hypothesis for how APOE4 causes damage to the blood-brain barrier, potentially leading to the onset of Alzheimer’s disease.

“APOE4 seems to speed up the breakdown of the blood-brain barrier by activating an inflammatory pathway in blood vessels, which is associated with pericyte injury,” says Prof. Zlokovic.

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Treating the damage
Some parts of the theory need fleshing out, for example, how damage to the blood-brain barrier causes the symptoms of Alzheimer’s disease. Nevertheless, these findings are a step forward in our understanding of how APOE4 shapes Alzheimer’s disease risk.

Future work will be necessary to better understand the genetic risk factors for the disease and, potentially, developing personalized treatments.

Experiments in mice have already shown that blocking the inflammatory process that APOE4 triggers can restore the blood-brain barrier and improve neuronal function, raising hope that doctors could use similar treatments for Alzheimer’s.

First 72 Hours After Acute Kidney Injury Matter

Acute kidney injury (AKI) — even when it resolved quickly — was tied to poorer long-term renal outcomes in a prospective cohort study.
People who experienced non-resolving AKI saw more than a two-fold higher risk for a major adverse kidney event (MAKE) compared with those who didn’t have AKI (adjusted hazard ratio 2.30, 95% CI 1.52-3.48, P<0.001), reported Pavan Bhatraju, MD, MSc, of the University of Washington in Seattle, and colleagues. Even those whose kidney function resolved within 72 hours after a diagnosis of AKI also had a 52% higher risk for a long-term MAKE compared with those with AKI (aHR 1.52, 95% CI 1.01-2.29, P=0.04), according to the study online in JAMA Network Open. However, when the researchers compared cases of AKI, those whose AKI did not resolve saw a significantly higher rate of a MAKE -- a composite of progressive kidney disease, need for long-term dialysis, or all-cause mortality (aHR 1.51, 95% CI 1.22-1.88, P<0.001) compared with those whose AKI resolved. These associations were adjusted for demographic factors like age, sex, and race, as well as for clinical factors including diabetes status, chronic kidney disease status, cardiovascular disease, and sepsis. The associations were also still significant after the group controlled for the magnitude of increased serum creatinine concentrations -- or the AKI stage -- in those who recovered from their AKI. Nearly three-quarters of those with AKI had injury classified as stage 1. "The use of AKI recovery subgroups to risk stratify patients with AKI we believe is clinically intuitive," Bhatraju's group wrote. The observational study included 1,538 hospital patients: half of whom did not experience AKI, 31% of whom had resolving AKI, and 19% who had non-resolving AKI within 3 months of admission. AKI was defined according to standard diagnostic criteria: an increase in serum creatinine concentration of 50% or more or 0.3 mg/dL or more above an outpatient, non-emergency department baseline value within 7 to 365 days prior to the initial hospital admission. AKI that resolved was considered to be a decrease in serum creatinine concentration of 0.3 mg/dL or more or at least 25% from maximum within the initial 72 hours following an AKI diagnosis. During median follow-up of 4.7 years, 36% of the entire cohort had a MAKE. "[These findings] provide evidence for considering the timing of functional recovery from AKI as a factor associated with future adverse events," Ravindra Mehta, MBBS, MD, DM, of the University of California San Diego, said in an accompanying commentary. He also noted that while these findings highlight the value of using AKI recovery pattern to predict long-term kidney outcomes, the study simultaneously underscores how current AKI staging criteria was not helpful in predicting these outcomes "as the severity stage by itself did not differentiate among which patients would develop MAKE." "It is ... clear that clinicians managing patients with AKI should consider the severity of the disease and the ensuing course and tailor their diagnostic and therapeutic interventions to facilitate rapid and complete recovery of kidney function," he concluded.