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Archive for the ‘Science process’ 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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What is important for your career in the Faculty of Health and Life Sciences at the University of Liverpool

With Project SHAPE progressing in the Faculty of Health and Life Sciences at the University of Liverpool, we have now moved onto the compulsory redundancy stage. As a senior member of staff who went back to the trenches after ten years in management, I have been contacted informally by a number of staff who have been sent a notice that they are at risk of redundancy. So I used my experience in management and my knowledge of the University to figure what may be important for retention in the Faculty of Health and Life Sciences at the University of Liverpool and, perhaps more important, what may kill your career and result in a P45.

(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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An article in the New Statesman this summer argues that the British degree has lost its value. The evidence is largely restricted to:

  1. A complaint by students at the University of Sheffield (course not mentioned) which resulted in an uplift of the marks, particularly at the bottom end.

Without context this is a non-argument. Was the course new and there was a mismatch between what was delivered and examined? Was the marking rogue (not everyone does their job with due diligence…)?  And so on.

There follow a few paragraphs that provide no evidence, but plenty of hand waving.

The last paragraphs consider the increase in the number of students going to university and asks the question, sure, if access if wider, there should be more at the bottom, more failures. A corollary is that schools are doing no better now than they used to.

I agree there has been some grade inflation, which has two sources. The first is using the full range of marks available, rather than deciding in advance that there will be no more than one first class degree each year. Current practice is the right thing to do and past practice was wrong. The second source of grade inflation is due to the law of unintended consequences. Legal challenge, now possible because students can access their marks (transparency can only be a good thing) means there are issues at degree borderlines. Common responses have been to avoid all marks at borders (of course this fails singularly to solve the problem, since the final mark is an average of many, so student still end up under the border) and to push students up a % or two if their final marks are below a border. These and other responses to the problem have had an inflationary effect, but I would estimate it to be more more than a few %.

Counter arguments to very substantial and continual grade inflation are:

GCSEs and A-levels are harder than they were, and students are better prepared for university (just as primary students are much better prepared for the jump to secondary). While every year ministers and sections of the press whinge that the all time high level of passes represent a failure, the teaching profession (who have forgotten more about teaching than ministers or members of the 4th estate ever knew) argue the opposite. I always take the expert over others and my limited personal experience of the matter supports the views of the teaching profession.

University courses have changed. At least for STEM courses, they are much harder and demand a lot more effort on the part of the students (my personal opinion is we have gone too far) than 40 years ago, when I was an undergraduate. There is far greater challenge and courses develop skills that in STEM subjects were not even touched on, such as critical thinking and critical analysis of data. Back in the day you either figured this out or you didn’t, so this was learned by the time-honoured system of osmosis. Importantly, a student’s abilities in these areas had no impact on the degree awarded. There is perhaps a generational difference between the young (18-35 and the middle aged and older graduates >35), with the former better at critical thinking  and analysis than their elders.

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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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A discussion today with a student asking about the use of the Royal “we” in a report about his work. I agree, this is wrong. My suggestions were the first person singular and the passive. The passive gets a bad press in places, but it does work; the repetition of “we” or “I” grates, the latter particularly so because it can convey a strong sense of ego. Though as I pointed out, this depends how it is used. It was common in single author papers for the author to use “I”. The practice has disappeared due to multiauthorship and the urge to make scientific observations look objective. We finished by joking about the feudalism implicit in the use of ‘my laboratory’, as if this was some sort of sentient being, and then I wondered out loud whether one might not, in a multiauthor paper state:

“In experiment X (Fig. X), blogs demonstrated that….” And then later “In experiment Y (fig. Y) Doe indicated….”

Tonight a tweet from @UtopianCynic

UtopianCynic tweet

reminded me of my earlier conversation. Indeed, why bother with all the rubbish associated with authorship position? Why not have a list of authors and in the paper report who did what and who thought what?

It would then be clear (i) who pulled together the original hypothesis; (ii) who did the experiments; (iii) who thought up the interpretations of the data.

I think I might try this out.

This also solves the long-standing problem of blaming whoever is at the bottom of the pile when a paper is found to have manipulated data. Someone will be explicitly on watch and someone else will have done a particular measurement under that person’s watch.

It will be obvious who should walk the plank, and reaching for lawyers will only result in keel hauling, because it will be all written down and signed off.

 

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A recent article on bioarchiv “Amending published articles: time to rethink retractions and corrections?” puts forwards ideas on how we might change the way we deal with retractions and corrections. (more…)

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A little late this year, but then there are many calendars, so it is surely the start of the New Year for someone, somewhere, today. (more…)

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I made my first New Year’s resolution on December 31, 2013: to only undertake reviews for open access and learned society journals.  This I have stuck to well, as I noted a year later for the simple reasons that it makes sense and it frees up my time.

Today I had a request to review a manuscript for Nature Publishing Group’s Scientific Reports, and I realised that I need to clarify my position.

I am on strike. (more…)

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This is a question raised at the end of the excellent article by @Amy_Harmon regarding Open Access and preprints is can biomedical scientists evaluate each other without journals?

The short answer is a resounding yes.  Physical scientists and mathematicians have been posting much of their research as preprints on arXiv for a few decades, with no prejudice to their ability to evaluate the quality of work or of individuals.

The counter argument raised by many in biomedical sciences, from scientists to some journal editors can be boiled down quite simply: We are special and cannot possibly do this.

Various arguments are put forward, from competition (=fear of scooping) to intellectual property. These arguments are heard in many biomedical/biology departments, sometimes leading to quite heated discussions. It is also interesting to note that the defenders of the status quo are not necessarily the older members of the community.

There is a simple answer. Yes you are special, but not in the good sense of the word. (more…)

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