Khalid Al Sulaiman, Ohoud Aljuhani, Maram Al Dossari, Asma Alshahrani, Aisha Alharbi, Rahmah Algarni, Majed Al Jeraisy, Shmeylan Al Harbi, Abdulmalik Al Katheri, Fahad Al Eidan, Abdulkareem M. Al Bekairy, Nouf Al Qahtani, Mashael Al Muqrin, Ramesh Vishwakarma, Ghassan Al Ghamdi
Background: Thiamine is a precursor of the essential coenzyme thiamine pyrophosphate (TPP) required for glucose metabolism; it improves the immune system function and has been shown to reduce the risk of several diseases. The role of thiamine in COVID-19 critically ill patients is still unclear, however, its role in the critically ill septic patient has been addressed in multiple studies. The objective of this study was to evaluate the use of thiamine as adjunctive therapy on the mortality in COVID 19 critically ill patients.
Methods: This is a multicenter, non-interventional, retrospective cohort study for all critically ill patients admitted to intensive care units (ICUs) with a confirmed diagnosis of COVID19. All patients aged 18 years or older who were admitted to ICUs between March 1st to December 31st, 2020 with positive PCR COVID-19 were included in the study. We investigated the association between thiamine use as an adjunctive therapy and clinical outcomes in COVID -19 after propensity score matching using baseline severity scores, systemic use of corticosteroids and study centers.
Results: A total of 738 critically ill patients with COVID-19 who had been admitted in ICUs at the two governmental hospitals included in the study. Among 166 patients matched using propensity score, 83 had received thiamine as adjunctive therapy. There was significant association between thiamine use with in-hospital mortality (OR=0.49; 95% CI = 0.25- 0.97; P=0.04) as well with 30-day ICU mortality (OR=0.45; 95% CI = 0.215- 0.935; P=0.03). Moreover, patients who received thiamine as an adjunctive therapy were less likely to have thrombosis during ICU stay by 81 % (OR (95%CI): 0.19 (0.040,0.884), p-value=0.034).
Conclusion: Thiamine use as an adjunctive therapy may have potential survival benefits in critically ill patients with COVID-19.
A phase 3 trial of Romark’s antiviral drug NT-300 has missed the main objective in a phase 3 trial in mild to moderate COVID-19 patients, but could still have a shot at emergency use authorisation (EUA), according to the US company.
The Florida-based firm has just released top-line results from the 1,092-patient study, showing that patients treated NT-300 – an orally-active, long-acting formulation of the established drug nitazoxanide – didn’t differ significantly from a placebo group in the time it took to recover from COVID-19.
The median time to sustained response was 13 days in both groups, although a subgroup analysis of people with mild symptoms found a three-day reduction with Romark’s drug.
The company is highlighting a secondary finding in the trial, which showed that NT-300 reduced progression to severe disease in all evaluable patients by 85% compared to placebo. Severe disease was seen in 0.5% of the NT-300 group (one patient), compared to 3.5% of those taking placebo.
That is at the top end of the range of reductions achieved with monoclonal antibodies targeting SARS-CoV-2 that have been granted EUAs by the FDA, it says. So far, Eli Lilly’s bamlanivimab and etesevimab and Regeneron’s casirivimab and imdevimab are the only antibody drugs cleared by the US regulator for this use.
At the moment, the only antiviral drug approved for use in COVID-19 is Gilead Sciences’ Veklury (remdesivir), which has to be administered by intravenous infusion and is only used for hospitalised patients aged 12 or over.
A spokesperson for Romark said that there is a need for an oral medicine that can be taken at home, after COVID-19 symptoms start to appear, to protect people from progressing to severe disease.
If cleared, NT-300 could be used in a similar way to Roche’s Tamiflu (oseltamivir), a drug used to reduce the time to recovery for people with flu, she suggested. Based on the findings, Romark says it is working with the FDA to try to get an EUA for NT-300.
“Along with vaccines and treatments for severe illness, oral treatments that can be administered outside of a hospital setting to effectively reduce disease progression are urgently needed,” said Romark’s chief medical officer Jean-François Rossignol.
“Our results compare favourably with therapeutics that have been granted [EUAs] for use in a hospital setting in patients at high risk of developing serious COVID-19,” he added.
Romark started testing the drug for COVID-19 after lab studies showed it was able to inhibit the replication of a broad range of respiratory viruses, including SARS-CoV-2.
NT-300 is also in phase 3 development for treating and preventing acute respiratory illnesses caused by a broad range of respiratory viruses, including influenza, parainfluenza and respiratory syncytial virus (RSV).
Romark already markets an immediate-release formulation of the drug as Alinia for the parasitic diseases Cryptosporidium parvum and Giardia lamblia.
As COVID-19 cases surge again in the United States, coronavirus variants are on the rise. But researchers fear that the country is ramping up surveillance of the coronavirus SARS-CoV-2 too slowly, allowing these variants — which evidence shows1,2could make vaccines less effective — to spread undetected in one of the countries hit hardest by the disease.
Laboratories supported by the US government have doubled the rate at which they are sequencing SARS-CoV-2 genomes over the past two months. Still, the number of genomes that the country shared in the online genome repository GISAID in March represented only 1.6% of its positive COVID-19 cases that month. And the United States lags behind at least 30 countries in terms of the sequencing it has done throughout the pandemic, according to GISAID data.
This frustrates researchers because the United States possesses the equipment and expertise to be doing far more. “We have enough sequencers to sequence SARS-CoV-2 from every case, 100 times over,” says Kristian Andersen, an immunologist at the Scripps Research Institute in La Jolla, California.
A dozen academic researchers at some of the leading virus-sequencing labs in the United States tell Nature that a series of problems is holding the country back. Last year, university labs were doing the majority of coronavirus sequencing in the country. They are still responsible for approximately 40% of the sequences on GISAID, with companies and government labs now adding to the effort.
US President Joe Biden listed variant surveillance as a priority for his administration immediately after taking office in January, and it was specified as a response measure that will receive some of the US$19 billion in COVID-19 relief funds announced that month. But researchers say federal money isn’t flowing fast enough and systemic problems in sharing samples and data are preventing them from ramping up.
It’s not for lack of trying. The US Centers for Disease Control and Prevention (CDC) is additionally investing $200 million to expand surveillance at university, government and company labs, and it has launched initiatives to connect researchers at these labs and track data. The agency is continuing to fund several universities as part of its long-standing Emerging Infections Program, in which academic labs partner with state health departments. But genomic surveillance at this scale has never happened anywhere before — and the fragmented US health system makes coordination a gargantuan task, researchers agree. Hospitals, diagnostic testing labs, local health departments and sequencing centres have rarely worked in unison with one another.
“The biggest challenge is that we don’t have a single health system,” says Art Reingold, an epidemiologist at the University of California, Berkeley. “It’s a nightmare.”
Spotty surveillance
To test for SARS-CoV-2, researchers extract RNA from a specimen and search for genetic fragments indicative of the virus. Some university labs that became testing centres during the pandemic sequenced the entire genomes of viruses when time and money allowed, putting them at the forefront of surveillance efforts last year. “Our sequencers have been humming since the start of the pandemic,” says Pavitra Roychoudhury, a computational biologist at the clinical virology department at the University of Washington (UW) in Seattle. But a lack of money for supplies and for paying researchers has frequently prevented Roychoudhury’s lab from sequencing its total capacity of about 1,000 genomes per week.
Sources: GISAID, COVID-19 Genomics UK Consortium, and Covid-19 CG
Despite financial limitations, her lab and others have demonstrated the importance of sequencing. For example, at Scripps, Andersen’s team identified the first coronavirus variant to appear in California in early January — the B.1.1.7 variant, which emerged in the United Kingdom. “San Diego is now at 50% B.1.1.7, and very soon everything we have will be B.1.1.7,” he says, adding that this variant has been shown3 to correlate with a higher risk of death from COVID-19.
The CDC tried to help with surveillance last spring by launching a programme, called Sequencing for Public Health Emergency Response, Epidemiology and Surveillance (SPHERES), to connect researchers at universities, companies and government labs. Although it was successful at creating a flow of information between these entities, SPHERES didn’t dole out funding and therefore didn’t significantly increase sequencing rates.
With the CDC now awarding funds to university, health-department and company labs, the country’s sequencing will soon accelerate, says Duncan MacCannell, the chief science officer at the CDC’s Office of Advanced Molecular Detection. In March, nearly 29,000 coronavirus sequences from the United States were uploaded onto GISAID, which has the most SARS-CoV-2 sequences in the world, even though it doesn’t contain all of the genomes sequenced. But at the current pace of COVID-19 infections in the United States, the country must reach about 23,000 sequences per week to sequence 5% of all cases, a benchmark considered sufficient to detect emerging variants. (This figure comes from a modelling study4 published on the medRxiv preprint server without peer review and funded by the biotechnology company Illumina, based in San Diego, California.)
Saving samples
But researchers at several labs say a lack of samples is as big of a problem as a lack of funding. “We could easily run 1,500 samples each week, but we’re running about 380,” says Lea Starita, a genomicist at the UW Northwest Genomics Center in Seattle. “Someone needs to be willing to fork samples over.”
The problem is that most COVID-19 tests are conducted in diagnostic labs at companies that don’t regularly do genomic sequencing. These labs frequently discard samples after testing, because saving them requires extra labour and storage.
But if a health department wants a deeper investigation into an individual case, officials might ask researchers at a nearby university to sequence the sample. “So we have to scramble to go back to the [testing] lab, and say, do you still have the specimen for Mr. Jones? Save it! Save it! And that’s a huge challenge,” explains William Schaffner, an infectious-disease specialist at Vanderbilt University in Nashville, Tennessee, who works with the Tennessee Department of Health as part of the CDC’s Emerging Infections Program. Some testing sites won’t have saved the sample. Others won’t share it for privacy or proprietary reasons, explains Reingold.
The CDC is all too aware of the issues. “We have a very distributed testing system, and private testing labs that aren’t incentivized to hang onto samples,” says MacCannell. He and his colleagues are helping diagnostic labs either ramp up their own sequencing or connect with labs that can. The agency has also provided guidance on how public-health labs can partner with academic institutions for coronavirus surveillance. “One of our long-standing goals,” MacCannell says, “is to figure out better ways to engage with academics throughout the public-health system.”
Data flow
Certain university labs, such as the Broad Institute of MIT and Harvard in Cambridge, Massachusetts, don’t have a problem getting samples, because they’ve served as major testing centres throughout the pandemic. Health departments and hospitals in their states were already shipping specimens to these labs. But every researcher interviewed by Nature — including MacCannell at the CDC — complained about a lack of information connected to samples.
Such data are needed to uncover where variants are spreading, if variants make the coronavirus more contagious and whether variants help the coronavirus to evade vaccines or natural immunity from a prior infection. This information is scattered like crumbs along the path that a sample travels, but hospitals, health departments and labs are often reluctant to release data because of privacy or proprietary reasons. Stacia Wyman, a computational genomicist at the Innovative Genomics Institute at the University of California, Berkeley, says, “It’s tough to know what’s allowed, and public-health departments don’t have a huge bandwidth for this.”
MacCannell says siloed data have been a problem for the CDC for many years. “Historically, disease surveillance has been very difficult because many states are uncomfortable with details being provided in public databases.” But he’s heartened that the need to keep tabs on coronavirus variants has raised the profile of this issue, and hopes that it will help researchers at disconnected institutions to find ways to share information that could save lives.
In that vein, a platform to share de-identified data on individual COVID-19 cases launched last month. And a philanthropic organization funding the platform, the Rockefeller Foundation, has announced plans to build an even larger version, with the goal of including data from genomic sequencing and analyses presented in ways to help inform policies.
However, MacCannell and other researchers argue that a government agency, such as the CDC, is best positioned to cut through the red tape that prevents samples from moving to sequencing labs or data from flowing. “I’m convinced that we can do this, and that we can be nimble,” says MacCannell. “But, you know, it is challenging in a pandemic.”
Two proteins in blood -- plasma neurofilament light chain (NfL) and total tau -- were associated with cognition and neuroimaging outcomes, strengthening their potential as blood-based biomarkers of neurodegeneration, a large longitudinal study showed.
At baseline, NfL was more strongly associated with brain atrophy in multiple areas, white matter alterations, and changes in global cognition, reported Michelle Mielke, PhD, of the Mayo Clinic in Rochester, Minnesota. The combination of elevated NfL and total tau at baseline was more strongly associated with worse global cognition and memory loss and with neuroimaging measures, including temporal cortex thickness and increased number of infarcts.
However, total tau did not add to the prognostic value of NfL over the 6-year study, Mielke said.
Previous research has linked elevated levels of plasma total tau and NfL with worse cognition and neuroimaging measures of cortical thickness, cortical atrophy, white matter hyperintensity, or white matter integrity, but have not compared the two proteins, Mielke noted. "The emergence of neurofilament light and total tau in recent years as candidate plasma biomarkers of neurodegeneration merits direct comparison of their relationships with cognition and neuroimaging," she told MedPage Today.
"It is important to understand which plasma neurodegeneration marker would be most useful for clinical trials and for diagnosis or prognosis in clinical settings," Mielke added. "Our results suggest that plasma NfL had better utility as a prognostic marker of cognitive decline and neuroimaging changes. Plasma total tau added some cross-sectional value to NfL in specific contexts related to memory performance."
Neurodegeneration, or brain cell loss, is characteristic of many disorders including Alzheimer's disease, vascular dementia, and Lewy body dementia. Causes and location of neurodegeneration in the brain vary with disease. "For example, in Alzheimer's disease, amyloid plaques and neurofibrillary tangles contribute to neurodegeneration and there tends to initially be more brain cell loss in the temporal lobe," Mielke said. "In vascular-related cognitive impairment, infarct, white matter hyperintensities, and microbleeds can contribute to cognitive changes."
In their study, Mielke and colleagues followed 995 participants in the community-based Mayo Clinic Study of Aging who had plasma NfL and total tau measurements, cognitive assessments, and neuroimaging data. Follow-up tests were repeated about every 15 months for a median of 6.2 years. Results were similar when researchers replicated their analyses in the multicenter Alzheimer's Disease Neuroimaging Initiative cohort of 387 people without dementia who were followed for a median of 3 years.
Having information about total tau did provide additional insights, Mielke pointed out. "For example, the combination of having both elevated NfL and total tau was more strongly associated with worse memory performance at the time of assessment," she noted. It may be useful to add measurements of total tau to NfL as a diagnostic tool, she suggested.
But "for prognosis purposes, neurofilament light better predicted the rate of neurodegeneration and cognitive decline, regardless of what the cause of neurodegeneration might be," Mielke said. NfL also may help determine how fast someone declines and how effective future therapies might be in slowing this decline, she added.
Disclosures
This research was funded by National Institutes of Health and National Institute on Aging grants, the GHR Foundation, and the Rochester Epidemiology Project.
Precision Biosciences’ allogeneic Car-T cell projects have, over the past five years, been passed from Baxalta to Shire to Servier. As of yesterday they are back with Precision after the biotech company paid $1.3m, and waived its right to future milestones, to buy the assets back from Servier.
Though the markets might question this strange turn of events, the projects had sat oddly at Servier, which already had a deal covering allogeneic Car-T therapy with a rival of Precision’s, Cellectis. Still, their clinical progress has been slow, and the fact that their reacquisition has coincided with a major C-suite overhaul at Precision might not give investors confidence.
The most significant senior departure is Precision’s founding chief executive, Matt Kane, who is to leave once a successor has been found, it was announced 10 days ago. Yesterday Precision dropped the additional bombshell that its chief medical officer, Chris Heery, was being replaced by Alan List.
Allo players
As far as allogeneic Car-T therapy goes, Precision is part of a handful of biotechs with clinical assets, its technology being based on genome editing via Arcus nucleases. The other players are Cellectis/Allogene with Talen meganucleases, and Crispr Therapeutics with Crispr Cas9.
Precision first licensed its tech to Baxalta, when it was still a private start-up (Genome editing attracts big bucks from Bayer and Baxalta, February 29, 2016). That move was peculiar because Baxalta had no oncology presence to speak of, and moreover was in the process of being taken over by Shire, another non-oncology player.
For Shire an allogeneic cell therapy programme made a bizarre fit, and when the Ireland-domiciled group faced a takeover approach of its own, from Takeda, it swiftly offloaded this together with other small oncology assets to Servier (Shire taunts Takeda with oncology sale, April 16, 2018).
And so this uneasy arrangement, whereby Servier held rights to two competing allogeneic Car-T technologies, neither of which it was developing very fast, remained – until yesterday.
Precision: a timeline
Jan 2006
Precision Biosciences is founded
Mar 2008
Cellectis sues Precision, alleging infringement of meganuclease patents licensed from Institut Pasteur; Precision later countersues
Jan 2014
Cellectis/Precision litigation is resolved by a cross-licence
Feb 2014
Cellectis licenses allogeneic Car-T assets to Servier
Jan 2016
Shire to buy Baxalta
Feb 2016
Baxalta licenses Precision's Arcus nuclease technology for allogeneic Car-T use for $105m up front
Jun 2016
Shire closes acquisition of Baxalta
Apr 2018
Takeda makes unsolicited bid for Shire
Apr 2018
Shire sells oncology assets, including the Precision allogeneic Car-T assets, to Servier for $2.4bn
Mar 2019
Precision raises $126m in IPO
Apr 2021
Precision reacquires allogeneic Car-T assets from Servier for $1.25m plus milestones and royalties; Precision forgoes future milestones
Source: company filings.
Apparently the impetus to bring the assets back in house had come from Precision. On an investor call yesterday the group said it had analysed the Car-T field last year and realised it was “holding what could be a very strong hand”.
It therefore took the opportunity of what appeared to be a strategic shift Servier was undergoing – suggesting that with Servier’s focus elsewhere Precision could get a decent price – to reclaim the rights, achieving what it viewed as “vastly better backend economics”.
A next-generation CD19 Car, PBCAR19B, additionally expresses anti-beta-2 microglobulin shRNA and an HLA-E transgene; both elements aim to counteract graft rejection, by T cells and NK calls respectively. The first lymphoma patient in a phase 1 trial of this asset is to be dosed next month, Precision says.
Meanwhile, clinical data with PBCAR0191 in lymphoma are expected at Asco. And interim updates from phase 1 studies of PBCAR20A and PBCAR269A are due by the end of this year.
Stifel wrote that the Servier deal’s unwinding was a short-term negative, and Precision stock slipped 3% this morning. If the group can now sign up a cell therapy big hitter that would strengthen its case, but for now a decision on partnering the assets again has not been taken.
Over the past year, the National Institutes of Health has led “Shark Tank”-style competitions and funded radical approaches to help develop COVID-19 testing into a more seamless, ubiquitous part of daily life.
Now, the NIH is looking to steer those efforts, plus new government money, toward making it safer to return to classrooms, starting in school districts with the most vulnerable children.
It’s beginning with $33 million in awards to 10 institutions across the U.S. over the next two years to help restart in-person learning while regularly screening students, teachers and staff.
Using funding from the government’s most recent COVID package, the American Rescue Plan, the grants will be made through the NIH’s Rapid Acceleration of Diagnostics initiative, and its program focused on underserved populations.
“Many children have inequitable access to reliable virtual learning, and it is important they are able to participate safely in person while also maintaining the health and safety of the of the school and general communities,” said Eliseo Pérez-Stable, director of NIH’s National Institute on Minority Health and Health Disparities and co-chair of the program.
The NIH's projects will combine frequent COVID-19 testing with additional safety measures to help set an example for other schools to establish their own screening strategies, Pérez-Stable said in a statement.
While many schools are currently offering both in-person and virtual learning options, some students may lack computer equipment, high-speed internet access or assistance at home. At the same time, many children may go without school-provided meals, speech or occupational therapy and after-school programs. This has disproportionately affected minorities, socially and economically disadvantaged children, and children with medical conditions or developmental disabilities, the NIH said.
Managed by the NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development, the program selected public and chartered schools spanning early childhood through kindergarten to 12th grade, with attendances ranging from 50 to 3,500 children. This includes schools in urban, rural and tribal communities with racially and ethnically diverse populations, and districts with at least half of students receiving free or reduced-price lunches.
The projects will include at-home testing, as well as pooled, in-school screening approaches, employing molecular and rapid antigen tests using nasal swabs or saliva. The program also plans to make additional awards in the coming months to expand the initiative to more locations, depending upon the availability of funds.
Hey Siri, can the Apple Watch predict someone's risk of contracting COVID-19?
Apple has launched a study to determine just that. The Apple Respiratory Study will rely on the wearable’s optical heart sensor and self-reported weekly surveys to uncover patterns among participants who end up catching COVID, the flu and other viral infections.
The study—led by researchers from Apple, the University of Washington School of Medicine, the Seattle Flu Study and the Brotman Baty Institute for Precision Medicine—began recruiting Seattle-area iPhone owners to participate this week.
Researchers are especially interested in studying people ages 22 and older who are at an increased risk of infection because of their frontline jobs or group-living situations, as well as those from Latinx, Black and Indigenous communities, which have been disproportionately affected by the coronavirus pandemic.
Each participant will receive one of the latest versions of the Apple Watch to wear day and night for six months. The device will track heart rate, blood oxygen levels, physical activity and sleep throughout that time.
Participants will also be asked to log into the Apple Research app each week to answer questions about their lifestyle and to log any respiratory symptoms.
If any participants get sick during the study period, they’ll undergo an extra analysis by the Apple Watch, and the research team will provide at-home nasal swab testing for COVID, the flu and other acute respiratory illnesses.
At the same time, researchers will be testing whether receiving simple behavioral nudges like handwashing reminders can help decrease an Apple Watch user's likelihood of contracting viral infections.
“The hope is that physiological signals from the Apple Watch will make it possible to identify people who are falling ill and get them tested quickly so they can self-isolate and break the chain of transmission of the virus in the community,” Jay Shendure, a professor of genome sciences at the UW School of Medicine and director of the Brotman Baty Institute, said in a statement when the study was announced in September.
The Apple Respiratory Study follows in the smartwatch-tracked footsteps of a handful of other similar studies before it. Last August, Fitbit released preliminary findings of its own study, reporting that its wearable device was able to detect almost half of all positive COVID cases at least one day before symptoms set in.
And in October, researchers from the Scripps Research Translational Institute said their smartwatch-equipped DETECT study and accompanying smartphone app, both launched the previous March, had successfully identified patterns in heart rate, sleep quality and activity levels that were linked to new COVID infections.
