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‘Humanised’ worms for the discovery of new anti-epileptic drugs

Written by Lucy Job: https://www.linkedin.com/in/lucyjob/

Caenorhabditis elegans is a type of tiny soil-dwelling worm, found to accept certain human genes into their own genome [1]. These ‘humanised’ worms are a very useful tool to study human disease, with researchers at the University of Liverpool now using them to study human epilepsy and discover new anti-epileptic drugs [1] [2].

“C. elegans, model organism in life sciences” by ZEISS Microscopy

What is epilepsy?

Epilepsy is one of the most common conditions affecting the brain, shaping the lives of an estimated 50 million people worldwide [3]. In the UK alone, there are an estimated 600,000 epilepsy patients, which is almost 1 in every 100 people, with 87 people diagnosed every day [4]. There are a lot of different causes of epilepsy, and it can affect people of all ages [5].

Known causes of epilepsy, adapted from the World Health Organisation Infographics of Epilepsy [5]

Those with epilepsy suffer from recurrent seizures, which is caused by sudden bursts of electrical activity within the brain. The most well-known seizure type affects movement, causing muscle jerking, twitching, and/or weakness. Lesser known seizures affect the person’s awareness to their surroundings and can cause changes in sensation or emotion [6].

Currently, there are over 20 anti-epileptic drugs available with many different drug targets [7]. These drugs try to stop the sudden uncontrolled bursts of electrical activity within the brain. However, these anti-epileptic drugs do not work for one third of patients, named ‘refractory epilepsy’, with the reason for this not fully understood [8]. Therefore, new drugs are desperately needed for those patients with refractory epilepsy.

Why worms for drug development?

Making new drugs is controversial as testing on mammals, like mice and primates, has many ethical and financial issues. As these worms are invertebrates, less complex animals, they do not require extensive ethical training for use [9]. Also, these worms have a short reproduction time (~3 days) and lifespan (~3 weeks) and do not need expensive equipment take care of them, making them a much cheaper alternative [10]. Therefore, it is beneficial to test new drugs on less complex animals first, and then move onto more complex animals later in the drug development process. However, it is hard to justify using tiny soil-dwelling worms to test drugs for humans when we are so different [9].

Humanising the worm

To tackle this, researchers led by Professor Alan Morgan at the University of Liverpool have created humanised worms to study severe forms of epilepsy, such as Ohtahara syndrome [1]. This was achieved, in part, using the highly specialised gene editing process CRIPSR-Cas9 and which is used to insert, delete, or substitute target genes, to fix or introduce gene mutations [11].

Brief summary of CRISPR-Cas9. The Cas9 enzyme cuts the target genetic code, causing a DNA break. Once broken, a DNA repair process, leads to the desired insertion, deletions, or substitution at the target site.

GABA is a neurotransmitter (a biological chemical) which can prevent sudden electrical activity in the human brain. Studies by multiple different research teams have found GABA mutations (more specifically GABAA receptors) in patients with a spectrum of epileptic encephalopathies, such as Lennox-Gastaut syndrome and West syndrome [12].

In this project we aim to introduce mutated human GABAA receptor genes found in epilepsy patients into worms. We will then induce seizures in the worms and test a range of new anti-seizure drugs to see which compounds are most effective. Therefore, we will be able to assess the effect the new anti-seizure drugs may have in humans with the same genetic mutations.

Humanised worms used to study anti-epileptic drugs at the University of Liverpool.

Using these humanised worms as a first step in drug development is beneficial as it gives researchers the opportunity to fast-track the selection process, whittling down large numbers of drug candidates to a select few in a short space of time [2].

References

1.              Zhu, B., et al., Functional analysis of epilepsy-associated variants in STXBP1/Munc18-1 using humanized Caenorhabditis elegans. Epilepsia, 2020. 61(4): p. 810-821.

2.              Wong, S.Q., et al., A Caenorhabditis elegans assay of seizure-like activity optimised for identifying antiepileptic drugs and their mechanisms of action. J Neurosci Methods, 2018. 309: p. 132-142.

3.              Organization, W.H., Epilepsy: a public health imperative. 2019: World Health Organization,.

4.              Action, E. What is epilepsy? 2019 2019 [cited 2020 29.06.2020]; Available from: https://www.epilepsy.org.uk/info/what-is-epilepsy.

5.              Organization, W.H. Infographics on epilepsy. 2016-2017  [cited 2020 29.06.2020]; Available from: https://www.who.int/mediacentre/infographic/mental-health/epilepsy/en/.

6.              NHS. Symptoms – Epilepsy. 2017  [cited 2020 29.06.2020]; Available from: https://www.nhs.uk/conditions/epilepsy/symptoms/.

7.              Loscher, W., et al., New avenues for anti-epileptic drug discovery and development. Nat Rev Drug Discov, 2013. 12(10): p. 757-76.

8.              Kwan, P. and M.J. Brodie, Early identification of refractory epilepsy. N Engl J Med, 2000. 342(5): p. 314-9.

9.              Cunliffe, V.T., et al., Epilepsy research methods update: Understanding the causes of epileptic seizures and identifying new treatments using non-mammalian model organisms. Seizure, 2015. 24: p. 44-51.

10.            Chen, X., et al., Using C. elegans to discover therapeutic compounds for ageing-associated neurodegenerative diseases. Chem Cent J, 2015. 9: p. 65.

11.            Zhang, F., Y. Wen, and X. Guo, CRISPR/Cas9 for genome editing: progress, implications and challenges. Hum Mol Genet, 2014. 23(R1): p. R40-6.

12.            O’Reilly, L.P., et al., C. elegans in high-throughput drug discovery. Adv Drug Deliv Rev, 2014. 69-70: p. 247-53.

13.            Hernandez, C.C. and R.L. Macdonald, A structural look at GABAA receptor mutations linked to epilepsy syndromes. Brain Res, 2019. 1714: p. 234-247.

Read more Guest blogs here:

  1. The COVID-19 Vaccine Landscape
  2. Back to school. What do the students think? 49% of students say no.
  3. Natural or Nasty? Traditional Chinese Medicine and COVID-19
COVID-19 Infographics PPE

Lockdown eases, but the virus has not gone away.

Post originally on instagram

So things are opening up again this weekend (4th of July 2020) in the UK. The lockdown eases.

It is everyones individual choice where they wish to go now and what they want to do – if you are looking for ways to reduce risk while going out and seeing friends, here are some science-based suggestions:

Effective hand washing is still extremely important! Make sure you’re washing frequently and efficiently!

 Masks are still growing in evidence for their effect in slowing disease transmission. When you’re in close contact with people outside of your household, consider wearing one as often as you can!

Check out yesterday’s post for how to put on and wear your mask safely!

If possible, meet outdoors! Respiratory droplets have a reduced risk of reaching the people you’re with if you’re outside – a walk or a picnic are good alternatives to a sit-down meal.

Reduce the number of people you see in short spaces of time. By distancing the different groups you see you can reduce the number of potential infections in a social group.

Do you feel ready for when lockdown eases? Let us know your thoughts – info@thesciencesocial.com

lock down eases
lockdown is easing
The current state of cases
social distancing, hand washing and PPE advice for when lockdown eases
Meet outside when you can
Reduce the number of interactions in short spaces of time
second wave
sources

Infographics The Science Social News Uncategorized

Science News: 1st July 2020

‼️ SCIENCE NEWS ‼️

This week’s news in science brought to you by Serat @touchthebeardagain .

👩‍🔬 Scientists have developed a portable 30 minute COVID-19 testing machine

🦠 The 10th Ebola outbreak in the Democratic Republic of Congo has been declared over.

🧠 University of Liverpool lead a neuro-surveillance study to assess how COVID-19 affects brain function

🍭 Common food additive used in sweets has been found to have adverse effects

For a brief history of Ebola and details on the most recent Ebola outbreak, read our blog post here.

Blog COVID-19 Guest Blog

The COVID-19 Vaccine Landscape

Written by Miguel Leon Rios
Read about Miguel’s research here:
https://news.liverpool.ac.uk/2019/05/15/becoming-an-expert-investigating-vaccines-against-viral-stomach-bugs/

The COVID-19 Vaccine Landscape

The global COVID-19 pandemic picture is still unclear as the novel coronavirus outbreak shifts constantly around the world. While the number of cases rise critically in South America’s first wave, the UK and European countries have begun to lift their lockdown measures amidst this COVID-19 pandemic. At the same time, South Korea and China, where coronavirus cases seemed to have disappeared, have seen a second wave of infections. However, a common question emerges among this COVID-19 rollercoaster: Will we have a vaccine soon? 

A matter of time 

Timing is crucial in vaccine research. More than five months have passed since the genetic sequence of SARS- CoV-2, the virus that causes COVID-19, which was published on 11th January 2020. This discovery sparked an unprecedented global research effort to develop a vaccine against this disease1, involving next-generation technology platforms and novel approaches with a hope to speed up this process. However, vaccine development involves a multi-stage process of research and testing, which typically takes more than ten years to be completed2 (Fig. 1). Therefore, we must remain cautious in light of a new vaccine.

Fig. 1. Vaccine research and development. Adjusted from The Association of the British Pharmaceutical Industry (ABPI)

What is the current picture?

A recent overview of the global landscape of COVID-19 vaccines by the World Health Organisation (WHO) included more than 140 vaccine candidates from different research groups and developers around the world3. From those, 129 candidate vaccines are under preclinical evaluation, which means a preliminary laboratory exploration but not yet in human trials. On the other hand, 13 candidate vaccines have entered the clinical evaluation stage, which is a three-phase process involving human subjects (Fig. 2). 

Fig. 2. How a new vaccine is developed. Adjusted from The Journey of Your Child’s Vaccine. Centres for Disease Control and Prevention (CDC)

OK, but can we speed up this process?

In terms of vaccine research time we are progressing at super-fast speed in this scenario. Just consider that the first set of COVID-19 cases, a new type of viral pneumonia, were reported to WHO on 4th January 2020 (Fig.3). Two months later, the first COVID-19 vaccine entered first-in-human trials within record breaking time on 16th March 2020. Scientists and international organizations around the world are still racing to produce and deliver a safe and effective vaccine within an 18-month period1-3.

Fig. 3. Source: Word Health Organization (WHO) official twitter account.

So, do we have a vaccine yet? 

From the array of advanced COVID-19 candidates under clinical development, only one promising study has started their phase 3 trial in Brazil4 (Fig. 4). This a non-replicative viral vector vaccine developed by the University of Oxford and the British-Swedish company AstraZeneca5. As we previously described, this candidate works as an inactive vaccine by using a different non-live virus to deliver coronavirus genes into our cells. In other terms, it can´t reproduce itself but it can still provoke an immune response.

COVID-19 Vaccine Tracker
Fig. 4. Coronavirus Vaccine Tracker. Source: The New York Times.

Currently, this vaccine is also moving to Phase II/III in England and will hopefully deliver positive results by next year. A different approach has been employed by The Murdoch Children’s Research Institute in Australia. The experimental coronavirus vaccine, which is currently in phase 3 trial, utilises the Bacillus Calmette-Guerin vaccine6.  The BCG vaccine is made from a weakened strain of tuberculosis bacteria and been widely used since the 1920s to fight TB7.

Researchers expect to observe partial protection against SARS-COV-2 as observed for other diseases7,8.  Only data and results will decide if the remaining vaccine candidates could progress to phase 3 human trials and if this global effort could be translated into a successful vaccine by early 2021. 

References

  1. Usher AD. COVID-19 vaccines for all?. Lancet. 2020;395(10240):1822-1823. doi:10.1016/S0140-6736(20)31354-4
  2. Thanh Le T, Andreadakis Z, Kumar A, et al. The COVID-19 vaccine development landscape. Nat Rev Drug Discov. 2020;19(5):305-306. doi:10.1038/d41573-020-00073-5
  3. Draft landscape of COVID-19 candidate vaccines. WHO. 2020; June 22. [cited 2020 Jun 23]. Retrieved from https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines
  4. Corum.J, Grady. D and Zimmer. C. 2020. Coronavirus Vaccine Tracker. The New York Times. Available from: https://www.nytimes.com/interactive/2020/science/coronavirus-vaccine-tracker.html
  5. Current Controlled Trials. ISRCTN89951424. A phase III study to investigate a vaccine against COVID-19, [cited 2020 Jun 23]. Available from: https://doi.org/10.1186/ISRCTN89951424
  6. ClinicalTrials.gov. NCT04327206, BCG Vaccination to Protect Healthcare Workers Against COVID-19 (BRACE) [cited 2020 Jun 23]. Available from: https://clinicaltrials.gov/ct2/show/NCT04327206
  7. World Health Organization. BCG vaccine: WHO position paper, February 2018 Recommendations. Vaccine. 2018;36(24):3408-3410. doi:10.1016/j.vaccine.2018.03.009
  8. Caryn Rabin R. 2020, April 5. Can an Old Vaccine Stop the New Coronavirus?. The New York Times. Available from: https://nyti.ms/2JCcTxx 
fasciola hepatica worm of the week
Infographics Worm of the Week

Worm of the Week: Fasciola hepatica

Concept by Shannan Summers @Shannan_tropmed, design by The Science Social.

The worm of the week is the good old Liver Fluke, specifically Fasciola hepatica. Worms are a type of parasite that can cause disease in humans and livestock!

Fasciola hepatica is an important zoonotic infection. Zoonotic means in this context means the worm has jumped from a non-human species to a human. 2 million human cases have been estimated worldwide!

Fasciola hepatica worm can be found all over the world, particularly in areas where sheep or cattle are farmed.

There is an acute phase of infection, and a chronic stage of infection. Depending on the phase of infection, the diagnosis differs.

For example, during an acute infection, the immature worms penetrate the gut (after ingestion). The body is able to produce an immune response, resulting in the presence of antibodies against the worms!? The presence of these antibodies are then detectable in a diagnostic test.

During a chronic infection, the worms have matured in the bile duct of the liver. The presence of the infection is detected by examining the faeces for eggs! – A glamorous diagnostic test, for sure!

Fasciola hepatica infections are often treated with antihelmintic drug triclabendazole. This drug works by expelling the worm by either stunning it or killing it. Without harm to the host, such as the human. However, drug resistance is becoming an issue?!

International women in engineering day 2020
Engineering Infographics Women in STEM

International Women in Engineering Day

Now in its 7th year, International Women in Engineering Day (INWED) aims to raise the profile of women engineers and encourage more people to consider engineering as a profession for all!

📊 In studies from 2018, women only made up just over 12% of the engineering workforce and only 25% of girls aged 16-18 would consider a career in engineering. .

👷‍♀️ Here are three influential women engineers from history through to today to get you started! How do you think they helped to “shape the world”? .

Mary Jackson, Gwynne Shotwell and Emily Warren Roebling.

Check out our fresh sip of science history post about Gerty Cori here.

science history
A Sip of Science History Infographics

A sip of science history: Gerty Cori

👨🏽‍🏫 A sip of science history! ⁣Introducing… Gerty Cori!

🔬 Gerty Cori was a pioneering biochemist and America’s first ever female Nobel Prize winner. ⁣

💫 Gerty and her husband Carl Ferdinand Cori, collaborated to define the process of sugar metabolism, known as the Cori Cycle. ⁣

👩🏻‍🔬 Despite her credentials she was denied many of the career opportunities her husband and collaborator was afforded because of her gender. Her contributions to science were eventually recognised, as she gained full professorship just months before her Nobel Prize success. ⁣

Swipe through to read more about Gerty’s story! ⁣

References:

Blog COVID-19 Guest Blog Research Summaries

Back to school. What do the students think? 49% of students say no.

Freya is a year 12 student A-level student who has recently conducted her first research project.

“This is the first research project I have conducted, and I did it because I want to advocate for young people. I think it is important that young people have a say in the decisions which impact them. They do not vote, and it seems unfair that their thoughts and valid contributions are not taken into account by the Government. I hope that through this research project I can provide some insight into what young people are saying and so that their concerns with returning to partial schooling can be addressed.”
Written by Freya Semple

Back to school

On May 10th, 2020 the UK Government announced that Secondary Schools, Sixth Forms and Further Education Colleges could provide some face-to-face support for year 10 and year 12 students after June 1st 2020. This was subsequently deferred to start on 15th June (1). Students in these year groups have national exams in Summer 2021. This means this time in year 10 and year 12 is critical as the bulk of the curriculum is delivered.   

To reduce the spread of COVID-19 in schools on the return of students, the government has advised the  regular cleaning of frequently touched surfaces, changing classroom layouts to reduce student contact and to stagger timetables (2). However, what are the students’ views on returning to school?

It was important to me to get this question answered, so I designed a study in aim to voice the views of students.

Why is this research important?

It is not apparent that the Government has engaged with the school students affected most by this decision. Students have not been given a platform to raise their concerns about returning to education. Their views have not been heard.

This motivated me to conduct a prospective study to collate the views of young people and publicise their concerns. It is important to involve young people in decisions that affect their situation so that they engage with the policy (3). Year 10 and year 12 students are also of an age where their opinions should be taken into account.

Aims of the research project:

This study was conducted to explore the opinions of year 10s and 12s concerning returning to partial school after the first wave of the covid-19 outbreak in June 2020. The aim was to provide a voice to young people on returning to partial schooling in June 2020.

Students were invited to express:

  • Their preferences on returning to school
  • Their views about safety with respect to government guidance on return to school
  • How they feel COVID-19 will impact on their future
  • How COVID-19 has impacted on their education

This study will inform members of the public and policy makers about the opinions of year 10 and 12 students returning to school in the UK at the end of the first wave of the SARS-CoV-2 outbreak.

How the research was conducted:

The aims of this study were addressed with qualitative research using a prospective survey conducted from the 20th to 27th May 2020. Participants were year 10 (age 14 to 15 years old) and year 12 (age 16 to 17 years old) school students in the United Kingdom.

A 12-question survey was compiled on Google Forms™ with 9 close-ended questions and 3 open-ended questions. The survey was distributed to the students via two online Facebook™ forums specific to their year groups: The A level Forum (6,500 members) and a GCSE forum (36,000 members). The survey was accessible on multiple platforms (computers and smartphones) and multiple web browsers.

The 3 open ended questions were subject to Braun and Clarke themed analysis. Thematic analysis is a method for identifying and interpreting patterns of meaning across qualitative data. This meant recurring themes in the written data could be addressed and the reasons behind students’ answers could be found without influence. Braun and Clarke analysis provides a qualitative six phased method of thematic analysis. Firstly, I familiarised myself with the qualitative data and noted general ideas. NVIVO (v12) software was used to group the qualitative data into codes (similar patterns in the data). Themes were then put together by grouping the codes. I then reviewed and defined each theme in relation to the research measures.

The results:

There was a rapid uptake from students with 1534 responses in 7 days.

An infographic breaking down the key findings in "Year 10 and 12 school students' opinions on returning to partial schooling during the COVID-19 pandemic: an action research prospective survey" DOI: 10.31235/osf.io/mdjsn

Conclusions:

Year 10 and 12 school students are evenly divided in opinion about whether they should return to school on 15th June. This uncertainty appears based on the majority of students having concerns about schools’ ability to comply with government guidance, particularly around social distancing and the risk of transmission. Some students recognised a need to return to education despite this perceived risk. This uncertainty could be addressed by better engagement from policy makers with school students. School students expressed desire that their students’ concerns are addressed by the Government and better explanation of the reasoning behind returning certain students to school at this time whilst other members of the community continue to isolate.

Policy makers should standardise remote learning. This will ensure all students receive some educational support during pandemics, ensuring the educational divide caused by a lockdown is minimized.

If you would like to read the full report click here! https://osf.io/preprints/socarxiv/mdjsn/

Reference list:

1. Actions for schools during the coronavirus outbreak [Internet]. GOV.UK. 2020 [cited 2020 Jun 9]. Available from: https://www.gov.uk/government/publications/covid-19-school-closures/guidance-for-schools-about-temporarily-closing

2. Coronavirus (COVID-19): implementing protective measures in education and childcare settings [Internet]. GOV.UK. 2020 [cited 2020 Jun 9]. Available from: https://www.gov.uk/government/publications/coronavirus-covid-19-implementing-protective-measures-in-education-and-childcare-settings/coronavirus-covid-19-implementing-protective-measures-in-education-and-childcare-settings

3. Mitchell C. “The Girl Should Just Clean Up the Mess”: On Studying Audiences in Understanding the Meaningful Engagement of Young People in Policy-Making. Int J Qual Methods [Internet]. 2017 Dec 1 [cited 2020 Jun 6];16(1):1609406917703501. Available from: https://doi.org/10.1177/1609406917703501

Read our other guest blogs here:

Blog Virology

Ebola Strikes Again in the DRC

A second simultaneous Ebola outbreak has been confirmed in the Democratic Republic of Congo (DRC), (World Health Organization, 2020). This marks the 11th Ebola outbreak in central Africa which comes at a time when the continent also battles the COVID-19 pandemic.

First discovered in 1976, ebola viruses have since re-emerged across the African continent. The virus reached international attention during the longest and most extensive Ebola outbreak in West Africa between 2013 – 2015.

Historical Ebola outbreaks have fatality rates as high as 88%, almost 9 out of 10 people would die as a result of infection. The West Africa outbreak, however, saw a drastic reduction in fatality rate, to around 40%. The reduction in fatality rate was likely a result of the increased basic support, advanced and more appropriate care for those infected and earlier case detection, allowing for better management of both patients and outbreak spread (Baseler et al., 2017).

The most recent outbreak is in Mbandaka in the Équateur region, 600 miles from the ongoing Kivu Ebola epidemic in the North Kivu and Ituri provinces. The cases in Mbandaka are thought to be separate from the Kivu Ebola epidemic and instead the result of a new ‘spillover’ event from an animal reservoir to humans.

As of the 10th of June, a total of 12 cases have been reported; 9 confirmed cases, 3 suspected cases and 6 deaths, (Bujakera, Holland and Heavens, 2020)*. Positive samples were confirmed via testing at the Institut National de Recherche Biomédicale (INRB) – the countries national medical research organisation.

Although case number is relatively small at present, this is likely to rise as contacts are traced and the incubation period of 2-21 days elapses. Whilst the outbreak has presented at an already challenging time, scientists and doctors are on the ground with capacity to trace and diagnose. This service was expanded and refined in 2018 in response to previous outbreaks (World Health Organization, 2020).

The Kivu Ebola epidemic began in August 2018, over 3,400 people have been infected and sadly 2,200 lives lost despite the implementation of aggressive control measures. A number of factors have hindered this operation including; stigmatization, civil unrest and logistical issues.

Community level prevention and outbreak measures are dependent on the public trusting local authorities, however 31.9% of 961 individuals surveyed in North Kivu trusted that local authorities were acting in their best interests. The same survey reported 25.5 % of those surveyed believed the outbreak was a hoax, (Vinck et al., 2019). Complicating this were populist politicians publishing their own doubts on the outbreak validity to gain support in the 2018 elections. The country had not yet had a peaceful transition of power since decolonialisation in 1960, (Moran, 2018).

However, deployment of an experimental vaccine, coupled with rapid diagnostics helped to halt the outbreak. Following emergency use in 2016, the Ervebo vaccine was finally approved for use in 2019, after clinical trial demonstrated safety and efficacy; 97.5% efficacy in preventing Ebola infection compared to no vaccination, (Regules et al., 2015; World Health Organization, 2019).

Although an effective vaccination is now available, this is by no means the end of the problem. Availability, difficulties in contact tracing and public perception are all challenges that must be addressed to manage the outbreak during an already arduous time.

It is hoped that authorities and individuals alike can action their learnings from previous outbreaks, to bring this new outbreak to a swift end.

The DRC is currently contending with outbreaks of cholera, SARS-CoV-2, measles and two separate Ebola clusters. This serves as a stark reminder that whilst the world fights against the SARS-CoV-2 pandemic, Ebola outbreaks will stop for no country and no person.

Viruses emerge, or spillover often in nature, ebola virus is an example of this. Check out our blog on viral emergence here, or our post about bats and viruses.

*Please note that this article is not by a scientific body and reports figures from a WHO press conference which could not be confirmed on WHO.int.

Written by Charlotte Rigby

Citations

Baseler, L. et al. (2017) ‘The Pathogenesis of Ebola Virus Disease’, Annual Review of Pathology: Mechanisms of Disease, 12(1), pp. 387–418. doi: 10.1146/annurev-pathol-052016-100506.

Bujakera, S., Holland, H. H. and Heavens, A. (2020) Up to 12 infected in Congo’s new Ebola outbreak: WHO, Reuters.

Moran, B. (2018) ‘Fighting Ebola in conflict in the DR Congo’, The Lancet. Elsevier, 392(10155), pp. 1295–1296. doi: 10.1016/S0140-6736(18)32512-1.

Regules, J. A. et al. (2015) ‘A Recombinant Vesicular Stomatitis Virus Ebola Vaccine’, New England Journal of Medicine. Massachusetts Medical Society, 376(4), pp. 330–341. doi: 10.1056/NEJMoa1414216.

Vinck, P. et al. (2019) ‘Institutional trust and misinformation in the response to the 2018–19 Ebola outbreak in North Kivu, DR Congo: a population-based survey’, The Lancet Infectious Diseases, 19(5), pp. 529–536. doi: https://doi.org/10.1016/S1473-3099(19)30063-5.

World Health Organization (2019) Preliminary results on the efficacy of rVSV-ZEBOV-GP Ebola vaccine using the ring vaccination strategy in the control of an Ebola outbreak in the Democratic Republic of the Congo: an example of integration of research into epidemic response. doi: 10.1016/j.surfcoat.2019.125084.

World Health Organization (2020) New Ebola outbreak detected in northwest Democratic Republic of the Congo; WHO surge team supporting the response. Available at: https://www.who.int/news-room/detail/01-06-2020-new-ebola-outbreak-detected-in-northwest-democratic-republic-of-the-congo-who-surge-team-supporting-the-response (Accessed: 2 June 2020).

COVID-19 Research Summaries

Report Summary: Features of 20,133 UK patients in hospital with COVID-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study

Written by Rebekah Penrice-Randal and Lucia Livoti

Features of 20,133 UK patients in hospital with COVID-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study 1 was published in The British Medical Journal (BMJ) this week. This report defines clinical characteristics of patients in hospital in the UK, using the ISARIC WHO Clinical Characterisation Protocol. We have written a brief summary to define what this means, discuss the report itself and highlight the key findings to aid public understanding.


What is ISARIC?

ISARIC is the acronym for International Severe Acute Respiratory and emerging Infections Consortium. ISARIC are a global federation of clinical research networks, with a core goal of generating evidence to improve clinical care and public health responses. They provide a “proficient, coordinated and agile research response to outbreak-prone infectious diseases”.

You can follow the study on twitter for more updates: @CCPUKstudy


What is the ISARIC WHO Clinical Characterisation Protocol?

A research protocol is the set of documents that includes the instructions for conducting a study, the participant information sheets and consent forms. A clinical research protocol has to be approved by an independent Research Ethics Committee to ensure patient safety and dignity, and in the UK, by the Health Research Authority to ensure that health care resources are used appropriately.

 The ISARIC WHO Clinical Characterisation Protocol for Severe Emerging Infection (ISARIC WHO CCP-UK) was designed in 2012 to understand the clinical characteristics  of “any severe or potentially severe acute infection of public health interest”.

In other words, the study was set up in advance of an outbreak to ask the “who, what and why” of a new disease. Who is affected means, age, sex, ethnicity and underlying medical problems. What means, what does the disease cause any of: breathing problems, diarrhoea, vomiting, sepsis or bleeding.

The ISARIC WHO CCP allows for the collecting of clinical data and biological samples, and their analysis and processing to be done in a globally-harmonised manner. This protocol has been curated by multidisciplinary experts across the world 2, and employed in response to outbreaks such as:

  • Middle Eastern Respiratory Virus Syndrome coronavirus (MERS-CoV) in 2012,
  • Influenza in 2013,
  • Ebola virus in 2014,
  • Monkeypox and MERS-CoV in 2018,
  • Tick-borne encephalitis virus (TBEV) in 2019 and
  • SARS-CoV-2 in 2020.

The ISARIC WHO CCP has been central to the swift and cohesive research response to COVID-19. As a free, readily available resource it has been instrumental in the standardised collection of samples and data for the COVID-19 outbreak. This in turn has allowed clinical investigation to progress as quickly as possible. Global generic documents can be accessed here. Countries are also encouraged to develop “localised” instructions and seek local research permissions. The documents pertaining to UK protocols are available here.


Definitions:

Cohort: a cohort of patients are a group of individuals affected by a common factor, such as a disease, treatments or environmental factors.

Cohort study: cohort studies are central to the study of epidemiology and are often used in the fields of medicine, nursing, psychology and social sciences.

Comorbidity: presence of one or more medical conditions in addition to the condition being studied.

Epidemiology: the study and analysis of factors contributing to disease and health outcomes. In this case it may refer to the frequency and pattern of COVID-19 infection, risk factors, super-spreader events and study of specific populations. 

Median: the median is defined as the ‘middle’ value of a data set, such that other values are equally likely to be above or below.

Risk factor: a factor that increases an individual’s risk or susceptibility to a disease.


Aim of the study:

  • To rapidly understand the clinical characteristics of people severely affected by COVID-19. Severely affected, meaning those who need hospital care.


Why is this work important?

This work is essential to appreciate the clinical features of patients that present with COVID-19 and identify risk factors associated with poor outcome. It is only through the understanding of such aspects that public policy can be informed, particularly around shielding of vulnerable groups and planning of resources such as oxygen and ventilator provision.   


Who took part?

20,133 hospital in-patients with COVID-19 from 208 acute care hospitals across the UK were enrolled into the study. Clinical data was collected from patients admitted to hospital between 6th February and 19th April 2020. Patient outcomes are described as known on 3rd May 2020, as people admitted on the 19th April need at least 14 days to complete their admission or “declare the nature of their illness”.


The Results


Conclusions

The ISARIC WHO CCP-UK is a large ongoing study of patients hospitalised with COVID-19. This study found that the mortality rate was high in those admitted to hospital. Certain risk factors were associated with higher mortality rate such as; increasing age, male sex, and chronic comorbidity, including obesity. This report provides the first clinical insight of hospital patients with COVID-19 in the UK. The data gathered throughout this study will assist decision-making in the management of COVID-19, from patient to nation.

This report acknowledges the 2648 frontline NHS clinical and research staff, volunteer medical students and many researchers, who have worked tirelessly to make this study happen. Thank you to all involved and congratulations from The Science Social.


A note on ‘open access’

Open access journal articles are available to everyone and are not behind a pay wall. This article is freely available to all, if you would like to read the original article click here.

References

1          Docherty, A. B. et al. Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study. BMJ 369, m1985, doi:10.1136/bmj.m1985 (2020).

2          Dunning, J. W. et al. Open source clinical science for emerging infections. The Lancet Infectious Diseases 14, 8-9, doi:10.1016/S1473-3099(13)70327-X (2014).

Thank you to Professor Calum Semple (@tweediechap), an ISARIC investigator and co-author of the original article for permission to write this blog, and for the valuable comments.

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