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Letters to the Editor Issue 288

by Letters(more info)

listed in letters to the editor, originally published in issue 288 - August 2023

Covid Fatalities Plummet, As Dementia and Heart Disease Become No 1 Killers

New Government figures show a higher than average number of deaths last month. Dementia was the biggest killer in England and heart disease in Wales. Covid deaths plummeted, however, prompting a testing expert to call for routine dementia and heart screening to match the success of the UK’s Covid testing campaign.

It’s official: COVID’s disappearance from England’s top ten list of UK killers is ‘statistically significant’, say scientists. New figures from the Office for National Statistics (ONS) show Covid was responsible for just 1.5% of all deaths in England and Wales in the week ending 16 June. It also dropped from being England’s eighth largest killer in April to 13th in May. Last month, Covid killed 785 people in England, tumbling from 1,260 deaths in April.

However, a leading testing expert says that this success shouldn’t disguise the fact that deaths for the year to date are 7.6% above average in England and up 6.5% in Wales. The leading killers are dementia / Alzheimer’s in England, and heart disease in Wales.

Leading testing expert, Dr Avinash Hari Narayanan (MBChB), Clinical Lead at London Medical Laboratory, says:

“We might have won the Covid battle for now, but the UK is far from winning the health war. In England, dementia/Alzheimer’s was the leading cause of death for the 23rd month in a row in May. It claimed 4,872 lives last month – that’s 97.9 lives per 100,000 people. In Wales, ischaemic (better known as coronary) heart disease was the leading cause of death for the second month. 319 people died of this generally treatable condition in Wales during May – that’s 106.8 deaths per 100,000 people.

“There’s no doubt that the Covid screening programme during the pandemic helped reduce the virus’ spread while vaccines were developed.  Why hasn’t there been a similar effort in the face of dementia and heart disease? Dementia has been the leading killer in England for two years now, but there’s been no surge in testing. Likewise, there has been no movement similar to the UK’s Covid response to take on the potentially devastating impact of heart disease. This is despite the fact it’s such a treatable condition if caught early.

“While coronary heart disease isn’t reversible, it’s certainly manageable. If detected in good time, lifestyle changes, medication and, if necessary, surgery significantly reduce the chances of problems such as heart attacks.

“Similarly, the Alzheimer’s Society says timely diagnosis helps people make important decisions about treatment, support and care. Earlier diagnosis helps people with this disease live as well as possible and manage symptoms. It’s small wonder that, in a recent Alzheimer’s Society survey, three out of five people with dementia wish they had got a diagnosis sooner. 

“That’s why the UK needs universal screening for heart disease, ideally from the age of 50 onwards, and dementia/Alzheimer’s from the age of 65.

“Testing for ischaemic/coronary heart disease should be routine. A simple blood pressure and cholesterol level blood test can detect if heart disease is a possibility. That will lead to further tests and, if necessary, treatments.

“Testing for dementia/Alzheimer’s is also relatively simple. A GP, or other health surgery professional, will take a personal and medical history and talk to someone who knows the patient well, if they are showing symptoms. They are also likely to perform a physical examination and undertake a cognitive assessment. Once again, blood testing is vital. This is to check for other conditions that could be causing similar symptoms, such as thyroid problems or vitamin deficiencies.

“For both dementia and heart disease, blood testing is crucial, either in detecting high ‘bad’ cholesterol levels or in eliminating other conditions that might be mistaken for dementia/Alzheimer’s. Blood tests can help identify many conditions early, which is especially useful for diseases that are not routinely screened for yet in the UK.

“Of course, people don’t have to wait for a doctor’s appointment to get a blood test. London Medical Laboratory’s General Health Profile blood test provides a comprehensive check-up of general health, including diabetes (HbA1c), gout, liver & kidney function, bone health, iron levels and a full cholesterol profile. It can be taken at home through the post, or at one of the many drop-in clinics that offer these tests across London and nationwide in over 95 selected pharmacies and health stores. For full details, see: https://www.londonmedicallaboratory.com/product/general-health

Further Information and contact

London Medical Laboratory’s Clinical Lead, Dr Avinash Hari Narayanan, is available to supply exclusive written comment or for interview. To contact Dr Hari Narayanan, or for more information, please email London Medical Laboratory’s Head of Public Relations, David Jinks M.I.L.T., at david.jinks@londonmedicallaboratory.co.uk

 

 

Key Gene That Blocks The ‘Spillover’ of Avian Flu to Humans Discovered

Understanding the genetic make-up of currently circulating avian flu strains may offer one of the best lines of defence against widespread human transmission. This is according to new research which has found a key human gene responsible for blocking most avian flu viruses from spilling over into people.

The latest international study into the pandemic potential of avian flu, which is led by scientists at the MRC-University of Glasgow Centre for Virus Research (CVR) and published in Nature,[1] identified the human gene BTN3A3, which is commonly expressed in our airways, as a key human defence against avian flu. Through a series of extensive tests, the study team were able to show that the BTN3A3 gene is vital to protecting humans against avian flu, as most strains of the virus cannot get past its defences.

Avian flu, also commonly referred to as bird flu, primarily spreads among wild birds such as ducks and gulls and can also infect farmed and domestic birds such as chickens, turkeys and quails. Since 2022 there has been a rise in bird flu cases around the world in both domestic and wild birds. While the disease mainly affects birds, it has been known to spill over into other species, including, in rare cases, humans. For example, the 1918 Spanish flu virus which caused more than 25 million deaths worldwide is believed to have originated from an avian strain.

However, experts agree there are still several gaps in our scientific knowledge that make it difficult to be able to predict which variant of avian influenza virus might spill over into the human population and when.

Keen to know why some avian flu transmission does occur in humans, the team behind this important study compared the behaviour of hundreds of genes normally expressed by human cells during a viral infection with either human seasonal viruses or avian flu viruses. The study showed that the BTN3A3 gene was able to block the replication of avian flu in human  cells. In contrast, the seasonal human flu viruses, which infect the human population regularly, are resistant to BTN3A3 meaning it cannot successfully block them.

The team also looked at avian flu viruses that occasionally do infect humans, for example H7N9, which since 2013 has infected more than 1,500 individuals with 40% case fatality rate. Researchers were able to show that avian flu viruses like H7N9 have a genetic mutation that allows them to ‘escape’ the blocking effects of the BTN3A3 gene.

Finally, when studying the evolution of avian flu strains, the scientists were also able to show that there had been increase in the number of BTN3A3-resistant strains circulating in poultry around the same time as spill over events in humans.

Professor Massimo Palmarini, Director of CVR, who also led this study, said:

“We know that most emerging viruses with human pandemic potential come from animals. It is therefore critical to understand which genetic barriers might block an animal virus from replicating in human cells, thereby preventing infection.

“Of course, viruses are constantly changing and can potentially overcome some of these barriers by mutating over time. This is why virus genetic surveillance will be crucial to help us better understand and control the spread of viruses with zoonotic and pandemic potential.”

Dr Rute Maria Pinto, the first author of this study, said:

“Identifying BTN3A3 resistant variants when they first emerge in birds might help prevent human infections. Control measures against emerging avian flu viruses can be tailored specifically against those that are BTN3A3-resistant, in addition to other genetic traits known to be important for zoonotic transmission.”

Dr Stephen Oakeshott, Head of Infections and Immunity at the MRC, part of UKRI, said: “This interesting study illustrates an important piece of the very complex puzzle underpinning viral transmission between species, and shows the continued need for One Health research for infectious disease.

“This type of mechanistic scientific insight, coupled with genetic surveillance, can offer a window into future disease risks to inform public health planning.”

Tracking the history of influenza pandemics in humans, the researchers were also able to link BTN3A3 resistance with key influenza virus types. All the human influenza pandemics, including the devastating 1918-19 global flu pandemic and the swine flu psandemic in 2009 were caused by influenza viruses that were resistant to BTN3A3. As result, this study suggests that having resistance to this gene may be a key factor in whether any flu strain has human pandemic potential.

The study, ‘BTN3A3 evasion promotes the zoonotic potential of influenza A viruses’ is published in Nature.[1] The work was funded primarily by the Medical Research Council (MRC), and in part by the Wellcome Trust, BBSRC, NSERC (Canada), EU Horizon2020, and Medical Research Scotland. The full study can be found here: https://www.nature.com/articles/s41586-023-06261-8

Reference

  1. Pinto, R.M., Bakshi, S., Lytras, S. et al. BTN3A3 evasion promotes the zoonotic potential of influenza A viruses. Nature 28 June 2023. https://doi.org/10.1038/s41586-023-06261-8 . 28 June 2023.

Further Information

For more information contact the University of Glasgow Communications and Public Affairs Office on media@glasgow.ac.uk  For all inquiries, please contact us via elizabeth.mcmeekin@glasgow.ac.uk

 

 

Study Shows Promising Results for Immunotherapy Targeting Skin Cancer

A ground-breaking study was presented 10 June at the Hybrid Congress in Hamburg organized by the European Academy of Allergy & Clinical Immunology (EAACI). The study, conducted by researchers from King's College London and Guy's and St Thomas' NHS Foundation Trust, has revealed promising results for a new class of immunotherapy in the fight against aggressive skin cancer. The study investigates the efficacy of a novel antibody in targeting and treating melanomas, demonstrating its ability to activate the immune response and impede melanoma growth in mice.

Malignant melanoma, the most aggressive form of skin cancer, poses significant challenges with low survival rates for many patients within five years of diagnosis. While substantial progress has been made in the development of immunotherapies that harness the body's natural defence system to combat cancer, a significant number of patients fail to respond to existing treatments. The newly discovered antibody holds the potential to benefit patients with melanoma who do not respond to current therapies.

Unlike many existing immunotherapies, which belong to the antibody type called IgG, researchers at King's College London and Guy's and St Thomas' have developed an IgE antibody that leverages the patient's own immune system to target cancer in a distinct manner. The team developed a specific IgE antibody for a marker called chondroitin sulfate proteoglycan 4 (CSPG4), found on the surface of human melanoma cells in up to 70% of cases. While current immunotherapies broadly activate the immune system, this novel antibody was designed to specifically target immune responses towards melanoma cells.

The researchers demonstrated that CSPG4 IgE could attach to and activate immune cells present in the blood of melanoma patients, effectively killing human melanoma cancer cells. In mice implanted with human immune cells, including cells from melanoma patients, CSPG4 IgE treatment resulted in a slowdown of cancer growth. Furthermore, an allergy test conducted with patient blood indicated that CSPG4 IgE did not activate basophils, a type of white blood cell, suggesting the therapy's potential safety.

Dr Heather Bax, Postdoctoral Research Fellow from St. John's Institute of Dermatology, King’s College London, said:

“We have shown that an immune response can be triggered by IgE immunotherapy for melanoma and that this applies to human melanomas and to melanoma patient immune responses. Our findings replicate existing observations for MOv18 IgE, the first anti-cancer IgE, which targets ovarian cancer, and supports development of IgE therapies for other solid tumors”. 

Professor Sophia Karagiannis, from St. John's Institute of Dermatology, King’s College London, said:

“Four in ten people with advanced melanoma do not respond to available treatments. Our findings show that the human immune system reacts differently in the presence of drugs based on IgE antibodies and points to the potential of applying IgE to mount an effective response against melanoma. This opens up the possibility of this new class of drugs to benefit different patient groups and a new frontier in the battle against cancer.”

Professor James Spicer, from King’s College London and a Consultant at Guy’s and St Thomas’ NHS Foundation Trust, said:

"We have recently completed the first-ever trial testing an IgE therapy for cancer (MOv18 IgE), and are excited about the prospect of a whole new class of antibody drugs in oncology. The collaboration between the King's College London and Guy's and St Thomas' research groups is close and ever more productive."

The first IgE antibody (MOv18 IgE) generated at King’s College London has been trialled for ovarian cancer with results expected to be published later in 2023. Epsilogen Ltd owns rights to both CSPG4 IgE and MOv18 IgE. Epsilogen was spun out from King’s College London in 2017 and has attracted venture capital financing from multiple investors."Top of Form

 About EAACI

The European Academy of Allergy and Clinical Immunology (EAACI) is an association of clinicians, researchers and allied health professionals founded in 1956. EAACI is dedicated to improving the health of people affected by allergic diseases. With more than 15 000 members from 125 countries and over 75 National Allergy Societies, EAACI is the primary source of expertise in Europe and worldwide for all aspects of allergy. 

Further Information and Contact

EAACI Headquarters, Hagenholzstrasse 111, 3rd Floor 8050 Zurich, CH- Switzerland 
Tel: +41799561865; communications@eaaci.org    www.eaaci.org 

 

 

Potent New Compound Discovery has Breakthrough Potential for Certain Parasitic Diseases

Scientists have discovered a new class of compounds that is potentially active against trypanosome parasites that cause human African trypanosomiasis (or sleeping sickness) and Chagas disease. 

The ground-breaking findings – published in the journal Science [1]and led by researchers at the University of Glasgow and Novartis Global Health (formerly Novartis Institutes for Tropical Diseases) – reveal potent compounds discovered for the two separate types of trypanosomiases, showing potential for development as new medicines for these diseases.

The study demonstrated that the compounds were able to cure a mouse model of sleeping sickness with just a single dose, and a short course of daily doses across five days cured Chagas disease in the same models.

African trypanosomiasis (or sleeping sickness) is a major killer disease that puts around 70 million people at risk in sub-Saharan African countries and is invariably fatal if untreated or inadequately treated. Meanwhile, around seven million people are currently infected by Chagas disease, which can cause irreversible damage to the heart and digestive tract.

There are currently no drugs available that effectively cure Chagas disease; while for sleeping sickness, there have been some steps forward toward new therapies in recent years. 

The researchers also show in the study exactly how the compounds, called cyanotriazoles (or CTs for short), kill parasites without adversely affecting host cells. These compounds selectively bind to a parasite enzyme (called topoisomerase II) that is essential for the replication and maintenance of DNA, which carries the genetic blueprint vital for life. By binding to and inhibiting this enzyme, the compounds introduce breaks into the DNA that are lethal to the parasites. 

The Glasgow group – led by Professor Mike Barrett from the Wellcome Centre for Integrative Parasitology in the University’s School of infection & Immunity – made inroads into finding that mechanism of action using a technique known as metabolomics, through the Glasgow Polyomics facility, which showed how DNA was being degraded in the cells. Parasites resistant to the drugs had changed their topoisomerase protein structure such that they no longer bound the drug.  

The Novartis team, led by Srini Rao, worked out the three-dimensional structure of the trypanosome’s topoisomerase, revealing how CTs bind to a particular part of the trypanosome’s enzyme that is absent from the human version. 

Mike Barrett, Professor of Biochemical Parasitology at the University of Glasgow, said:

“Compounds with this degree of potency, working through a newly discovered mechanism, represent a major breakthrough. If they are proven to be safe in humans and retain the levels of activity seen in mice, they could offer the first effective therapy of Chagas disease which afflicts millions of people in Latin America.”

The paper, ‘Cyanotriazoles are selective topoisomerase II poisons that rapidly cure trypanosome infections,’ is published in Science.[1] The study was funded by the Wellcome Trust.

Reference

  1. Srinivasa et al. Cyanotriazoles are selective topoisomerase II poisons that rapidly cure trypanosome infections. Science 380 (6652): 1349-1356. DOI: 10.1126/science.adh0614 29 Jun 2023.

Further Information

For all inquiries, please contact us at: elizabeth.mcmeekin@glasgow.ac.uk

 

 

Insights into Redox-Independent Cellular Stress Response

Researchers identify the regulatory pathway that governs a type of redox-independent stress response involving NRF2. Nuclear factor erythroid 2-related factor 2 (NRF2) is a master transcription factor with a role in regulating oxidative stress response. It can be activated via redox-dependent and independent pathways. Regulatory mechanisms of the redox-dependent pathway are known; however, the same cannot be said for the redox-independent pathway. Now, researchers from Juntendo University have unraveled the roles of phase-separated liquid droplets, p62 bodies, in redox-independent NRF2 activation and the significance of phosphorylation in this process. 

Cellular stress, or oxidative stress, occurs when there is a buildup of reactive oxygen species (ROS), which interferes with cellular mechanisms and can even cause damage to proteins, lipids, and DNA. Owing to their destructive nature, all cells have robust mechanisms in place to remove ROS and reduce oxidative stress. One such mechanism is the nuclear factor erythroid 2-related factor 2 (NRF2)-mediated stress response, where NRF2 is a master transcription factor that aids in reducing oxidative stress.

Much is known about the redox-dependent activation of NRF2 and its subsequent role in stress response. In this pathway, Kelch-like ECH-associated protein 1 (KEAP1) senses oxidative stress in the cell through oxidation of its specific cysteine residues. This oxidation causes conformational changes in KEAP1, which, in turn, loses the ability to suppress NRF2. As a result, NRF2 is stabilized and induces a series of genes encoding anti-oxidative proteins that reduce and remove oxidative stress caused by ROS.

NRF2 can also be activated in a redox-independent manner. This activation involves p62 protein, which undergoes liquid-liquid phase separation to form p62 bodies when it binds to ubiquitinated proteins upon defective proteostasis. However, the precise mechanism of NRF2 regulation through p62 bodies had hitherto remained largely unknown.

Now, researchers in Japan have found how p62 bodies control redox-independent NRF2 activation. They conducted a study that was conceived by Professor Masaaki Komatsu and Associate Professor Yoshinobu Ichimura from Juntendo University School of Medicine and Dr. Nobuo N. Noda from Hokkaido University.

"We have reported in a previous study that phosphorylation of p62 inhibits the binding of KEAP1 to NRF2 competitively, thereby disabling the NRF2-repressive function of KEAP1. However, the regulatory mechanism and the physiological functions in vivo remain largely unclear. This is important as the accumulation of phosphorylated p62 has been found to cause many intractable diseases,"

explains Prof. Komatsu when asked about the team's motivation for pursuing the research. Their findings are all set to be published in The EMBO Journal [1 ](2023)e113349   DOI: https://doi.org/10.15252/embj.2022113349

Using advanced techniques like high-speed atomic force microscopy, fluorescence recovery after photobleaching, and fluorescence loss in photobleaching, the team conducted experiments that included those performed outside a living organism (in vitro) and those using cells and mice (in vivo) to thoroughly profile protein-protein interactions, cellular localization of specific components, and the effects of LLPS-induced p62 phosphorylation, during redox-independent NRF2 activation.

Summarizing the main findings of their study, Dr. Ichimura explains,

"We found that ULK1, a protein kinase, translocates to p62 bodies and then phosphorylates p62 within the bodies. The resulting phosphorylated p62 bodies retain KEAP1 within them, which drives the activation of NRF2."

KEAP1 usually cycles in and out of p62 bodies; however, phosphorylated p62 tightly binds to KEAP1, which causes KEAP1 to be retained and sequestered within the p62 body. This leads to activation of even more NRF2. The p62 bodies are degraded by autophagy, and this may contribute to shutdown of this pathway. The current study extends the scope of the antioxidative stress response and provides new insights into the role of phase separation in the process.

The importance of this redox-independent NRF2 activation was tested using phosphomimetic p62 knock-in mouse models where hyperactivation of NRF2 by extensive phosphorylation resulted in hyperkeratosis—a growth defect causing the outer layer of the stomach and esophageal lining to thicken, which in turn caused stunted growth due to malnutrition.

Prof. Komatsu is confident that his team has laid the foundation for future work to probe deeper into the mechanism and regulation of redox-independent stress responses. He concludes,

"Whether redox-dependent or independent, NRF2 activation is an important biological defense system. Understanding its regulatory mechanisms is crucial as its persistent activation leads to inordinate defense responses, like excessive keratinization. Our study is the first scientific validation of the physiological significance for redox-independent NRF2 activation. In the case of redox-independent stress responses, activation of NRF2 is very likely regulated by phosphorylation, dephosphorylation, and autophagic degradation of p62 bodies. p62 bodies have been found to accumulate in affected cells in patients with liver disorders, neurodegenerative diseases, and cancers. Thus, research such as ours will be useful in elucidating the pathogenesis of and developing improved therapies for FA-, NRF2-, and autophagy-related diseases."

Reference

  1. Ryo Ikeda1,2, Daisuke Noshiro3, Hideaki Morishita1, Shuhei Takada1, Shun Kageyama1, Yuko Fujioka3, Tomoko Funakoshi1, Satoko Komatsu-Hirota1, Ritsuko Arai4, Elena Ryzhii4, Manabu Abe5, Tomoaki Koga6, Hozumi Motohashi7, Mitsuyoshi Nakao6, Kenji Sakimura5, Arata Horii2, Satoshi Waguri4, Yoshinobu Ichimura1, Nobuo N Noda3, and Masaaki Komatsu1. Phosphorylation of phase-separated p62 bodies by ULK1 activates a redox-independent stress response. The EMBO Journal (2023)e113349   DOI: https://doi.org/10.15252/embj.2022113349

Affiliations:

1Department of Physiology, Juntendo University Graduate School of Medicine, Japan

2Department of Otolaryngology Head and Neck Surgery, Niigata University Graduate School of Medical and Dental Sciences, Japan

3Institute for Genetic Medicine, Hokkaido University, Japan

4Department of Anatomy and Histology, Fukushima Medical University School of Medicine, Japan

5Department of Animal Model Development, Brain Research Institute, Niigata University, Japan

6Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Japan

7Department of Gene Expression Regulation, Institute of Development, Aging and Cancer, Tohoku University, Japan

About Professor Masaaki Komatsu

Dr Masaaki Komatsu is a Professor in the Department of Organ and Cell Physiology at Juntendo University School of Medicine. He earned his Ph.D. in 2001 from the Juntendo University School of Medicine and researches autophagy, the UFM1-system, protein homeostasis, and organelle homeostasis. He has published over 190 peer-reviewed articles since 1999.

Source and Media Contact

Brijesh Manek <brijesh.manek@cactusglobal.com>

 

 

How to Prevent Deaths from Sepsis

by Max Langen and Dr med. Petra Wiechel

Originally published on orthomolecular.activehosted.com

https://orthomolecular.activehosted.com/index.php?action=social&chash=839ab46820b524afda05122893c2fe8e.288&s=c7ae1002d2f579a22c16a1b89c854212

 

Sepsis is one of the leading causes of mortality worldwide and also one of the leading causes of death in intensive care units. It is an overreaction of the immune system to any viral, bacterial or fungal infection acquired in the community or in the hospital and is a common pathway to death from many different infectious diseases. Respiratory infections, (including severe colds, influenza or covid-19), pneumonia, ventilator-associated pneumonia, infections of the digestive system (including diarrhoeal diseases), urinary system or bloodstream and wound infections are among the leading causes of this life-threatening syndrome. Symptoms include feeling light headed, shivering, fast shallow breathing, change in mental status and symptoms specific to the infection (like worsening of fever and cough during pneumonia). [1-3]

Annually, sepsis affects almost 50 million people and contributes to or causes more than 11 million deaths. [4] This number of deaths corresponds to 1.3 times the entire population of New York, the most populous city in the US. While many of these deaths occur in low income countries, sepsis is also a leading cause of death in wealthier countries. In the US alone, it claims 260,000 lives per year. A comprehensive analysis estimated that sepsis was involved in 20% (1 in 5) of all global deaths in 2017. [4] It constitutes a global emergency.

However, as many studies show, orthomolecular or natural medicine can solve or at least greatly improve this situation. This existing knowledge from the peer-reviewed literature only needs to be adopted. If healthcare practitioners world-wide could learn from these results and utilize them, this could save millions of lives every year.

Many of the following treatments are not only effective for therapy of acute septic shock, but also help prevent infections and reduce the risk of developing serious infectious disease complications like pneumonia or sepsis. Especially people at higher risk of getting sepsis, which includes older people, pregnant women, neonates, hospitalized patients or especially patients in the intensive care unit (ICU), people who received antibiotics recently and people with comorbidities like autoimmune diseases, overweight, diabetes, cancer, HIV, liver cirrhosis etc. should receive preventative care with high dose nutrients and herbal medicine to reduce the risk of community- or hospital-acquired infections and the development of sepsis.

Sepsis is characterized by increased inflammatory processes, oxidative stress, mitochondrial dysfunction and coagulation (risk of thrombi development). The following treatments have significant anti-infective, antiviral, antibacterial, anti-oxidative, anti-inflammatory, immunomodulatory, mitochondria-modulating, antithrombotic/anticoagulant effects. The earlier the treatment starts (in early stages of sepsis), the higher the chance of success. In the studies presented in this article, the investigated treatment was usually added to the standard treatment.

Coenzyme Q10

Patients with septic shock are deficient in coenzyme Q10 and have much lower Q10 levels than healthy controls. [5-6] This deficiency may contribute to the increased risk of developing serious complications (like pneumonia or sepsis) from different infectious diseases. The body's own Q10 synthesis declines continuously with increasing age and patients with chronic diseases also have lower Q10 levels. A recent study showed that supplementation of 200 mg of Q10 reduces inflammation in early phase septic ICU patients and can strongly reduce the mortality rate. While of those in the control group, 65% died, the Q10 group only had a 20% death rate (a 70% lower risk of death). [7] Of course, the earlier the treatment starts, the higher the chance of success. If the therapy is started very late (when the patients already progressed to a severe sepsis or septic shock), it is less likely to help. [8]

Q10 supplementation is also an effective therapy for pneumonia. Hospitalized pneumonia patients who received 200 mg of Q10 per day recovered significantly faster, had a lower risk of treatment failure and were able to leave the hospital earlier than the control group. [9] In a recent study, Q10 supplementation was also associated with a significantly lower risk of requiring hospitalization due to Covid-19. [10]

Omega-3 Fatty Acids

Omega-3 fatty acids also have an essential role in the regulation of the immune system. An omega-3 index (fraction of omega-3 fatty acids in red blood cells) of 8 to 11% in the blood is considered ideal and protects from many cardiovascular, neurological, inflammatory conditions etc. In many individuals blood index levels of omega-3 fatty acids (EPA and DHA) are insufficient (4 - 8%) and far from optimal ranges. [11] A recent meta-analysis of 49 RCTs showed that omega-3 supplementation in the hospital (added to the parenteral nutrition) reduced the risk of an infection by 40%, and the risk of developing sepsis was reduced by 56%. [12] Another study showed that in septic patients, omega-3 supplementation (for example 1000 mg three times daily) can reduce mortality, especially in those with both sepsis and gastrointestinal dysfunction. In those patients, the risk of death was reduced by 50% due to treatment with omega-3 fatty acids. [13] In ICU patients, omega-3-supplementation significantly accelerated the recovery time. Compared to standard parenteral nutrition, the additional administration of omega-3 reduced the costs per case by approximately $10,000, suggesting that orthomolecular medicine can also lead to significant cost-savings. [14] In some studies Covid-19 patients with a higher omega-3 index (> 5.7%) had a 75% lower risk of mortality, [15] and this also improved and accelerated the recovery of their clinical symptoms. [16]

Melatonin

Melatonin is one of the most powerful anti-oxidative and anti-inflammatory biomolecules. It is a hormone involved in controlling the day-night cycle of vertebrates, but it also regulates the immune system and prevents severe infectious disease outcomes. Yet the body's own nocturnal melatonin synthesis declines proportionally with increasing age. [17] Older people often suffer from both a severe deficiency of vitamin D and melatonin, which causes a state of increased oxidative stress, silent inflammation and mitochondrial dysfunction. All of these factors greatly increase the risk of developing sepsis. [18]

A recent study showed that melatonin treatment was associated with a 34% lower risk of mortality. [19] Both oral or intravenous melatonin (50 to 60 mg/d) are effective treatments. Septic patients who received melatonin required less vasopressors and less ventilator support, recovered faster and stayed fewer days in the ICU and the hospital, and had about 40% lower mortality. [20,21]

On the assumption that adequate melatonin may reduce the risk of sepsis mortality by 40%, 4 million lives per year could be saved. This number corresponds to the entire population of Los Angeles. However, active prevention of sepsis with melatonin could lead to even more lives saved. An RCT with Covid-19 patients showed that those who received melatonin (10mg/d) had a 70% lower risk of developing sepsis. [22] Several studies showed that early melatonin treatment (10 mg/d) can cut the recovery time of Covid-19 patients in half [23-25] and massively reduce mortality, especially when given early enough. Therefore, it is likely that many cases of sepsis could be prevented if hospitalized patients who are vulnerable to the development of sepsis, would receive melatonin early during an infection to prevent the progression to more severe outcomes like sepsis.

Neonates are susceptible to sepsis, and they do not produce melatonin during the first months after birth. [17] While breast milk contains melatonin, many neonates receive only infant formula, which lacks melatonin. [26] And neonates given formula are especially susceptible to severe infections and sepsis. Early administration of breast milk in neonates protects from critical illness and sepsis. [27,28] Of course, breast milk contains many protective ingredients besides melatonin. But its melatonin content may be one of the most important protective factors. A recent study showed that melatonin is an effective treatment for neonatal sepsis, significantly improving the clinical condition. [29]

Many viral and bacterial infections can likely be treated by melatonin, including influenza and even Ebola. [30-32] And it may also prevent viral (or vaccine-induced) myocarditis. However, in malaria high dose melatonin may be contraindicated (at least unless it is administered in combination with a melatonin antagonist). [33-34]

Vitamin C

According to cardiologist Dr Thomas Levy, an expert on the use of vitamin C, sepsis is due in large part to vitamin C depletion. Sepsis is essentially a rapid-and- acute-onset scurvy, and very high dose vitamin C can prevent sepsis mortality. Several studies and meta-analyses indicate that intravenous vitamin C can significantly reduce sepsis mortality. [35-40]

However, some studies have found no effect of vitamin C upon sepsis, and these results have been cited widely as "evidence" against intravenous vitamin C therapy in sepsis. [35,40] However, a problem with many studies that tested vitamin C against sepsis is that they administered an inadequate dose. For example, in some studies, sepsis patients received IV doses between 6 and 16 g/day. Although this has been described as "high dose" treatment, it may be insufficient in many cases.

Yet there is also clear evidence that the therapeutic effect of vitamin C is dose-dependent. Severely sick patients may require much higher doses of vitamin C than the doses administered in many of the failed "high dose" sepsis trials. Vitamin C has been used successfully for the treatment of infectious diseases, cancer and burn patients in much higher doses (often above 50 to 200 grams per day). [40-42]

Dr Robert Cathcart, who treated thousands of patients with very high dose vitamin C, described that if vitamin C is given orally, it should be administered according to the individual bowel tolerance level. [42] Each individual has a different requirement that depends upon the stage of illness and many other factors. Cathcart described that a severe cold or influenza may require treatment with 60 to 150 g of vitamin C per day. Viral pneumonia may require 150 to 200+ g/day. [42] Cathcart described that lower doses were much less effective. [42]

Oral intake is possible if no intravenous administration is available. Dr. Andrew Saul wrote:

"Robert F. Cathcart, MD, successfully treated pneumonia with up to 200,000 milligrams of vitamin C daily. One can, to a significant extent, simulate an IV of vitamin C by taking it by mouth very, very often. When I had pneumonia, it took 2,000 mg of vitamin C every six minutes to get me to saturation (bowel tolerance). In three hours, fever was reduced several degrees and coughing virtually stopped. At an oral daily dose of just over 100,000 mg, recovery took just a few days." [43]

However, intravenous administration can be more effective, as Cathcart explained:

"Symptoms from acute viral diseases can most frequently be more permanently eliminated with intravenous sodium ascorbate. While it is true that tolerance doses of oral ascorbate will usually eliminate complications of acute viral diseases; at times, such as with certain cases of influenza, the large amount of oral ascorbate necessary to suppress symptoms over a period of a week or more, sometimes makes intravenous ascorbate desirable. Clinically large amounts of ascorbate used intravenously are virucidal (...) Ascorbate is more efficient intravenously than orally probably because chemical processes in the gut destroy a percentage of that orally administered. Doses of 400 to 700 mg/kg of body weight per 24 hours usually suffice." [44]

So, if severely sick septic patients receive a dose of 6 to 16 g in a given study, this dose might be 10 to 20 times too low. In fact, a recent review suggests investigating the effect of much higher doses. [40] Also, published reports about covid-19 indicate that a dose of 50 g or more may be necessary to prevent mortality. For example, in a study with 50 Covid-19 patients, treatment with 10 to 20 g of vitamin C led to an improvement, and faster recovery and there was no mortality. However, one patient deteriorated rapidly, so a bolus dose of 50 g was administered over 4 hours. The patient's pulmonary status stabilized and improved immediately. Had this patient not received this truly high dose that he required in this moment, he would have likely died. [45,46] Similarly, another report about another critically ill Covid-19 patient with low blood pressure, acute respiratory distress syndrome and acute kidney injury showed that an IV vitamin C dose of 60 g led to immediate improvements. The patient survived and was discharged from the hospital several days later. [40]

In another case, a retired physician who got severely sick with Covid-19 only experienced a small temporary improvement following an intravenous infusion of 25 g of vitamin C. The disease progression could not be stopped, his condition kept deteriorating, and his oxygen levels decreased. However, a subsequent infusion of 50 g resulted in a greater improvement of his clinical condition -- and then the physician recalled that severe viral disease may require 200 g of vitamin C. So he prepared his treatment with 4 intravenous bags containing 5% dextrose, 50 g of vitamin C and 4 ml magnesium sulfate. They were administered one after another over several hours, which led to a dramatic improvement, the oxygen level increased, and the cough became much less severe. In the following days he continued high dose vitamin C (50 g/d) and got progressively better and was finally cured. [47]

The implication of these reports is that even 25 g of vitamin C (which is sometimes considered "high dose") would not have saved him from dying. He needed much more. However, modern clinical trials which claim use of "high dose" vitamin C rarely even give 25 g per day. The abstracts of all such clinical trials should be corrected. No matter what the result of the study was, the abstract should contain the sentence that "the dose was likely too low."

The fact that some of the sepsis trials and meta-analyses only found a small positive effect or no effect can likely be explained by: The chosen dose was too low, strong treatment delay, dangerous treatments which might increase sepsis mortality were given in combination with vitamin C, and the administration time was too short.

Therefore, the suggested approach for septic patients is to:

  • Receive a dose that is truly high enough. This dose is likely individual (some may require, for example, 20 g, others may require 200 g per day). Leading vitamin C experts recommend that if no improvement occurs with the chosen dose, the dose should be increased further and further, until improvement is seen.
  • Receive treatment as early as possible. Do not wait for the occurrence of septic shock before administering vitamin C.
  • Receive vitamin C in combination with other treatments which have shown to be effective for sepsis. For example, hydrocortisone, ascorbate, and thiamine (HAT) therapy is considered to be helpful in sepsis. [48]
  • Receive vitamin C for a long enough duration, until recovery is achieved -- and not only for 4 days, as has strangely been done in some studies. This is also important to prevent a rebound effect. Recently a study was published that administered vitamin C (16 g/d) for a short time (4 days) misleadingly concluded that vitamin C had a negative effect on clinical outcomes. A secondary analysis of this study showed that the negative effect did not occur during the treatment episode but thereafter, which indicates that the short administration time caused a rebound effect. The rationale for a rebound effect is that vitamin C levels decrease to an even lower level than pre treatment because administration leads to a higher activity of enzymes that metabolize vitamin C. Thus, by administering it only for a short time, the level may drop to an even lower level following treatment cessation, which can be detrimental if the patient is still severely sick. [49]

From this we can learn that it is of vital importance to administer vitamin C for a sufficient time, until recovery is achieved. And it might be reasonable to keep administering vitamin C following recovery, intravenously or at home in high oral doses, based on the bowel tolerance level [42] and only reduce the dose slightly over the following weeks, to make sure the body and the enzyme activity can adapt accordingly to the decreasing dose, so that the vitamin C level won't decline too strongly or too rapidly which might otherwise increase the risk of developing a new infection or other conditions.

"Start giving sepsis patients 25 grams of vitamin C every six hours, and all will be saved unless they were literally on death's doorstep when the vitamin C was started." - (Thomas E. Levy MD JD)

A review that investigated risk of adverse effects of very high dose vitamin C (50 to 100 g/d) therapy found no consistent evidence that this therapy is more harmful than a placebo. [35,50] However, adverse events cannot be excluded completely and in some rare cases, events like oxalate nephropathy or glucometer error are possible. Although the body metabolizes vitamin C to produce small quantities of oxalate, for individuals with normal kidney function IV vitamin C does not contribute to calcium oxalate kidney stones. More important sources of oxalate for most individuals are the amount of cruciferous vegetables, tea, and other sources in the diet. These oxalates bind with the excess calcium that is in our dairy, fortified foods, and supplements. To prevent oxalate stones, in general, and when taking oral vitamin C, it is important to drink adequate amounts of fluid and avoid excessive calcium levels in the diet. In addition, magnesium supplements (300-500 mg/day, in malate, citrate, or chloride form) can prevent calcium from precipitating with oxalate to form stones. [51] Elevated urine oxalate is a risk factor for stone disease in patients with pre-existing kidney disease only. [52] In patients with kidney disease or kidney injury (due to severe illness) it is recommendable to monitor the kidneys in association with the administration of vitamin C. Early treatment with high dose vitamin C during the initial stages of sepsis will be much less likely to cause problems like oxalate nephropathy compared with a situation when treatment starts late while organs like kidneys have already been harmed significantly. Therefore, kidney monitoring is important during high dose IV vitamin C treatment.

In patients with the enzyme deficiency G6PD (glucose-6-phosphate dehydrogenase deficiency) high dose vitamin C could lead to hemolysis. [50] However, this deficiency is not necessarily a contraindication against moderately high doses of vitamin C. "The G6PD level should be assessed before beginning intravenous vitamin C (IVC). (At the Riordan Clinic, G6PD readings have yielded five cases of abnormally low levels. Subsequent IVC at 25 grams [25,000 mg] or less showed no hemolysis or adverse effects.)" [53] Therefore, while IV-C is usually not recommended for patients with G6PD deficiency, IV-C appears to be safe for patients with G6PD deficiency at moderate infusion dosages of 25g. The Riordan Clinic recommends checking red blood cell G6PD levels prior to onset of IV-C therapy. In patients with severe iron overload, high dose vitamin C might also be contraindicated.

Vitamin D

Vitamin D is important for the activation of the immune defence and many studies show that a sufficient level is associated with a much lower risk of infections. Worldwide, 75% of adults have an insufficient vitamin D level, below 30 ng/ml, [54] which is an important risk factor for infectious diseases. Individuals with a level >38 ng/ml had a 50% lower risk of a community-acquired respiratory infection. [55] A sufficient level can also protect from hospital-acquired infections. [56]

Supplementation of vitamin D (cholecalciferol), daily or weekly, can reduce the risk of viral, and specific bacterial and fungal infections, and consequently can reduce the need for antibiotics. [56,57] A recent meta-analysis showed that vitamin D supplementation can reduce the risk of influenza by 22%. [58] Daily supplementation of 5000 IU. drastically reduced the risk of an influenza-like illness in healthcare workers. [59] Prophylactic vitamin D supplementation has shown to be associated with a reduced risk of SARS-Cov-2 infection, severe cases and Covid-19 mortality in several studies, especially when a level well above 30 ng/ml is achieved with supplementation. [60,61]

Recent studies showed that daily vitamin D supplementation can reduce the risk of a SARS-CoV-2 infection, [62] and those who received two bolus doses of vitamin D, followed by daily supplementation of 5000 IU for several months had a much lower risk of developing a symptomatic Covid-19 Infection than those who received no bolus doses and took only 2000 IU daily.

A recent study showed that individuals with low baseline levels of vitamin D are at greatest risk of upper respiratory infection, but also achieve the strongest risk reduction (70% lower) from supplementation. [63] The risk of urinary tract infections can be reduced by half from weekly vitamin D supplementation. [64] By reducing the risk of infections, a more healthy level of vitamin D can help prevent many sepsis cases.

For patients who are already suffering from a severe infection, treatment with a high dose of vitamin D (200,000 IU for 5 days) may promote recovery and reduce the risk of progression to sepsis. [65] In patients with ventilator-associated pneumonia, high dose vitamin D administration reduced the risk of death by 58%, [66] and vitamin D supplementation can reduce the risk of a repeat episode of pneumonia by 30%. [67]

In hospitalized patients with a severe viral infection, early administration of vitamin D as calcifediol reduced the risk of admission to the intensive care unit and mortality by 80% [68,69] -- suggesting that early administration of calcifediol may also be a great solution to prevent sepsis. Calcifediol has the advantage that it increases the vitamin D level (25(OH)D) much faster than cholecalciferol -- and especially in acutely ill patients, every second counts. Therefore, calcifediol (administered in repeated doses over several days and weeks) is the preferred form for use with an acute illness.

Vitamin D supplementation (parenteral administration) as cholecalciferol significantly reduced mortality in critically ill patients as well as improved and accelerated the recovery of neonatal sepsis and urosepsis. [70-72] However, cholecalciferol is not always effective in acute sepsis [73] which may be due to the delay in conversion. In acute sepsis, calcifediol may be preferable.

If calcifediol is not available, cholecalciferol can be administered to treat and improve the recovery of severe infectious diseases in order to reduce the incidence of sepsis. But a very important factor to consider is that whenever calcifediol or cholecalciferol is administered, it is of vital importance to provide repeated doses over several days or weeks rather than a single high dose. Even though some studies indicate that single high doses can also have positive effects, the results have not always been consistent. For example, in severely sick covid-patients, a single high-dose administration of cholecalciferol (like 200,000 or 500,000 IU during one day) has often been ineffective. [74,75]

On the other hand, the administration of repeated and somewhat lower doses of cholecalciferol or calcifediol led much more reliably to positive outcomes in hospitalized patients with severe covid-19, including faster recovery, and lower risk of disease progression, ICU admission and mortality. [68,76-78] This is because single high doses (very infrequent bolus doses) may sometimes even have an inhibitory effect on the immune system. They can trigger countervailing factors that turn off hormonal activation processes and result in a downregulation of active vitamin D (1,25(OH)2D). So, although high bolus doses can increase the vitamin D level (25(OH)D), the activation of vitamin D may be downregulated by such infrequent single high doses, which can inhibit immune regulation. On the other hand, a more moderate dosing in shorter intervals (daily or weekly) does not trigger such countervailing factors. Also, cholecalciferol, which has a 20 hour half life, has intracellular activity and even greater cellular effects than either the storage form 25(OH)D or the active/hormonal form 1,25(OH)2D of vitamin D. [79]

Therefore, frequent intake of moderate doses is biochemically reasonable and very infrequent dosing of very high doses is unnatural and biochemically inappropriate. Unfortunately, studies that administered single high doses of cholecalciferol and which therefore did not show high efficacy, have been cited widely as "evidence against vitamin D" for preventing or treating infectious diseases like covid-19. For the reasons explained above, such news reports are severely misleading. The studies referenced above [54-78] clearly showed that cholecalciferol or especially calcifediol, given in repeated doses, greatly improved Covid-19 outcomes.

Of note, even though a combination of both high-dose vitamin C and vitamin D can have positive synergistic effects and help save lives of severely sick patients, no clinical trials have tested this combination. Since vitamin D may increase calcium levels, including calcium levels in urine, when attempting this approach in patients with kidney disease or kidney injury it may be wise to monitor the kidneys and to make sure sufficient liquid is administered. Hydration with fresh lemon and water will help dilute the urine and greatly lower the risk of oxalate stone formation. And as suggested above, magnesium (as citrate, malate or chloride) also prevents calcium from precipitating with oxalate to form stones, so to further reduce the risk of stone formation, vitamin C or vitamin D can be taken in combination with magnesium. A recent study also suggested that intravenous magnesium sulfate may help improve and shorten the recovery of septic patients in the ICU. [80]

Note: This article does not provide or replace medical advice, as it is for educational purposes only. Before taking any supplements or drugs or before making any lifestyle changes, consult a qualified practitioner who can provide personalized advice and details of risks and benefits based on your medical history and situation. Both (prescription-free) supplements and drugs can have side effects that are not listed in this article. Interactions between drugs and supplements can be possible in some cases. This article does not claim to list all potential benefits and risks (including side effects) of the described treatments. Also, some of the treatments described here should not be used before a surgery due to their strong anti-thrombotic efficacy.

Editor's note: Part two of this paper will also be published by the Orthomolecular Medicine News Service. It will include discussion of zinc, N-Acetylcysteine (NAC) and glycine, probiotics, curcumin, black cumin, safflower yellow, xuebijing, acupuncture, nutrition, fasting, intestinal health, and psychological stress relief.

(Max Langen has found that his own health problems were greatly alleviated by orthomolecular medicine. He is currently working on a book about it, and has plans to qualify as a therapist. Dr Petra Wiechel is chief physician of the Swiss Mountain Clinic in Switzerland [ https;//www.swissmountainclinic.com]. She is expert in biological and orthomolecular medicine, and treats her patients holistically.)

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62: Villasis-Keever MA, López-Alarcón MG, Miranda-Novales G, et al. (2022) Efficacy and Safety of Vitamin D Supplementation to Prevent COVID-19 in Frontline Healthcare Workers. A Randomized Clinical Trial. Arch Med Res. 53:423-430. https://pubmed.ncbi.nlm.nih.gov/35487792

63: Karonova TL, Chernikova AT, Golovatyuk KA, et al. (2022)Vitamin D Intake May Reduce SARS-CoV-2 Infection Morbidity in Health Care Workers. Nutrients. 14:505. https://pubmed.ncbi.nlm.nih.gov/35276863

64: Jorde R, Sollid ST, Svartberg J, et al. (2016)Prevention of urinary tract infections with vitamin D supplementation 20,000 IU per week for five years. Results from an RCT including 511 subjects. Infect Dis (Lond). 48:823-828. https://pubmed.ncbi.nlm.nih.gov/27357103

65: Sarhan N, Abou Warda AE, Sarhan RM, et al. (2022) Evidence for the Efficacy of a High Dose of Vitamin D on the Hyperinflammation State in Moderate-to-Severe COVID-19 Patients: A Randomized Clinical Trial. Medicina (Kaunas). 58:1358. https://pubmed.ncbi.nlm.nih.gov/36295519

66: Miroliaee AE, Salamzadeh J, Shokouhi S, Sahraei Z. (2018) The study of vitamin D administration effect on CRP and Interleukin-6 as prognostic biomarkers of ventilator associated pneumonia. J Crit Care. 44:300-305. https://pubmed.ncbi.nlm.nih.gov/29248753

67: Yang C, Lu Y, Wan M, et al. (2021) Efficacy of High-Dose Vitamin D Supplementation as an Adjuvant Treatment on Pneumonia: Systematic Review and a Meta-Analysis of Randomized Controlled Studies. Nutr Clin Pract. 36:368-384. https://pubmed.ncbi.nlm.nih.gov/33037694

68: Nogues X, Ovejero D, Pineda-Moncusí M, et al. (2021) Calcifediol Treatment and COVID-19-Related Outcomes. J Clin Endocrinol Metab. 106:e4017-e4027. https://pubmed.ncbi.nlm.nih.gov/34097036

69: Alcala-Diaz JF, Limia-Perez L, Gomez-Huelgas R, et al. (2021) Calcifediol Treatment and Hospital Mortality Due to COVID-19: A Cohort Study. Nutrients. 13:1760. https://pubmed.ncbi.nlm.nih.gov/34064175

70: Menger J, Lee ZY, Notz Q, et al. (2022) Administration of vitamin D and its metabolites in critically ill adult patients: an updated systematic review with meta-analysis of randomized controlled trials. Crit Care. 26:268. https://pubmed.ncbi.nlm.nih.gov/36068584

71: Hagag AA, El Frargy MS, Houdeeb HA. (2020) Therapeutic Value of Vitamin D as an Adjuvant Therapy in Neonates with Sepsis. Infect Disord Drug Targets. 20:440-447. https://pubmed.ncbi.nlm.nih.gov/31241441

72: Jokar A, Ahmadi K, Taherinia A, et al. (2018) The Effects of Injected Vitamin D on Prognosis of Patients with Urosepsis. Horm Metab Res. 50:383-388. https://pubmed.ncbi.nlm.nih.gov/29621811

73: Ding F, Zang B, Fu J, Ji K. [Effect of vitamin D3 on the severity and prognosis of patients with sepsis: a prospective randomized double-blind placebo study]. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2017 Feb;29(2):106-110. Chinese.

74: Cannata-Andía JB, Díaz-Sottolano A, Fernández P, et al. A single-oral bolus of 100,000 IU of cholecalciferol at hospital admission did not improve outcomes in the COVID-19 disease: the COVID-VIT-D-a randomised multicentre international clinical trial. BMC Med. 20:83. https://pubmed.ncbi.nlm.nih.gov/35177066

75: Mariani J, Antonietti L, Tajer C, et al. (2022) High-dose vitamin D versus placebo to prevent complications in COVID-19 patients: Multicentre randomized controlled clinical trial. PLoS One 17:e0267918. https://pubmed.ncbi.nlm.nih.gov/35622854

76: De Niet S, Trémège M, Coffiner M, et al. (2022) Positive Effects of Vitamin D Supplementation in Patients Hospitalized for COVID-19: A Randomized, Double-Blind, Placebo-Controlled Trial. Nutrients. 14:3048. https://pubmed.ncbi.nlm.nih.gov/35893907

77: Torres M, Casado G, Vigón L, et al. (2022) Changes in the immune response against SARS-CoV-2 in individuals with severe COVID-19 treated with high dose of vitamin D. Biomed Pharmacother. 150:112965. https://pubmed.ncbi.nlm.nih.gov/35468580

78: Sánchez-Zuno GA, González-Estevez G, Matuz-Flores MG, et al. (2021) Vitamin D Levels in COVID-19 Outpatients from Western Mexico: Clinical Correlation and Effect of Its Supplementation. J Clin Med. 10:2378. https://pubmed.ncbi.nlm.nih.gov/34071293

79: Mazess RB, Bischoff-Ferrari HA, Dawson-Hughes B. (2021) Vitamin D: Bolus Is Bogus-A Narrative Review. JBMR Plus 5:e10567. https://pubmed.ncbi.nlm.nih.gov/34950828

80: Noormandi A, Khalili H, Mohammadi M, Abdollahi A. (2020) Effect of magnesium supplementation on lactate clearance in critically ill patients with severe sepsis: a randomized clinical trial. Eur J Clin Pharmacol. 76:175-184. https://pubmed.ncbi.nlm.nih.gov/31814044

Nutritional Medicine is Orthomolecular Medicine

Orthomolecular medicine uses safe, effective nutritional therapy to fight illness. For more information: http://www.orthomolecular.org

Find a Doctor

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