Other

Other
Here are some other peripherally related notes.

Here is a very good writeup: What every MD should know about vitamin D and the immune system/ https://link.springer.com/article/10.1007/s11154-019-09532-w Vitamin-D-wiki - Why many vitamin D trials fail to find benefits - Nov 2016

A pilot study assessing the effect of prolonged administration of high daily doses of vitamin D on the clinical course of vitiligo and psoriasis
A pilot study assessing the effect of prolonged administration of high daily doses of vitamin D on the clinical course of vitiligo and psoriasis

PMID: 24494059 PMCID: PMC3897595 DOI: 10.4161/derm.24808 https://pubmed.ncbi.nlm.nih.gov/24494059/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3897595/pdf/de-5-222.pdf

Abstract: Autoimmunity has been associated with vitamin D deficiency and resistance, with gene polymorphisms related to vitamin D metabolism frequently described in affected patients. High doses of vitamin D3 may conceivably compensate for inherited resistance to its biological effects. This study aimed to assess the efficacy and safety of prolonged high-dose vitamin D3 treatment of patients with psoriasis and vitiligo. Nine patients with psoriasis and 16 patients with vitiligo received vitamin D3 35,000 IU once daily for six months in association with a low-calcium diet (avoiding dairy products and calcium-enriched foods like oat, rice or soya "milk") and hydration (minimum 2.5 L daily). All psoriasis patients were scored according to "Psoriasis Area and Severity Index" (PASI) at baseline and after treatment. Evaluation of clinical response of vitiligo patients required a quartile grading scale. All patients presented low vitamin D status (serum 25(OH)D3 ≤ 30 ng/mL) at baseline. After treatment 25(OH)D3 levels significantly increased (from 14.9 ± 7.4 to 106.3 ± 31.9 ng/mL and from 18.4 ± 8.9 to 132.5 ± 37.0 ng/mL) and PTH levels significantly decreased (from 57.8 ± 16.7 to 28.9 ± 8.2 pg/mL and from 55.3 ± 25.0 to 25.4 ± 10.7 pg/mL) in patients with psoriasis and vitiligo respectively. PTH and 25(OH)D3 serum concentrations correlated inversely. The PASI score significantly improved in all nine patients with psoriasis. Fourteen of 16 patients with vitiligo had 25-75% repigmentation. Serum urea, creatinine and calcium (total and ionized) did not change and urinary calcium excretion increased within the normal range. High-dose vitamin D3 therapy may be effective and safe for vitiligo and psoriasis patients.

How to optimize vitamin D supplementation to prevent cancer, based on cellular adaptation and hydroxylase enzymology
Anticancer Res. 2009 Sep;29(9):3675-84. How to optimize vitamin D supplementation to prevent cancer, based on cellular adaptation and hydroxylase enzymology Reinhold Vieth

PMID: 19667164 https://pubmed.ncbi.nlm.nih.gov/19667164/

Abstract: The question of what makes an 'optimal' vitamin D intake is usually equivalent to, 'what serum 25-hydroxyvitamin D [25(OH)D] do we need to stay above to minimize risk of disease?'. This is a simplistic question that ignores the evidence that fluctuating concentrations of 25(OH)D may in themselves be a problem, even if concentrations do exceed a minimum desirable level. Vitamin D metabolism poses unique problems for the regulation of 1,25-dihydroxyvitamin D [1,25(OH)2D] concentrations in the tissues outside the kidney that possess 25(OH)D-1-hydroxylase [CYP27B1] and the catabolic enzyme, 1,25(OH)2D-24-hydroxylase [CYP24]. '''These enzymes behave according to first-order reaction kinetics. When 25(OH)D declines, the ratio of 1-hydroxylase/24-hydroxylase must increase to maintain tissue 1,25(OH)2D at its set-point level. The mechanisms that regulate this paracrine metabolism are poorly understood. I propose that delay in cellular adaptation, or lag time, in response to fluctuating 25(OH)D concentrations can explain why higher 25(OH)D in regions at high latitude or with low environmental ultraviolet light can be associated with the greater risks reported for prostate and pancreatic cancers.''' At temperate latitudes, higher summertime 25(OH)D levels are followed by sharper declines in 25(OH)D, causing inappropriately low 1-hydroxylase and high 24-hydroxylase, resulting in tissue 1,25(OH)2D below its ideal set-point. This hypothesis can answer concerns raised by the World Health Organization's International Agency for Research on Cancer about vitamin D and cancer risk. It also explains why higher 25(OH)D concentrations are not good if they fluctuate, and that desirable 25(OH)D concentrations are ones that are both high and stable.

Is ethnicity linked to incidence or outcomes of covid-19?
Is ethnicity linked to incidence or outcomes of covid-19?

BMJ 2020; 369 20 April 2020 BMJ 2020;369:m1548 DOI: 10.1136/bmj.m1548 https://doi.org/10.1136/bmj.m1548 https://www.bmj.com/content/369/bmj.m1548

Concerns about a possible association between ethnicity and outcome were raised after the first 10 doctors in the UK to die from covid-19 were identified as being from ethnic minorities. ==== COVID-19 ’ICU’ risk – 20-fold greater in the Vitamin D Deficient. BAME, African Americans, the Older, Institutionalised and Obese, are at greatest risk. Sun and ‘D’-supplementation – Game-changers? Research urgently required ==== Rapid response to: Is ethnicity linked to incidence or outcomes of covid-19? 24 April 2020 ''COVID-19 ’ICU’ risk – 20-fold greater in the Vitamin D Deficient. BAME, African Americans, the Older, Institutionalised and Obese, are at greatest risk. Sun and ‘D’-supplementation – Game-changers? Research urgently required.'' Robert A Brown et.al.

https://www.bmj.com/content/369/bmj.m1548/rr-6

Dr Hugh Sinclair almost 100 years ago observed; "The deficiency of any nutrient which is essential for every tissue will eventually lead to abnormal function in every tissue. That is so incontrovertibly obvious that I am continually astonished it must be repeatedly forcefully restated."

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Alipio’s results, viewed in the context of earlier recent vitamin D and COVID-19 publications,[2 9] must now lead to urgent research (Brown).[2, 13] Human nature is such that simple solutions to complex issues, for example vitamin C for scurvy, and hand washing prior to baby delivery, are often not readily embraced; but surely the scale and impact of the COVID-19 pandemic demands all avenues are fully explored; more so when no other effective treatment strategies as yet exist. A safe simple step, the correction of a deficiency state, vitamin D this time, convincingly holds out a potential, significant, feasible ‘COVID-19 mitigation remedy.

Adequate vitamin D levels in a Swedish population living above latitude 63°N: The 2009 Northern Sweden MONICA study
Int J Circumpolar Health. 2015; 74: 2015 May 13. Adequate vitamin D levels in a Swedish population living above latitude 63°N: The 2009 Northern Sweden MONICA study Anna Ramnemark, Margareta Norberg, Ulrika Pettersson-Kymmer, and Mats Eliasson

doi: 10.3402/ijch.v74.27963 PMCID: PMC4432023 PMID: 28417824

Results: Mean (median) level of vitamin D3 was 65.2 (63.6) nmol/l in men and 71.0 (67.7) nmol/l in women. Adequate levels were found in 79.2%, more often in women (82.7%) than in men (75.6%). Only 0.7% of the population were vitamin D3–deficient but 23.1% of men and 17.1% of women had insufficient levels. Levels of vitamin D3 increased with age and insufficient status was most common among those aged 25–34 years, 41.0% in men and 22.3% in women.

If subjects using vitamin D-supplementation are excluded, the population level of D3 is 1–2 nmol/l lower than in the general population across sex- and age groups. There were no differences between the northern or the southern parts, between urban or rural living or according to educational attainment. Those subjects born outside of Sweden or Finland had lower levels.

Conclusion: The large majority living close to the Arctic Circle in Sweden have adequate D3 levels even during the second half of the dark winter. Subjects with D3 deficiency were uncommon but insufficient levels were often found among young men.

Sunlight increases serum 25(OH) vitamin D concentration whereas 1,25(OH)2D3 is unaffected. Results from a general population study in Göteborg, Sweden (The WHO MONICA Project)
Eur J Clin Nutr 1995 Jun;49(6):400-7. ''Sunlight increases serum 25(OH) vitamin D concentration whereas 1,25(OH)2D3 is unaffected. Results from a general population study in Göteborg, Sweden (The WHO MONICA Project)'' K Landin-Wilhelmsen, L Wilhelmsen, J Wilske, G Lappas, T Rosén, G Lindstedt, P A Lundberg, B A Bengtsson

PMID: 7656883 https://pubmed.ncbi.nlm.nih.gov/7656883/

Results: The concentration of 25(OH)D3 was similar in both sexes whereas 1,25(OH)2D3 concentration was higher in women than in men (P = 0.01). 25(OH)D3 correlated positively to sun exposure, physical activity and negatively to intact parathyroid hormone (PTH) in both sexes, and also negatively to blood pressure in men. The remaining significant relationship for 25(OH)D3, when age and sun exposure were taken into account in multivariate analyses, was a negative correlation to intact PTH in both sexes. 1,25(OH)2D3 correlated positively to intact PTH in both men and women, negatively to height in men, positively to fibrinogen in men and positively to psychological stress and osteocalcin in women. When all variables were included in multivariate analyses 1,25(OH)2D3 concentration correlated negatively to age and positively to intact PTH and osteocalcin in both sexes together.

Conclusions: Sunlight was the only external factor that influenced 25(OH)D3 concentration whereas 1,25(OH)2D3 was unaffected by sun exposure. 1,25(OH)2D3 was not related to environmental or life style factors but declined by age and correlated positively to intact PTH and osteocalcin.

It is clear that the body regulates the 1,25(OH)2D3 levels if there is some 25(OH)D3 available. (KMP)

Vitamin D requirement and setting recommendation levels – current Nordic view
Nutrition Reviews, Volume 66, Issue suppl_2, 1 October 2008, Pages S165–S169, 01 October 2008 Vitamin D requirement and setting recommendation levels – current Nordic view Jan I Pedersen

https://doi.org/10.1111/j.1753-4887.2008.00101.x

There is a strong seasonal variation in serum 25(OH)D. A Danish study illustrates the marked downward shift during the winter months, with levels falling below desirable vitamin D status in one half of the population

Under Nordic climatic conditions, exposure to sunlight is thus insufficient for enough vitamin D to be formed in the skin and for vitamin D status to be maintained during the winter months. A study from northern Finland in 1980 showed that vitamin D status was satisfactory during the summer months but that a large number of subjects had unsatisfactory vitamin D status during winter.8 On the other hand, more satisfactory serum levels of 25(OH)D and greater seasonal variation was found among adults in a similar study from Tromsö in northern Norway.9 The results of these studies indicate that the light intensity at 70 degrees north is sufficient during summer to elicit vitamin D formation in the skin. One explanation for the difference observed in vitamin D status between the two population groups during the winter months is that, at the time of these studies, the consumption of fish and margarine fortified with vitamin D was much higher in Norway than in Finland. Dietary vitamin D is thus essential to ensure satisfactory vitamin D status at northern latitudes, particularly during the winter months. The question is how much is needed and what intake should be recommended?

CONCLUSION: Vitamin D intake is at about the same low level in Norway and the other Nordic countries. It is slightly higher in Iceland due to widespread use of cod liver oil and slightly lower in Denmark because, until recently, food fortification has not been used. In all Nordic countries, steps are now taken to increase vitamin D intake at the population level in order to reach the new increased recommendations. In addition to disseminating information, increased fortification of foods is essential to reach this goal.

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As expected, there was considerable variation in prevalence of vitamin D deficiency among the European Union countries, which appeared to be dependent on age group. In studies of adult and older adult populations, the prevalence of vitamin D deficiency was much less in the more northerly latitude countries such as Norway, Iceland, and Finland, whereas more mid-latitude countries such as the United Kingdom, Ireland, Netherlands, and Germany had a higher prevalence, even accounting for ethnicity. The amplitude of an increase in prevalence in vitamin D deficiency in extended winter compared with extended summer was also much lower in the northerly latitude countries, which is likely attributable to higher rates of vitamin D supplement and/or food fortification use in these countries (49–51). In the case of the childhood population studies, the relatively mid-latitude countries (47–60°N) had a higher prevalence range (5–20%) than did southern countries (<41°N) at 4.2–6.9%.

Vitamin D deficiency and bone health in healthy adults in Finland: could this be a concern in other parts of Europe?
J Bone Miner Res. 2001 Nov;16(11):2066-73. Vitamin D deficiency and bone health in healthy adults in Finland: could this be a concern in other parts of Europe? C J Lamberg-Allardt, T A Outila, M U Kärkkainen, H J Rita, L M Valsta

PMID: 11697803 DOI: 10.1359/jbmr.2001.16.11.2066 https://pubmed.ncbi.nlm.nih.gov/11697803/

Abstract: A low vitamin D status could be a concern not only in children and the elderly in Europe, but also in adults. We do not know the effect of mild vitamin D deficiency on bone in this age group. The aim of this study was to detect the prevalence of low serum 25-hydroxyvitamin D [S-25(OH)D] and elevated serum intact parathyroid hormone (S-iPTH) concentrations in healthy young adults in the winter in northern Europe and to characterize the determinants of these variables. In addition, we studied the association between vitamin D status and forearm bone mineral density (BMD) in this population group. Three hundred and twenty-eight healthy adults (202 women and 126 men, 31-43 years) from southern Finland (60 degrees N) participated in this study conducted in February through March 1998. Fasting overnight blood samples were collected in the morning. Forearm BMD was measured by dual-energy X-ray absorptiometry (DXA). The mean daily vitamin D intake met the recommendations in the men (5.6 +/- 3.2 microg) and almost met it in the women (4.7 +/- 2.5 microg). The mean S-25(OH)D concentrations did not differ between genders (women, 47 +/- 34 nM; men, 45 +/- 35 nM; mean +/- SD), but the women had significantly higher mean S-iPTH levels than the men (women, 30 +/- 13 ng/liter; men, 24 +/- 12 ng/liter; p < 0.001). Low S-25(OH)D concentrations (<25 nM) were found in 26.2% of the women (53 women) and 28.6% of the men (36 men), respectively. Based on nonlinear regression analysis between S-25(OH)D and S-iPTH concentration, the S-iPTH concentration started to increase with S-25(OH)D concentrations lower than approximately 80 nM in the women and lower than approximately 40 nM in the men. Based on this relation between S-25(OH)D and S-iPTH concentrations, 86% of the women and 56% of the men had an insufficient vitamin D status. In linear regression analysis, the main positive determinants of S-25(OH)D were dietary vitamin D intake (p < 0.02), the use of supplements (p < 0.005), alcohol intake (p < 0.05), and age (p < 0.005). Smoking associated negatively with the S-25(OH)D concentration (p < 0.03). The main determinants of S-iPTH were S-25(OH)D (p < 0.01), dietary calcium intake (p < 0.02), and body mass index (BMI; p < 0.01). In addition, female gender was associated with higher S-iPTH concentration. The mean daily dietary calcium intake was 1,037 +/- 489 mg and 962 +/- 423 mg, in the men and women, respectively. Significantly lower forearm BMD was found in the men (p = 0.01) but not in the women (p = 0.14) with higher S-iPTH concentrations. Low vitamin D status was prevalent in these young adults in northern Europe in winter, although the vitamin D intake met the recommendation. This probably is not a local problem for northern Europe, because the natural sources of vitamin D are scarce and fortification is not very common in Europe, and with the exception of the southern part of Europe, sunshine is not very abundant in this part of the world. Thus, the results of this study indicate that more attention should be focused on vitamin D status and the sources of vitamin D in these countries.

Worldwide status of vitamin D nutrition
J Steroid Biochem Mol Biol. 2010 Jul;121(1-2):297-300. Worldwide status of vitamin D nutrition P Lips

PMID: 20197091 DOI: 10.1016/j.jsbmb.2010.02.021 https://pubmed.ncbi.nlm.nih.gov/20197091/

Abstract: The vitamin D status depends on the production of vitamin D3 in the skin under the influence of ultraviolet radiation and vitamin D intake through the diet or vitamin D supplements. The serum 25-hydroxyvitamin D (25(OH)D) concentration is the parameter of choice for the assessment of vitamin D status. Low serum levels of calcium and phosphate and an elevated level of alkaline phosphatase can also point to vitamin D deficiency. Usually, between 50% and 90% of vitamin D in the body is coming from the production in the skin and the remainder is from the diet. The production of vitamin D3 in the skin depends on sunshine exposure, latitude, skin-covering clothes, the use of sun block and skin pigmentation. In general, serum 25(OH)D is lower with higher latitudes and with darker skin types, but there are exceptions. Vitamin D deficiency (serum 25(OH)D<25 nmol/l) is highly prevalent in India and China while vitamin D status is better in Japan and South-East Asia. Vitamin D deficiency is very common in the Middle-East and there is a relationship with skin covering clothes and staying outside of the sun. A poor to moderate vitamin D status is also common in Africa, probably caused by the dark skin types and cultural habits of staying outside of the sunshine. Vitamin D status is much better in North America where vitamin D deficiency is uncommon but vitamin D insufficiency (serum 25(OH)D between 25 and 50 nmol/l) is still common. In the United States and Canada milk is usually supplemented with vitamin D and the use of vitamin supplements is relatively common. Vitamin D status in Latin America usually is reasonable but there are exceptions and vitamin D insufficiency still occurs quite often. In Australia and New Zealand a poor vitamin D status was seen in the elderly who were often vitamin D deficient and also in immigrants from Asia. Vitamin D deficiency also occurred in children when the mother was vitamin D deficient. '''Within Europe, vitamin D status usually is better in the Nordic countries than around the Mediterranean. This may be due to a lighter skin and sun seeking behaviour and a high consumption of cod liver oil in the Northern countries while in Southern Europe people stay out of the sunshine and have a somewhat darker skin. A very poor vitamin D status was observed in non-western immigrants, especially in pregnant women. In conclusion, vitamin D deficiency and insufficiency are globally still very common especially in risk groups such as young children, pregnant women, elderly and immigrants.'''

America does a lot of supplementation with Vitamin-D2 as opposed to Vitamin-D3 which is a mistake. (KMP)

1 in 4 COVID patients hospitalized while vitamin D deficient die – Israeli study
1 in 4 COVID patients hospitalized while vitamin D deficient die – Israeli study

Vitamin D helps the body fight coronavirus, major Israeli study claims

Low plasma 25(OH) vitamin D level is associated with increased risk of COVID-19 infection: an Israeli population-based study

Real-World Evidence: The Case of Peru
Real-World Evidence: The Case of Peru

[https://www.researchgate.net/publication/344469305_Real-World_Evidence_The_Case_of_Peru_Causality_between_Ivermectin_and_COVID-19_Infection_Fatality_Rate Real-World Evidence: The Case of Peru. Causality between Ivermectin and COVID-19 Infection Fatality Rate]

Peru Embraces Ivermectin as Key Drug to Fight Coronavirus

Ivermectin crushes Delhi cases
Ivermectin crushes Delhi cases

Is Ivermectin turning the COVID tide in India?

Early Multidrug Outpatient Treatment of SARS-CoV-2 Infection (COVID-19) and Reduced Mortality Among Nursing Home Residents

India: COVID-19 cases plummet as the country turns to Ivermectin and hydroxychloroquine

Tamil Nadu leads India in new infections, denies citizens Ivermectin

WHO warns against the use of Ivermectin a day after Goa approves use for treating COVID-19

WHO warns against use of ivermectin suggested in India's national Covid management protocol

COVID Cases Drop Substantially In India After Government Promotes Ivermectin and Hydroxychloroquine Use

WHO to probe use of Ivermectin for Covid-19 treatment after ’promising’ results in trials
WHO to probe use of Ivermectin for Covid-19 treatment after ’promising’ results in trials

This is dated from 21 January 2021. South Africa, Zimbabwe, Peru, parts of Argentina and India have started using it since then but the WHO is still sitting on its hands. (KMP)

Cops investigate Durban hospital for dispensing anti-parasite drug Ivermectin

Around the same time in 8 January 2021 criminal charges were being laid on a pharmacist and hospital manager for dispensing Ivermectin. (KMP)

Doctors can now prescribe ivermectin as treatment for Covid-19

In 7 April 2021 the High court in South Africa said doctors could treat with locally compounded or imported Ivermectin. (KMP) The use of Ivermectin is spreading. Mostly in countries that do not have resources to waste and have to do the right thing for their citizens. The penetration is illustrated on this updated map of IVERMECTIN ADOPTION.

WHO Deletes Naturally Acquired Immunity from Its Website
American Institute for Economic Research WHO Deletes Naturally Acquired Immunity from Its Website Jeffrey A. Tucker – December 23, 2020

https://www.aier.org/article/who-deletes-naturally-acquired-immunity-from-its-website/

Coronavirus lived on surfaces until it didn’t. Masks didn’t work until they did, then they did not. There is asymptomatic transmission, except there isn’t. Lockdowns work to control the virus except they do not. All these people are sick without symptoms until, whoops, PCR tests are wildly inaccurate because they were never intended to be diagnostic tools. Everyone is in danger of the virus except they aren’t. It spreads in schools except it doesn’t.

On it goes. Daily. It’s no wonder that so many people have stopped believing anything that “public health authorities” say. In combination with governors and other autocrats doing their bidding, they set out to take away freedom and human rights and expected us to thank them for saving our lives. At some point this year (for me it was March 12) life began feeling like a dystopian novel of your choice.

Well, now I have another piece of evidence to add to the mile-high pile of fishy mess. The World Health Organization, for reasons unknown, has suddenly changed its definition of a core conception of immunology: herd immunity. Its discovery was one of the major achievements of 20th century science, gradually emerging in the 1920s and then becoming ever more refined throughout the 20th century.

....

In effect, this change at WHO ignores and even wipes out 100 years of medical advances in virology, immunology, and epidemiology. It is thoroughly unscientific – shilling for the vaccine industry in exactly the way the conspiracy theorists say that WHO has been doing since the beginning of this pandemic.

The elusive definition of pandemic influenza (WHO, CoE)
The elusive definition of pandemic influenza Peter Doshi

https://www.who.int/bulletin/volumes/89/7/11-086173.pdf

Abstract; There has been considerable controversy over the past year, particularly in Europe, over whether the World Health Organization (WHO) changed its definition of pandemic influenza in 2009, after novel H1N1 influenza was identified. Some have argued that not only was the definition changed, but that it was done to pave the way for declaring a pandemic. Others claim that the definition was never changed and that this allegation is completely unfounded. Such polarized views have hampered our ability to draw important conclusions. This impasse,  combined  with  concerns  over  potential  conflicts  of  interest  and  doubts  about  the  proportionality  of  the  response to the H1N1 influenza outbreak, has undermined the public trust in health officials and our collective capacity to effectively respond to future disease threats. WHO did not change its definition of pandemic influenza for the simple reason that it has never formally defined pandemic influenza. While WHO has put forth many descriptions of pandemic influenza, it has never established a formal definition and the criteria for declaring a pandemic caused by the H1N1 virus derived from “pandemic phase” definitions, not from a definition of “pandemic influenza”. The fact that despite ten years of pandemic preparedness activities no formal definition of pandemic influenza has been formulated reveals important underlying assumptions about the nature of this infectious disease. In particular, the limitations of “virus-centric” approaches merit further attention and should inform ongoing efforts to “learn lessons” that will guide the response to future outbreaks of novel infectious diseases.

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What sparked the controversy: Since 2003,  the  top  of  the  WHO  Pandemic  Preparedness  homepage has contained the following statement: “An influenza pandemic  occurs  when  a  new  influenza  virus  appears  against  which  the  human  population  has  no  immunity,  resulting  in  several simultaneous epidemics worldwide with enormous numbers of deaths and illness.”6 However, on 4 May 2009, scarcely one month before the H1N1 pandemic was declared, the web page was altered in response to a query from a CNN reporter.7 The phrase “enormous numbers of deaths and illness” had been removed and the revised web page simply read as follows: “An influenza pandemic may occur when a new influenza virus appears against which the human population has no immunity.” Months later, the Council of Europe would cite this alteration as evidence that WHO changed its definition of pandemic influenza to en-able it to declare a pandemic without having to demonstrate the intensity of the disease caused by the H1N1 virus.3

The document has a very interesting round table discussion that is worth reading. (KMP)

Covid-19 vaccines: ethical, legal and practical considerations (CoE)
Parliamentary Assembly of the Council of Europe Resolution 2361 (2021) Assembly debate on 27 January 2021 (5th Sitting) (see Doc. 15212, report of the Committee on Social Affairs, Health and Sustainable Development, rapporteur: Ms Jennifer De Temmerman). Text adopted by the Assembly on 27 January 2021 (5th Sitting). Covid-19 vaccines: ethical, legal and practical considerations Parliamentary Assembly

https://pace.coe.int/en/files/29004/html

7.3	with respect to ensuring a high vaccine uptake: 7.3.1	ensure that citizens are informed that the vaccination is not mandatory and that no one is under political, social or other pressure to be vaccinated if they do not wish to do so; 7.3.2	ensure that no one is discriminated against for not having been vaccinated, due to possible health risks or not wanting to be vaccinated;

120 doctors ask JAMA to retract misleading Colombian study downplaying efficacy of ivermectin
Horowitz: 120 doctors ask JAMA to retract misleading Colombian study downplaying efficacy of ivermectin - Why is there such an agenda to discredit cheap, repurposed drugs?

Consensus statement from 2nd International Conference on Controversies in Vitamin D
SpringerLink Open Access Published: 17 March 2020 Consensus statement from 2nd International Conference on Controversies in Vitamin D A. Giustina, R. A. Adler, N. Binkley, J. Bollerslev, R. Bouillon, B. Dawson-Hughes, P. R. Ebeling, D. Feldman, A. M. Formenti, M. Lazaretti-Castro, C. Marcocci, R. Rizzoli, C. T. Sempos & J. P. Bilezikian

Reviews in Endocrine and Metabolic Disorders volume 21, pages 89–116 (2020)

Abstract: The 2nd International Conference on Controversies in Vitamin D was held in Monteriggioni (Siena), Italy, September 11-14, 2018. The aim of this meeting was to address ongoing controversies and timely topics in vitamin D research, to review available data related to these topics and controversies, to promote discussion to help resolve lingering issues and ultimately to suggest a research agenda to clarify areas of uncertainty. Several issues from the first conference, held in 2017, were revisited, such as assays used to determine serum 25-hydroxyvitamin D [25(OH)D] concentration, which remains a critical and controversial issue for defining vitamin D status. Definitions of vitamin D nutritional status (i.e. sufficiency, insufficiency and deficiency) were also revisited. New areas were reviewed, including vitamin D threshold values and how they should be defined in the context of specific diseases, sources of vitamin D and risk factors associated with vitamin D deficiency. Non-skeletal aspects related to vitamin D were also discussed, including the reproductive system, neurology, chronic kidney disease and falls. The therapeutic role of vitamin D and findings from recent clinical trials were also addressed. The topics were considered by 3 focus groups and divided into three main areas: 1) “Laboratory”: assays and threshold values to define vitamin D status; 2) “Clinical”: sources of vitamin D and risk factors and role of vitamin D in non-skeletal disease and 3) “Therapeutics”: controversial issues on observational studies and recent randomized controlled trials. In this report, we present a summary of our findings.

Some good summaries but nothing radical or progressive really. (KMP)

==== Dr Alex Vasquez (2019) Response to Editorial "remarkable impact of bivalent HPV vaccine in Scotland": Scotland's public health campaigns to improve vitamin D nutriture occurred within the same timeframe as HPV vaccination. ==== BMJ.com [rapid response], 2019 Dr Alex Vasquez (2019) Response to Editorial "remarkable impact of bivalent HPV vaccine in Scotland": Scotland's public health campaigns to improve vitamin D nutriture occurred within the same timeframe as HPV vaccination.

https://www.academia.edu/39207517/Dr_Alex_Vasquez_2019_Response_to_Editorial_remarkable_impact_of_bivalent_HPV_vaccine_in_Scotland_Scotlands_public_health_campaigns_to_improve_vitamin_D_nutriture_occurred_within_the_same_timeframe_as_HPV_vaccination_rapid_response_BMJ_com

In Scotland, programs advocating HPV vaccination (started in 2008) and vitamin D supplementation (started not later than 2006 and again in 2009) occurred in close chronologic proximity; use of nutritional supplements that contain or potentiate vitamin D had started to increase in the population by 2003. Crediting the reduction in HPV-related disease solely to vaccination via retrospective population study is potentially misleading, especially when these authors make no account whatsoever of the national program for vitamin D supplementation which started in the same time-frame. Numerous studies have shown that vitamin D provides immunomodulatory, anti-inflammatory, microbiome-modifying, antiviral and anti-HPV benefits with high safety, good efficacy, low cost, wide availability, and clinically important collateral benefits.

Vitamin D-regulated Gene Expression Profiles: Species-specificity and Cell-specific Effects on Metabolism and Immunity
Endocrinology. 2021 Feb 1;162(2):bqaa218. Vitamin D-regulated Gene Expression Profiles: Species-specificity and Cell-specific Effects on Metabolism and Immunity Vassil Dimitrov, Camille Barbier, Aiten Ismailova, Yifei Wang, Katy Dmowski, Reyhaneh Salehi-Tabar, Babak Memari, Emilie Groulx-Boivin, John H White

PMID: 33249469 PMCID: PMC7751191 DOI: 10.1210/endocr/bqaa218 https://pubmed.ncbi.nlm.nih.gov/33249469/

Vitamin D Receptor Gene Polymorphisms and the Risk of Metabolic Syndrome (MetS): A Meta-Analysis
Endocr Metab Immune Disord Drug Targets. 2021;21(5):943-955. doi: 10.2174/1871530320666200805101302 Vitamin D Receptor Gene Polymorphisms and the Risk of Metabolic Syndrome (MetS): A Meta-Analysis Hamidreza Totonchi, Ramazan Rezaei, Shokoofe Noori, Negar Azarpira, Pooneh Mokarram, Danyal Imani

PMID: 32767922 DOI: 10.2174/1871530320666200805101302 https://pubmed.ncbi.nlm.nih.gov/32767922/

Vitamin D status and Parkinson's disease: a systematic review and meta-analysis
Neurol Sci. 2014 Nov;35(11):1723-30. Vitamin D status and Parkinson's disease: a systematic review and meta-analysis Zheng Lv, Huiping Qi, Le Wang, Xiaoxue Fan, Fei Han, Hong Wang, Sheng Bi

PMID: 24847960 DOI: 10.1007/s10072-014-1821-6 https://pubmed.ncbi.nlm.nih.gov/24847960/

Impact of nonpharmaceutical interventions on laboratory detections of influenza A and B in Canada
Can Commun Dis Rep. 2021 Mar 31; 47(3): 142–148. Influenza and Other Respiratory Viruses Impact of nonpharmaceutical interventions on laboratory detections of influenza A and B in Canada Philippe Lagacé-Wiens, Claire Sevenhuysen, Liza Lee, Andrea Nwosu, and Tiffany Smith

doi: 10.14745/ccdr.v47i03a04 PMCID: PMC8109283 PMID: 34012338 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8109283/

Abstract:

....

Results: While influenza detections the week prior to the implementation of social distancing measures did not differ statistically from the previous nine seasons, a steep decline in positivity occurred between epidemiologic weeks 10 and 14 (March 8–April 4, 2020). Both the percent positive on week 14 (p≤0.001) and rate of decline between weeks 10 and 14 (p=0.003) were significantly different from mean historical data.

Conclusion: The data show a dramatic decrease in influenza A and B laboratory detections concurrent with social distancing measures and nonpharmaceutical interventions in Canada. The impact of these measures on influenza transmission may be generalizable to other respiratory viral illnesses during the study period, including COVID-19. Keywords: social distancing, physical distancing, influenza, COVID-19, SARS-CoV-2, public health, nonpharmaceutical interventions, NPI

Proof that Vitamin D Works: Vitamin D prevents or treats 89 health problems
Proof that Vitamin D Works: Vitamin D prevents or treats 89 health problems

https://vitamindwiki.com/tiki-index.php?page_id=1336

POST-ACUTE OR PROLONGED COVID-19: IVERMECTIN TREATMENT FOR PATIENTS WITH PERSISTENT SYMPTOMS OR POST-ACUTE
July 2020   Project: COVID 19 POST-ACUTE OR PROLONGED COVID-19: IVERMECTIN TREATMENT FOR PATIENTS WITH PERSISTENT SYMPTOMS OR POST-ACUTE Gustavo Aguirre Chang et al

FDA Ivermectin study list, tabulated.
FDA Ivermectin study list, tabulated.

https://www.covid19treatmentguidelines.nih.gov/tables/table-2c/

Review of the Emerging Evidence Demonstrating the Efficacy of Ivermectin in the Prophylaxis and Treatment of COVID-19
Review of the Emerging Evidence Demonstrating the Efficacy of Ivermectin in the Prophylaxis and Treatment of COVID-19 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088823/

Already from April 2021 (KMP)

Ivermectin in Long-Covid Patients: A Retrospective Study
Ivermectin in Long-Covid Patients: A Retrospective Study Del Franco Haroldo, Carvallo Hector, Hirsch Roberto

https://www.academia.edu/45584941/Ivermectin_in_Long_Covid_Patients_A_Retrospective_Study

A five-day course of ivermectin for the treatment of COVID-19 may reduce the duration of illness
Int J Infect Dis. 2021 Feb;103:214-216. A five-day course of ivermectin for the treatment of COVID-19 may reduce the duration of illness Sabeena Ahmed, Mohammad Mahbubul Karim, Allen G Ross, Mohammad Sharif Hossain, John D Clemens, Mariya Kibtiya Sumiya, Ching Swe Phru, Mustafizur Rahman, Khalequ Zaman, Jyoti Soman, Rubina Yasmin, Mohammad Abul Hasnat, Ahmedul Kabir, Asma Binte Aziz, Wasif Ali Khan

PMID: 33278625 PMCID: PMC7709596 DOI: 10.1016/j.ijid.2020.11.191

Novel 2019-coronavirus on new year's Eve
Indian J Med Microbiol. Oct-Dec 2019;37(4):459-477. Novel 2019-coronavirus on new year's Eve Parakriti Gupta, Kapil Goyal, Poonam Kanta, Arnab Ghosh, Mini P Singh

PMID: 32436867 PMCID: PMC7836853 DOI: 10.4103/ijmm.IJMM_20_54 https://pubmed.ncbi.nlm.nih.gov/32436867/

Abstract: An ongoing apocalyptic outbreak of a new virus causing pneumonia-like clusters in Wuhan city, China, has gleamed the world. The outbreak, confirmed on the New Year's Eve 2020, has known no boundaries since then. The number has surpassed that of Severe Acute Respiratory Syndrome (SARS) and Middle East respiratory syndrome (MERS), and is uninterruptedly escalating. Being an RNA virus, it has a propensity to mutate due to the low proofreading capacity of RNA-dependent RNA polymerase. Step-wise mutations have led to the gradual spillover of virus and after crossing the inter-species interface, the virus has adapted itself for a stable human-to-human transmission. The disease caused by severe acute respiratory syndrome coronavirus (CoV)-2 (SARS-CoV-2) can prove deadlier if the so-called 'super-spreading events' emerge with time. Recent research has shown the maximum homology of 99% of SARS-CoV-2 to pangolins associated coronavirus, owing to which these can serve as potential intermediate host. India is responding swiftly to the emergency situation, and the whole of the country is under lockdown since 25 March 2020, to ensure social distancing. All the international flights are padlocked and the travellers are being screened at airports and seaports via thermal sensors, and quarantine for a period of 14 days is recommended. Three hundred and forty-five patients across the country tested positive with six fatalities as of 22 March 2020. No specific anti-CoV drugs are currently available. Patients are being treated with protease drugs are inhibitors, remdesivir, chloroquine, angiotensin-converting enzyme 2 inhibitors, ivermectin, sarilumab and tocilizumab, though none of these is Food and Drug Administration approved and are undergoing trials. Preventive measures such as social distancing, quarantine, cough etiquettes, proper hand washing, cleaning and decontaminating the surfaces are the mainstay for curbing the transmission of this virus. The present review highlights the update of novel SARS-CoV-2 in context to the Indian scenario.

Keywords: Angiotensin-converting enzyme-2; RNA-dependent RNA polymerase; SARS-CoV-2; Wuhan; bats; hand hygiene; quarantine; social distancing.

It is almost funny that Ivermectin was considered as a potential drug in 2019 already yet still only of accepted value in some circles in mid 2021. (KMP)

Ajustar el déficit nada más contagiarse reduce las muertes por Covid-19 un 75%
Ajustar el déficit nada más contagiarse reduce las muertes por Covid-19 un 75%

https://www.larazon.es/salud/20210606/46smcvjpp5fnpaip67efrburp4.html

Capitol Clarity: Covid-19, Vitamin D and mRNA-Vaccine Concerns | Dr. Ryan Cole, MD (March 4th, 2021)
Capitol Clarity: Covid-19, Vitamin D and mRNA-Vaccine Concerns | Dr. Ryan Cole, MD (March 4th, 2021)

https://odysee.com/@SaveMedia:5/capitol-clarity-ryan-cole-on-covid-19-vitamin-d-vaccine-concerns:2

The Safety of COVID-19 Vaccinations—We Should Rethink the Policy
Vaccines 2021, 9(7), 693; The Safety of COVID-19 Vaccinations—We Should Rethink the Policy Harald Walach, Rainer J. Klement and Wouter Aukema

https://doi.org/10.3390/vaccines9070693

A Quantitative Benefit–Risk Analysis of ChAdOx1 nCoV-19 Vaccine among People under 60 in Italy
Vaccines 2021, 9(6), 618; A Quantitative Benefit–Risk Analysis of ChAdOx1 nCoV-19 Vaccine among People under 60 in Italy Raffaele Palladino, Daniele Ceriotti, Damiano De Ambrosi, Marta De Vito, Marco Farsoni, Giuseppina Seminara and Francesco Barone-Adesi

https://doi.org/10.3390/vaccines9060618

Effects of high doses of vitamin D3 on mucosa-associated gut microbiome vary between regions of the human gastrointestinal tract
Eur J Nutr. 2016; 55: 1479–1489. Published online 2015 Jul 1. Effects of high doses of vitamin D3 on mucosa-associated gut microbiome vary between regions of the human gastrointestinal tract Mina Bashir, Barbara Prietl, Martin Tauschmann, Selma I. Mautner, Patrizia K. Kump, Gerlies Treiber, Philipp Wurm, Gregor Gorkiewicz, Christoph Högenauer,corresponding author and Thomas R. Pieber

doi: 10.1007/s00394-015-0966-2 PMCID: PMC4875045 PMID: 26130323

Role of Magnesium in Vitamin D Activation and Function
Role of Magnesium in Vitamin D Activation and Function

https://www.degruyter.com/document/doi/10.7556/jaoa.2018.037/html

Understanding cycle threshold (Ct) in SARS-CoV-2 RT-PCRA guide for health protection teams
Understanding cycle threshold (Ct) in SARS-CoV-2 RT-PCRA guide for health protection teams

https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/926410/Understanding_Cycle_Threshold__Ct__in_SARS-CoV-2_RT-PCR_.pdf

Nice diagram showing how more false positives will show up at the tail end than at the front end. How increased cycle times will increase the false positives as the test becomes more sensitive to fragments and noise (KMP)

Explained: COVID-19 PCR Testing and Cycle Thresholds
Explained: COVID-19 PCR Testing and Cycle Thresholds

https://www.publichealthontario.ca/en/about/blog/2021/explained-covid19-pcr-testing-and-cycle-thresholds

Association between vitamin D and respiratory outcomes in Canadian adolescents and adults
J Asthma. 2015 Sep;52(7):653-61. Association between vitamin D and respiratory outcomes in Canadian adolescents and adults Selvanayagam John Niruban, Kannayiram Alagiakrishnan, Jeremy Beach, Ambikaipakan Senthilselvan

PMID: 25563060 DOI: 10.3109/02770903.2015.1004339

Results: The proportion of subjects with current and ever asthma was greater in the lower 25(OH)D category than in moderate and high categories. After adjusting for potential confounders, subjects in the low 25(OH)D levels were more likely to have current asthma than those in the moderate levels (OR: 1.54, 95% CI: 1.01-2.36). Low 25(OH)D levels were also associated with ever asthma (OR: 2.12, 95% CI: 1.40-3.21) among those with a family history of asthma and this association was stronger in those with asthma onset before 20 years of age. High 25(OH)D levels were associated with lower mean value of FEV1/FVC ratio. No significant association was observed between 25(OH)D levels and other lung function measurements.

Conclusion: In this study, 25(OH)D levels below 50 nmol/L were associated with an increased risk of current and ever asthma. Further exploration of this relationship is needed to determine the optimal level of vitamin D in the management of asthma in adolescents and adults.

Ecological studies of the UVB-vitamin D-cancer hypothesis
Anticancer Res. 2012 Jan;32(1):223-36. Ecological studies of the UVB-vitamin D-cancer hypothesis William B Grant

PMID: 22213311 https://ar.iiarjournals.org/content/32/1/223/tab-article-info

Abstract: Background/aim: This paper reviews ecological studies of the ultraviolet-B (UVB)-vitamin D-cancer hypothesis based on geographical variation of cancer incidence and/or mortality rates.

Materials and methods: The review is based largely on three ecological studies of cancer rates from the United States; one each from Australia, China, France, Japan, and Spain; and eight multicountry, multifactorial studies of cancer incidence rates from more than 100 countries.

Results: This review consistently found strong inverse correlations with solar UVB for 15 types of cancer: bladder, breast, cervical, colon, endometrial, esophageal, gastric, lung, ovarian, pancreatic, rectal, renal, and vulvar cancer; and Hodgkin's and non-Hodgkin's lymphoma. Weaker evidence exists for nine other types of cancer: brain, gallbladder, laryngeal, oral/pharyngeal, prostate, and thyroid cancer; leukemia; melanoma; and multiple myeloma.

Conclusion: The evidence for the UVB-vitamin D-cancer hypothesis is very strong in general and for many types of cancer in particular.

Update on evidence that support a role of solar ultraviolet-B irradiance in reducing cancer risk
Anticancer Agents Med Chem. 2013 Jan;13(1):140-6. Update on evidence that support a role of solar ultraviolet-B irradiance in reducing cancer risk William B Grant

PMID: 23094927 https://pubmed.ncbi.nlm.nih.gov/23094927/

This ecological study provides additional evidence that UVB doses at high latitudes are adequate to reduce the risk of cancer, but requires considerable time outside to produce sufficient vitamin D. Because only vitamin D production has been proposed to explain the UVB-cancer link, studies reviewed in this paper should be considered strong evidence for the hypothesis.

Vitamin D and Health
SACN 2016 Vitamin D and Health

https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/537616/SACN_Vitamin_D_and_Health_report.pdf

7.8 The IOM noted the paucity of long term studies with vitamin D intakes >250μg/d (10,000IU) or where serum 25(OH)D concentrations above 250nmol/L were observed but, based on the available data, considered it unlikely that symptoms of toxicity would be observed at daily vitamin D intakes below 250μg (10,000IU). .... 7.15 A number of case reports of vitamin D intoxication, following high medicinal doses or excessive use of food supplements, have been reported in the literature. In these case reports, serum 25(OH)D concentrations of 300 to more than 1000nmol/L were associated with intoxication. However, case reports provide limited information for risk assessment purposes because the doses consumed, where known, have varied in amount and duration. .... 7.17 Heaney et al. (2003) investigated the relationship between steady state vitamin D3 intake and serum 25(OH)D concentration. Vitamin D3 doses of 0, 25, 125 or 250 μg/d (0, 1000, 5000 or 10,000IU/d) were administered to healthy men (n=67) for 20 weeks over the winter in Omaha, US. Mean serum 25(OH)D concentration was 70nmol/L at baseline, which increased in proportion to the dose. Limited information was provided on changes in serum calcium concentrations but indicated that none of the men in the top two dose groups (n=31) had concentrations above the normal reference range after treatment. The IOM observed that vitamin D intakes of 125μg/d (5000IU/d) achieved serum 25(OH)D concentrations of 100-150nmol/L (but not exceeding 150nmol/L) after 160 days of administration.

7.18 Barger-Lux et al. (1998) investigated the relationship between graded oral dosing with vitamin D3 for 8 weeks and changes in serum 25(OH)D concentration in healthy young men (n=116; mean age, 28y). Doses of 25, 250 or 1250μg/d (1000, 10,000, or '''50,000 IU/d) resulted in mean increases in serum 25(OH)D concentration of 28.6, 146.1 and 643.0nmol/L respectively above the mean baseline concentration (67nmol/L). No statistically significant changes were detected in mean baseline serum calcium concentration (2.41mmol/L).''' .... 9.28 As outlined in the previous section, making recommendations on sunlight exposure as a means of achieving and maintaining serum 25(OH)D concentration ≥25nmol/L for 97.5% of the population is problematic. Taking account of sunlight exposure in setting the RNI (i.e.,dietary intake) for vitamin D is also complicated by the number of factors that impact on cutaneous production of vitamin D. .... 10.38 '''Case reports of vitamin D toxicity are associated with serum 25(OH)D concentrations >300nmol/L and more usually 600-1000nmol/L. In adults, a single dose of 7500μg (300,000IU) vitamin D at 3 month or longer intervals would not be expected to cause any adverse effects but there is greater uncertainty at higher doses.''' For infants, limited data suggest that toxicity could occur at single vitamin D doses ≥15,000μg (600,000IU).

This relatively recent 2016 UK report contains 300 pages of caution and avoidance of potential extra-skeletal benefits. Well researched and clear trail of how inadequate choices are made from promising research results. Section 9 goes into good detail about gaining Vitamin-D through sunlight exposure (must be done around midday) and comes to the conclusion that in England it would not be possible to use sunshine to maintain a population wide paltry minimum of 25nmol/l (10ng/ml) through winter. The tragedy is that the goal of 25nmol/l (10ng/ml) is only met if everyone actually takes 10ug (400IU) of Vitamin-D3 daily. If you believe that year round equatorial sunlight every day is an evolutionary expectation then the target of 25nmol/l (10ng/ml) is woefully inadequate. (KMP)

Cholecalciferol (Vitamin D3) – Pharmacological Properties, Therapeutic Utility and Potential New Fields of Clinical Application
PHARMACIA, vol. 63, No. 1/2016 Cholecalciferol (Vitamin D3) – Pharmacological Properties, Therapeutic Utility and Potential New Fields of Clinical Application G. Momekov, Y. Voynikov, P. Peikov

https://www.researchgate.net/publication/312164408

Vitamin D is a secosteroid produced in the skin from 7-dehydrocholesterol under the influence of ultraviolet irradiation. Vitamin D is also found in certain foods and is used to supplement dairy products. Both the natural form (vitamin D3, cholecalciferol) and the plant-derived form (vitamin D2, ergocalciferol) are present in the diet. These forms differ in that ergocalciferol contains a double bond (C22–23) and an additional methyl group in the side chain. Ergocalciferol is less potent and has some pharmacokinetic disadvantages that have unambiguously outlined cholecalciferol as the optimal agent for vitamin D supplementation. Vitamin D is a prohormone that serves as a precursor to a number of biologically active metabolites. It is first hydroxylated in the liver to form 25-hydroxyvitamin D (25(OH)D). This metabolite is further converted in the kidney to a number of other forms, the best studied of which are 1,25-dihydroxyvitamin D (1,25(OH)2D) and 24,25-dihydroxyvitamin D (24,25(OH)2D). Of the natural metabolites, only vitamin D and 1,25(OH)2D (as calcitriol) are available for clinical use. Moreover, a number of analogs of 1,25(OH)2D are being synthesized to extend the usefulness of this metabolite to a variety of nonclassic conditions. Calcipotriol, for instance, is being used to treat psoriasis, a hyperproliferative skin disorder. Doxercalciferol and paricalcitol have recently been approved for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease. Other analogs are being investigated for the treatment of various disease states. The regulation of vitamin D metabolism is complex, involving calcium, phosphate, and a variety of hormones, the most important of which is PTH, which stimulates the production of 1,25(OH)2D by the kidney. Despite the specific advantages of analogs/metabolites, cholecalciferol has been well appreciated as effective in diverse conditions due to primary or secondary vitamin D deficiency and moreover has superior safety profile and is less expensive. The present paper is focused on a concise outline of the clinically-validated therapeutic applications of cholecalciferol with a prospectus for further therapeutic utilities, based on its pleiotropic effects beyond the calcium homeostasis and bone health.

Zn(2+) inhibits coronavirus and arterivirus RNA polymerase activity in vitro and zinc ionophores block the replication of these viruses in cell culture
PLoS Pathog. 2010 Nov 4;6(11):e1001176. Aartjan J W te Velthuis 1, Sjoerd H E van den Worm, Amy C Sims, Ralph S Baric, Eric J Snijder, Martijn J van Hemert

PMID: 21079686 PMCID: PMC2973827 DOI: 10.1371/journal.ppat.1001176 https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1001176

Abstract: Increasing the intracellular Zn(2+) concentration with zinc-ionophores like pyrithione (PT) can efficiently impair the replication of a variety of RNA viruses, including poliovirus and influenza virus. For some viruses this effect has been attributed to interference with viral polyprotein processing. In this study we demonstrate that the combination of Zn(2+) and PT at low concentrations (2 µM Zn(2+) and 2 µM PT) inhibits the replication of SARS-coronavirus (SARS-CoV) and equine arteritis virus (EAV) in cell culture. The RNA synthesis of these two distantly related nidoviruses is catalyzed by an RNA-dependent RNA polymerase (RdRp), which is the core enzyme of their multiprotein replication and transcription complex (RTC). Using an activity assay for RTCs isolated from cells infected with SARS-CoV or EAV--thus eliminating the need for PT to transport Zn(2+) across the plasma membrane--we show that Zn(2+) efficiently inhibits the RNA-synthesizing activity of the RTCs of both viruses. Enzymatic studies using recombinant RdRps (SARS-CoV nsp12 and EAV nsp9) purified from E. coli subsequently revealed that Zn(2+) directly inhibited the in vitro activity of both nidovirus polymerases. More specifically, Zn(2+) was found to block the initiation step of EAV RNA synthesis, whereas in the case of the SARS-CoV RdRp elongation was inhibited and template binding reduced. By chelating Zn(2+) with MgEDTA, the inhibitory effect of the divalent cation could be reversed, which provides a novel experimental tool for in vitro studies of the molecular details of nidovirus replication and transcription.

Author Summary '''Positive-stranded RNA (+RNA) viruses include many important pathogens. They have evolved a variety of replication strategies, but are unified in the fact that an RNA-dependent RNA polymerase (RdRp) functions as the core enzyme of their RNA-synthesizing machinery. The RdRp is commonly embedded in a membrane-associated replication complex that is assembled from viral RNA, and viral and host proteins.''' Given their crucial function in the viral replicative cycle, RdRps are key targets for antiviral research. Increased intracellular Zn2+ concentrations are known to efficiently impair replication of a number of RNA viruses, e.g. by interfering with correct proteolytic processing of viral polyproteins. Here, we not only show that corona- and arterivirus replication can be inhibited by increased Zn2+ levels, but also use both isolated replication complexes and purified recombinant RdRps to demonstrate that this effect may be based on direct inhibition of nidovirus RdRps. The combination of protocols described here will be valuable for future studies into the function of nidoviral enzyme complexes.

Other
Methods for producing recombinant coronavirus How to make a non-replicating corona virus to use as a vector to use as a HIV vaccine delivery agent. '''Hmm. (KMP)'''

Absorption of Magnesium varies depending on the selected compound Magnesium Oxide Delivers More Magnesium with Far Fewer Pills

The elusive definition of pandemic influenza "The phrase enormous numbers of deaths and illness had been removed and the revised web page simply read as follows: An in-fluenza pandemic may occur when a new influenza virus appears against which the human population has no immunity."

Speculation that the definition of a pandemic is politically adjusted - The classical definition of a pandemic is not elusive

https://pubmed.ncbi.nlm.nih.gov/33795896/ COVID-19: The Ivermectin African Enigma '''Africa has had a better time with CoViD-19, either because of Ivermectin prophylaxis programs (for River-Blindness but works on CoViD-19 as well) or because of additional equatorial sunshine provided UVB that supplies generous Vitamin-D. (KMP)'''

https://www.ncbi.nlm.nih.gov/nucleotide/NC_004718 SARS coronavirus Tor2, complete genome NCBI Reference Sequence: NC_004718.3

https://doi.org/10.5620/eaht.2021010 Blocking the interactions between human ACE2 and coronavirus spike glycoprotein by selected drugs: a computational perspective

https://doi.org/10.1016/j.nmni.2021.100915 Early COVID-19 therapy with azithromycin plus nitazoxanide, ivermectin or hydroxychloroquine in outpatient settings significantly improved COVID-19 outcomes compared to known outcomes in untreated patients