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Archive for the ‘Biochemistry’ Category


Where are we in the pandemic?

The bottom line here is that anyone making the statement ‘coming out of the Covid environment’ has not kept up with the data, which demonstrate the following:

1. Transmission is ~ 98% via airborne aerosols, known since March 2020 and firmly established by initial rules on masking and regions where this is maintained.

2. The pandemic is unabated. Cases remain high, with several waves a year. This to the extent that hospital beds fill up every wave, world-wide health care workers are burning out due to overwork and waiting lists are getting so long that the best option is becoming the avoidance of ill health.

3. Deaths are lower due to vaccines, but SARS-CoV-2 is an adept immune escapologist

4. Long Covid is a growing socio-economic problem, a consequence is the loss of members of an organisation’s workforce.

5. Viral persistence is measurable 15 months after recovery, and among the targets is bone marrow and the immune system.

6. There is no cure and no efficacious treatment, and this is true  for acute infection (when you have overt symptoms for ~ 10 days), viral persistence (months/years, see below) and LongCovid (see below). This is in contrast to HIV.

The consequences of the above are that organisations need to:

A. Explicitly state that masks are expected to preserve the health of yourself and of your co-workers and provide masks to the workforce.

B. Explicitly provide details on ventilation of rooms occupied by the workforce and/or install HEPA filters in all such rooms.

C. Expect those with even partial symptoms have a clear LFTs before returning to work.

D. Provide updates on the status of current variants, how much we don’t know and the extent to which Public Health surveillance is reliable.

Anything else is a gross dereliction of duty on the part of an organisation’s management.

Below I take each of the above statements and provide the evidence, including links. If any reader from my workplace, the University of Liverpool can come up with an argument based on evidence why we should not take all possible measures against transmission, then I will accept that the University does not need to take such measures. Until then, not doing so remains a gross dereliction of duty.

Transmission

Transmission is ~98% by airborne aerosols. Aerosols DO NOT drop to the ground, they remain airborne, and the only protection is to reduce their concentration. This is achieved by two complementary routes:

Masks to reduce the amount of aerosols put into the air by an infected person;

Ventilation and filtration to ensure rapid dilution.

Some resources and comments on these

A nice article in PNAS on how secondary physical measures work, which should be on the desk of every organisations’ Health and Safety Office.

A very simple message from JAMA in an article on this subject

“Because no single approach is 100% effective in preventing COVID-19, prevention measures work best when layered, including vaccination and nonpharmacologic interventions that reduce inhalation of infectious particles.”

The same article makes further excellent points. One on the long-term implications for building design

“Reducing contaminants in shared air by improving air handling systems in buildings is an attractive, broadly effective structural measure that does not require repeated individual actions.”

There is a nice Sci-Comm piece here.

The evidence on the efficacy of the different layers of is that you are safer in a small room with an unvaccinated person, both wearing a FFP2/N95 masks, than in the same room, both vaccinated but  without masks.

We should of course as far as possible have all measures in place.

Pandemic is unabated

Data acquisition is being dismantled, so it is essential to employ critical faculties. The testing programme is no longer functional, since you cannot report the results of tests purchased privately. Moreover, the excellent ONS survey will soon be limited, so we will have even less information on the number infected later in the year, and the only proxy will then be NHS data on admissions and bed occupancy.

For the record the ONS survey data are here and for the week ending 29 June 2022 for England the estimated number of people testing positive for COVID-19 was 2,154,000 (95% credible interval: 2,062,600 to 2,247,100), equating to 3.95% of the population, or around 1 in 25 people.

There are very useful analyses of these data, which I recommend, e.g., @TravellingTabby on Twitter who maintains an excellent data web page from the ONS data

The idea that the virus is attenuating is WRONG. As usually small numbers, large effect sizes, when we go to a good sized study (130 k patients) there is no evidence that Omicron is milder

Deaths are lower

The estimate from WHO is that vaccines have avoided 20 M deaths. However, excess deaths over historical average still substantial. The problem is that the efficacy of the vaccines is good, but not nearly good enough. This is compounded by giving the virus a free reign so that natural selection can operate at extremely high throughput. The result is a virus that was already good at immune escape is now a master. Some data in the links below.

The Tweetorial from Deepti Gurdasani covers a recent Science paper that demonstrates immune escape and that T-cell immunity to Omicron is poor at best

The paper is here.

Long Covid

This occurs in a significant number of people after they recover from acute infection. The risk only reduced a little by vaccination according to this large study of 33 k people infected after vaccination with over 13 M controls!

A key take home message from this paper is:

Altogether, the findings suggest that vaccination before infection confers only partial protection in the post-acute phase of the disease; hence, reliance on it as a sole mitigation strategy may not optimally reduce long-term health consequences of SARS-CoV-2 infection. The findings emphasize the need for continued optimization of strategies for primary prevention of BTI and will guide development of post-acute care pathways for people with BTI. 

Importantly, the risk of LongCovid increases with each infection.

The ONS (UK) data form early April 2022 indicate 1.7 million people with LongCovid in the UK (2.7% of the population), and it also affects the young…:

“40,000 aged 2-11 (confidence intervals 32K-48K) 59,000 aged 12-16 (confidence intervals 52K-66K) That’s a total of 99,000 children “

For those aged 17-24, that’s 89,000 (CI 77K-102K)

For those with an illness duration of at least A YEAR: 14,000 aged 2-11 (confidence intervals 9K-19K) 17,000 aged 12-16 (confidence intervals 13K-20K) That’s a total of 31,000 children. For those aged 17-24, that’s 45,000 (CI 36K-54K).

Unfortunately, those affected cannot pursue their usual lives and work, studies, hobbies, etc., are largely or completely suspended.

There is good evidence that micro clots are part of the problem and it seems likely that viral persistence in our organs may also contribute.

Viral persistence

Data from autopsies demonstrate viral persistence in organs in even moderate cases (so no hospitalisation) up to 15 months post infection. These data are likely to get worse, rather than better as we progress into the pandemic and we acquire more time-dependent data.

There is no cure and vaccines are an aid, but not a solution

The drugs we have are merely re-purposing existing ones, and their efficacy is modest, at best. It will be some time, 5 to 10 years  perhaps, before we have drugs that specifically target SARS-CoV-2 functions such as its polyprotein protease. There is good evidence for microclots playing a role in LongCovid, but we haven’t yet got a clinical trial running with preregistered outcomes etc. – so far we have case reports only.

Current vaccines are losing efficacy against variants more adept at immune escape, an entirely predictable outcome given near zero measures to reduce transmission, so the virus has had an evolutionary field day exploring host-pathogen interactions, to our detriment of course.

The future without measures beyond vaccination

Attrition of the workforce, most pronounced in those exposed to large numbers of humans in small spaces, such as healthcare and education.

Attrition of the student population able to undertake studies.

The outcome is that society is not sustainable, in the same way that Medieval societies were not sustainable in the face of population loss due to the Plague. One only has to consider the complex chain of skills that underpin basic everyday aspects of life:

The mobile phone, needs cutting edge sills in materials, chips, telecommunications networks, GPS satellites, electricity production, and of course software in all elements of the chain. 

Take out 10% of the workforce and we struggle. Currently over 2.7 % of the population are affected, ~0.9 % to the extent they cannot work, and this after just 2.5 years of the pandemic. What can we withstand? 5%, 10 %? I don’t know, but I cannot see a valid argument for testing the hypothesis that society can withstand X% of LongCovid. If you have one, let me know.

The Future 

Future A We continue to ignore the evidence, and see whether our society can withstand the impact of a large % of its population with LongCovid requiring care and being unable to work. This is a course of action taken by an ideologue, and is not possible for a scientist to act in this way, since in science we critically evaluate evidence.

Future B We apply mitigation measures so as to reduce the frequency of transmission, reduce infections and so the number with LongCovid, until such time as the pandemic is over and/or we have drugs that really work. This is the course of action of any organisation that has the well being of its staff (and students) as a core value, it is evidence- and knowledge-driven, and aims to be sustainable, that is to exist in a recognisable form in 10-50 years time.

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After an interaction on Twitter with a colleague who is associated with #LongCovid and #TeamClots, he asked me for some references. I thought what to send, and then realised that references plus something a bit more than a Tweet might be useful, so here goes.

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Our building complex of Biosciences and the research parts of the connected Life Sciences and MerseyBio buildings opened this week – a two week pilot and the first research building complex on campus to re-open after the lockdown. In reality, like a number of buildings in the Faculty, these had never closed. A small number of covid-related projects were running during lockdown, including our glyco one. These required skeletal support services. Moreover, key maintenance, from plants, to fly strains and flushing the water system to prevent a Legionella outbreak had to continue during lockdown.

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With new data in hand, our first preprint on SARS-cov-2 receptor binding domain (RBD) interacting with heparin now has a sibling, which demonstrates that heparin inhibits the infection of Vero cells by SARS-cov-2

Some of the key points of the team’s new work are:

  1. Inhibition of viral infectivity in a Vero cell model by heparin, which is a better inhibitor for SARS-cov-2 than SARS-cov.
  2. Analysis of the interactions of a more extended library of model heparins with the SARS-cov-2 receptor binding domain. As with many other heparin-binding proteins, these data show that while sulfation is critical for RBD binding, the amount of sulfate is not, but instead it is the spatial arrangement of sulfate groups that is most important.

Together the data point to heparin being a potentially useful therapeutic to reduce infectivity. (more…)

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E-mail I sent out to the research group today.

Dear All,

From now on we really do need to reduce lab work and enforce strictly social distancing, something we stated last week.

The first transmissions from Scousers who picked up the virus on match night (bars, clubs, hotels) from Athletico fans will occur this coming week and next week; we will then get F2, F3 (F number related to contact: primary = F1, a contact’s contact = F2 etc.) transmission. (more…)

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Thursday last week (Feb 27) Mark was up from Keele and popped his head around my office door – not a surprise, as he is often here to do circular dichroism on various heparin-binding proteins – to announce that Marcelo had managed to make some SARS-CoV-2 S1 receptor binding domain. Mark had asked Hao,  my postdoc, to do some SPR measurements to see if it bound heparin.

Later in the day I went over to the SPR/CD lab to find Courtney, Mark’s PhD student and Mark beavering away on the CD. A quick discussion. Hao had finished some work on our first grade A heparin functionalised SPR surface, so we set about injecting the SARS-CoV-2 surface protein (Spike) S1 Receptor Binding Domain – a one shot experiment, as amounts of protein were limited, so we injected 1 mL at 500 µL/min (I like high flow rates as mixing is way better, though still far from perfect).

Bingo. (more…)

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I have written the following to my Brexit Party Representatives in the European Parliament. At the heart of parliamentary democracy is the idea that our representatives do indeed represent the interests of their constituents, regardless of Party politics. Of course interests have to be balanced but when these are win-win, there can be no reason for not representing a particular interest. As the matter is not a personal one, then I have also put it on my blog, since there is no reason for secrecy.

I will, of course, post any further correspondence, unless it is confidential for some reason.

“Dear Ms Fox (& cc’ed to Mr Nielsen and Mr Bull)

I am writing to you as one of your constituents regarding an issue which affects me personally and the region. As a University Professor I have over the years been awarded research funds from various Framework Programmes. Most recently, I am part of the €4M FET-OPEN programme “ArrestAD”. This aims to test a new paradigm for Alzheimer’s Disease screening and lay the foundation for a new class of drugs that would arrest the disease.

FET-OPEN projects are very much blue skies and in our case we appear to have hit the jackpot. The trials of the diagnostic in Paris and Warsaw  are quite spectacular and our own work has shown that the targets which ArrestAD has proposed are eminently druggable.

ArrestAD is a 4 year programme. As in any blue skies research, towards the end of the penultimate year a decision is made by the research team whether we should apply for a new, larger project, under one of the translational programmes available under H2020, or to can the idea, in the event it isn’t going to deliver.

Since ArrestAD is delivering its promise, the team will be going forward and applying for a translational programme. This will involve further clinical centres and greater industry participation, since we need more patients and, for drug development, far greater resource.

Alzheimer’s being what it is, ArrestAD obviously impacts widely and not just on myself: there are substantial social and economic ramifications for our region, the UK, and beyond.

The problem we face is that with a so-called No Deal Brexit, the UK loses access to funding from H2020 and the future framework programme. There is no  legislation in the UK Parliament that would guarantee funding as a 3rdcountry. The upshot is that Brexit will prevent my continued contribution to this likely life-changing research programme. Importantly, it will prevent the UK from reaping economic benefit (clinical trials, pharmaceutical industry).

As my representative in the European Parliament, it is imperative that you work to find a solution, which ensures that the drug development arm of this project remains based in the UK, and that the UK is able to participate fully in the wider clinical trials of the diagnostic. I think you would agree that given the impact of this dreadful disease, this is in everyone’s interests.”

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For those who follow the news, though helium is rather common in the solar system, it is rare on earth. The shortages were predicted some years ago, and were put off only by the Pentagon agreeing to put some of its strategic reserve into the market.

We now face the first self-inflicted shortage: helium is now rationed in the UK. Self-inflicted, because we waste it, e.g., balloons and no recovery of the gas at point of use. This of course is all down to cost, and testimony, in a small way, to the failure of applying market principles across the board without any strategic consideration.

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Universities are always cash strapped, and over the last few decades there has been a drop  in the number of PhDs funded by the UK government. In essence stipends have been increased (absolutely necessary and credit to The Wellcome Trust for pushing this), but funding has not increased commensurately. So numbers have dropped.

The response of institutions has been to push for more overseas students and to develop, from internal monies various funding  schemes. However, generally this has only served to replace losses in numbers funded by government. Gone are the days when every PI expected a new PhD student every year. This has a detrimental effect on research culture, as it leads to centralisation, a reduction in diversity (in the broadest sense of the word) and fewer trained scientists. The UK relies extensively on scientists trained elsewhere for its R&D and we need to do more in relation to training. Granted science is a mobile and international profession, but without contributing proportionally to the global talent pool, our R&D may wither in the long run.

The problem is money: institutions have limited funds they can use for PhD studentships. Our European model, where PhD students are fully funded for a set number of years (usually 3-4, sometimes a few more) is in my view preferable to the US one, where students work to support themselves. This is for the simple reason that the latter model can lead to feudalism and abuse of power, which is well documented.

There is money available for institutions willing to take leadership on the Open Access Agenda.

An aggressive pursuit of an Open Access agenda, as has been done in Germany, The Netherlands and Sweden, and most recently UC, means cancelling subscriptions to the journals of the Big Four. This frees up a substantial budget, with no ill effect on research and scholarship. A portion of the funds would, of course, need to be used to hire librarians supporting document sourcing by UG and researchers and the balance to fund PhD students. I note that teaching UGs these skills is important, since most STEM workplaces (industry, where many STEM graduates and postgraduates work) do not have large libraries. One advantage of using internal funds is that one can select and so only take the very best candidates, rather than restricting enrolment to those with access to funding. While such proposals will likely be met with horror by a good many academic staff, once in place it appears that no one notices much change and continues to work productively. This is the experience of countries and institutions that have cancelled subscriptions to one or more of the Big Four.

Sadly, with my University running workshops on “How to get published in Nature”, it appears that we are 20 years behind the times and this simple and effective means to improve teaching and research (PhD students being an engine room for research) is unlikely to see the light of day here.

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Today was the culmination of Zaid’s PhD journey, when he successfully defended his thesis on the use of gold nanoparticles to probe the mechanism of action of a peptide that inhibits ‘flu virus infectivity. Though he approached his viva with trepidation, his beaming face afterwards told a different story. The usual smattering of corrections, a paper already up on Bioarxiv ready to submit for peer review and another to put up on Bioarxiv, and in a few weeks he will be truly done, with a CV to match.

 

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