Cambridge Open Exascale Lab

Cambridge Open Exascale Lab
Recently I have been occupyed writing coronavirus-related blog posts, but with the first round of the COVID-19 vaccination programme almost at its final stage in the UK, and the recovery of business activities, I plan to start writing more about spin-offs and other initiatives from Cambridge University that involve with latest innovative technologies.

In this blog post, I would like to introduce you a world-class supercomputer laboratory, Cambridge Open Exascale Lab, the University of Cambridge. It is dedicated to designing fast supercomputers to bring the UK’s science, health and industry into the levels of complexity and performance that previously were out of reach.

Cambridge Open Exascale Lab is part of the Cambridge Research Computing Services (RCS), formerly called the High Performance Computing (HPC) Facility when it was founded in 1996. Cambridge Research Computing Services was established with the aim of providing high performance computing services to leading scientists, medics and engineers across the whole of the UK.

Cambridge Research Computing Services currently runs two supercomputers, called Peta4 and Wilkes (named after Cambridge computing pioneer Sir Maurice Wilkes, 1913-2010). These are running at rates of peta (10¹⁵) floating-point operations per second (FLOPS, a measure of supercomputer performance when totalled across thousands of CPU cores, useful when handling scientific tasks that are highly parallelisable between many CPUs). The newly established Cambridge Open Exascale Lab aims to develop supercomputing systems running at the speed of exascale (10¹⁸) FLOPS, some 1,000 times the scale of the current systems.

What exascale supercomputing systems could bring
Countries from the United States to Europe to Japan are in the race to produce the world’s first exascale computing system. The United States Department of Energy and Intel announced that the first exaFLOPS supercomputer, Aurora, would be operational at Argonne National Laboratory in Lemont, Ilinois, by the end of 2021. The European Union has a range of exascale programmes in the works under its European High-Performance Computing Joint Undertaking. Japan is aiming for the exascale version of its Fugaku supercomputer to be available to users within a couple of years.¹ You may wonder why exascale computing systems are so urgently being developed. Let’s explore.

Take the example of my field of expertise, biomedical science. In the last 10 years, a huge amount of biological data, such as genomic and proteomic data, has been generated, mainly due to the fall in price of sequencing. Combining this biological data with clinical data could help develop personalized medicine (also called precision medicine). Analysing an amalgamation of all this data tends to require computing systems with high processing capacity (and also high storage space, although this tends to be only a secondary consideration for supercomputers, because managing the processor interconnects is the most difficult task, whereas adding more storage is easy by comparison). With the invention of the exascale computing system, analysis of data from different data sources, which currently takes weeks or even months, could be shortened to hours or days, and thus allow more calculations to be explored within a research project’s time-frame. Personalized medicine could therefore be developed in a much faster pace.

In addition, exascale supercomputers will enable simulations that are more complex and of higher resolution. This allows researchers to explore the molecular interactions of viruses and their hosts, which aids in the design of vaccines.¹ Imagine how it might have helped if we could have had a vaccine against SARS-CoV-2 with more than 95% efficacy designed in a few days, or even in a few hours, during the initial stages of the COVID-19 pandemic.

The exascale power will allow climate forecasters to swiftly run thousands of simulations, introducing tiny variations in the initial conditions, to provide better insight into the potentially disastrous effects of climate change.¹

Besides life sciences, exascale computing is expected to benefit chemical design, pattern modelling, high-energy physics, materials science, oil exploration, and transportation.¹

In view of the benefits of exascale computing systems, the opening of Cambridge Open Exascale Lab could help the UK remain at the forefront of different fields of science.

Goals of Cambridge Open Exascale Lab
An exascale supercomputer will contain some 135,000 GPUs and 50,000 CPUs, each one being a multi-core chip with many individual processing units. This immediately creates the problems of huge power consumption, and a potentially difficult method of programming to enable almost a billion instructions being executed simultaneously. Furthermore, if the system is upgraded, researchers may need to re-examine millions of lines of code and optimize them to make use of the extra hardware, so that the programs can reach as close to the theoretical maximum processing power as possible. In addition, the ability to access memory (RAM or long-term storage) and retrieve data quickly is an issue in highly interconnected supercomputers, as evidenced by Cambridge startup Ellexus (recently sold to Altair), which focused on profiling the bottlenecks of I/O (input and output) to the storage devices in supercomputers, and found this was frequently more of an issue than the software designers had realised.

The Cambridge Open Exascale Lab’s plans include: analyse supercomputer power consumption with a view to how to reduce it; provide a method of giving supercomputer time more quickly to scientists that need it for urgent work (such as those responding to pandemics and other disasters); apply an Intel-made programming framework that allows loads to be shared across heterogeneous computers (those involving more than one type of processor, which should make upgrades easier because any new processors do not have to be exactly matched to the existing ones); install faster storage systems (based on solid-state memory chips); improve fast communication between the parts of the computer; and work on new types of graphics to visualise the data produced by the supercomputer.

Cambridge Open Exascale Lab works with a broad range of industry, government, University and other partners. Its industry partners include Dell and Intel Corporation. With its aim to recruit 20 more staff in 2021, hopefully the lab will have sufficient support from talented people to achieve its goal in developing an exascale computing system very shortly.

Cambridge Open Exascale Lab is situated in the West Cambridge Data Centre (WCDC) built by the University of Cambridge at a cost of £20m. This centre is designed to accommodate the rapid growth in demand for high performance computing, and is one of UK’s most energy-efficient high performance computer data centres. It has a high level of security and provides research computing services at a national level.



Most information written in this blog post is mainly from the website of Cambridge Open Exascale Lab.

References:
1. Adam Mann. Core Concept: Nascent exascale supercomputers offer promise, present challenges. PNAS, September 15, 2020 117 (37) 22623-22625).

Coronavirus (46) NHS website on vitamins and minerals

Coronavirus (46) NHS website on vitamins and minerals
After reading the last two blog posts, you might be eager to start a balanced diet in order to strengthen your immune system. The NHS website on vitamins and minerals provides examples of food that can be easily found in UK supermarkets.¹ Here in this blog post, I would like to tabulate the information from the website to make it easier for you to have a look. The harmful effects if we have too much of the vitamins/minerals and the suggested maximum daily intake amount for an adult in the website are also included in the table.

As the daily intake requirement for the vitamins/minerals between adults and children, male and female are different, you might have an interest to have a look at the report from the Public Health of England on dietary recommendations for both children and adults before you plan for your diet.²

Table 1. Sources of vitamins and minerals

	Sources of Vitamin	Can it be stored in the body?	Effects if having too much
Vitamin A	cheese, eggs, oily fish such as trout, salmon, sardines, pilchards, fortified low-fat spreads milk and yoghurt, liver and liver products such as liver pâté	Yes	Having more than an average of 1.5 mg a day of vitamin A over many years may affect your bones, making them more likely to fracture when you're older..Having large amounts of vitamin A can harm your unborn baby.
Beta-carotene (Precursor of vitamin A)	Yellow, red and green (leafy) vegetables, such as spinach, carrots, sweet potatoes and red peppers, yellow fruit, such as mango, papaya and apricots	Yes	If you eat more beta-carotene, less is converted, and the rest is stored in fat reserves in the body. So too much beta-carotene can make you turn yellow, but will not kill you with hypervitaminosis.
Vitamin B1 (Thiamine)	Peas, some fresh fruits (such as bananas and oranges), nuts, wholegrain breads, some fortified breakfast cereals, liver	No	There's not enough evidence to know what the effects might be of taking high doses of thiamin supplements each day. Taking 100mg or less a day of thiamin supplements is unlikely to cause any harm.
Vitamin B2 (Riboflavin)	Milk, eggs, fortified breakfast cereals, mushrooms, plain yoghurt	No	There's not enough evidence to know what the effects might be of taking high doses of riboflavin supplements each day. Taking 40mg or less a day of riboflavin supplements is unlikely to cause any harm.
Vitamin B3 (Niacin: nicotinic acid and nicotinamide. )	Meat, fish, wheat flour, eggs	No	Taking high doses of nicotinic acid supplements can cause skin flushes. Taking high doses for a long time could lead to liver damage. Taking 17mg or less of nicotinic acid supplements a day, or 500mg or less of nicotinamide supplements a day, is unlikely to cause any harm.
Vitamin B5 (Pantothenic acid)	Chicken, beef, liver and kidney, eggs, mushrooms, avocado	No	If you take supplements, do not take too much as this might be harmful. Taking 200mg or less a day of pantothenic acid in supplements is unlikely to cause any harm.
Vitamin B6 (Pyridoxine)	Pork, poultry, such as chicken or turkey, some fish, peanuts, soya beans, wheatgerm, oats, bananas, milk, some fortified breakfast cereals. The bacteria that live naturally in your bowel are also able to make vitamin B6.	No	Taking 200mg or more a day of vitamin B6 can lead to a loss of feeling in the arms and legs known as peripheral neuropathy. This will usually improve once you stop taking the supplements. But in a few cases when people have taken large amounts of vitamin B6, particularly for more than a few months, the effect can be permanent.
Vitamin B7 (Biotin)	Biotin is also found in a wide range of foods, but only at very low levels. The bacteria that live naturally in your bowel are able to make biotin, so it's not clear if you need any additional biotin from the diet.	No	If you take biotin supplements, do not take too much as this might be harmful. Taking 0.9mg or less a day of biotin in supplements is unlikely to cause any harm.
Vitamin B9 (Folate or folic acid)	Broccoli, brussels sprouts, leafy green vegetables such as cabbage, kale, spring greens and spinach, peas, chickpeas and kidney beans, liver (but avoid this during pregnancy), breakfast cereals fortified with folic acid	No	Taking doses of folic acid higher than 1mg can mask the symptoms of vitamin B12 deficiency, which can eventually damage the nervous system Taking 1mg or less a day of folic acid supplements is unlikely to cause any harm.
Vitamin B12	Meat, fish, milk, cheese, eggs, some fortified breakfast cereals	No	There's not enough evidence to show what the effects may be of taking high doses of vitamin B12 supplements each day. Taking 2mg or less a day of vitamin B12 in supplements is unlikely to cause any harm.
Vitamin C (Ascorbic acid)	Citrus fruit, such as oranges and orange juice, peppers, strawberries, blackcurrants, broccoli, brussels sprouts, potatoes	No	Taking large amounts (more than 1,000mg per day) of vitamin C can cause stomach pain, diarrhoea, flatulence. These symptoms should disappear once you stop taking vitamin C supplements.
Vitamin D	The body creates vitamin D from direct sunlight on the skin when outdoors. Vitamin D is also found in a small number of foods. Sources include oily fish – such as salmon, sardines, herring and mackerel, red meat, liver, egg yolks, fortified foods – such as some fat spreads and breakfast cereals	Yes	Taking too many vitamin D supplements over a long period of time can cause too much calcium to build up in the body (hypercalcaemia). This can weaken the bones and damage the kidneys and the heart. If you choose to take vitamin D supplements, 10 micrograms a day will be enough for most adults.
Vitamin E	Plant oils – such as rapeseed (vegetable oil), sunflower, soya, corn and olive oil; nuts and seeds; wheatgerm-found in cereals and cereal product	Yes	There is not enough evidence to know what the effects might be of taking high doses of vitamin E supplements each day. Taking 540mg (800 IU) or less a day of vitamin E supplements is unlikely to cause any harm.
Vitamin K	Green leafy vegetables such as broccoli and spinach, vegetable oils, cereal grains. Small amounts can also be found in meat and dairy foods.	n.a	There's not enough evidence to know what the effects might be of taking high doses of vitamin K supplements each day. Adults need approximately 1 microgram a day of vitamin K for each kilogram of their body weight.
Calcium	Milk, cheese and other dairy foods, green leafy vegetables such as curly kale, okra but not spinach (spinach does contain high levels of calcium but the body cannot digest it all), soya drinks with added calcium, bread and anything made with fortified flour, fish where you eat the bones such as sardines and pilchards	n.a.	Taking high doses of calcium (more than 1,500mg a day) could lead to stomach pain and diarrhoea. Adults aged 19 to 64 need 700mg of calcium a day.
Chromium	Meat, nuts, cereal grains	n.a.	There's not enough evidence to know what the effects might be of taking high doses of chromium each day. Having 10mg or less a day of chromium from food and supplements is unlikely to cause any harm.
Copper	Nuts, shellfish, offal	n.a.	Taking high doses of copper could cause stomach pain, sickness, diarrhoea, damage to the liver and kidneys (if taken for a long time). Having 10mg or less a day of copper supplements is unlikely to cause any harm.
Iodine	Sea fish, shellfish, plant foods such as cereals and grains (the levels vary depending on the amount of iodine in the soil where the plants are grown)	n.a.	Taking high doses of iodine for long periods of time could change the way your thyroid gland works. This can lead to a wide range of different symptoms, such as weight gain. However, taking 0.5mg or less a day of iodine supplements is unlikely to cause any harm.
Iron	Liver (but avoid this during pregnancy); red meat; beans such as red kidney beans, edamame beans and chickpeas; nuts; dried fruit such as dried apricots; fortified breakfast cereals; soy bean flour	n.a.	Side effects of taking high doses (over 20mg) of iron include: constipation, feeling sick, being sick, stomach pain. Very high doses of iron can be fatal, particularly if taken by children. Taking 17mg or less a day of iron supplements is unlikely to cause any harm. But continue taking a higher dose if advised to by a GP.
Manganese	Bread, nuts, breakfast cereals (especially wholegrain), green vegetables such as peas	n.a.	Taking high doses of manganese for long periods of time might cause muscle pain, nerve damage and other symptoms, such as fatigue and depression. For most people, taking 4mg or less of manganese supplements a day is unlikely to cause any harm. For older people, who may be more sensitive to manganese, taking 0.5mg or less of manganese supplements a day is unlikely to cause any harm.
Molybdenum	Molybdenum is found in a wide variety of foods. Foods that grow above ground tend to be higher in molybdenum than foods that grow below the ground, such as potatoes or carrots.	n.a.	There's some evidence to suggest taking molybdenum supplements might cause joint pain.
Phosphorus	Red meat, dairy foods, fish, poultry, bread, brown rice, oats	n.a.	Taking high doses of phosphorus supplements for a short time can cause diarrhoea or stomach pain. Taking high doses for a long time can reduce the amount of calcium in the body, which means bones are more likely to fracture. Taking 250mg or less a day of phosphorus supplements on top of the phosphorous you get from your diet is unlikely to cause any harm.
Potassium	Bananas, some vegetables such as broccoli, parsnips and brussels sprouts, beans and pulses, nuts and seeds, fish, beef, chicken, turkey	n.a.	Taking too much potassium can cause stomach pain, feeling sick and diarrhoea. Taking 3,700mg or less of potassium supplements a day is unlikely to have obvious harmful effects. But older people may be more at risk of harm from potassium because their kidneys may be less able to remove potassium from the blood.
Selenium	Brazil nuts, fish, meat, eggs	n.a.	Too much selenium causes selenosis, a condition that, in its mildest form, can lead to loss of hair and nails. Taking 350μg or less a day of selenium supplements is unlikely to cause any harm.
Sodium chloride (salt)	Ready meals, meat products such as bacon, some breakfast cereals, cheese, tinned vegetables with added salt, some bread, savoury snacks	n.a.	Having too much salt is linked to high blood pressure, which raises your risk of serious problems like strokes and heart attacks. You should have no more than 6g of salt (around 1 teaspoon) a day.
Zinc	Meat, shellfish, dairy foods such as cheese, bread, cereal products such as wheatgerm	n.a.	Taking high doses of zinc reduces the amount of copper the body can absorb. This can lead to anaemia and weakening of the bones. Do not take more than 25mg of zinc supplements a day unless advised to by a doctor.

By now, you might have an idea what you would like to have in your meals. However, before you start the next meal, you can think about preparing it by yourself: buy fresh and unprocessed foods, add less salt and sugar, and use moderate amounts of oil for cooking. This way, you can get the most value of vitamins/minerals from the meal. Last but not least, don’t forget to drink enough water and exercise regularly.³



References
1. Vitamins and minerals. NHS. https://www.nhs.uk/conditions/vitamins-and-minerals/
2. Government dietary recommendations. Government recommendations for energy and nutrients for males and females aged 1 – 18 years and 19+ years. https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/618167/government_dietary_recommendations.pdf
3. Nutrition advice for adults during the COVID-19 outbreak. WHO. http://www.emro.who.int/nutrition/news/nutrition-advice-for-adults-during-the-covid-19-outbreak.html

Coronavirus (45) Nutrients help to combat COVID-19 (cont'd)

Coronavirus (45) Nutrients help to combat COVID-19 (cont’d)
In addition to the vitamins mentioned in my last blog post, minerals such as iron, zinc, selenium and copper are also essential for good immunity. They are required in smaller quantities and are therefore called trace minerals. Let us have a look at the same two review articles^1,2 used in the last blog post, on how different trace minerals can protect ourselves from infectious diseases.

Copper
Copper itself is an antimicrobe. Copper supports neutrophil, monocyte and macrophage function and natural killer cell activity.

People on a low copper diet have decreased lymphocyte proliferation and decreased production of IL-2, which is important for immune response. Children with Menke’s syndrome, a rare congenital disease with no circulating copper-carrying protein caeruloplasmin, show immune impairments and have increased bacterial infections and pneumonia. Analysis of studies on Chinese children showed that those with recurrent respiratory tract infection were more likely to have low levels of copper in their hair.¹

Iron
Iron is a trace mineral that we should be careful about the amount we take in. Iron is required for both host and pathogen. Iron deficiency can impair host immunity, while iron overload can cause oxidative stress to propagate harmful viral mutations.²

Iron deficiency has harmful effects on immune function, including impairment of: 1. the ability to generate reactive oxygen species for the killing of harmful microorganisms; 2. bacterial killing; 3. natural killer cell activity; 4. T lymphocyte proliferation, and 5. production of T helper 1 cytokines. These in turn increase susceptibility to infection.¹

On the other hand, infections caused by organisms that spend part of their life-cycle intracellularly may actually be enhanced by iron. In the children living in tropical regions, iron at doses above a particular threshold has been associated with increased risk of malaria and other infections, including pneumonia. Thus, iron intervention in malaria-endemic areas is not advised.¹ Moreover, a study giving iron (50 mg on each of 4 days a week) to iron-deficient schoolchildren in South Africa increased the risk of respiratory infections.¹

In general, the harmful consequences of iron overdoses on infections include: 1. Impairment of immune function; 2. Excess iron favours damaging inflammation; 3. Helping the growth of pathogens that require iron.

Selenium
Selenium deficiency adversely affects several components of both innate* and acquired immunity,** and increases susceptibility to infections.¹

It is of concern to find that dietary selenium deficiency induces rapid mutation of benign variants of RNA viruses to virulence. Deficiency in selenium can cause oxidative stress in the host, and can alter a viral genome so that a normally benign or mildly pathogenic virus can become highly virulent.² Selenium could assist a group of enzymes that, in concert with vitamin E, work to prevent the formation of free radicals and prevent oxidative damage to cells and tissues.

It was reported that combination of selenium with ginseng stem-leaf saponins could induce immune response to a live bivalent infectious bronchitis coronavirus vaccine in chickens.² Therefore, the review article written by Zhang et al suggests that selenium supplementation could be an effective choice for the treatment of novel variants of COVID-19.²

You may wonder how much selenium we need to maintain the normal function of our immunity. It was found that selenium supplementation with 100 to 300 µg/day could improve various aspects of immune function in humans including in the elderly. Selenium supplementation of 50 or 100 µg/day in adults in the UK with low selenium status improved some aspects of their immune response to a poliovirus vaccine.¹

Zinc
Zinc has an important role in maintaining and developing immune cells of both the innate* and adaptive immune system.***

Especially you may find it interesting that zinc seems to play an important role in antiviral defence. It was found to inhibit the RNA polymerase required by RNA viruses to replicate. Moreover, zinc supports proliferation of CD8+ cytotoxic T lymphocytes, key cells in antiviral defence. These findings suggest that zinc might play a key role in host defence against the RNA virus SARS-CoV-2 that cause COVID-19.¹ In fact, the combination of zinc and pyrithione at low concentrations inhibits the replication of SARS coronavirus.²

Zinc deficiency has a marked impact on bone marrow by decreasing the number of immune precursor cells. Therefore, zinc is important in maintaining T and B lymphocyte numbers. Moreover, antibody production is decreased in zinc deficiency. Zinc deficiency also impairs many aspects of innate immunity, including phagocytosis and natural killer cell activity. Patients with the zinc malabsorption syndrome, acrodermatitis enteropathica, display severe immune impairments and increased susceptibility to bacterial, viral and fungal infections.¹

Correcting zinc deficiency lowers the likelihood of respiratory and skin infections. Recent reviews and analysis of trials with zinc reported shorter durations of common cold in adults, reduced incidence and prevalence of pneumonia in children, and reduced mortality when given to adults with severe pneumonia.¹

Conclusion
After reading the two blog posts on the different nutrients and their importance in fighting against infection, we understand we should have a balanced diet in order to maintain our immune system to prevent respiratory diseases such as COVID-19. No single nutrient should be left out in order to attain the optimum condition of our immune system for health.

As new pathogens responsible for influenza continually emerge, and outbreaks of new variants of the SARS-CoV-2 virus are highly possible, it is especially necessary to have a dietary regimen that includes all the nutrients in order to reduce the adverse effects from new or mutating pathogens.



*The innate immune system is the body’s first line of defense against germs. The innate immune system consists of 1. skin and mucous membranes that forms a physical barrier against germs; 2. immune system cells (defense cells) and proteins that are activated upon inflammation; 3. white blood cells (leukocytes) that kill bacteria or viruses, by phagocytosis, that enter the body; 4. natural killer cells specialized in identifying cells that are infected by a virus, and then destroy the cell surface using cell toxins.³
Since the innate immune system responds in the same way to all germs and foreign substances, it is also referred to as the "nonspecific" immune system. It acts very quickly: it makes sure that bacteria that have entered the skin through a small wound are detected and destroyed on the spot within a few hours. However, the innate immune system has only limited power to stop germs from spreading.³
**“Acquired immunity is a type of immunity that develops when a person’s immune system responds to a foreign substance or microorganism, or that occurs after a person receives antibodies from another source. The two types of acquired immunity are adaptive and passive. Adaptive immunity occurs in response to being infected with or vaccinated against a microorganism. The body makes an immune response, which can prevent future infection with the microorganism. Passive immunity occurs when a person receives antibodies to a disease or toxin rather than making them through his or her own immune system.” (from online NCI (National Cancer Institute) dictionary. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/acquired-immunity)
***The adaptive immune system takes over if the innate immune system is not able to destroy the germs. The adaptive immune system is made up of 1. T lymphocytes in the tissue between the body's cells; 2. B lymphocytes which are also found in the tissue between the body's cells; 3. antibodies in the blood and other bodily fluids.
The adaptive immune system specifically targets the type of germ that is causing the infection. It first identifies the germ, which makes it slower to respond than the innate immune system, and then it destroys it. It can "remember" germs, so the next time a known germ is encountered, the adaptive immune system can respond faster.



References
1. P.C. Calder. Nutrition, immunity and COVID-19. Review. BMJ Nutrition, Prevention & Health. 2020 May 20;3(1):74-92.
2. L. Zhang, and Y. Liu. Potential interventions for novel coronavirus in China: A systematic review. Journal of Medical Virology, 2020 May 92(5):479-490.
3. The innate and adaptive immune systems. InformedHealth.org. Cologne, Germany: Institute for Quality and Efficiency in Health Care (IQWiG); 2006-. https://www.ncbi.nlm.nih.gov/books/NBK279396/

Coronavirus (44) Nutrients help to combat COVID-19

Coronavirus (44) Nutrients help to combat COVID-19
Since the outbreak of COVID-19 in the UK, which led to the first national lockdown in March 2020, the pandemic has already lasted for more than 15 months. During this period of time, many countries in the world experienced several waves of COVID-19 outbreaks, and quite a few major variants of the SARS-CoV-2 virus emerged. For the UK, the country has been attacked by the wild type, the variant from South Africa (Beta variant, B1.351), the variant from Kent (Alpha variant, B.1.1.7), and recently the variant that originated from India (Delta variant, B1.617.2).

The existing therapies and vaccines against COVID-19 were designed based on the SARS-CoV-2 virus first identified. The longer the virus spread among people, the higher the chances that the virus would mutate. The mutated variants that later become dominant are usually more virulent, and they are more resistant, to various degrees, to the existing therapies and vaccines. Unless we could produce a specific therapy or vaccine in time for an emerged variant, a good immune system, which is able to respond promptly and appropriately to different challenges, is very important to protect us against any SARS-CoV-2 variants.

Optimal nutritional status and lifestyle habits are essential to keeping our immune systems working properly. Here in this blog post, I would like to share with you findings from two review articles on how different nutrients can help us protect ourselves from infectious diseases.^1,2 This might give us an idea of what we could prepare for our meals in order to strengthen our health to combat coronavirus-related diseases.

Vitamin A
Vitamin A has been called an “anti-infective vitamin”. It is essential for body's defences against infection as it is important for normal differentiation of epithelial tissue.*^1,2 Lack of vitamin A is associated with increased susceptibility to respiratory infections, diarrhoea and severe measles.

Moreover, vitamin A is important for immune cell maturation and function: Vitamin A controls maturation of neutrophils, macrophages, natural killer cells, dendritic cells, and CD4+ T lymphocyte, which are involved in the killing of pathogens.¹

As we are undergoing a national vaccination program in the UK, it is also relevant to note that vitamin A deficiency can impair the body’s response to vaccination. Vitamin A’s metabolite, retinoic acid, is required for normal functioning of B lymphocytes, including antibody generation. An example from Indonesian children with vitamin A deficiency showed a higher antibody response to tetanus vaccination after providing them with vitamin A, suggesting that lack of vitamin A can impair the response to vaccination.¹

B group vitamins
B vitamins are water-soluble vitamins and work as part of coenzymes.² B vitamins are generally involved in intestinal immune regulation, thus contributing to gut barrier function.¹ Vitamins B6 and B12 and folate (Vitamin B9) all support the activity of natural killer cells and CD8+ cytotoxic T lymphocytes, effects which would be important in antiviral defence.¹ Lack of vitamin B6 deficiency causes thymus and spleen atrophy, low blood T lymphocyte numbers, and impaired lymphocyte proliferation and T lymphocyte-mediated immune responses,¹ while vitamin B12 deficiency decreases phagocytic** and bacterial killing capacity of neutrophils. In general, shortage of B vitamins weakens the host immune response.

Other B vitamins also has their special functions.1 Vitamin B2 (riboflavin) and UV light effectively reduced the amount of MERS-CoV in human plasma products.^2,3 Vitamin B3 (nicotinamide) could enhance the killing of Staphylococcus aureus (bacteria which often cause skin infections, pneumonia, heart valve infections, and bone infections). Moreover, lung injury during mechanical ventilation is usually seen in the severe cases of COVID-19 who need ventilators to get oxygen into body. Vitamin B3 treatment to these patients has a strong anti-inflammatory effect as it significantly inhibits neutrophil infiltration into the lungs.² Neutrophil infiltration in inflamed lung causes damage to the lung, and is a hallmark of Acute Respiratory Distress Syndrome in severe COVID-19 cases.

Vitamin C
Vitamin C is involved in collagen biosynthesis in connective tissues and is important for maintaining epithelial integrity (tissue in glands and linings).***^1,2

Its roles in immunity include leucocyte migration to sites of infection, phagocytosis** and bacterial killing, natural killer cell activity, T lymphocyte function (especially of CD8+ cytotoxic T lymphocytes) and antibody production1 (similar to the function of vitamin A).

Vitamin C supplementation has been shown to decrease the duration and severity of upper respiratory tract infections such as the common cold.¹ People deficient in vitamin C are susceptible to severe respiratory infections such as pneumonia.¹ This suggests that vitamin C might prevent the susceptibility to lower respiratory tract infections. Furthermore, vitamin C may also protect against infection caused by a coronavirus, as vitamin C increased the resistance of cultures of chick embryo tracheal organ to avian coronavirus infection.² As COVID-19 is related to lower respiratory tract infection, the Chinese researchers of a review article even suggest vitamin C could be one of the choices for COVID-19 treatment.²

Vitamin D
Vitamin D receptors are found in most immune cells. Vitamin D stimulates the maturation of many immune cells, and enhances epithelial integrity. Vitamin D also induces antimicrobial peptide synthesis in epithelial cells and macrophages, directly enhancing host defence.¹ Moreover, vitamin D increases phagocytosis, superoxide^# production and bacterial killing by innate immune cells.¹

A study from Taiwan found that people with vitamin D deficiency has lower antibody response, after vaccination with influenza A virus subtype H3N2 and B strain, than the group of people with normal vitamin D levels.¹ Studies using data from British and American populations suggested that vitamin D levels is inversely correlated with respiratory infection. This means the lower the vitamin D levels, the higher the risk of viral respiratory tract infection.¹

Vitamin D can be synthesized in our body with the help of sunlight. Summer is the time with sufficient sunlight, but over a year it is only a short time, so a high proportion of healthy adults in the UK are reported to have low levels of vitamin D. Moreover, the reduced outdoor journies due to the COVID-19 pandemic, further decreases the chance of people to absorb sunlight. Therefore, in addition to absorbing vitamin D from food, vitamin D deficient patients in the UK are usually prescribed vitamin D supplements by a GP. Meanwhile, a study in Japan found that supplementation of Japanese schoolchildren with vitamin D for 4 months during winter reduces the risk of influenza A by about 40%.¹

Vitamin E
Vitamin E is a lipid-soluble antioxidant that plays an important role in reducing oxidative stress through binding to free radicals.²

Vitamin E also plays a role in immune response and enhances antibody production.¹ The effect of vitamin E is especially obvious in healthy adults over 60 years of age. Research found a positive association between plasma vitamin E and cell-mediated immune response, and a negative association between plasma vitamin E and the risk of infections in this age group.¹ Studies by the Nutrition Research Center on Ageing at Tufts University in Boston demonstrated that vitamin E supplementation at high doses (800 mg/day) enhanced T helper 1 cell-mediated immunity (lymphocyte proliferation and IL-2 production), and improved vaccination response to the hepatitis B virus.¹ The same research group also reported that a daily intake of vitamin E supplement (135mg/day) for a year decreased upper respiratory tract infections, particularly the common cold, in elderly residents of a nursing home.¹ A study from Spain provided further evidence that supplementation of older adults with vitamin E improved their immunity defences.¹

Information on other nutrients to protect ourselves from infectious diseases will be presented in my next blog post.



*Epithelial tissue covers most of the external and internal surfaces of the body and its organs. These tissues serve as the first line of defence against inorganic, organic, and microbial intruders. Epithelial cells are the main cell type of these tissues.⁴
**Phagocytosis is a process of ingesting harmful foreign particles, bacteria, and dead or dying cells.
***Epithelial cells are the main cell type of epithelial tissues, which cover most of the external and internal surfaces of the body and its organs.⁴ Epithelial integrity is very important as a first line of defence against inorganic, organic, and microbial intruders.
^#Superoxide is a reactive oxygen species. It is generated by the immune system to kill invading pathogens in oxygen-dependent killing mechanisms.




References
1. P.C. Calder. Nutrition, immunity and COVID-19. Review. BMJ Nutrition, Prevention & Health. 2020, May 20;3(1):74-92.
2. L. Zhang, and Y. Liu. Potential interventions for novel coronavirus in China: A systematic review. Journal of Medical Virology, 2020, May 92(5):479-490.
3. S.D. Keil, R. Bowen, and S. Marschner. Inactivation of Middle East Respiratory Syndrome coronavirus (MERS-CoV) in plasma products using a riboflavin-based and ultraviolet light-based photochemical treatment. Transfusion. 2016;56:2948-2952.
4. J. Gunther, & H-M. Seyfert. The first line of defence: insights into mechanisms and relevance of phagocytosis in epithelial cells. Semin Immunopathol. 2018; 40(6): 555–565.

Coronavirus (43) Mass asymptomatic testing of SARS-CoV-2 using lateral flow devices (cont’d)

Coronavirus (43) Mass asymptomatic testing of SARS-CoV-2 using lateral flow devices (cont’d)
Continued from my last blog post.
Limitation of lateral flow tests
The lateral flow test kit from Innova for detection of SARS-CoV-2 infections has been tested by Public Health England and validated by the UK government.^1,2 It was initially tested among 132 candidates when the UK government were considering the use of lateral flow devices (LFDs) in mass-testing for COVID-19 in an asymptomatic population.¹

The test report showed that all the tested lateral flow devices have a viral antigen detection rate of >90% at 100,000 RNA copies/ml (for comparison, only 3,600 to 10,000 copies/ml of virus in the sample is already enough to be detected by RT-PCR, which is more than ten times as sensitive). The study found a kit failure rate of 5.6% from 8951 Innova SARS-CoV-2 Antigen Rapid Qualitative Tests. The most common reason for kit failure was poor transfer of the liquid within the device from the reservoir onto the test strip. ¹

The false positive rate was 0.32% from 6954 Innova tests. This means that for every 1,000 people tested, only 3 people would get a false positive result. The study also found that the sensitivity (the detection rate of positive cases) across the sampling cohort is significantly dependent on the test operator. Sensitivity of the tests performed by laboratory scientists was 78.8%, trained healthcare-workers was 70%, while the self-trained members of the public was 57.7%.¹

The above study showed that the kit failure rate for the tests is not low, and they tend to give a more accurate result only if a sample with higher viral concentration is being tested and the user performing the test is well-trained. This means the overall accuracy of the lateral flow tests is generally lower among asymptomatic people who are not well-trained and who have a generally lower viral concentration.

When it comes to the real world evaluation of Innova SARS-CoV-2 Antigen Rapid Qualitative Test, the sensitivity of the test is found to be much lower than the above report. The Innova lateral flow test was used in a mass test of the population in Liverpool last November.³ By evaluation of the performance of the Innova lateral flow test against RT-PCR testing using data from 5,869 people, it was found that 60% of infected people could not be detected by the lateral flow tests. On the other hand, the test performed better for detecting cases in people with higher viral loads, with test sensitivity in this group at 66.7%.³ Similar to the result from the other study, the specificity was 99.9% in this study.^1,3 This means the positive results from the lateral flow tests are highly accurate.

Based on these research studies, the general sensitivity of the lateral flow tests are 40–76%, which means that about half of infected people may be missed.^1,3,4 Those carrying COVID-19 who were wrongly told they were free of the virus could transmit to more people than those who do not have the tests, due to a false sense of security. Therefore, many scientists called on the government at least to pause the rollout of rapid asymptomatic testing using the Innova tests, as they are sceptical that the lateral flow tests are able to control effectively the transmission of infection.^5,6

Can the lateral flow test detect COVID-19 variants?
There has no research paper or data available yet on the efficiency of the Innova SARS-CoV-2 Antigen Rapid Qualitative Test to detect the Kent and Indian variants which are now prevalent in the UK. The planned rollouts of lateral flow tests in schools were paused because of concerns about the risk of missing cases caused by the new and more transmissible SARS-CoV-2 variants.⁷

Where can we get the free lateral flow test?
After reading all the information about the free of charge lateral flow test scheme, you might want to try to have one yourself. The free rapid lateral flow tests are being made available by the government in England. As long as you are in England, aged 11 or above, and have no COVID-19 symptoms, you can order one pack of lateral flow tests per day online and it will be delivered to your home. Each pack contains 7 tests.⁶

​ The tests can also be collected at local PCR test sites and most of the local pharmacies in England. It is very important to remember that the tests are just for asymptomatic people: if you have COVID-19 symptoms, you should not go outside to collect a test; instead, you should order a PCR test and self-isolate.⁶

Who could benefit from the free lateral flow tests?
The sensitivity of lateral flow tests are in doubt, and the usefulness of the lateral flow tests being used as a tool to control the transmission of infection is being questioned by some scientists. However, as long as the tests are repeated twice a week as suggested by the government, there is still a chance of the asymptomatic infections being detected. Therefore, the free lateral flow test scheme available in England provides certain degree of protection for the households who have members working in patient-facing or customer-facing sectors.

However, you have to remember that the test on average misses about half of the COVID-19 infectious cases, i.e. a negative result does not rule out a COVID-19 infection. If your result is negative from the lateral flow test, it is very important to still follow all the current restrictions imposed by the government.



References
1. Peto T & UK COVID-19 Lateral Flow Oversight Team. COVID-19: rapid antigen detection for SARS-CoV-2 by lateral flow assay: a national systematic evaluation for mass-testing. medRxiv. 2021; (published online Jan 26.) (preprint). https://doi.org/10.1101/2021.01.13.21249563
(Later published online in Lancet, May 29, 2021. DOI:https://doi.org/10.1016/j.eclinm.2021.100924)
2. Order coronavirus (COVID-19) rapid lateral flow tests. GOV.UK website. https://www.gov.uk/order-coronavirus-rapid-lateral-flow-tests
3. Liverpool COVID-19 community testing pilot. Interim evaluation report by the University of Liverpool. 23 December, 2020. https://www.liverpool.ac.uk/media/livacuk/coronavirus/Liverpool,Community,Testing,Pilot,Interim,Evaluation.pdf
4. RT-LAMP assay: Fail to detect positive cases more than 50% in November in Manchester. “Covid-19: Rapid test missed over 50% of positive cases in Manchester pilot. BMJ 2020; 371 doi: https://doi.org/10.1136/bmj.m4323 (Published 06 November 2020) Cite this as: BMJ 2020;371:m4323”
5.UK government must urgently rethink lateral flow test roll out, warn experts. The BMJ news, 11/01/21. https://www.bmj.com/company/newsroom/uk-government-must-urgently-rethink-lateral-flow-test-roll-out-warn-experts/
6. Covid-19: UK regulator approves lateral flow test for home use despite accuracy concerns. BMJ news, 2020; 371 doi: https://doi.org/10.1136/bmj.m4950 (Published 23 December 2020)
7. Mass testing of COVID-19: January update on lateral flow tests. UK Parliament Post, 29 January 2021. https://post.parliament.uk/mass-testing-for-covid-19-january-update-on-lateral-flow-tests/

Coronavirus (42) Mass asymptomatic testing of SARS-CoV-2 using lateral flow devices

Coronavirus (42) Mass asymptomatic testing of SARS-CoV-2 using lateral flow devices
In order to contain the spread of COVID-19, in addition to the national lockdown and nationwide COVID-19 vaccination, the UK government also use reverse-transcription polymerase chain reaction (RT-PCR) testing of nose/throat swabs, contact tracing procedures, and mobile applications to identify close contacts of infected symptomatic individuals.

In addition to the above measures, the government also rolled out mass asymptomatic testing on 9th April, aiming to identify people with COVID-19 who are not displaying any symptoms. This testing programme allows everyone in England to access two COVID-19 tests a week, free of charge, even if they do not have any symptoms.¹ Ideally, by quickly identifying the asymptomatic patients and having these people self-isolate, and through the rapid finding and testing of their close contacts, the spread through the community could be interrupted.¹

The programme uses the lateral flow test kit, SARS-CoV-2 Rapid Antigen Lateral Flow Qualitative Test, from Innova. Since many may have heard of the programme but not used the test kit, this and the coming blog posts provide more information about the test so that you can have a better idea of it.

What are lateral flow tests?
Lateral flow tests are basically assays designed to test for different protein targets. A sample is placed on a conjugation pad where the analyte (or antigen) of interest is bound by conjugated antibodies. The analyte-antibody mix then migrates along a membrane by capillary flow, across both ‘test’ and ‘control’ strips. These strips are coated with antibodies detecting the analyte of interest, and a positive test is confirmed by the appearance of coloured control and test lines.²

As no laboratory processing is needed, lateral flow tests can be performed in the area convenient to the person being tested. Moreover, a short turnaround time, relatively higher test accuracy and the economic affordability make the tests suitable for mass testing. In fact, the tests have been used for rapid testing in communities and workplaces.³

Innova SARS-CoV-2 Antigen Rapid Qualitative Test is a disposable test kit, like a home pregnancy test kit. It detects nucleocapsid protein antigen from SARS-CoV-2 in direct nose and/or throat swabs. A positive result is seen as a dark band or a fluorescent glow on the “test” strip after about 30 minutes.⁴ The appearance of two lines on both the “test” and “control” strips indicates that the test is positive. The appearance of one line on the “control” strip only indicates a negative result. However, if the “control” strip line does not appear after 30 minutes of waiting, this means the test has failed to work and should be retaken.

The whole procedure to perform the test by yourself is written clearly in the instruction booklet included in each pack of the test kit. It is interesting to find that, according to the instruction booklet distributed to NHS staff, NHS recommends only a nasal swab is used and the sample is taken in a different way to that described in the packaged instructions for use, with more rotation of the swab at a lower level of penetration, to enable easier self-administration of the test.⁵

Storage precautions
Test kits should be stored at room temperature. It is very important to keep the test kits in an area with no direct sunlight, neither should the test kit be kept in a fridge or freezer. High or low temperatures can denature or inactivate the antibodies in the kit and affect the result.

Instructions after knowing the results
If you are taking the lateral flow test at home, you should register the results, whether positive or negative, online or by calling 119. If you get a positive test result, everyone in your household must self-isolate according to the government guidelines.⁶ Moreover, you need to take an RT-PCR test to further confirm the result.^1,6

If the test result is invalid, you need to retake the test with a new test kit.



References
1. Mass asymptomatic COVID-19 testing: Strategy and accuracy. Research briefing, House of Commons Library, 12 May, 2021. https://commonslibrary.parliament.uk/research-briefings/cbp-9223/
2. O'Farrell B. Evolution in lateral flow-based immunoassay systems. Lateral Flow Immunoass. 2009; p 1-33. https://doi.org/10.1007/978-1-59745-240-3_1.
3. Peto T & UK COVID-19 Lateral Flow Oversight Team. COVID-19: rapid antigen detection for SARS-CoV-2 by lateral flow assay: a national systematic evaluation for mass-testing. medRxiv. 2021; (published online Jan 26.) (preprint). https://doi.org/10.1101/2021.01.13.21249563
(Later published online in Lancet, May 29, 2021. DOI:https://doi.org/10.1016/j.eclinm.2021.100924)
4. Primary Care Supply webpage for Innova SARS-CoV-2 Antigen Rapid Qualitative Test. https://www.primarycaresupplies.co.uk/innova-sars-cov-2-antigen-lateral-flow-rapid-test-kit-box-of-20/
5. A guide for healthcare staff self-testing for coronavirus using a Lateral Flow Device (LFD). By NHS. https://www.england.nhs.uk/coronavirus/wp-content/uploads/sites/52/2020/11/LFD_NHSStaff_A4_161120_.pdf
6. Order coronavirus (COVID-19) rapid lateral flow tests. GOV.UK website. https://www.gov.uk/order-coronavirus-rapid-lateral-flow-tests

Coronavirus (41) Nationwide COVID-19 immunization in Israel

Coronavirus (41) Nationwide COVID-19 immunization in Israel
The nationwide vaccination programmes for COVID-19 have been rolled out in several countries. Surveillance report from the Israel vaccination programme which uses BNT162b2 (by Pfizer and BioNTech, mRNA vaccine) has been published early this month.¹ In contrast with the report from the UK which provides data on the effectiveness of the BNT162b2 Pfizer vaccine after the first dose, the surveillance report from Israel provides data on the effectiveness of BNT162b2 after the second dose. When taken together with the data from the report from the UK, the data from Israel should provide us a more comprehensive idea of the efficacy of BNT162b2 in the general population. Let us have a look at this report.

Background of the surveillance report from Israel
The report from Israel was done by the Israel Ministry of Health and by Pfizer. Israel launched the vaccination campaign on 20 December 2020, 12 days after the UK. Moreover, Israel used only BNT162b2 (Pfizer) for its nationwide vaccination programme.

The study analyzed nationwide surveillance data from 24 January to 3 April, 2021. The start of the study period corresponded to 14 days after the first individuals received their second BNT162b2 dose. By 3 April 2021, 72.1% of people aged 16 years and older were fully vaccinated with two doses of BNT162b2. Individuals with a history of severe allergic reactions to the vaccine components were not eligible to receive the vaccine.

The study aimed to estimate the effectiveness of two doses of BNT162b2 (second dose injected 21 days after the first dose, in accordance with the suggestion from Pfizer) against a range of SARS-CoV-2 outcomes (asymptomatic infection, symptomatic infection, and COVID-19-related hospitalisation, severe or critical hospitalisation, and death) in the general population in Israel. The study also evaluated the nationwide public-health impact following the widespread introduction of the vaccine.

The vaccine’s effectiveness against SARS-CoV-2 outcomes was calculated on the basis of incidence rates in fully vaccinated individuals (who had received the second dose of vaccine and had passed 7 days) compared with rates in unvaccinated individuals (who had not received any doses of the vaccine).

The data from the observational surveillance report from Israel vaccination campaign The report showed that BNT162b2 is highly effective across all age groups (16–24, 25–34, 35–44, 45–54, 55–64, 65–74, 75–84, and ≥85 years) in preventing a range of SARS-CoV-2 outcomes. Among adults aged 16 years and older, the vaccine effectiveness was 95.3% against SARS-CoV-2 infection at 7 days or longer after the second dose: 91.5% against asymptomatic SARS-CoV-2 infection, 97.0% against symptomatic COVID-19, 97.2% against COVID-19-related hospitalisation, 97.5% against severe or critical COVID-19-related hospitalisation, and 96.7% against COVID-19-related death.

According to the test samples of people with COVID-19 taken during the period of the study, 94.5% of the SARS-CoV-2 infections were from the B.1.1.7 variant. The test results indicated that BNT162b2 is highly effective against the SARS-CoV-2 variant B.1.1.7, which was first identified in the UK, and later reported in Israel on 23 December, 2020.

In all age groups, as vaccine coverage increased, the incidence of SARS-CoV-2 infection declined. The early reductions in incident cases of SARS-CoV-2 infections were observed in older age groups, which had higher and earlier vaccine coverage. The declines were observed for people aged 65 years and older starting in mid-January 2021, while the reductions were observed 3 to 4 weeks later among people aged between 16 and 24, when vaccine coverage for this age group began to increase. The incidence of COVID-19 hospitalisations, severe or critical hospitalisations, and deaths, were also declined accordingly.

The figures from the report showed that the declines of SARS-CoV-2 incidence continued even after the two phases of reopenings on 7 February and 21 February 2021, and the final lifting of the lockdown on 7 March 2021. These findings suggest that the vaccine coverage was the main contributor for the reductions in the incidence of SARS-CoV-2 infections, while the next is the nationwide lockdown measure.

Moreover, the SARS-CoV-2 incidence remained low even after the two phases of reopenings. This further suggests that vaccine coverage might provide a sustainable path towards resuming normal activity nationally.

Conclusion
The UK government has started giving BNT162b2 (Pfizer) to most adults aged under 40.² The report from Israel demonstrates that two doses of BNT162b2 are highly effective in preventing different SARS-CoV-2 infection outcomes, including severe disease and death, among different age groups. Moreover, there were steep and sustained declines in SARS-CoV-2 infection rate corresponding to increasing vaccine coverage. Therefore, unless you have a history of severe allergic reactions and are defined as not suitable to get the BNT162b2 Pfizer vaccination,³ it is worth receiving a full dosage of the vaccine in order to get protection from COVID-19.

References
1. E.J. Haas, F.J. Angulo, J.M. McLaughlin, et al. Impact and effectiveness of mRNA BNT162b2 vaccine against SARS-CoV-2 infections and COVID-19 cases, hospitalisations, and deaths following a nationwide vaccination campaign in Israel: an observational study using national surveillance data. Lancet, May 5, 2021 https://doi.org/10.1016/S0140-6736(21)00947-8 . Online ahead of print.
2. Under 40s to be offered alternative to AZ vaccine. By James Gallagher. BBC news, 7th May, 2021. https://www.bbc.co.uk/news/health-57021738
3. Pfizer-BioNTech COVID-19 vaccine overview and safety. Centers for Disease Control and Prevention. https://www.cdc.gov/coronavirus/2019-ncov/vaccines/different-vaccines/Pfizer-BioNTech.html